Current Therapy in Neurologic Disease, 7th Edition Textbook

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CURRENT THERAPY IN NEUROLOGIC DISEASE Copyright 2006, Mosby Inc.
ISBN 13: 978-0-323-03432-6 ISBN 10: 0-323-03432-2
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ISBN-13: 978-0-323-03432-6 ISBN-10: 0-323-03432-2
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Printed in United States of America. Last digit is the print number: 9 8 7 6 5 4 3 2
Contributors
Neha P. Amin, B.S., B.A.S.
Medical Student, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Optic Neuritis
Anish Bhardwaj, M.D., F.A.H.A., F.C.C.M.

Associate Professor of Neurology, Neurological Surgery, and Anesthesiology Critical Care Medicine; Director, Neuroscience Critical Care Fellowship Program; Vice Chairman, Department of Neurology, Johns Hopkins University School of Medicine; Co-Director, Neurosciences Critical Care Division; Attending Physician, Johns Hopkins Hospital and Bayview Medical Center, Baltimore, Maryland
The Unconscious Patient
Charles E. Argoff, Ph.D.

Assistant Professor of Neurology, New York University School of Medicine; Director, Cohn Pain Management Center, North Shore University Hospital, Bethpage, New York
Chronic Pain Management: General Principles
Kevin M. Biglan, M.D., M.P.H. Allen J. Askamit, Jr., M.D.

Associate Professor of Neurology, Mayo College of Medicine; Consultant, Department of Neurology, Mayo Clinic, Rochester, Minnesota
Acute Bacterial Meningitis
Assistant Professor of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York
Huntingtons Disease
Tom J. Blanchard, M.R.C.P., DTM&H, Ph.D.

Senior Lecturer in Tropical Medicine, Clinical Research Group, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
Cerebral Malaria
Alon Y. Avidan, M.D., M.P.H.

Assistant Professor of Neurology, University of Michigan Medical School; Director, Sleep Disorders Clinic, University of Michigan Health System, Ann Arbor, Michigan
Parasomnias
John B. Bodensteiner, M.D.

Professor of Clinical Pediatrics and Neurology, Department of Pediatrics, University of Arizona College of Medicine; Chief, Pediatric Neurology, St. Josephs Hospital and Childrens Health Center, and Barrow Neurological Institute, Phoenix, Arizona
Tuberous Sclerosis Complex
Laura J. Balcer, M.D., M.S.C.E.

Associate Professor of Neurology and Ophthalmology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Optic Neuritis
Tallie Z. Baram, M.D., Ph.D.

Professor of Pediatrics, Anatomy/Neurobiology, and Neurology and Danette Shepard Professor of Neurological Sciences, Department of Pediatrics, University of California, Irvine, School of Medicine, Irvine, California
Neonatal Seizures and Infantile Spasms
Devin L. Brown, M.D.

Assistant Professor of Neurology, University of Michigan Medical School; Staff Neurologist, Stroke Program, University of Michigan Health System, Ann Arbor, Michigan
Emboli of Cardiac Origin
Allan J. Belzberg, M.D.

Associate Professor of Neurosurgery, Johns Hopkins University School of Medicine; Attending Neurosurgeon, Johns Hopkins Hospital, Baltimore, Maryland
Peripheral Nerve Injury
John C. M. Brust, M.D.

Professor of Clinical Neurology, Columbia University College of Physicians and Surgeons; Director, Department of Neurology, Harlem Hospital Center, New York, New York
Alcohol Intoxication and Withdrawal
Sara E. Benjamin, M.D.

Chief Resident, Department of Neurology, George Washington University School of Medicine and Health Sciences, Washington, DC
Wernicke Disease and Korsakoff Psychosis
Arthur L. Burnett, M.D.

Professor of Urology, Johns Hopkins University School of Medicine; Active Staff, Johns Hopkins Hospital, Baltimore, Maryland
Urinary and Sexual Dysfunction in Multiple Sclerosis and Myelitis
Anthony S. Burns, M.D.

Assistant Professor of Rehabilitation Medicine, Jefferson Medical College of Thomas Jefferson University; Assistant Director, Regional Spinal Cord Injury Center of the Delaware Valley, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
Acute Spinal Cord Injury
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iv
Contributors
Peter Calabresi, M.D.

Associate Professor of Neurology, Johns Hopkins University School of Medicine; Director, Multiple Sclerosis Center, Johns Hopkins Hospital, Baltimore, Maryland
Multiple Sclerosis
Ricardo Cruciani, M.D., Ph.D.

Assistant Professor, Department of Neurology and Anesthesiology, Albert Einstein College of Medicine of Yeshiva University, Bronx; Director, Research Division, Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, New York, New York
Herpes Zoster and Postherpetic Neuralgia
Grant L. Campbell, M.D., Ph.D.

Chief, Arboviral Diseases Branch, Epidemiology Section, Division of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado
Arthropod-Borne Virus Infections
Marinos C. Dalakas, M.D.

Chief, Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
Immune-Mediated Inflammatory Myopathies
Vinay Chaudhry, M.D., F.R.C.P.

Professor of Neurology, Johns Hopkins University School of Medicine; Vice Chair, Clinical Affairs, Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland
Intravenous Immunoglobulin and Plasmapheresis in the Treatment of Neurologic Disease
Josep Dalmau, M.D., Ph.D.

Associate Professor of Neurology, University of Pennsylvania School of Medicine; Attending Neurologist, Section of Neuro-oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
Remote Effects of Cancer: Treatment of Paraneoplastic Neurologic Syndromes
William P. Cheshire, Jr., M.D., M.A.

Associate Professor of Neurology, Mayo Clinic College of Medicine, Jacksonville, Florida
Trigeminal and Glossopharyngal Neuralgia
Stephanie K. Daniels, Ph.D.

Adjunct Assistant Professor, Department of Psychiatry and Neurology, Tulane University School of Medicine; Research Speech Pathologist, Research Service, VA Medical Center, New Orleans, Louisiana
Dysphagia: Diagnosis and Treatment
Kenneth Cohen, M.D., M.B.A.

Associate Professor of Oncology and Pediatrics, Johns Hopkins University School of Medicine; Director, Pediatric Neuro-oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland
Childhood Brain Tumors
Larry E. Davis, M.D., F.A.A.N., F.A.C.P.

Professor of Neurology, University of New Mexico School of Medicine; Chief, Neurology Service, New Mexico VA Health Care System, Albuquerque, New Mexico
Fungal Infections
Andrew J. Cole, M.D., F.R.C.P.C.

Associate Professor of Neurology, Harvard Medical School; Director, MGH Epilepsy Service, Neurology Service, Massachusetts General Hospital, Boston, Massachusetts
First Generalized Seizure
David W. Dodick, M.D.

Professor of Neurology, Mayo Clinic College of Medicine, Scottsdale, Arizona
Chronic Daily Headache
Anne Comi, M.D.

Assistant Professor of Neurology and Pediatrics, Johns Hopkins University School of Medicine; Director, Johns HopkinsKennedy Krieger Sturge-Weber Syndrome Center, Baltimore, Maryland
Sturge-Weber Syndrome
Heinrich Elinzano, M.D.

Postdoctoral Fellow in Neuro-oncology, Medical Oncology Department, Johns Hopkins University School of Medicine, Baltimore; Clinical Fellow in Neuro-oncology, Neuro-oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
Epidural Spinal Cord Compression and Leptomeningeal Metastasis
James J. Corbett, M.D.

McCarly Professor and Chair, Department of Neurology, and Professor of Ophthalmology, University of Mississippi School of Medicine, Jackson, Mississippi; Lecturer in Ophthalmology, Harvard Medical School/Massachusetts Eye and Ear Infirmary, Boston, Massachusetts
Idiopathic Intracranial Hypertension
Robert D. Fealey, M.D.

Consultant, Department of Neurology, Mayo Clinic, Rochester, Minnesota
Neurogenic Orthostatic Hypotension
Andrea M. Corse, M.D.

Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Attending Neurologist and Director, Neuromuscular Pathology Laboratory, Johns Hopkins Hospital, Baltimore, Maryland
Myasthenia Gravis
Anne L. Foundas, M.D.

Professor of Neurology, Department of Psychiatry and Neurology, Tulane University School of Medicine; Research Clinician, Neurology Service, VA Medical Center, New Orleans, Louisiana
Dysphasia: Diagnosis and Treatment
Nathan E. Crone, M.D.

Assistant Professor of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Absence Seizures
Jacqueline A. French, M.D.

Professor of Neurology, University of Pennsylvania School of Medicine; Co-Director, Penn Epilepsy Center, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
Treatment of Newly Diagnosed Complex Partial Seizures
Contributors
Linda P. Fried, M.D., M.P.H.

Professor of Medicine, Epidemiology, Health Policy, and Nursing, Johns Hopkins University School of Medicine; Director, Division of Geriatric Medicine and Gerontology; Director, Center on Aging and Health, Johns Hopkins Medical Institutions, Baltimore, Maryland
Frailty in Older Adults
Benjamin M. Greenberg, M.D., M.H.S.

Instructor, Johns Hopkins University School of Medicine; Fellow, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland
Adam L. Hartman, M.D. Scott Fromherz, M.D.

Fellow, Sleep Disorders Clinic, Stanford University Hospital and Clinics, Stanford, California
Narcolepsy
Fellow, Department of Pediatric Neurology, Johns Hopkins Hospital, Baltimore, Maryland

Febrile Seizures
Susan T. Herman, M.D. Bhuwan P. Garg, M.B., B.S.

Professor of Neurology, Section of Child Neurology, Indiana University School of Medicine; Pediatric Neurologist, James Whitcomb Riley Hospital for Children, Indianapolis, Indiana
Neurofibromatosis
Assistant Professor of Neurology, University of Pennsylvania School of Medicine; Director, Epilepsy Monitoring Unit, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
Donald L. Gilbert, M.D., M.S.

Associate Professor of Pediatrics and Neurology, Division of Neurology, University of Cincinnati School of Medicine; Director, Movement Disorders Clinics, Cincinnati Childrens Hospital Medical Center, Cincinnati, Ohio
Tourettes Syndrome
Argye E. Hillis, M.D., M.A.

Associate Professor of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Acute Ischemic Stroke
Michio Hirano, M.D.

Associate Professor of Neurology, Columbia University College of Physicians and Surgeons; Associate Attending, Department of Neurology, New YorkPresbyterian Hospital, Columbia University Medical Center, New York, New York
Mitochondrial Encephalomyopathies
Mark R. Gilbert, M.D.

Associate Professor and Deputy Chairman, Department of Neuro-oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Glioma
David Irani, M.D. Donald H. Gilden, M.D.

Louise Baum Professor and Chairman, Department of Neurology, University of Colorado Health Sciences Center School of Medicine; Staff Physician, University of Colorado Hospital, Denver, Colorado
Bells Palsy
Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Attending Neurologist, Johns Hopkins Hospital, Baltimore, Maryland
Transverse Myelitis
Sallu Jabati, M.D.

Attending, Spine Institute, Department of Surgery, Cleveland Clinic Foundation, Cleveland, Ohio
Frank G. Gilliam, M.D., M.P.H.

Professor of Neurology, Columbia University College of Physicians and Surgeons; Director, Columbia Comprehensive Epilepsy Center; Staff Neurologist, New YorkPresbyterian Hospital, New York, New York
Recurrent Generalized and Partial Seizures
Alan C. Jackson, M.D., F.R.C.P.C.

Professor, Departments of Medicine (Neurology) and Microbiology and Immunology, Queens University Faculty of Medicine; Attending Neurologist, Kingston General Hospital, Kingston, Ontario, Canada
Rabies Virus Infection
Jonathan P. Gladstone, B.Sc., M.D.

Division of Neurology, University of Toronto, Faculty of Medicine, Toronto, Ontario, Canada
Jee-Hyang Jeong, M.D.

Fellow, Department of Neurology, University of California, San Francisco, School of Medicine, San Francisco, California
Frontotemporal Degeneration
Jonathan D. Glass, M.D.

Professor of Neurology and Pathology, Emory University School of Medicine, Atlanta, Georgia
Toxic Neuropathy
H. A. Jinnah, M.D., Ph.D.

The Dystonias
David S. Goldstein, M.D., Ph.D.

Chief, Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
Complex Regional Pain Syndromes
S. Claiborne Johnston, M.D., Ph.D.

Associate Professor, Departments of Neurology and Epidemiology, University of California, San Francisco, School of Medicine; Director, Stroke Service, UCSF Medical Center, San Francisco, California
Management of Intracranial Aneurysms and Other Vascular Malformations
Joao A. Gomes, M.D.

Neurocritical Care Fellow, Departments of Neurology, Anesthesia, and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
Management of Subarachnoid Hemorrhage
vi
Contributors
Burk Jubelt, M.D.

Professor of Neurology, Department of Microbiology/Immunology; Director, Neuroscience Program, State University of New York Upstate Medical University College of Medicine; Attending Neurologist, University Hospital, Syracuse, New York
Enterovirus Infections
Robert Laureno, M.D.

Professor of Neurology, George Washington University School of Medicine and Health Sciences; Chairman, Department of Neurology, Washington Hospital Center, Washington, DC
Wernicke Disease and Korsakoff Psychosis
Rafael H. Llins, M.D., F.A.H.A. Douglas Kerr, M.D., Ph.D.

Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Active Staff, Johns Hopkins Hospital, Baltimore, Maryland
Cervical Spondylosis
Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Director, Cerebrovascular Disease Section, Department of Neurology, Johns Hopkins Bayview Medical Center, Baltimore, Maryland
Transient Ischemic Attacks
Richard M. Kimball, M.S.

Research Nurse, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
Amyotrophic Lateral Sclerosis
Elan D. Louis, M.D., M.S.

Associate Professor of Neurology, Columbia University College of Physicians and Surgeons; Associate Attending Neurologist, G.H. Serievsky Center, Columbia University Medical Center, New York, New York
Essential Tremor
Kleopas A. Kleopa, M.D.

Senior Consultant Neurologist, Division of Clinical Neurosciences, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
Familial Neuropathies
Yukari Manabe, M.D.

Assistant Professor of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
Tuberculous Meningitis
Carol Lee Koski, M.D.

Professor of Neurology, University of Maryland School of Medicine; Director, Neuromuscular Division, University of Maryland Medical Systems, Baltimore, Maryland
Chronic Inflammatory Demyelinating Polyneuritis
Nicholas J. Maragakis, M.D.

Morri E. Markowitz, M.D. Eric H. Kossoff, M.D.

Assistant Professor of Neurology and Pediatrics, Johns Hopkins University School of Medicine; Staff, John M. Freeman Pediatric Epilepsy Center, Baltimore, Maryland
Headaches in Children
Professor of Pediatrics, Albert Einstein College of Medicine of Yeshiva University; Director, Pediatric Environmental Science Clinic, Childrens Hospital at Montefiore, Bronx, New York
Management of Lead Poisoning in Children
Allan Krumholz, M.D.

Professor of Neurology, University of Maryland School of Medicine; Director, Epilepsy Center, University of Maryland Medical Center, Baltimore, Maryland
Psychogenic Nonepileptic Seizures
Christina M. Marra, M.D.

Professor of Neurology, University of Washington School of Medicine; Attending, Harborview Medical Center, Seattle, Washington
Neurosyphilis
Roger W. Kula, M.D.

Associate Professor of Clinical Neurology, State University of New York Downstate Medical Center College of Medicine, Brooklyn; Medical Director, The Chiari Institute, North Shore University Hospital, Manhasset; Director, Neuromuscular Clinic, Long Island Jewish Medical Center, New Hyde Park; Co-Director, Neuromuscular Clinic, Pediatric Neurology, Schneider Childrens Hospital, New Hyde Park, New York
Chiari Malformations and Syringomyelia
Laura Marsh, M.D.

Associate Professor of Psychiatry and Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Depression in Neurological Disorders
James A. Mastrianni, M.D., Ph.D.

Assistant Professor of Neurology, The University of Chicago Pritzker School of Medicine; Co-Director, Center for Comprehensive Care and Research on Memory Disorders, The University of Chicago Hospitals, Chicago, Illinois
The Prion Diseases
Ralph W. Kuncl, M.D., Ph.D.

Adjunct Professor of Neurology, University of Pennsylvania School of Medicine; Staff, Hospital of the University of Pennsylvania, Philadelphia; Professor of Biology and Provost, Bryn Mawr College, Bryn Mawr, Pennsylvania
Use and Misuse of Corticosteroids
Justin C. McArthur, M.B.B.S., M.P.H.

Professor of Neurology, Pathology, and Epidemiology and Acting Chair, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Giant Cell Arteritis and CNS Vasculitis
John Laterra, M.D., Ph.D.

Professor, Departments of Neurology, Oncology, and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland
Una D. McCann, M.D.

Associate Professor of Psychiatry, Johns Hopkins University School of Medicine; Attending, Johns Hopkins Bayview Medical Center, Baltimore, Maryland
Overdose and Withdrawal in Drug Abuse
Contributors
vii
Micheline McCarthy, M.D., Ph.D.

Associate Professor of Neurology, University of Miami Leonard M. Miller School of Medicine; Associate Chief, Neurology Service, Miami Veterans Affairs Medical Center, Miami, Florida
Herpesvirus Infections
Avindra Nath, M.D.

Professor of Neurology, Johns Hopkins University School of Medicine; Director, Division of Neuroimmunology and Neurological Infections, Johns Hopkins Hospital, Baltimore, Maryland
Human Immunodeficiency Virus Infections
Emmanuel Mignot, M.D., Ph.D.

Professor of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford; Director, Stanford Center for Narcolepsy; Investigator, Howard Hughes Medical Institute, Palo Alto, California
Narcolepsy
Elizabeth OHearn, M.D.

Assistant Professor, Department of Neurology and Neurosciences, Johns Hopkins University School of Medicine; Staff Neurologist, Johns Hopkins Hospital, Baltimore, Maryland
Inherited Cerebellar Ataxia
Bruce Miller, M.D.

A.W. Margaret Clausen Distinguished Professor, Department of Neurology, University of California, San Francisco, School of Medicine, San Francisco, California
Richard K. Olney, M.D.

Professor of Neurology, University of California, San Francisco, School of Medicine, San Francisco, California
Guillain-Barr Syndrome
Steven P. Miller, M.D., C.M., F.R.C.P.C.

Assistant Adjunct Professor, Departments of Neurology and Pediatrics, University of California, San Francisco, School of Medicine, San Francisco, California; Assistant Professor, Department of Pediatrics, University of British Columbia Faculty of Medicine, Vancouver, British Columbia, Canada
Neonatal Encephalopathy
Andrew R. Pachner, M.D.

Professor of Neurology, UMDNJNew Jersey Medical School, Newark, New Jersey
Lyme Disease
Carlos A. Pardo-Villamizar, M.D.

Assistant Professor of Neurology and Pathology, Johns Hopkins University School of Medicine; Staff Neurologist, Johns Hopkins Hospital, Baltimore, Maryland
Neurosarcoidosis
Lewis B. Morgenstern, M.D.

Associate Professor of Neurology, Emergency Medicine, Neurosurgery, and Epidemiology, University of Michigan Medical School and School of Public Health; Director, Stroke Program, University of Michigan Health System, Ann Arbor, Michigan
Roy A. Patchell, M.D.

Chief, Neuro-oncology Division, Department of Neurosurgery, University of Kentucky Chandler Medical Center, Lexington, Kentucky
Brain Metastases
Richard T. Moxley III, M.D.

Professor of Neurology and Pediatrics, Department of Neurology, University of Rochester School of Medicine and Dentistry; Attending Physician, Strong Memorial Hospital; Director, Neuromuscular Disease Center, Department of Neurology, University of Rochester Medical Center, Rochester, New York
Muscular Dystrophies
Michael Polydefkis, M.D.

Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Active Staff, Johns Hopkins Hospital, Baltimore, Maryland
Diabetic Neuropathies
Beth S. Porter, M.D., Ph.D.

Assistant Professor, Department of Medicine, Division of Infectious Diseases, University of New Mexico School of Medicine; Staff Physician, Spinal Cord Injury Center and Department of Infectious Diseases, New Mexico VA Health Care System, Albuquerque, New Mexico
Fungal Infections
Beth Murinson, M.S., M.D., Ph.D.

Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Active Staff, Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland
Painful Neuropathy
Neal J. Naff, M.D.

Assistant Professor of Neurosurgery, Johns Hopkins University School of Medicine; Chief of Neurosurgery, Sinai Hospital of Baltimore, Baltimore, Maryland
Failed Back Syndrome
Michael Pourfar, M.D.

Staff Physician, Center for Parkinsons Disease and Other Movement Disorders, Columbia University Medical Center, New York, New York
Essential Tremor
Vinodh Narayanan, M.D.

Associate Professor of Clinical Pediatrics and Neurology, Department of Pediatrics, University of Arizona College of Medicine; Pediatric Neurologist, St. Josephs Hospital and Childrens Health Center and Barrow Neurological Institute, Phoenix; Adjunct Professor, School of Life Sciences, Arizona State University, Tempe, Arizona
Tyler Reimschisel, M.D.

Assistant Professor of Neurology, Washington University, St. Louis, Missouri
The Dystonias
George A. Ricaurte, M.D., Ph.D.

Associate Professor of Neurology, Johns Hopkins University School of Medicine; Attending, Johns Hopkins Bayview Medical Center, Baltimore, Maryland
viii
Contributors
Daniele Rigamonti, M.D.

Professor of Neurosurgery, Johns Hopkins University School of Medicine; Director, Division of Stereotatic Radiosurgery; Co-Director, Adult Hydrocephalus Program, Johns Hopkins Hospital, Baltimore, Maryland
Normal Pressure Hydrocephalus
Jehuda Sepkuty, M.D.

Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Director, Intraoperative Neuromonitoring; Attending Neurologist, Epilepsy Monitoring Unit, Johns Hopkins Hospital, Baltimore, Maryland
Status Epilepticus
Stacie L. Ropka, Ph.D., M.B.A.

Research Assistant Professor, Department of Neurology, State University of New York Upstate Medical University College of Medicine, Syracuse, New York
Barbara E. Shapiro, M.D., Ph.D.

Associate Professor of Neurology, Case School of Medicine; Director, Neuromuscular Research, University Hospitals of Cleveland, Cleveland, Ohio
The Periodic ParalysesCurrent Therapy
Paul Rosenberg, M.D.

Assistant Professor of Psychiatry and Behavioral Sciences, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore; Director of Neuropsychiatry, The Copper Ridge Institute, Sykesville, Maryland
Depression in Neurological Disorders
Rachelle Smith Doody, M.D., Ph.D.

Effie Marie Cain Chair in Alzheimers Disease Research, Department of Neurology, Baylor College of Medicine; Active Staff, Department of Neurology, The Methodist Hospital, Houston, Texas
Alzheimers Disease
Robert L. Ruff, M.D., Ph.D.

Professor of Neurology, Case School of Medicine; Director, Spinal Cord Injury Unit, Cleveland VA Medical Center, Cleveland, Ohio
The Periodic Paralyses
Yuen T. So, M.D., Ph.D.

Professor of Neurology, Department of Neurology and Neurological Sciences, Stanford University School of Medicine; Director, Neurology Clinic, Stanford Hospital and Clinics, Stanford, California
Entrapment Neuropathies
David B. Rye, M.D., Ph.D.

Associate Professor of Neurology, Emory University School of Medicine; Director, Emory Healthcare Program in Sleep Medicine, Atlanta, Georgia
Restless Legs Syndrome
Tom Solomon, M.D., Ph.D.

Senior Lecturer in Neurology, Department of Neurological Science; Senior Lecturer in Medical Microbiology and Genitourinary Medicine, University of Liverpool; Honorary Consultant Neurologist, Walton Centre for Neurology and Neurosurgery and Royal Liverpool University Hospital, Liverpool, United Kingdom
Cerebral Malaria
Steven S. Scherer, M.D., Ph.D.

William N. Kelley Professor, Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Elijah W. Stommel, M.D., Ph.D.

Associate Professor of Medicine, Section of Neurology, Dartmouth Medical School, Hanover; Attending Neurologist, Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
Marine Toxins and Assorted Biological Toxins
Jacob P. Schwarz, M.D.

Instructor in Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
Erick Scott, M.D.

Fellow, Department of Psychiatry and Behavioral Sciences, Stanford Center for Narcolepsy, Stanford, California
Gene Sung, M.D., M.P.H.

Director, Neurocritical Care and Stroke Section, Department of Neurology, Keck School of Medicine of USC, Los Angeles, California
Intracerebral Hemorrhage
James J. Sejvar, M.D.

Neuroepidemiologist, Division of Vector-Borne Infectious Diseases and Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia
Tricia Ting, M.D.

Assistant Professor of Neurology, University of Maryland School of Medicine; Director, Ambulatory Services, Maryland Epilepsy Center, University of Maryland Medical Center, Baltimore, Maryland
Michael E. Selzer, M.D., Ph.D.

Professor of Neurology, Departments of Neurology and Physical Medicine and Rehabilitation, University of Pennsylvania School of Medicine; Attending Physician, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
B. Todd Troost, M.D.

Professor of Neurology Emeritus, Wake Forest University School of Medicine; Chief Emeritus, Department of Neurology, North Carolina Baptist Hospital, Winston-Salem, North Carolina
Migraine and Cluster Headache
Contributors
ix
Eileen P. G. Vining, M.D.

Professor of Neurology and Pediatrics, Johns Hopkins University School of Medicine; Associate Director, Pediatrics Epilepsy Clinic, Johns Hopkins Hospital, Baltimore, Maryland
Febrile Seizures
Michael A. Williams, M.D.

Associate Professor of Neurology, Johns Hopkins University School of Medicine; Director, Adult Hydrocephalus Program, Johns Hopkins Hospital, Baltimore, Maryland
Max Wiznitzer, M.D. Jerrold L. Vitek, M.D., Ph.D.

Co-Chairman, Center for Neurological Restoration, Cleveland Clinic Foundation, Cleveland, Ohio
Parkinsons Disease
Associate Professor of Pediatrics, Neurology, and International Health, Case School of Medicine; Pediatric Neurologist, Rainbow Babies and Childrens Hospital, Cleveland, Ohio
Attention Deficit Hyperactivity Disorders and Learning Disabilities
Kathryn R. Wagner, M.D., Ph.D.

Wendy L. Wright, M.D.

Professor of Neurology, Emory University School of Medicine; Active Staff, Neuroscience Critical Care Division, Emory University Hospital, Atlanta, Georgia
Brain Abscess and Parameningeal Infection
Mark F. Walker, M.D.

Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Active Staff, Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland
Vertigo and Disequilibrium
Kaleb Yohay, M.D.

Instructor, Department of Neurology, Division of Child Neurology, Johns Hopkins University, Baltimore, Maryland
Laurence Walsh, M.D.

Assistant Professor of Clinical Neurology and Medical and Molecular Genetics; Director, Child Neurology Section, Department of Neurology, Indiana University School of Medicine; Director, Pediatric Neurology, James Whitcomb Riley Hospital for Children, Indianapolis, Indiana
Neurofibromatosis
Phyllis C. Zee, M.D., Ph.D.

Professor of Neurology, Northwestern University Feinberg School of Medicine; Director, Sleep Disorders Center, Department of Neurology, Northwestern Memorial Hospital, Chicago, Illinois
Parasomnias
Benjamin L. Walter, M.D.

Associate Staff, Center for Neurological Restoration, Cleveland Clinic Foundation, Cleveland, Ohio
Parkinsons Disease
Wendy C. Ziai, M.D.

Assistant Professor, Departments of Neurology and Anesthesia/Critical Care Medicine, Johns Hopkins University School of Medicine; Attending Physician, Neurocritical Care, Johns Hopkins Hospital and Bayview Medical Center, Baltimore, Maryland
Michael R. Watters, M.D., F.A.A.N.

Professor of Medicine, Division of Neurology, University of Hawaii JAB School of Medicine; Core Neurologist, Office of Neurology and Aging Research, Specialized Neuroscience Research Program in NeuroAIDS; Associate Director of Medical Education, Queens Neuroscience Institute, Honolulu, Hawaii
Andrew W. Zimmerman, M.D.

Associate Professor of Neurology, Psychiatry, and Pediatrics, Johns Hopkins University School of Medicine; Pediatric Neurologist, Kennedy Krieger Institute and Johns Hopkins Hospital, Baltimore, Maryland
Autism
Preface
Current Therapy in Neurologic Disease 7 marks the 20th anniversary of this series. Technically, this is not the seventh edition, since each of the seven volumes has been a fresh collection of statements on management and therapy by a new group of specialists. This series was launched to fill a perceived shortcoming in the neurology literature. Many fine textbooks and monographs cover the etiology, pathogenesis, clinical symptoms and signs, imaging, and pathology of neurology diseases. Instruction on management, specific therapy, and patient education, however, tends to be presented in generalizations replete with conflicting views. The practical issues of when and how to initiate drugs and at what doses, the management of complications of the disease and the drugs, and advice on when to call for aid of colleagues in other fields are left to the informal education of corridor or curbstone consultation. Since its introduction, this series has presented a specific stepby-step approach to patient management given by a seasoned clinician. It has provided an informal practical consultation for the neurologist, neurosurgeon, internist, pediatrician, or family practitioner. Because authors, and therefore options, are changed with each volume, you, like the editors, may wish to save volumes 5 and 6 for a second opinion that you may favor over an opinion in this volume. The advice of the contributors is not necessarily the approach of the editors or a consensus of the neurologic community; they are the management techniques of an experienced clinician. Today, neurologic practice should be driven by evidencebased neurology, and obviously class I evidence from randomized clinical trials plays a major role in the choice of therapy. Usually, however, this evidence is not adequate to provide advice regarding specifics of management of the patient. This book provides not only evidence-based approaches but experience-based approaches from expert authors. As before, some new topics have been added and others droppedat least for this edition. New additions include daily headache, autism, Sturge-Weber syndrome, Bells palsy, Creutzfeldt-Jakob disease, and new general topics of the fragile elderly, plasmapheresis and intravenous immunoglobulin G, and the use and abuse of corticosteroids in neurologic practice. Each author has been given the same charge: to describe his or her approach to treatment and management of patients. Drug dosages have been checked, but the reader should always scrutinize product information sheets or online sources for dosage, interactions, and contraindications. The editors thank Sofia Rodriguez for editorial assistance. Richard T. Johnson, M.D., F.R.C.P. John W. Griffin, M.D. Justin C. McArthur, M.B.B.S., M.P.H.
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SECTION 1
Disorders of Consciousness
Anish Bhardwaj, M.D.
vasopressors to keep mean arterial blood pressure above 70 mm Hg Hypertension can result from brain injury (intracranial hypertension, drug intoxication with cocaine or amphetamines)administer labetalol 10 to 20 mg intravenously (IV) every 10 minutes (up to a maximum of 300 mg) Hypothermia can result from neuroendocrine disorders (hypopituitarism, hypothyroidism), drug ingestion (barbiturates, alcohol, general anesthetics), Wernickes encephalopathy, diencephalic injury Hyperthermia can result from thyrotoxicosis, sepsis, hypothalamic injury, malignant hyperthermia, heat stroke Tachycardia can result from hypo`volemia, infection/ sepsis, pain and discomfort, pulmonary embolism Bradycardia can result from intracranial hypertension, drug overdose (e.g., tricyclic antidepressants) Malignant cardiac arrhythmias can result from ventricular fibrillation, ventricular tachycardia (e.g., amphetamine overdose)
INITIATE FLUID MANAGEMENT
States of Altered Consciousness

Consciousness is a state of awareness of self and environment and is dependent on two essential elements that have an anatomic basis: arousal, which is related to the integrity of the ascending reticular activating system, and awareness, which is related to the integrity of the cerebral cortex. Derangement in the level of consciousness comprises a spectrum of disorders ranging from acute confusional states to coma (Table 1). Disturbances in its content range from global cognitive impairment to more focal brain dysfunction, including deficits in language, memory, sensation and perception, motivation, and executive function.
Initial Diagnostic Work-up and Emergent Management of an Unconscious Patient

The classification and major causes of altered consciousness are presented in Table 2. The diagnosis and management of an unconscious patient are presented here in algorithmic fashion as follows:
ESTABLISH AND MAINTAIN THE AIRWAY, BREATHING, AND CIRCULATION (ABCs)
Establish IV access and commence IV infusion of isotonic fluids (1 to 1.5 mL/kg/hr of 0.9% saline)
ASSESS NEUROLOGIC FUNCTION
Place oropharyngeal airway and provide bag-mask ventilation, intubation (fiberoptic if spinal cord injury is suspected) Monitor oxygenation with pulse oximetry and maintain SaO2 higher than 90% with supplemental O2
MONITOR VITAL SIGNS
Assess level of consciousness Cranial nervesObserve eye movements, pupillary and corneal responses, oculocephalic/vestibulo-ocular reflex, cough and gag reflexes Motor examinationObserve resting posture, spontaneous motor activity, response to stimulation
ORDER LABORATORY SCREENING
Hypotension can result from hypovolemia, myocardial infarction, pulmonary embolism, sepsis, acidosis provide fluid resuscitation with isotonic fluids and
Johnson: Current Therapy in Neurologic Disease (7/E)
Obtain blood samples for Glucosehypoglycemia, hyperglycemia (nonketotic) Arterial blood gaseshypoxemia, hypercarbia, acidosis (drug ingestion, ketoacidosis, lactic acidosis) Electrolyteshyponatremia/hypernatremia, hypocalcemia/hypercalcemia, hypomagnesemia/hypermagnesemia, azotemia 1
TABLE 1 States of Altered Consciousness

Type of State Acute confusional state Delirium Akinetic mutism Manifestations Impaired attention, memory, and thinking Incoherent conversation with easy distraction Acute confusional state accompanied by autonomic dysfunction (fever, hypertension, sweating, and tachycardia) Little or no awareness of surroundings Absence of spontaneous motor activity Minimal motor response to noxious stimuli Intact sleep-wake cycles Consciousness preserved Selective deafferentation of all extremities and lower cranial nerves resulting in quadriplegia and inability to vocalize Sparing of vertical eye movements, blinking, hearing, and respiratory function Usually results from an acute pontine lesion Complete unawareness of self and surroundings Spontaneous eye opening may occur with some response to verbal stimuli that is not meaningful Inability to follow commands or localize to noxious stimulus Intact sleep-wake cycles and circulatory, respiratory, and brainstem reflexes Identified as such if state persists for >1 mo for nontraumatic etiology and >1 yr following traumatic brain injury Mental dullness or blunting with increased sleeping time Can be aroused to follow commands but with slowed responses and little interest in surroundings Reduced mental and physical activity Can be aroused with repeated and vigorous stimuli Restlessness; stereotypic motor responses Sleeplike state of unresponsiveness with absence of awareness of self and environment; does not respond to stimuli Motor impairment variable No spontaneous eye opening or reaction to stimulus Absent sleep-wake cycles
Locked-in syndrome
Persistent vegetative state
Obtundation Stupor Coma
Thyroid function testshypothyroidism, myxedema Liver function testshyperammonemia White blood cell countleukocytosis (infection/ sepsis) Obtain urine specimen for urinalysis and urine toxicology screenurosepsis, drug intoxication Check serum glucose level at bedside
INITIATE SPECIFIC TREATMENT
PERFORM ADDITIONAL DIAGNOSTIC TESTS
Administer thiamine, 100 mg IV, followed by 25 gm of glucose (50 mL of 50% solution) Naloxone (0.4 to 2 mg IV every 3 minutes or continuous IV infusion 0.8 mg/kg/hr) if narcotic overdose is suspectedmay precipitate rapid and florid withdrawal syndrome Flumazenil, 0.2 mg/min, maximum dose 1 mg IV, only if benzodiazepine overdose is suspectedmay precipitate cardiac arrhythmias and lower seizure threshold Lavage with activated charcoal (60 to 100 gm) and normal saline for suspected drug ingestion
OBTAIN DETAILED HISTORY AND PERFORM SYSTEMATIC EXAMINATION
Obtain the following diagnostic tests as needed: Nonenhanced computed tomographic (CT) scan of the brain, particularly in patients with focal neurologic findings Lumbar puncture for suspected infection (meningitis, encephalitis), subarachnoid hemorrhage Cerebral angiography for suspected vertebrobasilar insufficiency Electroencephalography for suspected nonconvulsive seizures Magnetic resonance imaging with venography for suspected basilar artery thrombosis and sinus venous thrombosis
Neurologic Evaluation of Altered Consciousness

Neurologic examination of an unconscious patient is focused on four major components: level of consciousness, cranial nerve and motor examinations, and respiratory pattern.
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TABLE 2 Classification and Major Causes of Alterations in Consciousness

Structural Brain Injury Hemisphere Unilateral (with midline shifts/displacement) Intracerebral and subarachnoid hemorrhage Large hemispheric ischemic stroke with accompanying edema Hemorrhagic contusion Cerebral abscess Brain tumor Bilateral Penetrating traumatic brain injury, traumatic brain contusions, diffuse axonal injury Multiple cerebral cortical infarcts (vasculitis, coagulopathy, cardiac embolism) Bilateral thalamic infarcts Malignancy (lymphoma, gliomatosis, multiple brain metastasis) Encephalitis (viral, paraneoplastic) Acute disseminated encephalomyelitis Anoxic-ischemic encephalopathy Cerebral edema Acute hydrocephalus Leukoencephalopathy (chemotherapy or radiation) Brainstem Pontine hemorrhage Basilar artery occlusion Central pontine myelinolysis Brainstem hemorrhagic contusion Brainstem tumor Cerebellum (with displacement causing brainstem compression) Cerebellar infarct Cerebellar hematoma Cerebellar abscess Cerebellar glioma or metastatic tumor Acute Metabolic-Endocrine Derangement Disturbances in serum glucose (hypoglycemia, hyperglycemia) Disturbances in serum sodium (hyponatremia, hypernatremia) Addisons disease Hypercalcemia Acute panhypopituitarism Hypothyroidism (myxedema coma) Acute azotemia/uremia Hypoxia, hypercapnia Diffuse Physiologic Brain Dysfunction Drug overdose and poisoning Generalized tonic-clonic seizures or nonepileptic seizures Hypothermia Gas inhalation (carbon monoxide) Basilar migraine Psychogenic Unresponsiveness Acute (lethal) catatonia, malignant neuroleptic syndrome Hysterical coma Malingering
Adapted from Wijdicks EFM: Neurologic complications of critical illness, ed 2, New York, 2002, Oxford University Press; and Bhardwaj A, Mirski MA, Ulatowski JA, editors: Handbook of neurocritical care, Totowa, NJ, 2004, Humana Press.
LEVEL OF CONSCIOUSNESS Level of unresponsiveness should be established. Special attention should be paid to body position, spontaneous motor activity, and eye movements. The Glasgow Coma Scale (GCS), originally designed for patients with traumatic brain injury, is used widely in patients with neurologic impairments as an objective scoring system because of its easy interexaminer reliability and reproducibility. GCS comprises eye opening and motor and verbal responses; however, it does not incorporate focal sensory-motor deficits and is limited in patients with craniofacial trauma resulting in orbital swelling. CRANIAL NERVE EXAMINATION Pupillary Responses Pupillary dilation indicates ipsilateral uncal herniation secondary to a lesion (e.g., tumor, abscess, intraparenchymal hematoma, cerebral edema) impinging on the pupillary dilator fibers encasing the oculomotor nerve. Unilateral miosis is suggestive of Horners syndrome due to sympathetic denervation. Bilateral fixed, dilated pupils are indicative of massive drug overdose (e.g., tricyclic antidepressants, amphetamines, carbamazepine), extensive brainstem injury, or central herniation leading to brain death. Bilateral miotic pupils are indicative of narcotic overdose, pontine injury, organophosphate ingestion, or local instillation of miotic eye drops. Other Changes Spontaneous eye opening does not necessarily reflect awareness, in that patients in coma (e.g., persistent vegetative state) may have spontaneous eye opening. Nystagmus at primary gaze is indicative of seizure activity or of diffuse brain injury. A variety of other gaze abnormalities and spontaneous eye movements (skew deviation, ocular bobbing, ping-pong gaze, tonic upward or downward gaze deviation, roving eye movements, convergence nystagmus) that are of localizing value have been well described. Impaired oculocephalic and vestibulo-oculocephalic reflexes are indicative of brainstem dysfunction. The corneal response tests the integrity of the trigeminal (afferent) and facial (efferent) nerves. Facial asymmetry may be indicative of central or peripheral facial nerve palsy. The glossopharyngeal and vagus nerves are tested with the cough and gag reflexes by stimulation of the posterior pharynx. MOTOR EXAMINATION Special attention should be paid to resting posture and spontaneous movements or those in response to stimulation. Motor responses that are commonly observed include (1) involuntary movements that may suggest focal or generalized seizures, myoclonic activity, or enhanced tremor frequently associated with toxicmetabolic etiologies; and (2) those to stimuli that may be absent, reflexic, or purposeful and may be of localizing value.
Flexor (decorticate) posturing characterized by flexion and abduction of the arms and wrists and extension of the lower extremities is indicative of loss of inhibitory influences from the higher centers and suggests damage to the cerebral hemispheres and the thalamus with structures below the diencephalons remaining intact. Extensor (decerebrate) posturing characterized by adduction, extension, and pronation of the arms and wrists and extension of the lower extremities is indicative of injury to deep bilateral cerebral hemispheres, midbrain and pons, above the vestibular nuclei, and may accompany severe toxicmetabolic brain injury. Triple flexion in the lower extremities is a spinal reflex of no localizing value. Flaccidity accompanied by no response to painful stimuli is indicative of injury to the lower medulla or severe injury to the central and peripheral nervous systems. RESPIRATORY PATTERN Altered states of consciousness are frequently accompanied by changes in respiratory patterns that may reflect injury to brainstem respiratory centers. Hypotonia of the upper airway due to bulbar dysfunction (oropharynx, tongue) manifests itself as hypoxia and hypercapnia, whereas lower airway dysfunction, secondary to weakness of intercostal muscles or diaphragmatic paralysis, leads to reduced vital capacity and hypercarbia. Localizing value of respiratory patterns is frequently obscured by a combination of toxic-metabolic and neurogenic etiologies. Cheyne-Stokes breathing (tachypnea alternating with apnea) is usually indicative of severe bilateral hemispheric dysfunction. Biots breathing (irregular Cheyne-Stokes) suggests a localization in the lower brainstem. Central neurogenic hyperventilation typically accompanies damage to the rostral brainstem tegmentum and the paramedian pontine reticular formation. Apneustic breathing (brief end-inspiratory pauses alternating with end-expiratory pauses) is indicative of injury to the respiratory centers in midcaudal pons. Ataxic breathing is commonly seen with injury to the reticular formation of the dorsomedial medulla extending to the obex and occurs with acute medullary compression.
hyperventilation to maintain a PaCO2 level of 25 to 30 mm Hg, osmotherapy (mannitol 1 gm/kg IV) and diuretics (furosemide 10 to 20 mg IV), and neurosurgical consultation for external drainage of cerebrospinal fluid or emergent surgical procedures for decompression. Admission and emergent transfer of such a patient to a critical care unit setting are necessary for appropriate further management.
SUMMARY
Although the causes of coma are numerous, the principles of management of an unconscious patient center on early recognition and timely evaluation of possible reversible or treatable causes. These principles include (1) providing cardiopulmonary support to maintain oxygenation and cerebral perfusion to limit propagation of secondary brain injury; (2) close and frequent neurologic follow-up examinations to detect early deterioration; and (3) emergent measures for brain resuscitation in patients with severe brain injury. Following emergent critical care, the clinician has the luxury of time to embark on a more thorough evaluation of history of illness and further diagnostic tests to arrive at an etiologic diagnosis. Adherence to these principles can frequently lead to good outcomes in patients with treatable causes of coma from brain injury. SUGGESTED READING
Bhardwaj A: Cerebral edema and intracranial hypertension. In Bhardwaj A, Mirski MA, Ulatowski JA, editors: Handbook of neurocritical care, Totowa, NJ, 2004, Humana Press. Plum F, Posner JB: The pathologic physiology of signs and symptoms of coma. In The diagnosis of stupor and coma, ed 3, New York, 1982, Oxford University Press, 1-86. Wijdicks EFM: Coma and other states of altered awareness. In Neurologic complications of critical illness, ed 2, New York, 2000, Oxford University Press, 3-27. Ziai WC: Coma and altered consciousness. In Bhardwaj A, Mirski MA, Ulatowski JA, editors: Handbook of neurocritical care, Totowa, NJ, 2004, Humana Press.
Brain Resuscitation
Alterations in the level of consciousness from catastrophic brain injuries including trauma and subdural, subarachnoid, and intraparenchymal hemorrhage are encountered commonly in clinical practice. Early recognition of herniation syndromes or clinical evidence of intracranial hypertension warrants an emergent response to confirm clinical diagnosis with a noncontrast CT scan of brain and institution of therapies for brain resuscitation. General measures include avoidance of agitation and fever, maintenance of a euvolemic state and systemic blood pressure, facilitating venous outflow by elevating the head to 30 degrees, and maintaining the neck in a midline position. Specific therapies include emergent endotracheal intubation for controlled

Dizziness is a common complaint because it encompasses a wide variety of symptoms, and terms such as dizziness, light-headedness, and even disequilibrium may have many different meanings. Thus, an important first step in the treatment of patients with dizziness is to make the correct diagnosis. Too often, patients are simply labeled as having vertigo and given a vestibular suppressant medication without an adequate attempt to characterize the actual symptom or its underlying cause.
Flexor (decorticate) posturing characterized by flexion and abduction of the arms and wrists and extension of the lower extremities is indicative of loss of inhibitory influences from the higher centers and suggests damage to the cerebral hemispheres and the thalamus with structures below the diencephalons remaining intact. Extensor (decerebrate) posturing characterized by adduction, extension, and pronation of the arms and wrists and extension of the lower extremities is indicative of injury to deep bilateral cerebral hemispheres, midbrain and pons, above the vestibular nuclei, and may accompany severe toxicmetabolic brain injury. Triple flexion in the lower extremities is a spinal reflex of no localizing value. Flaccidity accompanied by no response to painful stimuli is indicative of injury to the lower medulla or severe injury to the central and peripheral nervous systems. RESPIRATORY PATTERN Altered states of consciousness are frequently accompanied by changes in respiratory patterns that may reflect injury to brainstem respiratory centers. Hypotonia of the upper airway due to bulbar dysfunction (oropharynx, tongue) manifests itself as hypoxia and hypercapnia, whereas lower airway dysfunction, secondary to weakness of intercostal muscles or diaphragmatic paralysis, leads to reduced vital capacity and hypercarbia. Localizing value of respiratory patterns is frequently obscured by a combination of toxic-metabolic and neurogenic etiologies. Cheyne-Stokes breathing (tachypnea alternating with apnea) is usually indicative of severe bilateral hemispheric dysfunction. Biots breathing (irregular Cheyne-Stokes) suggests a localization in the lower brainstem. Central neurogenic hyperventilation typically accompanies damage to the rostral brainstem tegmentum and the paramedian pontine reticular formation. Apneustic breathing (brief end-inspiratory pauses alternating with end-expiratory pauses) is indicative of injury to the respiratory centers in midcaudal pons. Ataxic breathing is commonly seen with injury to the reticular formation of the dorsomedial medulla extending to the obex and occurs with acute medullary compression.
hyperventilation to maintain a PaCO2 level of 25 to 30 mm Hg, osmotherapy (mannitol 1 gm/kg IV) and diuretics (furosemide 10 to 20 mg IV), and neurosurgical consultation for external drainage of cerebrospinal fluid or emergent surgical procedures for decompression. Admission and emergent transfer of such a patient to a critical care unit setting are necessary for appropriate further management.
SUMMARY
Although the causes of coma are numerous, the principles of management of an unconscious patient center on early recognition and timely evaluation of possible reversible or treatable causes. These principles include (1) providing cardiopulmonary support to maintain oxygenation and cerebral perfusion to limit propagation of secondary brain injury; (2) close and frequent neurologic follow-up examinations to detect early deterioration; and (3) emergent measures for brain resuscitation in patients with severe brain injury. Following emergent critical care, the clinician has the luxury of time to embark on a more thorough evaluation of history of illness and further diagnostic tests to arrive at an etiologic diagnosis. Adherence to these principles can frequently lead to good outcomes in patients with treatable causes of coma from brain injury. SUGGESTED READING
Bhardwaj A: Cerebral edema and intracranial hypertension. In Bhardwaj A, Mirski MA, Ulatowski JA, editors: Handbook of neurocritical care, Totowa, NJ, 2004, Humana Press. Plum F, Posner JB: The pathologic physiology of signs and symptoms of coma. In The diagnosis of stupor and coma, ed 3, New York, 1982, Oxford University Press, 1-86. Wijdicks EFM: Coma and other states of altered awareness. In Neurologic complications of critical illness, ed 2, New York, 2000, Oxford University Press, 3-27. Ziai WC: Coma and altered consciousness. In Bhardwaj A, Mirski MA, Ulatowski JA, editors: Handbook of neurocritical care, Totowa, NJ, 2004, Humana Press.
Brain Resuscitation
Alterations in the level of consciousness from catastrophic brain injuries including trauma and subdural, subarachnoid, and intraparenchymal hemorrhage are encountered commonly in clinical practice. Early recognition of herniation syndromes or clinical evidence of intracranial hypertension warrants an emergent response to confirm clinical diagnosis with a noncontrast CT scan of brain and institution of therapies for brain resuscitation. General measures include avoidance of agitation and fever, maintenance of a euvolemic state and systemic blood pressure, facilitating venous outflow by elevating the head to 30 degrees, and maintaining the neck in a midline position. Specific therapies include emergent endotracheal intubation for controlled

Dizziness is a common complaint because it encompasses a wide variety of symptoms, and terms such as dizziness, light-headedness, and even disequilibrium may have many different meanings. Thus, an important first step in the treatment of patients with dizziness is to make the correct diagnosis. Too often, patients are simply labeled as having vertigo and given a vestibular suppressant medication without an adequate attempt to characterize the actual symptom or its underlying cause.
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Vertigo is an illusory sense of motion, such as spinning, rocking, or tilting, that is caused by an imbalance in the labyrinthine inputs or their central connections. It is important to ask patients with vertigo whether it has happened just once or if there have been multiple attacks, the duration of the episodes (e.g., minutes, hours, days), whether there are any provoking factors (e.g., head movement), and what, if any, are the associated symptoms (e.g., hearing loss, ear pain/pressure, posterior circulation symptoms). A basic differential diagnosis of common causes is given in Table 1. Disequilibrium is a less precisely defined symptom. I use this term to describe feelings of imbalance or unsteadiness, most prominent when standing and generally minimal when at rest. Other symptoms that may be labeled dizziness but should be distinguished from true vertigo include motion sickness, whether evoked by true motion or by motion of the visual scene (e.g., when watching television), presyncopal sensations, and anxiety. Obviously, this is important, because faintness due to intermittent hypotension requires a cardiovascular evaluation, and an anxiety disorder may need psychiatric treatment. In addition to the history, a careful examination is essential. Patients with dizziness should be evaluated for any evidence of reduced vestibular function in one or both ears. The most useful bedside test of peripheral vestibular function is the head impulse or head thrust test. This is a rapid small-amplitude manual rotation performed while the subject fixates the examiners nose. If vestibular function is reduced on the side to which the head is rotated, the eyes will move with the head, and after the head stops, a catch-up saccade will be seen as the eyes return to the original target. Hearing should also be tested, including audiometry, particularly to look for a unilateral hearing loss that would support a peripheral problem. The other cranial
TABLE 1 Causes of Vertigo and Disequilibrium
Cause Acute Prolonged Vertigo, Single Episode Vestibular neuritis/labyrinthitis Labyrinthine infarction Cerebellar or brainstem infarction or hemorrhage Recurrent Vertigo Benign paroxysmal positional vertigo Transient ischemic attacks Menieres disease (endolymphatic hydrops) Migraine Autoimmune (systemic or labyrinthine only) Anxiety
nerves should also be tested, keeping in mind the need to rule out a cerebellar or brainstem lesion. Finally, patients with recurrent vertigo should be subjected to positional testing (i.e., the Dix-Hallpike maneuver) to look for evidence of positional vertigo and nystagmus. Laboratory testing of vestibular function includes caloric testing, which is best for identifying a unilateral vestibular deficit, and rotatory chair testing, which is best for identifying bilateral vestibular hypofunction.
Treatment of Vertigo
The treatment of vertigo depends on the underlying cause. We consider the most common entities here. ACUTE PROLONGED VERTIGO Acute prolonged vertigo refers to a single episode (nonrecurrent) of spontaneous vertigo, usually accompanied by nausea, vomiting, and imbalance, that lasts for hours to days. It is important to make sure that the vertigo is continuous rather than occurring in multiple frequent but brief episodes (e.g., positional vertigo). Causes of acute prolonged vertigo include vestibular neuritis (labyrinthitis) and labyrinthine ischemia. In patients who are older or otherwise at risk for vascular disease, an ischemic cause should be ruled out by magnetic resonance (MR) imaging and MR angiography of the posterior circulation, including visualization of the neck vessels from the vertebral origins. Patients in whom there is any suspicion of a central lesion should be imaged emergently to look for a brainstem or cerebellar infarct or hemorrhage. Vestibular neuritis generally improves over several days, with subsidence of vertigo and nystagmus, although there is often a lingering imbalance and
Comments
Vertigo, nausea, and vomiting lasting hours to days; slow recovery over weeks to months Similar to vestibular neuritis but caused by ischemia
Attacks provoked by changes in head position relative to gravity, lasting for seconds; positive Dix-Hallpike maneuver Episodes generally last minutes, often accompanied by other posterior circulation symptoms Severe vertigo, nausea, and vomiting, lasting hours; accompanied by transient low-frequency hearing loss, low-pitched tinnitus, ear pain and/or fullness in the affected ear Wide range of symptoms from brief attacks of vertigo to prolonged disequilibrium; may be similar to Menieres disease, but without hearing loss; vestibular symptoms often occur without headache Fluctuating vertigo and hearing loss; may progress to bilateral deafness if not treated Panic attacks and chronic anxiety may include vertiginous sensations and disequilibrium
motion sensitivity that may last for months. It has been proposed to treat acute vestibular neuritis with steroids and/or antiviral agents, based on the hypothesis that an inflammatory process, perhaps related to a herpesvirus, is responsible. A recent randomized study found that patients begun on a methylprednisolone taper within 3 days of symptom onset had less caloric asymmetry 12 months later (implying greater recovery in the affected ear). Valacyclovir had no effect. Thus, it is reasonable to treat patients with steroids in the acute stage if there are no contraindications, keeping in mind that it is not yet known whether there is a difference in functional outcome. If acute hearing loss is present, high-dose steroids (e.g., a prednisone taper beginning at 60 to 100 mg/day) should be given, and the patient should be referred to a neuro-otologist; autoimmune inner ear disease can cause severe bilateral hearing loss, if not treated promptly. Patients with vestibular neuritis usually benefit from a vestibular suppressant and/or an antiemetic (see later), which should only be given for several days, while symptoms are most severe. Long-term vestibular suppression should be avoided because it may interfere with central compensatory mechanisms that promote functional recovery. To facilitate compensation, it is important that normal activity be resumed as quickly is possible. Patients should be referred for vestibular therapy, if it is available. MENIERES DISEASE Menieres disease, also called endolymphatic hydrops, is thought to be due to an excess of endolymph fluid in the inner ear. Clinically, it produces recurrent episodes characterized by pain, pressure, and fullness in the affected ear; a low-pitched, roaring tinnitus; low-frequency hearing loss; and acute vertigo with nausea and vomiting. Episodes typically last for hours. Although hearing generally recovers between attacks, over time, after repeated episodes, there may be a permanent loss. The hearing loss associated with Menieres disease is most severe at low frequencies; this helps to distinguish it from other causes of sensorineural hearing loss, which typically affect the high frequencies. Diagnosis of Menieres disease is made on clinical grounds. Audiometry is important, and transtympanic electrocochleography may help, by demonstrating abnormal evoked electrical potentials that occur with hydrops. Patients who have recurrent vertigo without hearing loss or other aural symptoms are more likely to have another cause, such as vestibular migraine. Patients in whom Menieres disease is suspected should be tested for inflammatory and infectious causes with an erythrocyte sedimentation rate, C-reactive protein, antinuclear antibodies, rheumatoid factor, thyroidstimulating hormone, and rapid plasma reagin/fluorescent treponemal antibody (autoimmune disease and otosyphilis can mimic Menieres disease). Initial treatment of Menieres disease includes sodium restriction (1 gm of Na+ per day) and diuretic therapy. Options include acetazolamide hydrochlorothiazide and hydrochlorothiazide/triamterene. If attacks persist, the patient should be referred to a
neuro-otologist for consideration of ablative therapy. Intratympanic gentamicin is the current treatment of choice. If this is done properly, enough hair cell damage can be effected to alleviate attacks without causing severe vestibular hypofunction or significant hearing loss. Since the advent of gentamicin therapy, surgical ablation (labyrinthectomy or vestibular nerve section) is seldom needed. When attacks are prolonged and cannot be fully controlled, a vestibular suppressant (see later) may be prescribed to be taken at the onset of an attack. VESTIBULAR MIGRAINE Migraine is one of the most common causes of episodic vestibular symptoms. Migraine-related dizziness may have many forms, including attacks of vertigo that last from minutes to hours, as well as disequilibrium and motion sensitivity that may last for days to weeks or longer. Sensitivity to visual motion (e.g., watching movies or television) is common. Occasionally, vertigo occurs as an aura followed by headache, but most often dizzy spells and headaches occur independently. There is also a vestibular form of migraine in children (benign paroxysmal vertigo of childhood). Vestibular migraine is treated similarly to other forms of migraine (see Chapter 18). In general, vestibular symptoms are reduced or prevented by the usual migraine prophylactic agents. The choice of a particular drug often is based on comorbidities (e.g., anxiety, depression, hypertension). It is important to be aware that depression and anxiety are common in these patients, particularly those with more severe chronic symptoms. In those cases, assessment by a psychiatrist may be helpful. If a prophylactic medication is given, the dose must be titrated up to a therapeutic level, and sufficient time (weeks to several months) must be given to determine its full effect. I most commonly begin treatment with an antidepressant (e.g., nortriptyline or venlafaxine). I begin with nortriptyline 10 to 25 mg at bedtime and titrate the daily dose by 10 to 25 mg once a week, up to a total dose of 75 to 100 mg if needed and tolerated. Venlafaxine XR is started at 37.5 mg per day, usually best taken in the morning, and titrated by 37.5 mg per day once a week. Most patients need doses of 150 to 300 mg per day for adequate prophylaxis. Other options include beta blockers (if the blood pressure will tolerate them), calcium channel blockers (e.g., verapamil), and anticonvulsants (e.g., gabapentin, topiramate, valproate). BENIGN PAROXYSMAL POSITIONAL VERTIGO Benign paroxysmal positional vertigo (BPPV) is caused by otoconial debris that dislodges from the otolith membrane and becomes free-floating in the endolymph. If it falls into one of the semicircular canals (usually the posterior), it can cause excitation of the canal when the head moves relative to gravity. The typical scenario is brief (<1 minute) vertigo provoked by lying back, rolling over in bed, or putting the head back to look up. Attacks do not occur spontaneously without head movement. BPPV is diagnosed by
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the Dix-Hallpike maneuver, which for posterior canal BPPV should produce a transient upbeating and torsional nystagmus when the affected ear is down. The aim of BPPV treatment is to facilitate movement of the otoconia out of the posterior canal and back into the vestibule, where they will hopefully dissolve and be reabsorbed. There are several repositioning maneuvers that are quite effective. I usually use the Epley maneuver. As shown in Figure 1, the treatment begins by putting the patient in the Dix-Hallpike position with the affected ear down. The head is then turned to the other side (without lifting it). Next the patient is asked to roll over on his or her side, with the head positioned such that the nose is pointing to the floor. Finally, the patient sits up on the side of the bed. If successful, there will be no more vertigo or nystagmus when the maneuver is repeated. The patient can be taught to perform this maneuver at home, using pillows under
the shoulders so that the head can hang back but still rest on the bed.* Vestibular suppressant medications are not generally helpful for BPPV, because the attacks are too short; by the time the medication has taken effect, the vertigo has subsided. TRANSIENT ISCHEMIC ATTACKS Recurrent vertigo may be caused by ischemia; it usually is accompanied by other posterior circulation symptoms but occasionally occurs in isolation. Patients suspected of having ischemic vertigo should be given antiplatelet
*Illustrations of this technique and an alternative treatment, the Semont maneuver, can be found at http://www.dizzinessand-balance.com/disorders/bppv/bppv.html#treatment and http:// www.neurology.org/cgi/content/full/63/1/150/DC1.
Posterior canal
Particles Vantage point
Gravity
A
Superior canal
Superior canal Utriculus Posteriorcanal ampulla
D
Posterior canal Superior canal Utriculus Particles
Gravity Particles
Vantage point
B
Superior canal Posterior canal
Posterior-canal ampulla
Vantage point
Gravity
Particles
FIGURE 1. Epley maneuver for treatment of right posterior canal BPPV. Gravity is used to move the otoconia out of the posterior canal. The position of the particles in the labyrinth at the end of each step is shown in red. Each position should be held for 30 seconds. A, The head is turned 45 to the affected side, and the patient is brought to the head-hanging supine position (this step is the same as the Dix-Hallpike maneuver). B, The head is turned 90 (away from the affected ear) without lifting it. C, The patient is brought into the seated position with the head tilted slightly down. (Reprinted from Furman JM, Cass SP: Benign paroxysmal positional vertigo. N Engl J Med 341:1590-1596, with permission.) Johnson: Current Therapy in Neurologic Disease (7/E)
agents and should have the appropriate cerebrovascular evaluation.
Treatment of Disequilibrium
Disequilibrium (see earlier) may have many different causes. In general, there are two groups of patients in this category: (1) those who have an objective balance deficit due to a specific central or peripheral neurologic disorder, including bilateral vestibular hypofunction; and (2) those who have the perception of imbalance, but whose neurologic and vestibular examinations are unremarkable. Treatment of neurologic causes of imbalance is focused on the underlying disorder. Common causes of disequilibrium without neurologic or vestibular deficits include migraine and anxiety disorders. These patients often respond to treatment with an antidepressant medication or another migraine prophylactic agent. BILATERAL VESTIBULAR HYPOFUNCTION Bilateral vestibular hypofunction causes imbalance, worse in the dark, and oscillopsia and visual blurring with head movement (due to the loss of the vestibulo-ocular reflex). This diagnosis may be missed, and thus, vestibular function should be explicitly tested in any patient who complains of disequilibrium or imbalance. The head impulse test described earlier is the best bedside test; in the laboratory, rotational testing is the most sensitive. The most common identified cause of bilateral vestibular hypofunction is ototoxicity, particularly from aminoglycosides. Other causes include hereditary degenerations, autoimmune disorders, bilateral internal auditory canal tumors (MR imaging should be done), bilateral vestibular neuritis, and bilateral Menieres disease. In the case of ototoxicity, an important part of treatment is to detect this early and stop the medication. Once damage has occurred, it is generally irreversible. In that case, the goal becomes to maximize the central compensatory process. To this end, vestibular rehabilitation therapy is helpful. Future use of potentially ototoxic drugs should be avoided. Vestibular suppressants are not helpful for bilateral vestibular hypofunction or other neurologic causes of disequilibrium; in fact, they may make balance worse.
preventive measures; and for occasional use for the prevention of motion sickness. In general, vestibular suppressants should not be used chronically, and they should not be given to patients with imbalance and nonvestibular dizziness. A limiting side effect is often sedation. Meclizine (12.5 to 25 mg up to three times a day) can be used for mild attacks of vertigo and for motion sickness. Promethazine (25 mg two to four times a day) is useful for more severe vertigo accompanied by nausea and vomiting. Benzodiazepines (e.g., diazepam, lorazepam, clonazepam) are also effective vestibular suppressants for short-term use. SUGGESTED READING
Baloh RW: Dizziness, hearing loss, and tinnitus, Los Angeles, 1998, FA Davis. Furman JM, Cass SP: Benign paroxysmal positional vertigo, N Engl J Med 341:1590-1596, 1999. Neuhauser H, Lempert T: Vertigo and dizziness related to migraine: a diagnostic challenge, Cephalalgia 24:83-91, 2004. Radtke A, von Brevern M, Tiel-Wilck K, et al: Self-treatment of benign paroxysmal positional vertigo: Semont maneuver versus Epley procedure, Neurology 63:150-152, 2004. Strupp M, Zingler VC, Arbusow V, et al: Methylprednisolone, valacyclovir, or the combination for vestibular neuritis, N Engl J Med 351:354-361, 2004.
PATIENT RESOURCES
Videos demonstrating the Semont maneuver and the Epley procedure: http://www.neurology.org/cgi/content/full/63/1/150/DC1 Information on vestibular disorders: http://www.dizziness-and-balance.com/disorders/ Patient support groups: http://www.vestibular.org/ http://www.menieres.org/

Orthostatic hypotension has been defined as a reduction in systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg, within 3 minutes of standing up. Orthostatic hypotension most often produces intermittent symptoms. Lightheadedness, weakness or tiredness, impaired concentration, and visual blurring or dimming are common symptoms. Typically these occur on standing in the morning, after heavy meals, during times of elevated core or environmental temperature, and with prolonged standing and exertion in the upright position. The symptoms are caused by cerebral hypoperfusion, their intermittent nature due to transient worsening by vasodilating stressors (alcohol, heat, meal-induced neurohumoral changes, medication effects) and variable degrees of dehydration, anemia, and postural deconditioning.
Vestibular Suppressant Medications

In general, the treatment of vestibular disorders should focus on the underlying cause. However, vestibular suppressants and antiemetics may be useful in some cases for the symptomatic management of vertigo. Their most appropriate use is in the acute phase of a unilateral vestibular syndrome (e.g., vestibular neuritis), when vertigo, nausea, and vomiting are most severe; for occasional symptomatic treatment of recurrent vertigo in patients with disorders such as Menieres disease and migraine, when attacks cannot be fully controlled by
agents and should have the appropriate cerebrovascular evaluation.
Treatment of Disequilibrium
Disequilibrium (see earlier) may have many different causes. In general, there are two groups of patients in this category: (1) those who have an objective balance deficit due to a specific central or peripheral neurologic disorder, including bilateral vestibular hypofunction; and (2) those who have the perception of imbalance, but whose neurologic and vestibular examinations are unremarkable. Treatment of neurologic causes of imbalance is focused on the underlying disorder. Common causes of disequilibrium without neurologic or vestibular deficits include migraine and anxiety disorders. These patients often respond to treatment with an antidepressant medication or another migraine prophylactic agent. BILATERAL VESTIBULAR HYPOFUNCTION Bilateral vestibular hypofunction causes imbalance, worse in the dark, and oscillopsia and visual blurring with head movement (due to the loss of the vestibulo-ocular reflex). This diagnosis may be missed, and thus, vestibular function should be explicitly tested in any patient who complains of disequilibrium or imbalance. The head impulse test described earlier is the best bedside test; in the laboratory, rotational testing is the most sensitive. The most common identified cause of bilateral vestibular hypofunction is ototoxicity, particularly from aminoglycosides. Other causes include hereditary degenerations, autoimmune disorders, bilateral internal auditory canal tumors (MR imaging should be done), bilateral vestibular neuritis, and bilateral Menieres disease. In the case of ototoxicity, an important part of treatment is to detect this early and stop the medication. Once damage has occurred, it is generally irreversible. In that case, the goal becomes to maximize the central compensatory process. To this end, vestibular rehabilitation therapy is helpful. Future use of potentially ototoxic drugs should be avoided. Vestibular suppressants are not helpful for bilateral vestibular hypofunction or other neurologic causes of disequilibrium; in fact, they may make balance worse.
preventive measures; and for occasional use for the prevention of motion sickness. In general, vestibular suppressants should not be used chronically, and they should not be given to patients with imbalance and nonvestibular dizziness. A limiting side effect is often sedation. Meclizine (12.5 to 25 mg up to three times a day) can be used for mild attacks of vertigo and for motion sickness. Promethazine (25 mg two to four times a day) is useful for more severe vertigo accompanied by nausea and vomiting. Benzodiazepines (e.g., diazepam, lorazepam, clonazepam) are also effective vestibular suppressants for short-term use. SUGGESTED READING
Baloh RW: Dizziness, hearing loss, and tinnitus, Los Angeles, 1998, FA Davis. Furman JM, Cass SP: Benign paroxysmal positional vertigo, N Engl J Med 341:1590-1596, 1999. Neuhauser H, Lempert T: Vertigo and dizziness related to migraine: a diagnostic challenge, Cephalalgia 24:83-91, 2004. Radtke A, von Brevern M, Tiel-Wilck K, et al: Self-treatment of benign paroxysmal positional vertigo: Semont maneuver versus Epley procedure, Neurology 63:150-152, 2004. Strupp M, Zingler VC, Arbusow V, et al: Methylprednisolone, valacyclovir, or the combination for vestibular neuritis, N Engl J Med 351:354-361, 2004.
PATIENT RESOURCES
Videos demonstrating the Semont maneuver and the Epley procedure: http://www.neurology.org/cgi/content/full/63/1/150/DC1 Information on vestibular disorders: http://www.dizziness-and-balance.com/disorders/ Patient support groups: http://www.vestibular.org/ http://www.menieres.org/

Orthostatic hypotension has been defined as a reduction in systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg, within 3 minutes of standing up. Orthostatic hypotension most often produces intermittent symptoms. Lightheadedness, weakness or tiredness, impaired concentration, and visual blurring or dimming are common symptoms. Typically these occur on standing in the morning, after heavy meals, during times of elevated core or environmental temperature, and with prolonged standing and exertion in the upright position. The symptoms are caused by cerebral hypoperfusion, their intermittent nature due to transient worsening by vasodilating stressors (alcohol, heat, meal-induced neurohumoral changes, medication effects) and variable degrees of dehydration, anemia, and postural deconditioning.
Vestibular Suppressant Medications

In general, the treatment of vestibular disorders should focus on the underlying cause. However, vestibular suppressants and antiemetics may be useful in some cases for the symptomatic management of vertigo. Their most appropriate use is in the acute phase of a unilateral vestibular syndrome (e.g., vestibular neuritis), when vertigo, nausea, and vomiting are most severe; for occasional symptomatic treatment of recurrent vertigo in patients with disorders such as Menieres disease and migraine, when attacks cannot be fully controlled by
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Although normal individuals can have orthostatic hypotension, this chapter concentrates on patients with disorders of the central or peripheral autonomic nervous system that disrupt the autonomous regulation of blood pressure. These patients are said to have neurogenic orthostatic hypotension. Some of the neurologic disorders that commonly cause neurogenic orthostatic hypotension include pure autonomic failure, multiple system atrophy, autonomic neuropathy (diabetic, amyloidosis, immune mediated), and high thoracic and cervical myelopathy. Many pathophysiologic factors are involved in neurogenic orthostatic hypotension; those having therapeutic implications are briefly discussed next. Reduction in effective blood volume can result from denervation of blood vessels. Resistance vessels fail to constrict on standing, and blood volume pools in the legs and abdomen in venous capacitance circuits having reduced vascular tone. Decreased red blood cell mass or a normochromic-normocytic anemia can develop from denervation of the kidney and relative decreased erythropoietin production. Denervation of arterial and lowpressure cardiopulmonary baroreceptors and mesenteric capacitance bed results in both upright hypotension and supine hypertension. Loss of afferent input to the brain also can cause excessive renal loss of water and sodium during recumbency, producing nocturnal polyuria. Neurogenic constipation and upper intestinal hypomotility with decreased appetite and food/fluid intake can result in dehydration, reduced blood volume, and muscle protein loss, further aggravating neurogenic orthostatic hypotension. Neurogenic diarrhea can occur, producing rapid dehydration and electrolyte abnormalities. Mindful of these pathophysiologic mechanisms and confounding medical conditions (bladder infections, anemia, dehydration and preexisting hypertension, secondary anxiety/depression) that often coexist in these patients, I next discuss the principles and specifics of treatment.
The steps of neurogenic orthostatic hypotension treatment include patient education; dietary changes and adjustments to the home environment and timing of activities; physical measures such as countermaneuvers; support garments; exercises; and, finally, drug therapy. PATIENT EDUCATION Patient education is most important, and both patient and caregiver need to hear the instructions. Patients learn the symptoms of low blood pressure (lightheadedness; slowed, confused thinking; visual blackening or blurring; loss of postural tone with falls or jerky movements) and when they are most likely to occur (when first arising in the morning, after a meal, in hot environments, when febrile). I provide a prescription for an automated digital sphygmomanometer for brachial blood pressure measurements and have patients log their readings several times a day, 3 days a week. One-minute supine and 1-minute standing blood pressure and heart rate are taken on first arising; just before and 1 to 2 hours after taking pressor medications; just before and 30 minutes after a meal; and at bedtime. The log is a self-education tool for patients who learn specific symptoms that correlate with low blood pressure and what their orthostatic stressors are. The log provides physicians with documentation of response to treatment and a way of recognizing supine hypertension that may require therapy. DIETARY MEASURES Increase salt and fluid intake, so that 6 to 8 gm of sodium (15 to 20 gm of salt) and 2.0 to 2.5 L of fluid is ingested daily. Foods rich in salt include canned soups, chili, ham, bacon, sausage, soy sauce, commercially processed canned products, fast food, and salty snacks; salt can be added during preparation and at the table. Patients taking the potassium-depleting mineralocorticoid fludrocortisone acetate (Florinef) should eat highpotassium foods such as fruits, vegetables, No-salt, poultry, fish, beef, and pork. Juices and sports drinks can make up some of the fluid intake. Sports drinks with less carbohydrate and more sodium and some potassium are preferred (e.g., per 8 oz: 2.5% to 6% carbohydrate and 110 to 244 mg sodium content.* One or two 8-oz (237-mL) bottles can be given with each meal. Tap water taken orally in amounts of 500 mL in 5 minutes with meals and 200 to 300 mL between major meals also can be an effective pressor agent. Salt tablets can be used for a portion of the extra salt intake. I use Thermotabs, which have 450 mg of sodium chloride and 30 mg of potassium chloride per tablet. Two or three tablets can be given two or three times a day. A 24-hour urinary sodium excretion of 170 mg or more suggests a high salt intake is being accomplished.
Specific Goals and Steps of Neurogenic Orthostatic Hypotension Treatment

One of the first steps in treating neurogenic orthostatic hypotension is to review the patients medications for drugs contributing to hypotension. Stopping or substituting for such a drug (Table 1) may provide dramatic improvement. Severe anemia, dehydration, or elevated core temperature should be corrected, if present. Further treatment is guided by four goals: (1) to eliminate or reduce symptoms of upright hypotension; (2) to minimize supine hypertension; (3) to measurably increase standing time and the patients ability to do upright activities of daily living; and (4) to provide practical advice on diet, lifestyle changes, nonpharmacologic measures, and monitoring of blood pressure so patients are actively involved in their treatment. The specific steps to accomplish these goals are given in the next section.
*I use Pedialyte, which has 2.5% carbohydrate and 244 mg sodium per 8 oz.
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TABLE 1 Medications that Worsen Orthostatic Hypotension: Alternative Treatment

Specific Agent or Class Antihypertensive Drugs Sympatholytic drugs (methyldopa, reserpine, guanethidine) Alpha-adrenergic blockers Beta-adrenergic blockers Diuretics Calcium channel blockers Peripheral vasodilators (hydralazine) Angiotensin-converting enzyme inhibitors and angiotensin blockers Coronary Vasodilators Nitroglycerin, isosorbide dinitrate, nitrate patches Urologic (Sphincter Inhibitor) Drugs Alpha-adrenergic inhibitors (prazosin, terazosin) Psychiatric Drugs Tricyclic antidepressants Neuroleptics Antiparkinson Agents Carbidopa-levodopa, dopamine D2 agonists Suggested Remedial Steps
Consider carefully stopping these drugs under physician observation Consider stopping under physician supervision Consider switch to a beta blocker with intrinsic sympathomimetic activity (e.g., pindolol) Reduce or stop agent under physician supervision Use ionotropics instead of diuretics for treating congestive heart failure Consider using only at bedtime (e.g., nifedipine 10 mg hs) to treat supine hypertension Use at bedtime to counteract disease- and treatment-related recumbent hypertension Often can be continued at lower dose, especially in diabetic autonomic neuropathyassociated neurogenic orthostatic hypotension Consider alternative treatment of coronary ischemia (e.g., angioplasty/stent) Nitrate patch can be used at bedtime for supine hypertension Consider switch to tamsulosin Consider stopping and performing a TURP if urodynamics and cystoscopy show significant obstructive component Consider switch to SSRI agents Consider switch to atypical antipsychotics (quetiapine) Add fludrocortisone and midodrine if dopa responsive Consider stopping if disorder is dopa unresponsive Switch to amantadine or cholinergic antagonist (e.g., benztropine, trihexyphenidyl)
SSRI, Selective serotonin reuptake inhibitor; TURP, transurethral resection of prostate.
A high-fiber diet (1 cup of bran daily, 1 tsp of methylcellulose up to three times a day) with increased protein and reduced carbohydrate and smaller, more frequent meals is important to avoid constipation and postprandial exacerbation of orthostatic hypotension. If supine hypertension is a problem, a carbohydrate-rich snack just before bedtime can reduce blood pressure for 1 to 2 hours. Vasodilators such as alcohol exacerbate orthostatic hypotension and should be avoided. Two cups of strong, caffeinated coffee (about 250 mg of caffeine) in the morning followed by 250 to 500 mL of liquid with pressor medications and 30 minutes of sitting in bed before getting up for the day is suggested for early-morning neurogenic orthostatic hypotension. Patients can be expected to gain from 2 to 4 kg (4 to 8 lb) above their ideal body weight when these dietary measures are coupled with volume-expanding pharmacologic treatment. PHYSICAL MEASURES Head-up tilt can be accomplished with 4-inch blocks under the bed legs, or a foam wedge can be used under the mattress; an electric hospital bed is essential in
severe cases, and some patients require a recliner chair. Head-up tilt helps to reduce supine blood pressure and provides a stimulus to recondition postural reflexes. Physical countermaneuvers are simple methods that patients can learn to combat orthostatic dizziness. Crossing legs above the knees and squeezing the thigh muscles together, bending forward as if to tie a shoe, raising a flexed leg up on a chair, or squatting when ableall act to increase thoracic blood volume, left ventricular filling pressure, cerebral perfusion, and upright blood pressure. While sitting, patients can cross their legs or sit in knee-chest position to produce the same effects. Such maneuvers can be applied instantly to prevent syncope or increase standing time (the amount of time after standing before orthostatic symptoms develop); the latter may increase by 1 to 2 minutes, allowing many activities done standing still to be accomplished. Exercise can consist of graded walks or timed treadmill sessions. A rolling walker with a seat may allow even severely affected patients to participate. I recommend compression tights (pantyhose style, compression 30 to 40 mm Hg) in patients who are able to get them on and tolerate them. In some patients,
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a well-fitting abdominal binder with a thigh-high stocking is better tolerated. Many companies make compression garments, which the patient needs to have fitted carefully and put on while still recumbent in the morning. I prescribe two pairs at onset so one can be washed while the other is worn. Elevating legs slightly during the night reduces pedal edema and permits continued use with volume expansion treatment. These dietary and physical measures constitute initial, basic, or standard steps of therapy. These are critical to have in place before initiating pharmacologic agents that cause blood volume expansion, adrenergic receptor stimulation, or vasodilation blocking.
Pharmacologic Therapy
Drug therapy is added to the initial steps for patients still symptomatic with neurogenic orthostatic hypotension. The principal medications I use for neurogenic orthostatic hypotension are shown in Table 2. Brief comments regarding each agent are given in the following sections. VOLUME-EXPANDING AGENTS Fludrocortisone acetate is a potent mineralocorticoid that remains a mainstay of therapy for neurogenic
orthostatic hypotension. Fludrocortisone has a half-life of 3 hours and is given twice a day. Its full effect requires 1 to 2 weeks and is accompanied by a 3- to 6-lb weight gain. Its renal cellular effects cause retained sodium and enhanced potassium excretion, resulting in hypokalemia commonly and hypomagnesemia rarely. The starting dose is usually 0.1 mg orally twice a day. Increments of 0.1 mg per dose per week are used until an effect on weight and blood pressure is realized. Doses higher than 0.4 mg per day are infrequently needed, and higher doses produce severe supine hypertension, glucocorticoid effect, headache, and congestive heart failure. Weekly potassium determinations for a month and then monthly should help determine the level of supplementation required. Supine blood pressure is checked daily, and patients are instructed not to lie flat. Supine hypertension (180/100 mm Hg) is treated by dose reduction or as specified in Table 2. Other drugs used for transient sodium retention and volume expansion include indomethacin (50 to 75 mg orally three times a day), ibuprofen (400 mg orally three times a day), and rofecoxib (Vioxx) 50 mg twice a day. SYMPATHOMIMETICS Midodrine is an alpha1-adrenergic receptor agonist acting peripherally and constricting both arterioles
TABLE 2 Pharmacologic Treatment of Neurogenic Orthostatic Hypotension

Drug Fludrocortisone (Florinef) Dose Purpose, Mechanism of Action, When to Start Volume expansion; start after high salt (6-8 gm sodium or 10-15 gm salt) and fluid (2-2.5 L/day) intake has been established Vasoconstrictor: alpha1- agonist; increases peripheral resistance and blood pressure, reduces venous capacitance; initiate alone in mild NOH, with fludrocortisone in severe NOH. Enhances sympathetic ganglionic transmission, GI tract smooth muscle contraction; for NOH with neurogenic constipation or supine hypertension Expand blood volume; correct anemia of autonomic failure; use when other treatments not working Renal V2 vasopressin receptor agonist, antidiuretic; advanced disease with nocturnal polyuria Used in patients with severe postprandial hypotension; combine with midodrine, 5-10 mg (30 min before meal), for best effect Side Effects and Precautions Expect 3-6 lb weight gain with mild pedal edema; supine hypertension, hypokalemia are common; hypomagnesemia, CHF rare; headache in young Piloerection, scalp itching, urinary urgency/hesitancy; supine hypertension; do not give after 5:00-6:00 PM Abdominal cramping and diarrhea, salivation, tearing, muscle twitches; may need to combine with low-dose midodrine; rule out GI mechanical obstruction before starting Must supplement iron, potassium before and during use; headache, supine hypertension, high cost, venous thrombosis Start in hospital setting in patients with severe nocturnal polyuria; check serum Na+, intake and output; avoid hyponatremia Given by SC injection; warm solution, give small volume to minimize pain; may alter insulin requirements; nausea, diarrhea, gallstones, cramps
Midodrine (ProAmatine)
Pyridostigmine (Mestinon)
Initial: 0.1 mg qAM; increase by 0.1 mg weekly to 0.1-0.2 mg bid, second dose at noon 2.5 mg PO, 30-45 min before breakfast and lunch; increase each dose by 2.5 mg/wk up to 10 mg PO qid if needed 30 mg PO bid (morning and noon); increase by 30 mg/day weekly up to 60 mg tid
25-50 U/kg daily SC for 2-3 wk, then maintenance 25-50 U/kg three times weekly for 3 mo 5-10 g intranasal (0.2 mg PO) qhs to start maintenance: 10-40 g intranasal (0.2-0.6 mg PO) Initial: 0.2 g/kg tid with meals; up to 1 g/kg given with breakfast
Erythropoietin (Epogen) Desmopressin (DDAVP) Octreotide (Sandostatin)
CHF, Congestive heart failure; GI, gastrointestinal; NOH, neurogenic orthostatic hypotension.
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and veins. It is currently the drug of choice. The drug is well absorbed and does not cause tachycardia or central stimulation. A pressor effect lasts 2 to 4 hours for a 10-mg dose. The starting dose is usually 2.5 to 5 mg two or three times a day given about 45 minutes before meals. Piloerection, scalp itching, supine hypertension, headache, urinary urgency and retention, and nocturnal natriuresis are the main side effects. The drug is used with fludrocortisone and dietary and physical measures for greatest benefit; use without fludrocortisone if supine hypertension is present. Do not give a dose after 6 PM. Do not lie down for 4 hours after a midodrine dose. Uncommonly midodrine is not tolerated and another sympathomimetic is used. Phenylpropanolamine (12.5 to 50 mg) and similar drugs (ephedrine, 12.5 to 50 mg, and pseudoephedrine, 30 to 60 mg) are indirect alpha1adrenergic agonists. The dose is given three times a day. Yohimbine is an alpha2-adrenergic antagonist that acts at central and peripheral presynaptic receptors to increase sympathetic output. The dose is 5.4 mg three times a day. Central nervous system stimulation and supine hypertension are common with these agents. They are hard to obtain as a result of a U.S. Food and Drug Administration decision to urge pharmaceutical companies to withdraw these agents from their formularies. There is evidence that 3,4-DL-threodihydroxyphenylserine (DL-DOPS) has promise as a novel agent that can increase endogenous norepinephrine and blood pressure in neurogenic orthostatic hypotension. It acts peripherally, and the decarboxylase inhibitor carbidopa lessens the pressor effect. However, DL-DOPS is still under investigation and is not generally available. ACETYLCHOLINESTERASE INHIBITORS Recently Singer and Schondorf and colleagues (see Suggested Readings) have described the use of acetylcholinesterase inhibition to treat neurogenic orthostatic hypotension. Pyridostigmine (Mestinon), 60 mg three times a day, reduced standing blood pressure fall and symptoms without raising supine blood pressure. Pyridostigmine may be combined with midodrine and allow a dose reduction in patients with supine hypertension or midodrine side effects. Pyridostigmine is useful in patients with neurogenic orthostatic hypotension and constipation. Diarrhea, nausea, cramping, muscle twitching, and bradycardia, are side effects.
hypotension. The treatment includes smaller, more frequent low-carbohydrate/high-protein meals and avoidance of alcohol; sitting with legs crossed at the thigh or in knee-chest position; water ingestion, 500 mL over 5 to 10 minutes, 15 minutes before each meal; and caffeine, 200 mg in the morning only. If additional treatment is needed, use indomethacin, 25 to 75 mg three times a day; midodrine, 5 to 10 mg 30 minutes before the meal; and, in severe cases, octreotide injections, 0.2 g/kg up to 1 g/kg subcutaneously just before meals. SUPINE HYPERTENSION Frequently, profound standing hypotension is complicated by worrisome supine hypertension that is both disease and treatment related. Sustained blood pressures higher than 200/120 mm Hg develop at night with recumbency, a characteristic of neurogenic orthostatic hypotension. Rarely a cerebral hemorrhage occurs; left ventricular strain and hypertrophy may develop. Increased renal perfusion produces nocturnal polyuria and subsequent sleep disruption. Helpful measures include increasing head-up tilt of the bed, a carbohydrate snack and exercise at bedtime, and the use of short-acting antihypertensive drugs such as hydralazine, 25 to 75 mg twice daily, during the night. Transdermal nitroglycerin, 0.025 to 0.1 mg/hr at bedtime, and nifedipine, 10 mg orally at bedtime, are alternatives. Measure supine blood pressure 1 to 2 hours after dosing to verify effect. Check antinuclear antibody titers periodically with hydralazine, and give supplemental pyridoxine, 50 mg daily. CHRONIC ANEMIA OF AUTONOMIC FAILURE Chronic anemia of autonomic failure may occur with neurogenic orthostatic hypotension. Serum erythropoietin levels are usually normal but relatively reduced. When anemia is moderate (hemoglobin between 8 and 10 gm/dL) and the patient is symptomatic on conventional orthostatic hypotension treatment, I will give erythropoietin. The caregiver and the patient are taught to give subcutaneous injections. Check iron stores and administer iron (ferrous sulfate, 200 mg orally two or three times a day). The dose is 25 to 50 U/kg, three times a week for 8 weeks, or until hematocrit normalizes. Supine hypertension, headache, and thrombotic events are potential adverse effects. SUGGESTED READING
Fealey RD, Robertson D: Management of orthostatic hypotension. In Low PA, editor: Clinical autonomic disorders, ed 2, Philadelphia, 1997, Lippincott-Raven, 763-775. Low PA: Neurogenic orthostatic hypotension. In Noseworthy JH, editor: Neurological therapeutics: principles and practice, New York, 2003, Martin Dunitz, 2267-2274. Robertson D: Primer on the autonomic nervous system, ed 2, San Diego, 2004, Elsevier, 403-421. Schondorf R: Acetylcholinesterase inhibition in the treatment of hypotension, J Neurol Neurosurg Psychiatry 74:1187, 2003. Johnson: Current Therapy in Neurologic Disease (7/E)
Treatment of Common Diseaseand Therapy-Related Problems of Neurogenic Orthostatic Hypotension

POSTPRANDIAL EXACERBATION OF ORTHOSTATIC HYPOTENSION Ingestion of food can cause severe supine and upright hypotension in patients with neurogenic orthostatic hypotension for up to 2 hours postprandially. Large, high-carbohydrate meals are most likely to produce
Parasomnias Singer W, Opfer-Gehrking TL, McPhee BR, et al: Acetylcholinesterase inhibition: a novel approach in the treatment of neurogenic orthostatic hypotension, J Neurol Neurosurg Psychiatry 74:1294-1298, 2003.
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(obstructive sleep apnea, periodic leg movement), stress, or environmental factors. CONFUSIONAL AROUSALS Confusional arousals are characterized by mental or behavioral confusion associated with arousals from sleep, typically from slow-wave sleep in the first part of the night. Episodes typically last several minutes, and patients are usually disoriented and amnesic when awoken. The underlying pathophysiology is thought to be an incomplete awakening from slow-wave sleep, leading to intensification and prolongation of the normal period for transition from sleep to wakefulness. Confusional arousals represent an admixture of wakefulness into non-REM sleep. Patients awaken partially, exhibiting marked confusion, slow mentation, disorientation, perceptual impairment, and errors of logic. Behaviors can be simple to complex and may be inappropriate and even violent. Talking, shouting, and bruxism may also be seen. Attempts to console the child or awaken an individual may further increase agitation. Predisposing factors for confusional arousals include other conditions that disrupt sleep architecture such as circadian rhythm sleep disorders (shift work), sleep apnea, narcolepsy, and encephalopathies. Furthermore, sleep deprivation, fever, alcohol, stimulants, drug abuse, and exposure to other agents that deepen sleep and impair alertness can be precipitating factors. Confusional arousals may be experimentally induced by attempts at forced arousal from slow-wave sleep. Differential diagnosis for confusional arousals include sleepwalking, sleep terrors, RBD, and, less frequently, nocturnal epileptic seizures of the complex partial type. Preventive measures include maintaining a regular sleep-wake schedule and avoidance of predisposing factors such as sleep deprivation, shift work, or central nervous system (CNS) depressants, which reduce slowwave sleep. During a confusional arousal, efforts to curtail the behavior should be avoided because they may lead to aggression and prolongation of the spell. The episode should simply be allowed to run itself out,
TABLE 1 Classification of Parasomnia
Disorders of arousal (from non-REM sleep) Confusional arousals Sleepwalking Sleep terrors Parasomnias usually associated with REM sleep REM sleep behavior disorder Recurrent isolated sleep paralysis Nightmare disorder Other parasomnias Sleep related dissociative disorder Nocturnal enuresis Sleep related groaning (Catathrenia) Exploding head syndrome Sleep-related eating disorder
REM, Rapid eye movement. Based on: The International Classification of Sleep Disorders. 2005, Westchester, IL: American Academy of Sleep Medicine.
PATIENT RESOURCES
American Autonomic Society: http://www.americanautonomicsociety.org/ Shy-Drager/Multiple System Atrophy online support group: http://health.groups.yahoo.com/group/shydrager/
Parasomnias
Alon Y. Avidan, M.D., M.P.H., and Phyllis C. Zee, M.D., Ph.D.
Parasomnias are undesirable, nondeliberate physical or emotional events that accompany sleep. They most often occur during entry into sleep or during arousals from sleep and may be augmented by the sleep state. Parasomnias may be extremely undesirable to some but may be of no concern to others. They may include abnormal movements, behaviors, emotions, perceptions, dream mentation, and autonomic activity. In addition, basic drives, such as hunger, sex, and aggression, may manifest as sleep-related eating, sleep-related sexual behaviors, and sleep-related violence. Parasomnias have a bizarre nature but are readily explainable, diagnosable, and treatable. They are related to a change in brain organization across states and are particularly apt to occur during the transition from one sleep stage to another. One hypothesis to help explain parasomnias is that sleep and wakefulness are not mutually exclusive states. Intrusion of wakefulness into non-rapid eye movement (REM) sleep produces arousal disorders, and intrusion of wakefulness into REM sleep produces REM sleep parasomnias, most notably REM sleep behavior disorder (RBD). The International Classification of Sleep Disorders lists 15 categories of parasomnias. In this chapter, we limit the discussion to some of the more common parasomnias encountered in the practice of neurology. These include disorders of arousal from non-REM sleep (confusional arousals, sleepwalking, sleep terrors) and REM sleep (RBD, nightmare disorder) (Table 1).
Disorders of Arousal
Disorders of arousal (confusional arousals, sleepwalking, and sleep terrors) share the common feature of arousals from non-REM sleep, typically slow-wave (delta) sleep, accompanied by abnormal behavior and impaired judgment. Arousal disorders are most common in children and young adults. These events usually begin within the first 1 to 2 hours after sleep onset and may be triggered by underlying primary sleep disorders
Parasomnias Singer W, Opfer-Gehrking TL, McPhee BR, et al: Acetylcholinesterase inhibition: a novel approach in the treatment of neurogenic orthostatic hypotension, J Neurol Neurosurg Psychiatry 74:1294-1298, 2003.
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(obstructive sleep apnea, periodic leg movement), stress, or environmental factors. CONFUSIONAL AROUSALS Confusional arousals are characterized by mental or behavioral confusion associated with arousals from sleep, typically from slow-wave sleep in the first part of the night. Episodes typically last several minutes, and patients are usually disoriented and amnesic when awoken. The underlying pathophysiology is thought to be an incomplete awakening from slow-wave sleep, leading to intensification and prolongation of the normal period for transition from sleep to wakefulness. Confusional arousals represent an admixture of wakefulness into non-REM sleep. Patients awaken partially, exhibiting marked confusion, slow mentation, disorientation, perceptual impairment, and errors of logic. Behaviors can be simple to complex and may be inappropriate and even violent. Talking, shouting, and bruxism may also be seen. Attempts to console the child or awaken an individual may further increase agitation. Predisposing factors for confusional arousals include other conditions that disrupt sleep architecture such as circadian rhythm sleep disorders (shift work), sleep apnea, narcolepsy, and encephalopathies. Furthermore, sleep deprivation, fever, alcohol, stimulants, drug abuse, and exposure to other agents that deepen sleep and impair alertness can be precipitating factors. Confusional arousals may be experimentally induced by attempts at forced arousal from slow-wave sleep. Differential diagnosis for confusional arousals include sleepwalking, sleep terrors, RBD, and, less frequently, nocturnal epileptic seizures of the complex partial type. Preventive measures include maintaining a regular sleep-wake schedule and avoidance of predisposing factors such as sleep deprivation, shift work, or central nervous system (CNS) depressants, which reduce slowwave sleep. During a confusional arousal, efforts to curtail the behavior should be avoided because they may lead to aggression and prolongation of the spell. The episode should simply be allowed to run itself out,
TABLE 1 Classification of Parasomnia
Disorders of arousal (from non-REM sleep) Confusional arousals Sleepwalking Sleep terrors Parasomnias usually associated with REM sleep REM sleep behavior disorder Recurrent isolated sleep paralysis Nightmare disorder Other parasomnias Sleep related dissociative disorder Nocturnal enuresis Sleep related groaning (Catathrenia) Exploding head syndrome Sleep-related eating disorder
REM, Rapid eye movement. Based on: The International Classification of Sleep Disorders. 2005, Westchester, IL: American Academy of Sleep Medicine.
PATIENT RESOURCES
American Autonomic Society: http://www.americanautonomicsociety.org/ Shy-Drager/Multiple System Atrophy online support group: http://health.groups.yahoo.com/group/shydrager/
Parasomnias
Alon Y. Avidan, M.D., M.P.H., and Phyllis C. Zee, M.D., Ph.D.
Parasomnias are undesirable, nondeliberate physical or emotional events that accompany sleep. They most often occur during entry into sleep or during arousals from sleep and may be augmented by the sleep state. Parasomnias may be extremely undesirable to some but may be of no concern to others. They may include abnormal movements, behaviors, emotions, perceptions, dream mentation, and autonomic activity. In addition, basic drives, such as hunger, sex, and aggression, may manifest as sleep-related eating, sleep-related sexual behaviors, and sleep-related violence. Parasomnias have a bizarre nature but are readily explainable, diagnosable, and treatable. They are related to a change in brain organization across states and are particularly apt to occur during the transition from one sleep stage to another. One hypothesis to help explain parasomnias is that sleep and wakefulness are not mutually exclusive states. Intrusion of wakefulness into non-rapid eye movement (REM) sleep produces arousal disorders, and intrusion of wakefulness into REM sleep produces REM sleep parasomnias, most notably REM sleep behavior disorder (RBD). The International Classification of Sleep Disorders lists 15 categories of parasomnias. In this chapter, we limit the discussion to some of the more common parasomnias encountered in the practice of neurology. These include disorders of arousal from non-REM sleep (confusional arousals, sleepwalking, sleep terrors) and REM sleep (RBD, nightmare disorder) (Table 1).
Disorders of Arousal
Disorders of arousal (confusional arousals, sleepwalking, and sleep terrors) share the common feature of arousals from non-REM sleep, typically slow-wave (delta) sleep, accompanied by abnormal behavior and impaired judgment. Arousal disorders are most common in children and young adults. These events usually begin within the first 1 to 2 hours after sleep onset and may be triggered by underlying primary sleep disorders
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Parasomnias
unless there is an attempt to leave the bed or to leave the premises. Pharmacologic treatment is rarely necessary because most episodes in children remit with age. Some patients are helped by tricyclic antidepressants such as clomipramine. Avoidance of the facilitating factors (e.g., sleep deprivation, stimulants) and treatment of underlying sleep disorders such as sleep apnea are key in the management of confusional arousals. Table 2 summarizes the key feature of this parasomnias with regard to treatment, semiology, and sleep stage propensity. SLEEPWALKING Sleepwalking (somnambulism) consists of complex behaviors that are initiated during slow-wave sleep and result in walking during sleep. In addition to routine behaviors such as walking and talking, sleepwalking is often accompanied by inappropriate behaviors, such as urinating in a trash can, moving furniture, or driving a car. The individual is usually extremely difficult to awaken and may become increasingly agitated and violent with vigorous attempts to awaken the subject. These episodes generally last from 1 to 5 minutes. The peak incidence is usually between 4 and 8 years of age with spontaneous remission thereafter. However, sleepwalking can persist beyond adolescence and rarely begins in adulthood. In children, calm sleepwalking may be considered part of the normal developmental process, but in adults, sleepwalking can often cause sleep disruption and injury. The male-to-female ratio is 1:1, and familial patterns are common. The differential diagnosis consists of RBD, confusional arousals, and, rarely, sleep-related partial complex seizures with ambulatory automatisms. Sleep-related respiratory events including obstructive sleep apnea are recognized triggers for sleepwalking in children. Other predisposing factors include sleep deprivation, unfamiliar sleep environment, fever, stress, alcohol, and medications such as chlorohydrate, lithium, perphenazine, and desipramine. Stimuli such as a distended bladder or disruption of the sleep environment by noise, light, and changes in temperature may also trigger episodes. The main concern with this parasomnia is the risk of injury. Patients may engage in activities that may produce cuts and bruises from bumping into objects or falling. Treatment is focused on avoiding the precipitating factors and providing patients with a safe sleeping environment: removing sharp objects from bedroom, locking doors, and arranging for a ground floor bedroom. The primary prevention of nocturnal events is based on reducing stress, improving sleep hygiene, and avoiding substances that may cause sleep deprivation and cognitive impairment. Patients with underlying sleep disorders (e.g., sleep apnea and circadian rhythm disturbances) and periodic limb movements should have these disorders appropriately treated to decrease the potential for sleep disruption. When sleepwalking spells are severe and refractory, the use of medications such as tricyclic antidepressants or benzodiazepines has been advocated. Table 2 summarizes key features of this parasomnia.
SLEEP TERRORS (PAVOR NOCTURNUS) Sleep terrors consist of a sudden arousal from slow-wave sleep manifested by a piercing scream accompanied by significant autonomic arousal and behavioral manifestations of intense fear. This is the most dramatic of the arousal disorders. On the sleep study, the episodes are associated with sympathetic activity manifested by tachycardia, tachypnea, reduced skin resistance that reflects diaphoresis, flushing of the skin, mydriasis, and increased muscle tone. Sleep terrors reflect a state of cerebral hyper-responsiveness consisting of incoherent vocalizations, extreme agitation, escape behavior, and marked confusion. The duration of sleep terrors is usually between 30 seconds to 3 minutes. Spells may be experimentally induced by forced arousals from slow-wave sleep. The prevalence of recurrent sleep terrors is 1% to 6% in prepubertal children, decreasing to less than 1% in adults, with no gender differences in either age group. Predisposing and precipitating factors are similar to those described for sleepwalking. Psychopathology is rare in affected children but may play a role in adult patients. There is evidence for comorbid mood and anxiety disorder in adults with sleep terrors. Differential diagnosis includes REM nightmares, nocturnal anxiety attack related to obstructive sleep apnea, nocturnal cardiac ischemia, and sleep-related epileptic seizures. Nightmares are distinguishable from sleep terrors in that they are often associated with a vivid recall of the dream event during which they occurred, they are less dramatic, and they do not have the typical autonomic hyperarousal that characterizes the latter. Treatment is often unnecessary when episodes are rare (see Table 2). As in the previous two parasomnias, the attacks should be left to terminate spontaneously. Facilitating and precipitating factors, such as poor sleep hygiene, sleep deprivation, stress, and ingestion of CNS-depressant substance should be identified and avoided. When episodes are frequent, intense, and disruptive to the patients sleep, a benzodiazepine such as diazepam or clonazepam may be used at low doses during the night. An example may include diazepam, 5 mg, at bedtime. Benzodiazepines may act by increasing arousal threshold, reducing slow-wave sleep, and suppressing the autonomic excitability that accompanies this behavior. Other treatment options include tricyclic antidepressants. Adult sufferers in the setting of a history of a psychiatric disorder may benefit from psychotherapy and stress reduction as well as reassurance.
Parasomnias Associated with REM Sleep

These parasomnias are exquisitely associated with REM sleep. The two most important ones to consider clinically include RBD and nightmare disorder. REM SLEEP BEHAVIOR DISORDER RBD is one of the most dramatic and potentially injurious parasomnias to consider. Spells consist of dream
TABLE 2 Features of Parasomnias

Somnambulism Stage REM sleep, typically in the last third of the night Sleep Terrors REM Sleep Behavior Disorder Nightmares
Feature
Confusional Arousals
Stage of sleep
Spell symptoms
Stage REM sleep, sometimes, stage II sleep typically in the second half of the night Sudden awakening with anxiety and dream recall
Duration Recall of the dream
Postspell symptoms EEG pattern during spell Transition from slow-wave sleep to stage I or diffuse and slow alpha; highamplitude burst of delta waves Arousal from non-REM (typically slow-wave sleep) associated with marked tachycardia, tachypnea, reduced skin resistance
Stage slow-wave sleep, typically in the first third of the night Sudden arousal, confusion, disorientation, inappropriate behavior Secondsseveral minutes Amnesia, confusion Limb twitching, yelling, talking, kicking, punching, singing correlating with reported dream mentation 1-10 min
Stage slow-wave sleep, typically in the first third of the night Complex ambulatory automatisms, getting out of bed, walking 1-5 min; 30-60 min in rare episodes Amnesia, confusion
Stage slow-wave sleep, typically in the first third of the night Sudden arousal, piercing scream, confusion, inconsolability, disorientation, extreme autonomic discharge, agitation Secondsseveral minutes Amnesia, confusion
Slow-wave activity, interspersed with alpha, poorly reactive alpha
Secondsseveral minutes Vivid recall of a frightening dream Increased eye movements during REM sleep
Pathophysiology
Disorders of partial arousal reflecting incomplete arousal from deep non-REM sleep Predisposing factors include any that deepen sleep and those that impair arousal from sleep such as CNS-acting drugs, previous sleep deprivation
Increased sympathetic arousal Precipitated by daytime stress, drugs (especially beta blockers, neuroleptics, cholinergic agents) and withdrawal from REMsuppressing agent No No No Avoid injury, protect patient, avoid precipitating factors Clonazepam at bedtime Other options include melatonin, L-dopacarbidopa, imipramine, carbamazepine Reassurance, reduction of stresses, improvement in sleep hygiene, psychotherapy, REM-suppressing agent (e.g., tricyclic antidepressants)
No
Augmentation of chin and limb EMG muscle activity during REM sleep Loss of EMG atonia, which typically occurs during REM sleep or during REM sleep-to-wake transition Nonidiopathic/nontoxic, metabolic form is related to dysfunction of the brainstem mechanism responsible for REM-associated muscle atonia Pathophysiology for idiopathic form is unknown Common
Identifiable neuropathology Genetic predisposition Treatments Avoid injury, protect patient, avoid precipitating factors, psychotherapy Benzodiazepines or tricyclic antidepressants
Yes Avoid precipitating factors such as poor sleep hygiene and sleep deprivation Benzodiazepines at bedtime, tricyclic antidepressants
Avoidance of precipitating factors Tricyclic antidepressants may be useful
Parasomnias
EEG, Electroencephalogram; EMG, electromyogram; REM, rapid eye movement; CNS, central nervous system.
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enactment associated with loss of muscle atonia during REM sleep. RBD was originally predicted by experiments in the cat model. This was a fascinating experiment of nature where bilateral lesions adjacent to the locus ceruleus of the pontine region induced absence of the atonia that is typically associated with the REM sleep. RBD was eventually confirmed to also occur in humans and became an officially recognized parasomnia in 1987. The characteristic polysomnogram (sleep study) demonstrates intermittent loss of REM sleep-associated muscle atonia (reflected by the polysomnogram) associated with the patient manifesting an elaborate motor activity associated with dream-mentation. During these spells, which rarely last more than a few minutes, patients are observed to be talking, yelling, punching, kicking, running, and screaming. RBD is often referred to as the Jekyll and Hyde syndrome because patients tend to have a peaceful demeanor during the day but become very combative during the night. The potential for self-injury and bed partner injury is high, especially during severe episodes. Most cases occur with advancing age; approximately 60% are idiopathic, whereas the remaining 40% may have an underlying neuropathology. RBD typically manifests itself in the 6th or 7th decade. This parasomnia has a particular predilection to occur in a number of synucleinopathies and other neurodegenerative disorders such as dementia of the diffuse Lewy body type, Parkinsons disease, olivopontocerebellar degeneration, Shy-Drager syndrome and multiple system atrophy (MSA). Patients with MSA are commonly affected with RBD. Investigators have studied polysomnographic records of patients with MSA of whom nearly two thirds reported nocturnal paroxysmal episodes related to dreams suggesting the clinical diagnosis of RBD. The data show that RBD represents the most common clinical sleep manifestation and polysomnographic findings in patients with MSA. RBD can frequently herald the appearance of other MSA symptoms by years; therefore, expanded polysomnographic montage including REM sleep behavior montage and video monitoring is recommended in patients with MSA. Secondary causes include disorders that disrupt brainstem centers involved in REM sleepgenerated muscle atonia such as multiple sclerosis, cerebral vascular accidents, and brainstem neoplasm. The acute onset of RBD is typically related to medications such as tricyclic antidepressants, monamine oxidase inhibitors, and selective serotonin reuptake inhibitors. Other acute cases are related to acute alcohol and barbiturate withdrawal. Caffeine use has also been recently implicated in causing RBD. In many cases, the diagnosis is suspected clinically by confirming the presence of recurrent and frequent dream-enacting behaviors with the help of the bed partner. Diagnosis of RBD is made if there is a clear history of nocturnal behavioral spells along with polysomnographic evidence of increased electromyographic (EMG) bursts of chin EMG or limb electrodes seen during REM sleep on polysomnography. The sleep study may also capture the actual spells during which the abnormal spell is demonstrated (limb jerk on
complex, vigorous-violent behaviors). If there is evidence of an abnormal neurologic examination, a full neurologic work-up, including brain magnetic resonance imaging, may be needed. The differential diagnosis of RBD is extensive and includes sleepwalking, nocturnal seizures, post-traumatic stress disorder (PTSD), psychogenic dissociative state, sleep terrors, nocturnal panic disorders, delirium, sleep-related gastroesophageal reflux, periodic limb movement disorder of sleep, and confusional arousals with sleep apnea. Distinguishing RBD from nocturnal seizures may be difficult. However, unlike nocturnal seizures, the typical RBD spell is usually not stereotypical and is often variable. Additional laboratory studies may be needed especially if the clinical history remains vague or ambiguous. When the possibility of nocturnal seizures cannot be reliably excluded, additional sleep testing may be warranted. Sleep studies on multiple nights may be needed for confirmation. For example, polysomnography with video monitoring using four-limb EMG electrodes done during the first night followed by polysomnography with expanded EEG montage performed on the subsequent night generally may be fruitful. Environmental safety is prudent in every patient with suspected RBD. Pharmacotherapy for RBD (summarized in Table 2) may be in the form of clonazepam, 0.252 mg orally at bedtime, which is effective in 90% of cases. There is little evidence of tolerance or abuse with this form of treatment. Treatment with this drug has little or no effect on the characteristic elevated limb EMG tone during the night, but it acts to prevent the arousals associated with the REM disassociation. Clonazepams safety for use during pregnancy has not been established. Caution should be exercised when using it in patients with chronic respiratory diseases or impaired renal function, and it is contraindicated in patients with documented hypersensitivity, severe liver disease, or acute narrow-angle glaucoma. Abrupt discontinuation of clonazepam can precipitate withdrawal symptoms. Other agents that may be helpful include imipramine, 25 mg orally at bedtime; carbamazepine, 100 mg orally three times a day; and levodopa in cases where RBD is associated with Parkinsons disease. Recent studies have also demonstrated improvement with the use of melatonin, which is believed to exert its therapeutic effect by restoring REM sleep atonia. One study reported that melatonin was effective in 87% of patients taking 3 to 9 mg at bedtime, whereas a later study reported resolution in those taking 6 to 12 mg of melatonin at bedtime. The reader is reminded that melatonin, a food supplement, is not approved by the U.S. Food and Drug Administration and is not strictly regulated for uniformity of pharmacologic preparation. Especially in elderly patients, it should be used only with great care because it is vasoactive in laboratory animals and side effects have not been widely studied. NIGHTMARE DISORDER Nightmares are almost always long, complicated dreams that become increasingly frightening during the end of
Parasomnias
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the dream event. Although quite common in children, predisposing factors among adult sufferers include anxiety disorders. Daytime stress may also play a major role. A sizable portionabout 20% to 40%of these patients have a history of schizotypal personality, borderline and schizoid personality disorder, or schizophrenia. A common cause of nightmares may be REM rebound. These spells may be more common especially during nights of recuperation after REM sleep deprivation. Certain medications, including L-dopa, monamine oxidase inhibitors, and beta-adrenergic blockers, or withdrawal of REM suppressants can induce or increase the incidence of nightmares. Ten percent to 50% of children 3 to 5 years of age have enough nightmares to disrupt the sleep of their parents. The sex ratio demonstrates an equal sex ratio in children, whereas in adults there is a ratio of 2:1 or 4:1, favoring women. A familial pattern has not been clearly documented. Treatment is often in the form of reassurance, reduction of stresses that have precipitated the nightmare, improvement in sleep hygiene, and occasional psychotherapy may be of help. Some have advocated the use of systematic desensitization and relaxation techniques to countercondition a relaxation response to anxiety-provoking nightmare contents, whereas others have also recommended the use of imagery rehearsal to reduce nightmare distress, and frequency. When the episodes are severe and refractory to nonpharmacologic therapy, the use of an REM-suppressing agent (tricyclic antidepressant or selective serotonin reuptake inhibitor) (see Table 2) for a short period may be helpful.
studies are usually not required. On the other hand, further evaluation, including a polysomnogram, is warranted if the parasomnias and associated behaviors are violent, cause injury, are frequent and disruptive to the sleep of the patient and/or household members, and result in excessive daytime sleepiness. The use of polysomnogram is also indicated to evaluate for the presence of coexisting obstructive sleep apnea, periodic limb movements disorders, as well as other parasomnias. The use of video and electroencephalographic (EEG) monitoring or polysomnogram with expanded EEG channels is indicated for the evaluation of nocturnal seizures when the episodes are repetitive and stereotypical and the distinction from other parasomnias by history is difficult.
Treatment of Parasomnias
Successful amelioration of disturbing parasomnias depends on accurate diagnosis. Reassurance, addressing safety issues, and education are important in the management of parasomnias. The patient and the family need to maintain a safe bedroom environment, to relocate the sleeping area to the ground floor of the house and if possible, to lock all windows, and to cover glass or windows with heavy drapes. The patient must be warned to avoid precipitants of parasomnias, including unusual stress, sleep deprivation, and ingestion of substances such as alcohol (which increases slow-wave sleep and may promote such parasomnias as sleepwalking) and caffeine-containing products (which have been implicated in parasomnias such as RBD). Often for the less severe presentations, behavioral and safety precautions are sufficient. However, when symptoms are severe or result in injury, the use of pharmacologic therapy is indicated. Pharmacologic therapy relies primarily on the use of benzodiazepines, such as clonazepam, diazepam, and alprazolam. Other treatment options may include tricyclic antidepressants, particularly in cases of sleep terrors. Treatment options for the common parasomnias are listed in Table 2. SUGGESTED READING
Aldrich MS: Sleep medicine, New York, 1999, Oxford University Press. Avidan ACR: Confusional arousal. In Gilman S, editor: Neurology MedLink, San Diego, 2004, MedLink. Boeve B: Melatonin for treatment of REM sleep behavior disorder: response in eight patients [abstract], Sleep 24(Suppl):A35, 2001. Boeve BF, Silber MH, Ferman T: REM sleep behavior disorder and degenerative dementia: an association likely reflecting Lewy body disease, Neurology 51:363-370, 1998. Broughton R: Behavioral parasomnias, Boston, 1998, ButterworthHeinemann, 635-660. Broughton R: NREM arousal parasomnias, Philadelphia, 2000, WB Saunders, 693-706. Dyken ME, Yamada T, Lin-Dyken DC: Polysomnographic assessment of spells in sleep: nocturnal seizures versus parasomnias, Semin Neurol 21:377-390, 2001. Ferini-Strambi L, Zucconi M: REM sleep behavior disorder, Clin Neurophysiol 111(Suppl):S136-S140, 2000. Guilleminault C, Palombini L, Pelayo R, Chervin RD: Sleepwalking and sleep terrors in prepubertal children: what triggers them? Pediatrics 111:e17-25, 2003.
Evaluation of Nocturnal Arousals

The clinical evaluation of a patient presenting with symptoms of parasomnia involves a careful neurologic, medical, psychiatric, and sleep history; an interview with a bed partner or family member; and complete physical examination. Some useful screening questions to ask include the following: Are you or your bed partner aware that you move your arms, legs, or body during sleep? Do you have unusual, vigorous, or violent behaviors during sleep? Do you physically act out your dreams? Have you hurt yourself or a bed partner during sleep? Do you shout, scream, or walk in your sleep? When the observers and the patient are interviewed, the following issues may be addressed: Timing of the event during the night Description of the behaviors Preservation of consciousness versus unresponsiveness Preservation of memory for the event versus amnesia Potential psychosocial factors Presence or absence of family history of similar events
In children with arousal disorders who have a normal neurologic and physical examination, further laboratory
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Narcolepsy
The International Classification of Sleep Disorders. 2005, Westchester, IL: American Academy of Sleep Medicine. Hobson JA, Silvestri L: Parasomnias, Harvard Mental Health Lett 15:3-5, 1999. Kales A, Soldatos CR, Kales JD: Sleep disorders: insomnia, sleepwalking, night terrors, nightmares, and enuresis, Ann Intern Med 106:582-592, 1987. Kavey NB, Whyte J, Resor SR Jr, Gidro-Frank S: Somnambulism in adults, Neurology 40:749-752, 1990. Klackenberg G: Incidence of parasomnias in children in a general population, New York, 1987, Raven Press, 99-113. Kowey PR, Mainchak RA, Rials SJ, et al: Things that go bang in the night, N Engl J Med 327:1884, 1992. Llorente MD, Currier MB, Norman SE, Mellman TA: Night terrors in adults: phenomenology and relationship to psychopathology, J Clin Psychiatry 53:392-394, 1992. Mahowald MW: Overview of parasomnias. In National sleep medicine course, Westchester, IL, 1999, American Academy of Sleep Medicine. Mahowald MW, Ettinger MG: Things that go bump in the night: the parasomnias revisited, J Clin Neurophysiol 7:119-143, 1990. Mahowald MW, Rosen GM: Parasomnias in children, Pediatrician 17:21-31, 1990. Mahowald MW, Schenck CH: Diagnosis and management of parasomnias, Clin Cornerstone 2:48-57, 2002. Mahowald MW, Schenck CH: NREM sleep parasomnias, Neurol Clin 14:675-696, 1996. Mahowald MW, Schenck CH: REM sleep behavior disorder, Philadelphia, 1994, WB Saunders, 574-588. Masand P, Popli AP, Weilburg JB: Sleepwalking, Am Family Physician 51:649-654, 1995. Milliet N, Ummenhofer W: Somnambulism and trauma: case report and short review of the literature, J Trauma Injury Infect Crit Care 47:420-422, 1999. Ohayon MM, Guilleminault C, Priest RG: Night terrors, sleepwalking, and confusional arousals in the general population: their frequency and relationship to other sleep and mental disorders, J Clin Psychiatry 60:268-276, 1999. Parkes JD: The parasomnias, Lancet 2:1021-1025, 1986. Plazzi G, Corsinin R, Provini F: REM sleep behavior disorders in multiple system atrophy, Neurology 48:1094-1097, 1997. Reid WH, Ahmed I, Levie CA: Treatment of sleepwalking: a controlled study, Am J Psychother 35:27-37, 1981. Rosen GM, Mahowald MW, Ferber R: Sleepwalking, confusional arousals, and sleep terrors in the child. In Ferber A, Kryger M, editors: Principles and practice of sleep medicine in the child, Philadelphia, 1995, WB Saunders, 99-106. Schenck CH, Bundlie SR, Mahowald MW: Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder, Neurology 46:388-393, 1996. Schenck CH, Bundlie SR, Patterson AL, Mahowald MW: Rapid eye movement sleep behavior disorder: a treatable parasomnia affecting older adults, JAMA 257:1786-1789, 1987. Schenck CH, Mahowald MW: REM sleep parasomnias, Neurol Clin 14:697-720, 1996. Schenck CH, Mahowald MW: Two cases of premenstrual sleep terrors and injurious sleepwalking, J Psychosom Obstet Gynaecol 16:79-84, 1995. Shneerson J: Handbook of sleep medicine, Malden, 2000, Blackwell Science, 136-162. Takeuchi N, Uchimura N, Hashizume Y, et al: Melatonin therapy for REM sleep behavior disorder, Psychiatry Clin Neurosci 55:267-269, 2001. Tassi P, Muzet A: Sleep inertia, Sleep Med Rev 4:341-353, 2000. Thorpy MJ, Glovinsky PB: Parasomnias, Psychiatr Clin North Am 10:623-639, 1987. Wise MS: Parasomnias in children, Pediatr Ann 26:427-433, 1997.
Narcolepsy
Scott Fromherz, M.D., and Emmanuel Mignot, M.D., Ph.D.
Together with obstructive sleep apnea (OSA), insufficient sleep, and idiopathic central nervous system hypersomnia, narcolepsy is a common cause of excessive daytime sleepiness. Even when narrowly defined by the presence of cataplexy, narcolepsy is not rare and affects 1 in 2000 individuals in North America and Western European countries.
Definition and Pathophysiology

The classic narcolepsy tetrad includes daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. Cataplexy, a sudden loss of muscle tone, triggered by strong emotions, is almost pathognomonic but is not required for diagnosis. Other symptoms include disrupted night-time sleep and automatic behaviors. Narcolepsy is associated with human leukocyte antigen (HLA) DQB1*0602. Postmortem studies have shown a selective loss of 50,000 to 100,000 posterior hypothalamic neurons, producing the neuropeptide hypocretin (orexin). The HLA association and associated hypocretin deficiency is particularly strong (>90%) in patients with definite cataplexy. This association lends support to the hypothesis that narcolepsy is an autoimmune disorder. Hypocretin has tight functional interactions with cholinergic and monoaminergic systems regulating sleep. Without hypocretin, narcoleptic patients have sleepiness, inappropriate rapid eye movement (REM) paralysis during wakefulness (cataplexy, sleep paralysis), REM dreaming before falling asleep (hypnagogic hallucinations), and disorganized night-time sleep. Rapid transitions into REM sleep (REM latency below 20 minutes) called sleep-onset REM periods (SOREMPs) can be observed during nocturnal sleep and while napping.
Clinical Characteristics
Cataplexy is a sudden, short-lived (seconds, rarely more than minutes), bilateral loss of muscle tone elicited by emotions. The existence of a typical trigger is crucial to the recognition of genuine cataplexy. It is usually produced by humor or laughter, especially when the patient himself or herself is telling a joke or relating a funny story. Less commonly, anger, surprise, elation, playful excitement may be involved. There is no sensory component or loss of consciousness. Attacks can be mild, such as an inability to retain facial muscle tone, or severe, leading to complete collapse. Reflexes are abolished, but the episodes are rarely long enough to evaluate by physical examination. Respiration can be hampered by position or made slightly more difficult, but it is always maintained.
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Narcolepsy
The International Classification of Sleep Disorders. 2005, Westchester, IL: American Academy of Sleep Medicine. Hobson JA, Silvestri L: Parasomnias, Harvard Mental Health Lett 15:3-5, 1999. Kales A, Soldatos CR, Kales JD: Sleep disorders: insomnia, sleepwalking, night terrors, nightmares, and enuresis, Ann Intern Med 106:582-592, 1987. Kavey NB, Whyte J, Resor SR Jr, Gidro-Frank S: Somnambulism in adults, Neurology 40:749-752, 1990. Klackenberg G: Incidence of parasomnias in children in a general population, New York, 1987, Raven Press, 99-113. Kowey PR, Mainchak RA, Rials SJ, et al: Things that go bang in the night, N Engl J Med 327:1884, 1992. Llorente MD, Currier MB, Norman SE, Mellman TA: Night terrors in adults: phenomenology and relationship to psychopathology, J Clin Psychiatry 53:392-394, 1992. Mahowald MW: Overview of parasomnias. In National sleep medicine course, Westchester, IL, 1999, American Academy of Sleep Medicine. Mahowald MW, Ettinger MG: Things that go bump in the night: the parasomnias revisited, J Clin Neurophysiol 7:119-143, 1990. Mahowald MW, Rosen GM: Parasomnias in children, Pediatrician 17:21-31, 1990. Mahowald MW, Schenck CH: Diagnosis and management of parasomnias, Clin Cornerstone 2:48-57, 2002. Mahowald MW, Schenck CH: NREM sleep parasomnias, Neurol Clin 14:675-696, 1996. Mahowald MW, Schenck CH: REM sleep behavior disorder, Philadelphia, 1994, WB Saunders, 574-588. Masand P, Popli AP, Weilburg JB: Sleepwalking, Am Family Physician 51:649-654, 1995. Milliet N, Ummenhofer W: Somnambulism and trauma: case report and short review of the literature, J Trauma Injury Infect Crit Care 47:420-422, 1999. Ohayon MM, Guilleminault C, Priest RG: Night terrors, sleepwalking, and confusional arousals in the general population: their frequency and relationship to other sleep and mental disorders, J Clin Psychiatry 60:268-276, 1999. Parkes JD: The parasomnias, Lancet 2:1021-1025, 1986. Plazzi G, Corsinin R, Provini F: REM sleep behavior disorders in multiple system atrophy, Neurology 48:1094-1097, 1997. Reid WH, Ahmed I, Levie CA: Treatment of sleepwalking: a controlled study, Am J Psychother 35:27-37, 1981. Rosen GM, Mahowald MW, Ferber R: Sleepwalking, confusional arousals, and sleep terrors in the child. In Ferber A, Kryger M, editors: Principles and practice of sleep medicine in the child, Philadelphia, 1995, WB Saunders, 99-106. Schenck CH, Bundlie SR, Mahowald MW: Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder, Neurology 46:388-393, 1996. Schenck CH, Bundlie SR, Patterson AL, Mahowald MW: Rapid eye movement sleep behavior disorder: a treatable parasomnia affecting older adults, JAMA 257:1786-1789, 1987. Schenck CH, Mahowald MW: REM sleep parasomnias, Neurol Clin 14:697-720, 1996. Schenck CH, Mahowald MW: Two cases of premenstrual sleep terrors and injurious sleepwalking, J Psychosom Obstet Gynaecol 16:79-84, 1995. Shneerson J: Handbook of sleep medicine, Malden, 2000, Blackwell Science, 136-162. Takeuchi N, Uchimura N, Hashizume Y, et al: Melatonin therapy for REM sleep behavior disorder, Psychiatry Clin Neurosci 55:267-269, 2001. Tassi P, Muzet A: Sleep inertia, Sleep Med Rev 4:341-353, 2000. Thorpy MJ, Glovinsky PB: Parasomnias, Psychiatr Clin North Am 10:623-639, 1987. Wise MS: Parasomnias in children, Pediatr Ann 26:427-433, 1997.
Narcolepsy
Scott Fromherz, M.D., and Emmanuel Mignot, M.D., Ph.D.
Together with obstructive sleep apnea (OSA), insufficient sleep, and idiopathic central nervous system hypersomnia, narcolepsy is a common cause of excessive daytime sleepiness. Even when narrowly defined by the presence of cataplexy, narcolepsy is not rare and affects 1 in 2000 individuals in North America and Western European countries.
Definition and Pathophysiology

The classic narcolepsy tetrad includes daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. Cataplexy, a sudden loss of muscle tone, triggered by strong emotions, is almost pathognomonic but is not required for diagnosis. Other symptoms include disrupted night-time sleep and automatic behaviors. Narcolepsy is associated with human leukocyte antigen (HLA) DQB1*0602. Postmortem studies have shown a selective loss of 50,000 to 100,000 posterior hypothalamic neurons, producing the neuropeptide hypocretin (orexin). The HLA association and associated hypocretin deficiency is particularly strong (>90%) in patients with definite cataplexy. This association lends support to the hypothesis that narcolepsy is an autoimmune disorder. Hypocretin has tight functional interactions with cholinergic and monoaminergic systems regulating sleep. Without hypocretin, narcoleptic patients have sleepiness, inappropriate rapid eye movement (REM) paralysis during wakefulness (cataplexy, sleep paralysis), REM dreaming before falling asleep (hypnagogic hallucinations), and disorganized night-time sleep. Rapid transitions into REM sleep (REM latency below 20 minutes) called sleep-onset REM periods (SOREMPs) can be observed during nocturnal sleep and while napping.
Cataplexy is a sudden, short-lived (seconds, rarely more than minutes), bilateral loss of muscle tone elicited by emotions. The existence of a typical trigger is crucial to the recognition of genuine cataplexy. It is usually produced by humor or laughter, especially when the patient himself or herself is telling a joke or relating a funny story. Less commonly, anger, surprise, elation, playful excitement may be involved. There is no sensory component or loss of consciousness. Attacks can be mild, such as an inability to retain facial muscle tone, or severe, leading to complete collapse. Reflexes are abolished, but the episodes are rarely long enough to evaluate by physical examination. Respiration can be hampered by position or made slightly more difficult, but it is always maintained.
Narcolepsy
19
This definition allows one to rule out possible mimics. Syncope, sleep attacks, and generalized seizures all involve a loss of consciousness. The bilateral distribution of weakness and temporal course are inconsistent with most strokes. The short duration and lack of correlation with intense exercise are inconsistent with episodic or fluctuating neuromuscular disorders. The lack of positive phenomena rules out most seizures. Because startle alone is not a typical trigger, hyperekplexia can be excluded. It is also important to differentiate genuine cataplexy from normal physiologic reactions. For example, a person may laugh so hard that his face hurts or feels weak. When laughing hard, non-narcoleptic patients might also feel rubber knees or roll onto the floor. In true cataplexy, muscle weakness is obvious and must occur more than a few times in a lifetime. Sleepiness in narcolepsy is usually more severe than in other sleep disorders; however, contrary to popular belief, it is not easy to differentiate from sleepiness due to insufficient sleep or OSA. Napping is common, and short naps are typically refreshing. A misperception in narcolepsy is the nature of sleep attacks. Some have a mistaken impression that the term sleep attack refers to sudden sleep that is so severe it may cause extraordinary events such as falling asleep into a soup bowl. Others are confusing cataplexy and sleep attacks. The correct definition of sleep attack is an irresistible desire to fall asleep that can lead to unintentional sleep. It can present rapidly, but its onset is not as acute as cataplexy. For example, people with narcolepsy may feel awake and nonsleepy until they are in a sedentary or nonstimulating situation, at which point they may rapidly fall asleep. It is not an attack so much as an unexpected nap. Other symptoms are more straightforward to identify but lack diagnostic specificity. Sleep paralysis is an inability to move that occurs at sleep onset or on awakening. Hypnagogic and hypnopompic hallucinations are dreamlike visual or auditory perceptions that occur at sleep onset and on awakening, respectively. Hallucinations and sleep paralysis may occur in combination and are typically frightening. Automatic behaviors are actions that occur without full awareness or memory, for example continuing to talk on the phone without making sense, because of sleepiness or microsleep. It is merely an indication of the severity of daytime sleepiness independent of any etiology. Disturbed nocturnal sleep is present in approximately 50% of patients and can be quite disabling. In narcolepsy, it is usually not characterized by a difficulty falling asleep but rather by recurrent night-time awakenings and a feeling of restlessness during the night. All symptoms except cataplexy can also be found in normal individuals, idiopathic hypersomnia, and OSA in some circumstances.
Diagnosis
The diagnosis of narcolepsy is primarily clinical, but confirmatory tests are usually necessary to verify the diagnosis (Figure 1). The presence of definite cataplexy is
most important (see later). Questions about sleep patterns, medications that cause somnolence, signs of sleep apnea such as snoring, symptoms of restless leg syndrome, and evidence of sleep insufficiency or a circadian rhythm disturbance must be asked. If there is suspicion of OSA, an overnight polysomnogram (PSG) is mandatory. Finally, evaluation must include questions about sleep paralysis, hypnagogic and hypnopompic hallucinations, automatic behaviors, and disrupted night-time sleep. Because of its importance to the diagnosis, questions regarding cataplexy should be asked carefully to avoid leading the patient. Cataplexy is rarely observed during interviews, although small facial attacks are sometimes observed when severely affected patients recount emotional events. A question like Does anything unusual happen when you are laughing? is more appropriate than Do you feel weak when you are laughing? Similarly, the clinician should not be satisfied with a simple affirmative response. Rather, the patient should be asked to recall the specific circumstances. In this regard, it is useful to ask for a description of the first or last episode experienced. Patients describing unclear events or events that have occurred only once should be considered without cataplexy for the purpose of further evaluation and treatment strategies (Figure 2; see also Figure 1). If a patient has both hypersomnia and definite cataplexy, a clinical diagnosis can be made. However, it is still recommended that a PSG followed by a multiple sleep latency (MSL) test be done to document sleepiness and evaluate comorbid sleep disorders. Proper documentation also permits more aggressive treatment in the future. Approximately 15% of patients with cataplexy do not display typical MSL test abnormalities, so the diagnosis must remain clinically based. If there is no cataplexy, an MSL test (preceded by PSG) is mandatory (see Figure 1). The MSL test objectively quantifies daytime sleepiness. It consists of five 20-minute daytime naps at 2-hour intervals. The amount of time it takes to fall asleep (sleep latency) and the occurrence of REM sleep is recorded. An MSL of less than 8 minutes and two or more SOREMPs is diagnostic for narcolepsy. The MSL test must always be preceded by a PSG to rule out other causes of short MSL or SOREMPs such as OSA, insufficient sleep, or delayed sleep phase syndrome. At least 6 hours of sleep must have occurred prior to the MSL test. Sleep logs or actigraphy for the preceding 2 weeks can be helpful to exclude chronic sleep deprivation. It must also be conducted after withdrawal of psychotropic medications (generally > 2 weeks). Antidepressants, most notably, suppress REM sleep and/or may create REM rebound if stopped too recently prior to testing. The PSG may also show a short sleep latency (< 10 minutes) and a SOREMP (< 20 minutes on the PSG). Periodic limb movements, fragmented sleep and low sleep efficiency are often observed. The MSL test may be difficult to interpret in the presence of disturbed nocturnal sleep or in patients with combined sleep pathologies (e.g., OSA or severe periodic limb movements and narcolepsy). When conducted
20
Narcolepsy
Hypersomnia
Clinical evaluation: Ask about cataplexy, evaluate severity of sleepiness and presence of sleep paralysis, hypnagogic hallucinations, or automatic behaviors. Rule out more common causes of hypersomnia such as obstructive sleep apnea, insufficient sleep syndrome, or a circadian rhythm disorder. Also, confirm that it is primarily a problem of sleepiness rather than fatigue.
Definite cataplexy
No cataplexy or atypical cataplexy
Diagnosis of narcolepsy Proceed with PSG/MSLT to objectively document a firm diagnosis and allow for more aggressive treatment later. Treat comorbid sleep disorders if needed (e.g. OSA, but rarely PLMs) If MSLT is negative (MSL > 8 or < 2 SOREMPs) the results should be interpreted within the context of the clinical history as the presence of cataplexy is sufficient to diagnose narcolepsy. If necessary, the MSLT can be repeated Consider LP for CSF hypocretin-1 levels if patient: 1. is already being treated with psychotropic medications 2. has clinically significant associated sleep disorders 3. has disabling neurological or psychiatric disorders, confounding the clinical picture or disrupting the ability to conduct an MSLT 4. is very young and cannot follow MSLT instructions properly
MSLT Must be preceded by PSG to rule out comorbid sleep disorders and document adequate nocturnal sleep. If significant sleep disorder detected on PSG, then disorder must be treated before proceeding with MSLT.
MSL > 8 minutes or < 2 SOREMPs
MSL < 8 minutes or 2 SOREMPs
Not narcolepsy (If clinical suspicion high, consider repeat MSLT or LP for CSF hypocretin-1 levels)
Diagnosis of narcolepsy
FIGURE 1. Evaluation of narcolepsy. MSLT, Multiple sleep latency test; MSL, mean sleep latency; PSG, polysomnogram; SOREMP, sleep-onset rapid eye movement period; OSA, obstructive sleep apnea; PLM, periodic limb movement; LP, lumbar puncture; CSF, cerebrospinal fluid.
in the absence of sleep deprivation or delayed sleep phase, it is considered to be a highly predictive test. Large sample populationbased MSL test evaluations in controls are lacking, but it is estimated that only a small percentage of the general population has SOREMPs during MSL testing. Cerebrospinal fluid (CSF) hypocretin-1 measurements can also be used to diagnose narcolepsy. In patients with cataplexy, CSF hypocretin-1 levels are absent or very low in more than 90% of the cases. In patients with various other neurologic disorders, only 2% have low CSF hypocretin-1, mostly in the context of severe neurologic conditions. Levels are normal in controls independent of psychotropic treatment and/or presence of other sleep disorders. Unfortunately, the test is less predictive in patients without cataplexy, with only 16% having low levels, often in younger subjects who may later develop cataplexy.
Positive MSL test findings may be absent in some narcoleptics, especially young children. Approximately 15% of patients with definite narcolepsy and hypocretin deficiency have a negative first-time MSL test. If the MSL test is negative, but clinical suspicion for narcolepsy is high, repeat the MSL testing or measure CSF hypocretin-1. Serum HLA typing for DQB1*0602 is positive in many patients with narcolepsy, but it is also positive in approximately 20% to 25% of normal subjects. DQB1*0602 positivity does not confirm narcolepsy.
Pharmacologic Treatments
Modafinil is now first-line standard-of-care treatment for sleepiness associated with narcolepsy. Headache can be a problematic side effect, but that usually resolves with time and can often be avoided by slowly increasing
Narcolepsy
21
Diagnosis of narcolepsy
Definite cataplexy
Behavioral methods: Scheduled naps Fixed wake-up time Regular sleep schedule
No cataplexy or atypical cataplexy
Disrupted nighttime sleep
No disrupted nighttime sleep
Sodium oxybate: Starting dose 4.5 grams split in two nightly doses (at bedtime and 2 hours later). Dose can be increased by 1.5 grams every two weeks, up to a maximum of 9 grams per night. Consider adding modafinil and anticataplectics on a short-term basis until sodium oxybate has full effect (up to 6 months later). If successful treatment, consider decreasing or stopping dose of anticataplectics and stimulants.
Treat cataplexy with anticataplectic monoamine reuptake inhibitors: Venlafaxine 75300 mg/day Atomoxetine 18100 mg qd or split bid Fluoxetine 2060 mg/day Clomipramine 25200 mg qhs Protriptyline 2.520 mg/bid If no (or minimal) response, consider reevaluating presence of true cataplexy. An LP for CSF hypocretin-1 levels may be necessary to confirm diagnosis. If patient responds to anticataplectics, but sideeffects are limiting, effect is insufficient, or disrupted nighttime sleep appears, consider sodium oxybate.
Treat daytime sleepiness with modafinil 200600 mg/day (if insufficient, can add two pulse doses of 5 mg methylphenidate at peak times of sleepiness)
Use caution before proceeding to stronger CNSstimulating agents, given the potential for abuse and tolerance. Confirm MSLT results and consider LP for CSF hypocretin-1. If patient is hypocretin-1 deficient, consider sodium oxybate.
Methylphenidate SR 20 mg in am with two pulse doses of 5 mg methylphenidate (non-SR) at peak times of sleepiness Dextroamphetamine SR 1015 mg in am with 5 mg pulse dosing as with methylphenidate
If onset is recent, adjust treatment with appearance of new symptoms Evaluate stable patients every six months Watch for weight gain and development of OSA or additional sleepiness FIGURE 2. Treatment of narcolepsy. CNS, Central nervous system; MSLT, multiple sleep latency test; CSF, cerebrospinal fluid; LP, lumbar puncture; OSA, obstructive sleep apnea.
the dose. The safest starting dose for modafinil is 100 mg in the morning, which can be gradually increased to a maximum of 400 to 600 mg. This may be split into a morning and a noon dose. Amphetamine-like stimulants, such as methylphenidate, dextroamphetamine, amphetamine racemic mixture, and methylamphetamine, can also be used but have a number of disadvantages. They are potentially addictive and should be reserved for patients with a well-established diagnosis. Additionally, side effects such as palpitations, hypertension, and nervousness may occur because of their action on the autonomic nervous system. The mode of action of amphetamine-like stimulants and modafinil on
wakefulness is thought to involve increase dopaminergic transmission. The most important concept in using stimulants for treating daytime sleepiness is timing. A typical scenario is to use modafinil or an extended-release amphetamine formulation in the morning, with pulse dosing of shortacting medication at appropriate times throughout the day. For example, a student who still has problems with sleepiness after lunch might take 5 to 15 mg of shortacting methylphenidate at that time in addition to the morning modafinil. Although stimulants are used primarily for daytime sleepiness, amphetamines (not modafinil) also have some effect on cataplexy at high doses.
22
Narcolepsy
Antidepressants are commonly used to treat cataplexy. They are also effective for sleep paralysis and hypnagogic hallucinations, a sometime disabling symptom. Tricyclic antidepressants are highly effective but have anticholinergic side effects. Selective serotonin reuptake inhibitors are efficacious, but relatively high doses are generally needed. Newer medications targeting norepinephrine reuptake, such as venlafaxine and atomoxetine, are most effective. The dual serotoninergic/noradrenergic reuptake inhibitor venlafaxine, 75 to 300 mg/day, is now a typical first-line treatment. If this is not helpful, atomoxetine, 18 to 100 mg daily or split to twice daily; fluoxetine, 20 to 60 mg/day; or even tricyclic antidepressants (e.g., protriptyline, 2.5 to 20 mg/day, or clomipramine, 25 to 200 mg/day) can be used. Atomoxetine is unique in being the only U.S. Food and Drug Administration approved medication that selectively blocks norepinephrine reuptake. Patients should be warned that rebound cataplexy usually occurs when medications are discontinued, changed, or skipped. Sodium oxybate (gamma-hydroxybutyrate [GHB]) is unique because it is efficacious on all symptoms. This naturally occurring compound is a potent but shortacting hypnotic that consolidates slow-wave and REM sleep, most likely via gamma-aminobutyric acid type B agonistic effect. It has been available since the 1970s but was only recently approved for the treatment of cataplexy. It is thought that the consolidation of nocturnal sleep and REM sleep leads to decreased daytime symptoms. The starting dose is 4.5 gm per night, divided in two nightly doses (before bedtime and 2 to 3 hours later, once the first dose has metabolized). The patient should prepare both doses, lie down after taking the drug, and possibly set up an alarm for the second dose. The dose can be increased every 2 weeks by 1.5-gm increments to a maximum of 9 gm per night. The most common side effects are dizziness, nausea, and, at a higher dose, enuresis. Sodium oxybate should not be taken with alcohol or other central nervous system depressants. Narcolepsy is frequently associated with other sleep disorders. OSA is common and must be treated, especially if GHB is to be used. Periodic limb movements are also common but rarely need treatment unless associated with restless leg syndrome.
The risk of driving while sleepy, especially prior to adequate therapy, must be discussed and if appropriate, regulatory agencies notified. Patients with narcolepsy must avoid jobs that put others in danger and should consider activities that are less sedentary. Jobs that involve repetitive tasks or sitting down and looking at a computer all day can be difficult. Employers or teachers should be asked to accommodate 15- to 30-minute scheduled naps. SUGGESTED READING
Dauvilliers Y, Billiard M, Montplaisir J: Clinical aspects and pathophysiology of narcolepsy, Clin Neurophysiol 114:2000-2017, 2003. Lammers GJ, Overeem S: Pharmacological management of narcolepsy, Expert Opin Pharmacother 4:1739-1746, 2003. Mignot E, Lammers GJ, Ripley B, et al: The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias, Arch Neurol 59:1553-1562, 2002. Mignot E, Lin L, Rogers W, et al: Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups, Am J Hum Genet 68:686-699, 2001. Taheri S, Zeitzer JM, Mignot E: The role of hypocretins (orexins) in sleep regulation and narcolepsy, Annu Rev Neurosci 25:283-313, 2002.
PATIENT RESOURCES
American Academy of Sleep Medicine One Westbrook Corporate Center, Suite 920 Westchester, IL 60154 Phone: 708-492-0930 http://www.aasmnet.org/ Narcolepsy Network, Inc. 10921 Reed Hartman Highway, Suite 119 Cincinnati OH 45242 Phone: 513-891-3522 E-mail: narnet@narcolepsynetwork.org http://www.narcolepsynetwork.org/ National Organization for Rare Disorders 55 Kenosia Avenue P.O. Box 1968 Danbury, CT 06813-1968 Phone: 800-999-6673 Email: orphan@rarediseases.org http://www.rarediseases.org/ National Sleep Foundation 1522 K Street NW, Suite 500 Washington, DC 20005 Phone: 202-347-3471 E-mail: nsf@sleepfoundation.org http://www.sleepfoundation.org/ Stanford Center for Narcolepsy Department of Psychiatry and Behavioral Sciences Psychiatry and Behavioral Sciences Building 401 Quarry RoadRoom 3354 Stanford, CA 94305-5730 Phone: 650-725-6512 http://www.med.stanford.edu/school/psychiatry/narcolepsy/ Talk About Sleep, Inc. P.O. Box 146 Chaska, MN 55318 Phone: 952-448-5511 http://www.talkaboutsleep.com/
Behavioral Treatments
Good sleep hygiene, education, and treatment compliance are important to the management of narcolepsy. Referral to support groups such as the Narcolepsy Network is helpful. Fixed wake-up times, sleep diaries, and regular sleep schedule are recommended. Obesity may develop, especially in young children when disease onset is abrupt. It is useful to restrict the diet, encourage exercise, and treat sleepiness aggressively at this stage.
SECTION 2
Seizures
Tallie Z. Baram, M.D., Ph.D.
is uncommon. If you add benzodiazepines, be prepared to intubate. If the seizures or the cause are focal, phenytoin may be considered. Here, if a dose of phenytoin, 20 mg/kg, with serum levels greater than 20 g/mL is ineffective, then further doses are unlikely to be helpful.
Infantile Spasms
Infantile spasms (Wests syndrome) are a severe, relatively common (~1:2400 births), and often missed diagnosis. It is important to recognize infantile spasms because they respond poorly to conventional anticonvulsants, but remit in most infants when treated with high-dose adrenocorticotropic hormone (ACTH) (see later) (Figure 2). A broad consensus suggests that cognitive outcome is better in infants with infantile spasms who are treated successfully. Infantile spasms are considered a form of myoclonic seizures that occur in clusters. They are prevalent in 3- to 12-month-old infants and are associated with a highly abnormal (interictal), chaotic electro-encephalogram (EEG) (hypsarrhythmia). This pathognomonic EEG pattern is most commonly observed during sleep. The seizures may be flexor, extensor, or mixed, subtle, or massive, and flattening of the EEG during a spasm is typical. Most infantile spasms are symptomatic, resulting from a large variety of insults or genetic causes. A variant associated with tuberous sclerosis may be particularly responsive to vigabatrin (100 to 150 mg/kg/day). This medication is available outside the United States, and the side effects of visual-restrictive retinal changes should be considered. In some cases the causes of infantile spasms may be treatable, with seizure remittance. Mostly, treatment of the spasms with a goal of eliminating them and normalizing the EEG is required. Early, successful therapy seems to improve cognitive outcome. The latter is grim in symptomatic cases but excellent in remitting idiopathic cases. The most efficacious treatment is high-dose ACTH, with greater than 85% success. A 2-week treatment with this potent hormone results in unpleasant but rarely dangerous side effects such as acne, hypertension, voracious appetite, and irritability. Long-lasting treatment may lead to immunosuppression or gastric bleeding. Because efficacy is a function of the dose, and 23
Neonatal Seizures
Most seizures in a newborn are symptomaticthey are caused by acute or remote insults to the developing brain. Some of these may be eliminated or reversed; others may require concurrent treatment. Therefore, a diagnostic evaluation should precede or coincide with therapeutic intervention (see later). A second unique feature of many neonatal seizures is their unusual or subtle nature compared with seizures later in life. In addition to tonic, clonic, focal, or apparent generalized motor seizures, neonatal seizures may consist of fragmented, nonrhythmic movements, eye blinking, singleextremity posture, or electroencephalographic seizures without overt motor manifestations. Thus, the clinician should have a high level of suspicion for seizures in an ill neonate. Tachycardia or bradycardia, unexplained oxygen desaturation, or abnormal mental status may signify ongoing seizures. Finally, the outcome of neonatal seizures is best predicted by their cause. For example, hypocalcemia-induced seizures in an otherwise normal fullterm infant typically remit, with good outcome. In contrast, seizures following severe hypoxia/ ischemia, severe neonatal infection, or congenital brain malformation may respond to treatment, but the infants prognosis would be guarded. TREATMENT (Figure 1) There is no absolute best drug. Phenobarbital is recommended here because it is both rapid and long acting and has no ceiling; repeated boluses can be used in severe cases as monotherapy with high likelihood of success. Ignore serum levels; in any event, they are not steady-state. Use remission as your guideline. With phenobarbital monotherapy, respiratory depression
24
ALGORITHM FOR MANAGEMENT OF NEONATAL SEIZURES 1. Assure adequate airway protection and oxygenation 2. Initiate diagnostic evaluation: History/physical for obvious causes (placenta previa, multiorgan failure with hypoxic ischemic encephalopathy (HIE), severe prematurity, etc). Metabolic: Glucose (in an infant of diabetic mother, give oral or iv glucose), calcium, electrolytes Infection: CBC, cultures, chest x-ray. Spinal tap mandatory (consider metabolic causes of low CSF glucose). Evaluate for congenital infection, particularly if petechiae, liver enlargement, cataracts or other clues present. CT/MRI: periventricular hemorrhage in severe prematurity, malformation, tuberous sclerosis, infarcts, abnormal basal ganglia signal indicating HIE, etc. Obtain EEG, if infant ill or seizures subtle consider continuous EEG to monitor results of therapy. 3. Treat A. Address treatable causes (calcium, glucose, infection) B. Give phenobarbital 20 mg/kg. This is a loading dose that should lead to barely therapeutic serum levels.
Seizures remit
Seizures persist
Cause transient or resolved: stop treatment Cause persistent or unknown, baby abnormal: continue treatment
Repeat PB at 1020 mg/kg* Obtain EEG. If seizures focal consider phenytoin (20 mg/kg) Barbiturates have no ceiling effect. May be used at very high doses, to seizure remission Mixing barbiturates and benzodiazepines should be done with caution in unintubated infants, because of potential respiratory depression.
Seizures remit
More PB or benzodiazepine. Reassess diagnostic workup. Consider intubation.
Seizures persist
FIGURE 1. Algorithm for management of neonatal seizures. CBC, Complete blood count; CSF, cerebrospinal fluid; EEG, electroencephalogram; PB, phenobarbital.
ALGORITHM FOR MANAGEMENT OF INFANTILE SPASMS 1. Establish the diagnosis History/physical: to rule out (sleep) myoclonus, myoclonic seizures, GE reflux The age, clusters of spasms, hypsarrhythmic EEG are diagnostic Consider treatable causes (mass lesion, metabolic derangement). Try to establish diagnosis, particularly tuberous sclerosis, infection, other genetic/acquired insult (CT/MRI, basic metabolic workup). Normal baby = idiopathic IS: prognosis better Abnormal baby with diagnosis (symptomatic IS), or no diagnosis (cryptogenic) prognosis for cognitive outcome guarded 2. Treat A. Address treatable causes (hydrocephalus, infection) B. Give ACTH depot (ACTHARGEL): 150 units/square meter per day (~ 80 U per 10 kg baby) in two daily divided doses for 2 weeks.
Spasms remit (>80%)
Spasms persist
Obtain EEG or video-EEG to verify. Often hypsarrhythmia will disappear revealing other abnormalities.
Verify that medication given as directed. Try another batch of ACTH.
Spasms persist No spasms, no hypsarrhythmia Consider vigabatrin 100 mg/kg/day. Consider topiramate, valproate, B-6, ketogenic diet.
Taper ACTH over 2 weeks
FIGURE 2. Algorithm for management of infantile spasms. EEG, Electroencephalogram; GE, gastroesophageal; IS, infantile spasm; ACTH, adrenocorticotropic hormone. Johnson: Current Therapy in Neurologic Disease (7/E)
Febrile Seizures
25
Seizures
side effects are a function of the duration of treatment, it is best to initiate ACTH treatment at the high dosage and limit duration to 2 weeks, with a 2-week taper. Complete dramatic remission of the spasms typically occurs during the first week. Note that twice-daily dosing at the high (ActharGel, 150 U/m2 of body surface area) is required. Occasional bad batches of the hormone have been described. In infants with a strong focal element of the spasms, particularly with focal lesion (e.g., tuber) and focal EEG, surgical therapy should be considered. A trial of ACTH may still be indicated and may convert apparent infantile spasms to focal seizures. Other therapies may be successful at a much lower rate. Consider pyridoxine (to exclude pyridoxinedependent seizures, or as therapy), 100-150 mg/day; valproate; topiramate; and the ketogenic diet. If seizures remit and recur, verify that these are indeed infantile spasms rather than a new seizure type with focal EEG. A second course of ACTH may be effective for infantile spasm recurrence. New seizure types, instigated by the original disorder, may respond to appropriate anticonvulsant therapy.
TABLE 1 Risk of Experiencing a Febrile Seizure

Factor General population Child in daycare Slow development Prolonged nursery stay (>28 days) Febrile seizure in first-degree relative (mother, father, sibling) Febrile seizure in two first-degree relatives Any two risk factors Risk of Febrile Seizure (%) 2 7 10 12 10 33 28
Adapted from Bethune P, Gordon K, Dooley J, et al: Which child will have a febrile seizure? Am J Dis Child 147:35-39, 1993.
What Is the Chance That My Child Will Have Febrile Seizures?

Families with a history of febrile seizures may ask this question, particularly when there are siblings with febrile seizures. Febrile seizures are more common in some families, and 10% to 20% of siblings of children with febrile seizures will also experience them. Certain other children may have an increased risk, as high as 25% if the child had a prolonged nursery stay, slow development, or daycare attendance. These factors suggest susceptibility to febrile seizures in a child who may have experienced some subtle neurologic changes and who is exposed on a more consistent basis to a wide range of infections in the daycare setting. When two or more of these factors exist, it may be appropriate at one of the early well-child visits to discuss management of fever and what to do if a febrile seizure occurs (Table 1).
Febrile Seizures
Adam L. Hartman, M.D., and Eileen P. G. Vining, M.D.
Febrile seizures occur in approximately 3% of children, making them the most common type of seizure in this age group. They are seizures in infancy or childhood (typically between 3 months and 5 years of age) associated with fever and without evidence of central nervous system infection or other defined cause, such as metabolic abnormalities due to dehydration. Ordinarily, they are generalized (tonic-clonic or tonic) in nature and brief. The fact that they are common to pediatric practices (and often to neurologic consultation) makes it important to understand many of the concerns associated with their occurrence and to understand the information that has reshaped our approach to this problem. In fact, this has resulted in reconsideration of our overall approach to seizures. Given the generally benign prognosis in febrile seizures, counseling the family is the primary form of therapy. One way to consider the issues involved in febrile seizures is to organize the information in a format that answers parents questions and provides a framework for providing ongoing care. This can even include anticipatory guidance, which is so vital to the practice of pediatrics.
What Should We Do If Our Child Has a Febrile Seizure?

Most febrile seizures are brief and do not need medical intervention. If, however, the seizure has persisted longer than 5 minutes, Emergency Medical Services (i.e., 911) should be called. Less than 5% of febrile seizures occur as status epilepticus, and it is likely that the seizure will end before medications can be given. The usual intervention is either lorazepam, 0.1 mg/kg intravenously (IV), up to 4 mg, or diazepam, 0.3 mg/kg IV given slowly at less than 1 mg/kg/min. Health care providers in emergency settings should recall that diazepam could be given rectally.* In essence, care during a febrile seizure should be the same as for any other generalized convulsion. When the seizure is over and the child has returned to baseline (often sleepiness if the seizure has occurred at night), a decision must be made concerning the
*Diastat, 0.5 mg/kg rectally for children 2 to 5 years, 0.3 mg/kg rectally for children 6 to 11 years, 0.2 mg/kg rectally for children older than 11 years, all rounded to the nearest syringe size; one dose may be repeated after 30 minutes, if necessary.
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Seizures
side effects are a function of the duration of treatment, it is best to initiate ACTH treatment at the high dosage and limit duration to 2 weeks, with a 2-week taper. Complete dramatic remission of the spasms typically occurs during the first week. Note that twice-daily dosing at the high (ActharGel, 150 U/m2 of body surface area) is required. Occasional bad batches of the hormone have been described. In infants with a strong focal element of the spasms, particularly with focal lesion (e.g., tuber) and focal EEG, surgical therapy should be considered. A trial of ACTH may still be indicated and may convert apparent infantile spasms to focal seizures. Other therapies may be successful at a much lower rate. Consider pyridoxine (to exclude pyridoxinedependent seizures, or as therapy), 100-150 mg/day; valproate; topiramate; and the ketogenic diet. If seizures remit and recur, verify that these are indeed infantile spasms rather than a new seizure type with focal EEG. A second course of ACTH may be effective for infantile spasm recurrence. New seizure types, instigated by the original disorder, may respond to appropriate anticonvulsant therapy.
TABLE 1 Risk of Experiencing a Febrile Seizure

Factor General population Child in daycare Slow development Prolonged nursery stay (>28 days) Febrile seizure in first-degree relative (mother, father, sibling) Febrile seizure in two first-degree relatives Any two risk factors Risk of Febrile Seizure (%) 2 7 10 12 10 33 28
Adapted from Bethune P, Gordon K, Dooley J, et al: Which child will have a febrile seizure? Am J Dis Child 147:35-39, 1993.
What Is the Chance That My Child Will Have Febrile Seizures?

Families with a history of febrile seizures may ask this question, particularly when there are siblings with febrile seizures. Febrile seizures are more common in some families, and 10% to 20% of siblings of children with febrile seizures will also experience them. Certain other children may have an increased risk, as high as 25% if the child had a prolonged nursery stay, slow development, or daycare attendance. These factors suggest susceptibility to febrile seizures in a child who may have experienced some subtle neurologic changes and who is exposed on a more consistent basis to a wide range of infections in the daycare setting. When two or more of these factors exist, it may be appropriate at one of the early well-child visits to discuss management of fever and what to do if a febrile seizure occurs (Table 1).
Febrile Seizures
Adam L. Hartman, M.D., and Eileen P. G. Vining, M.D.
Febrile seizures occur in approximately 3% of children, making them the most common type of seizure in this age group. They are seizures in infancy or childhood (typically between 3 months and 5 years of age) associated with fever and without evidence of central nervous system infection or other defined cause, such as metabolic abnormalities due to dehydration. Ordinarily, they are generalized (tonic-clonic or tonic) in nature and brief. The fact that they are common to pediatric practices (and often to neurologic consultation) makes it important to understand many of the concerns associated with their occurrence and to understand the information that has reshaped our approach to this problem. In fact, this has resulted in reconsideration of our overall approach to seizures. Given the generally benign prognosis in febrile seizures, counseling the family is the primary form of therapy. One way to consider the issues involved in febrile seizures is to organize the information in a format that answers parents questions and provides a framework for providing ongoing care. This can even include anticipatory guidance, which is so vital to the practice of pediatrics.
What Should We Do If Our Child Has a Febrile Seizure?

Most febrile seizures are brief and do not need medical intervention. If, however, the seizure has persisted longer than 5 minutes, Emergency Medical Services (i.e., 911) should be called. Less than 5% of febrile seizures occur as status epilepticus, and it is likely that the seizure will end before medications can be given. The usual intervention is either lorazepam, 0.1 mg/kg intravenously (IV), up to 4 mg, or diazepam, 0.3 mg/kg IV given slowly at less than 1 mg/kg/min. Health care providers in emergency settings should recall that diazepam could be given rectally.* In essence, care during a febrile seizure should be the same as for any other generalized convulsion. When the seizure is over and the child has returned to baseline (often sleepiness if the seizure has occurred at night), a decision must be made concerning the
*Diastat, 0.5 mg/kg rectally for children 2 to 5 years, 0.3 mg/kg rectally for children 6 to 11 years, 0.2 mg/kg rectally for children older than 11 years, all rounded to the nearest syringe size; one dose may be repeated after 30 minutes, if necessary.
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Febrile Seizures
evaluation of the precipitating fever. The American Academy of Pediatrics has published guidelines outlining the approach to these patients, summarized here and in Figure 1. If this is the patients first febrile seizure (particularly if in a young infant or toddler), the child should be examined immediately to detect and/or treat the cause of the fever. A seizure in the setting of a fever must be excluded from a seizure resulting from meningitis. Generally this is not difficult since an alternative source can be found or the child is acting normally without evidence of significant illness. A lumbar puncture (LP) should be done whenever there is concern about the possibility of meningitis. It is usually performed in children younger than 1 year of age who have had a first febrile seizure and in settings where there is concern about the reliability of remaining in contact with the medical care providers. There are certain indications that increase the likelihood that an LP will be positive: (1) a physician visit within the 48 hours preceding the seizure, (2) seizure occurring or persisting in the emergency department setting, (3) focal seizure, or (4) suspicious findings on either physical or neurologic examination. Additional laboratory work should be done depending on the nature of the illness and the questions being asked. A computed tomographic scan or magnetic resonance imaging is not necessary in simple febrile seizures. An EEG is also not necessary; if done within a
Simple FS, no meningeal signs
week of the seizure, it is often minimally abnormal, displaying evidence of the postictal features of the brain. There is no evidence that these findings are predictive of an outcome, either of recurrent seizures or of epilepsy. Usually, the child can be discharged from the emergency department without ongoing medications (other than those appropriate for infection). It is critical that followup be arranged to discuss the meaning of the febrile seizure and how the situation should be managed in the future. If the seizure is recurrent and brief, the physician should be called and plans should be made to assess the source of fever.
What Else Could It Have Been Besides a Febrile Seizure? What Causes Febrile Seizures?
The differential diagnosis of febrile seizures includes the first presentation of epilepsy unmasked by a lowered seizure threshold caused by the fever and illness. The distinction between a febrile seizure and new-onset epilepsy need not be made on the first presentation. There are a number of reasons for this. First, the pathophysiologic relationship between febrile seizures and epilepsy later in life is debated (see later). Second, tests that help make the diagnosis of certain epilepsy syndromes (e.g., EEG) are not predictive after a first simple febrile seizure. Epilepsy will declare itself over time. Even experienced epileptologists can be challenged when making the distinction between a first febrile seizure and a first seizure with fever. Recent work has shown that some patients with a combination of febrile and afebrile seizures, known as generalized epilepsy and febrile seizures plus (GEFS+) have mutations in voltage-gated sodium channel subunits. If there is a family history of febrile and afebrile seizures (particularly severe myoclonic epilepsy of infancy), referral can be made to research groups interested in the genetics of these conditions. Meningitis can manifest as seizures and fevers, as previously discussed. Toxic ingestions of certain medications and substances with anticholinergic properties can also cause seizures and hyperthermia, though there are other historical and clinical signs that should suggest their presence. The same is true for neuroleptic malignant syndrome. In the appropriate setting, intentional exposures (e.g., chemical exposures or bioterrorism) should be considered. Associations have been made between certain pathogens (e.g., human herpesvirus 6) and febrile seizures. Investigation for these viruses is not ordinarily indicated in otherwise healthy children. Certain pathogens can cause encephalopathies that include seizures and fevers. Encephalopathic patients need extensive investigations and are not the subject of this chapter.
Routine imaging, EEG, blood studies not indicated if first simple FS
Age < 12 months? Age 1218 months?
Age > 18 months?
Strongly consider LP
Consider LP
LP unnecessary
1. Manage concurrent illness (e.g., UTI or otitis media). 2. Manage fever, pain, and discomfort. 3. Counsel family at the appropriate time (preferably at office visit) about risk factors, recurrence risk, management of another seizure, risk of epilepsy.
First FS or duration < 15 min.?
Recurrent FS or duration > 15 min.?
No treatment necessary
Discuss option of rectal diazepam with caregivers
Did the Seizure Hurt My Child?

FIGURE 1. Neurology-centered management of febrile seizures (FS). EEG, Electroencephalogram; LP, lumbar puncture; UTI, urinary tract infection.
Parents witnessing a febrile seizure fear that their child will die. We must acknowledge this emotional turmoil,
Febrile Seizures
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Seizures
but their fears and worries can be allayed only by solid information. There is no evidence that a typical febrile seizure hurts the child. Parents need to know about the National Collaborative Perinatal Project, in which children were followed from birth to 7 years of age. Much was learned about the natural history of febrile seizures from this study. Three percent of a cohort of 54,000 children had a febrile seizure (1800 youngsters). No child died of a febrile seizure; no child developed mental retardation from a febrile seizure; and no child developed cerebral palsy from a febrile seizure. There is good evidence from this study that febrile seizures do not lower intelligence. Since the cohort was so large, establishing controls was possible (siblings without febrile seizures) for those who had febrile seizures. The IQ at age 7 years of children with febrile seizures, even recurrent febrile seizures, was not lower than their siblings who had not experienced febrile seizures. More recent studies have confirmed these findings. Parents need to be able to grasp the reality of this information as we help them understand the benign nature of febrile seizures and as they assess interventions.
occurred at a lower temperature (<101F) than if the seizure occurred with a fever higher than 105F. These two observations suggest that there are some children whose threshold for having a febrile seizure is lower than others. It takes a shorter exposure to fever and less of a fever to make them have a febrile seizure. Recurrences are also more likely (40% vs. 20%) if there is a family history of febrile seizures. Recurrence of febrile seizures is not more likely if the seizure is focal or prolonged or even if the child is neurologically or developmentally abnormal before the seizure occurred. About 50% recur in the first 6 months, and 90% will have recurred within the first year.
If the Seizure Is Very Long, Will It Hurt My Child?

There are no data to support the fear that a prolonged febrile seizure will harm the child. Most episodes of febrile status epilepticus occur as the first febrile seizure. Only about 10% of febrile seizures last longer than 15 minutes. Children do not die of febrile status epilepticus, and they do not experience new neurologic problems from it. In fact, they do not have a significantly greater risk of recurrence of simple febrile seizures than the population at large. Only children who have underlying neurologic abnormalities have an increased risk of recurrence of febrile seizures and febrile status epilepticus. These children are also at increased risk for developing afebrile seizures.
Will My Child Have Another Febrile Seizure? If So, When?

Unfortunately, febrile seizures recur in many children. One third of the children will have a second one, and there is a 50% chance that there will be a recurrence if the child is younger than 1 year of age. Parents should be told that there is no reason to expect that a subsequent febrile seizure will be worse than the first. In fact, the first febrile seizure is usually the worst one. There is an increased risk for recurrence under a variety of circumstances (Table 2). The risk of recurrence is increased to almost 50% if the febrile seizure happened in the first hour of fever and is only 15% if the febrile seizure happened more than 24 hours into the fever. The risk of recurrence is also higher (40%) if the febrile seizure
Will My Child Have Epilepsy?

Whether a child will develop epilepsy after a febrile seizure is a concern of families and of physicians and has certainly been one of the motivating forces for initiating prophylactic therapy, hoping to ward off not only recurrent febrile seizures but also epilepsy. Recurring afebrile seizures (epilepsy) is not a consequence of febrile seizures, even recurrent febrile seizures. In the National Collaborative Project, there was no significant increase in the incidence of epilepsy if children had febrile seizures (0.5% vs. 0.9%). The only group that had a significantly increased risk of developing epilepsy by 7 years of age was those children who had two or more risk factors. These risk factors included (1) family history of epilepsy in a first-degree relative; (2) abnormal neurodevelopmental status prior to the first febrile seizure; and (3) complex febrile seizure defined as any one or more of the following features: focal, lasting longer than 15 minutes, or recurring in 24 hours. A child who had a focal febrile seizure that lasted 20 minutes has only one risk factor. Figure 2 graphically demonstrates the overlap between risk factors. Only 6% of the cohort had two or more risk factors, and only 9% of these children developed epilepsy by 7 years os age. Thus, even when the risks appear great, more than 90% of children will not develop epilepsy. Other studies that were not prospective suggest that risks may be higher if people are assessed in their 20s.
TABLE 2 Risk of Recurrence of Febrile Seizure

Factor Overall First febrile seizure <1 yr old Duration of fever <1 hr >24 hr Temperature <101F >105F Family history of febrile seizures Negative family history of febrile seizures Risk of Recurrence (%) 30 50 46 15 42 12 40 23
Adapted from Berg AT, Shinnar S, Hauser WA, et al: A prospective study of recurrent febrile seizures, N Engl J Med 327:1122-1127, 1992.
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Febrile Seizures
Positive family history 5.3%
10%
Abnormal development 3.3%
23% 13% 8%
Complex febrile seizure 4.1%
FIGURE 2. Risks of developing epilepsy after a febrile seizure based on associated factors. (Data from Nelson KB, Ellenberg JH: Prognosis in children with febrile seizures, Pediatrics 61:720-727, 1978.)
These risks include more emphasis on the cumulative effects of a number of factors including the focality of the seizure, whether a Todds paralysis existed, the number of febrile seizures, the age at which the febrile seizure occurred, and the duration of the febrile seizure. Many physicians are worried that febrile seizures will lead to intractable complex partial epilepsy (temporal lobe epilepsy). This issue was raised long ago because of observations made in the setting of surgery to control complex partial seizures. Falconer noted that in the setting of finding mesial temporal sclerosis, there was an increased history of prolonged febrile seizures. Others have disputed these observations. There has been no objective evidence of this process, and many have postulated that prolonged febrile seizures may occur in the setting of an already abnormal mesial temporal lobe. This would need to be studied using magnetic resonance imaging at the time of the initial prolonged or atypical febrile seizure. It is this fear that febrile seizures will lead to intractable epilepsy that has fueled the fire to prevent febrile seizures. There is no evidence, however, that prophylaxis of febrile seizures actually prevents the development of epilepsy.
Can You Prevent These Seizures from Coming Back?

Febrile seizure recurrence can probably be prevented, but why should we even try? For more than 20 years we have known that chronic prophylaxis with phenobarbital levels maintained at more than 17 mg/L will decrease the risk of recurrence to about 10%. Higher levels might prevent more.
There are no convincing data demonstrating that assiduous use of antipyretics can prevent febrile seizure recurrences. We do not even understand enough about the role of fever in provoking the seizure to recommend appropriate antipyretic therapy. Many have believed that it was the rate of rise of fever that provoked the seizure, but this is probably not correct. More likely, the height of the fever itself, the cause of the fever, and other factors unique to the child during the illness (amount of rest, fluids, and so on) determine the predisposition for seizures. Other methods to try to prevent recurrence have been suggested. Other medications, with perhaps fewer side effects than phenobarbital, have been suggested. However, phenytoin and carbamazepine do not appear to prevent febrile seizure recurrences. The potential risks of valproic acid in younger children outweigh the fact that it seems as effective as phenobarbital. About 10 years ago, there was renewed interest in intermittent prophylaxis with diazepam. The results of one study were highly informative in describing why this can be a challenge. The lack of availability of a rectal preparation in the United States at that time led to the study of oral diazepam, 0.33 mg/kg orally every 8 hours, during the febrile illness. Rosman and colleagues showed a 44% reduction in febrile seizure recurrence but found many problems with adherence to the medication regimen. The reasons for this included the following: the temperature was not taken or the presence of illness was not recognized until the seizure occurred; the child was not with the parent when it happened; directions were misunderstood; the child vomited or did not tolerate the medicine; and fear of side effects. In addition, almost 40% of those treated with diazepam had side effects including ataxia, lethargy, and irritability. A recent meta-analysis by Rantala and associates concluded that prophylaxis was difficult to justify in the face of adverse events. An option newly available in the United States is rectal diazepam gel (Diastat) (see earlier). Europeans have used this technique for many years and have had some reasonable success. There are situations where this form of diazepam may be appropriate. This might include neurologically abnormal children who have experienced febrile status epilepticus and children who have a history of recurring, prolonged febrile seizures, especially those who live far from care. This could prevent a prolonged seizure and perhaps diminish the likelihood of recurrence within the next few hours. Unfortunately, large studies of its use have not been undertaken. It has been our anecdotal experience that just having the medicine available and caregivers knowledgeable in its use can lower anxiety levels at home, in the appropriate setting. In managing a patient over the phone, an inquiry should be made about whether rectal diazepam has been prescribed; some caregivers seek a physicians permission to use it, because they fear adverse reactions to the medicine. Physicians seeing children with recurrent febrile seizures should inquire about its use prior to arrival in an acute care setting, since it can alter the patients clinical presentation.
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Seizures
How Will the Treatment Affect My Child?

This depends on the treatment. Phenobarbital may have significant side effects. For decades we have known that it may make children hyperactive, inattentive, and irritable and that it may interfere with sleep. Studies have consistently found that phenobarbital appears to diminish cognitive function (on the average, 4 or 5 IQ points) and that behavior is adversely affected. It is not clear that this impact disappears when the medication has been discontinued, and this is a source of continuing concern since it is administered to children at such a vulnerable developmental period. The risks of intermittent prophylaxis with diazepam are less. Any source of anxiety about the seizures themselves or their treatment leads to strained interactions and increased vulnerability of the child to overprotectiveness.
be a slightly increased incidence of sleep problems, such as parasomnias.
Where Can We Learn More About This?

Parents, caregivers, and often the extended family, should be given an opportunity to learn more. They can accomplish this through several mechanisms. We have written a book specifically for parents that discusses these issues in detail (see Patient Resource). They can be referred to the Abilities Network, which maintains a toll-free hotline (1-800-EFA-1000). Parents will be sent appropriate literature and will be notified if there is a local affiliate that can probably provide even more services such as family counseling and focus groups. Frequently parents need to hear from other parents who have been through this difficult period that the outcome is truly good and that brief febrile seizures have not damaged their child. SUGGESTED READING
What Shall I Do If My Child Has Another Seizure?

The advice to give a family about what to do if the child has another febrile seizure is straightforward. Remember that everything was fine after the first seizure. Remember basic first aid. Provide supportiveprotective care. Stay calm. A child recovering from a seizure and perhaps feeling ill from the fever and cranky at being wakened from sleep does not need to see a panicked parent. Reassure the child that everything is fine. Be soothing. As in the first seizure, the childs pediatrician should be consulted so that they can properly manage the illness. The discussion about whether to use prophylaxis will resurface. Nevertheless, the risks and benefits have not really changed. There is still no significant risk from a febrile seizure. The risk of epilepsy does not substantially increase with recurrent febrile seizures, and there are no data to make us believe we can prevent epilepsy anyway. The risks from treatment remain the same: exposure to medication, the side effects, the constant observation, and the daily reminder that there is something wrong that needs constant medication. Most of these children will outgrow these seizures and experience no disability from having had febrile seizures. On the other hand, those parents who have been sensitized to be frightened of illness and those children who have been medicated over a protracted period may have problems. The risks of treatment generally are worse than the possible benefits that might accrue from therapy.
American Academy of Pediatrics. Committee on Quality Improvement, Subcommittee on Febrile Seizures: Practice parameter: long-term treatment of the child with simple febrile seizures, Pediatrics 103:1307-1309, 1999. American Academy of Pediatrics. Provisional Committee on Quality Improvement, Subcommittee on Febrile Seizures: Practice parameter: the neurodiagnostic evaluation of the child with a first simple febrile seizure, Pediatrics 97:769-772, 1996. Berg AT, Shinnar S, Hauser WA, et al: A prospective study of recurrent febrile seizures, N Engl J Med 327:1122-1127, 1992. Bethune P, Gordon K, Dooley J, et al: Which child will have a febrile seizure? Am J Dis Child 147:35-39, 1993. Farwell JR, Lee YJ, Hirtz DG, et al: Phenobarbital for febrile seizures: effects on intelligence and seizure recurrence, N Engl J Med 322:364-369, 1990. Maytal J, Shinnar S: Febrile status epilepticus, Pediatrics 86:611-616, 1990. Nelson KB, Ellenberg JH: Predictors of epilepsy in children who have experienced febrile seizures, N Engl J Med 295:1029-1033, 1976. Nelson KB, Ellenberg JH: Prognosis in children with febrile seizures, Pediatrics 61:720-727, 1978. Rantala H, Tarkka R, Uhari M: A meta-analytic review of the preventive treatment of recurrences of febrile seizures, J Pediatr 131:922-925, 1997.
PATIENT RESOURCES
Freeman JM, Vining EPG, Pillas DJ: Seizures and epilepsy in childhood: a guide for parents, Baltimore, 2003, Johns Hopkins University Press. Abilities Network: Hotline: 800-332-1000
What Else Can Happen to Children with Febrile Seizures?

Intellectual development is normal in previously developmentally normal children with febrile seizures. Some children can develop some behavioral problems, but this may not be due to the febrile seizures. There may
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Absence Seizures
Absence Seizures
Nathan E. Crone, M.D.
Diagnosis
Although patients and physicians often refer to absence seizures as petit mal, absence is the preferred term to describe seizures with staring, unresponsiveness, and characteristic generalized epileptiform discharges on electroencephalogram (EEG). Absence seizures may be differentiated into typical absence and atypical absence. Typical absence seizures are characterized by a brief lapse of consciousness and responsiveness, usually lasting less than 10 seconds, associated with characteristic generalized 3-Hz spike-and-wave discharges that abruptly appear and disappear against the background of an otherwise normal EEG. The EEG abnormalities are readily elicited by hyperventilation and less frequently by intermittent photic stimulation. Typical absence seizures have no auras or postictal confusion. Although amnestic for events during the seizure, patients may continue with activities that were temporarily interrupted by the seizure, often continuing where they left off mid-sentence. Typical absence seizures may be further subdivided into simple and complex absence seizures according to whether there are associated orofacial or limb automatisms, or other motor signs such as clonic, tonic, or atonic movements. Atypical absence seizures are most readily distinguished from typical absence seizures by their longer duration (usually > 20 seconds), slower generalized spikewave discharges (2 to 2.5 Hz), and their association with mental retardation and other seizure types, particularly atonic and tonic seizures. These seizures are clinically less stereotyped than typical absence seizures, with a less abrupt onset and offset and a longer duration, lasting up to several minutes. In addition, these seizures are often not precipitated by hyperventilation or photic stimulation. Atypical absence seizures are best known for their occurrence in Lennox-Gastaut syndrome (see later). Yet another type of absence seizure, myoclonic absence, is accompanied by rhythmic clonic jerking of bilateral upper and lower limbs. It is important to distinguish absence seizures from complex partial seizures, which may superficially resemble absence seizures in some patients. Patients may refer to either seizure type as a staring spell, and patients with complex partial seizures may refer to their seizures as petit mal simply because they are less severe than their grand mal seizures. Some complex partial seizures consist only of staring, behavioral arrest, and unresponsiveness, and absence seizures are often accompanied by automatisms that are more commonly seen in complex partial seizures. However, complex partial seizures can usually be clinically differentiated from absence seizures by their longer duration and the presence of auras and/or postictal confusion. The diagnosis of absence seizures can usually be confirmed by the characteristic
ictal and interictal discharges seen on EEG. The distinction between these seizure types is clinically relevant because absence seizures may be exacerbated by some medications used to treat complex partial seizures. In addition to carbamazepine, gamma-aminobutyric acid agonists such as tiagabine and vigabatrin may also exacerbate absence seizures by modulating the abnormal thalamocortical circuits that appear to be responsible for the characteristic 3-Hz spike-and-wave discharges. Absence seizures often present in children as deteriorating school performance and may be misdiagnosed as attention deficit disorder or other behavioral disturbances. Typical absence seizures often go unrecognized because of their brevity and subtle clinical appearance in otherwise normal children, but they may occur hundreds of times per day. If left untreated these brief but frequent lapses of consciousness can interrupt learning. Therefore, the academic performance of patients with newly diagnosed absence seizures should be closely monitored, and remedial instruction should be recommended if necessary. The EEG is a critical component in the diagnostic work-up for possible absence seizures. The ictal and interictal EEG abnormalities associated with typical absence seizures are stereotyped and diagnostic, consisting of high-voltage, rhythmic 3-Hz spike-and-wave complexes over widespread head regions, maximal over frontal regions and usually, but not always, bilaterally symmetrical. Briefly displacing an otherwise normal background EEG, these spike-wave complexes coincide with the abrupt onset and offset of ictal clinical manifestations. Brief interictal discharges may not be associated with appreciable clinical manifestations, but runs of spike-wave complexes lasting more than a few seconds are often associated with typical clinical absence seizures. Both interictal and ictal discharges, as well as typical absence seizures, may be evoked by hyperventilation and, less commonly, by intermittent photic stimulation. Atypical absence seizures are most commonly associated with slow spike-and-wave complexes (1.5 to 2.5 Hz) that often appear less stereotyped and symmetrical. This pattern usually occurs against an abnormal background of diffuse slowing with focal or multifocal spikes. Effective therapeutic decision making relies on a correct diagnosis of not only the seizure type but also the associated epilepsy syndrome. The most common syndromes presenting with absence seizures are childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), and juvenile myoclonic epilepsy (JME). CAE usually begins before 10 years of age, with peak incidence at 5 years of age, and usually remits (is outgrown) within a few years after onset. Remission occurs in 90% of cases before 12 years of age, and attempts to taper medications can be initiated during adolescence, before the patients driving license becomes an issue. JAE begins after 10 years of age, but unlike CAE, it does not usually remit and is often lifelong. Although CAE is manifest only by absence seizures, JAE may also be associated with myoclonic and generalized tonic-clonic seizures, which are the more common seizure types seen in JME. Absence seizures typically occur with much
Absence Seizures
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Seizures
lower frequency in JAE than in CAE, and typical spikewave discharges are not as reliably induced by hyperventilation in JAE. Infrequent absence seizures may also occur in 30% to 50% of patients with JME. A substantial minority of patients with typical absence seizures and generalized discharges on EEG does not fit the aforementioned syndromes. In addition, rare but well-recognized syndromes with absence seizures include myoclonic absence epilepsy, eyelid myoclonia with absences, and perioral myoclonia with absences. Atypical absence seizures are commonly seen in Lennox-Gastaut syndrome, which consists of mental retardation in association with mixed seizure types, including atypical absence, atonic, myoclonic, tonic, and/ or generalized tonic-clonic seizures. The peak age at onset is 3 to 5 years of age, and 20% of patients have a history of infantile spasms. This is considered a symptomatic epilepsy syndrome because it is often associated with preexisting cerebral insults, including hypoxic-ischemic and other perinatal brain injuries, central nervous system infections, developmental malformations, and neurogenetic diseases such as tuberous sclerosis. The diagnosis of typical absence seizures may be confirmed with careful clinical history and EEG, without additional ancillary tests. CAE, JAE, and JME appear to be genetic in origin with highly variable penetrance; therefore, a family history of similar seizures is helpful but not necessary for the diagnosis. Clinicians can often make the diagnosis in the office by observing clinical seizures during hyperventilation. However, a history of atypical absence seizures should prompt a search for an underlying neurologic disease, and the work-up should include magnetic resonance imaging of the brain, as well as screening for neurogenetic diseases. Absence status epilepticus usually presents as persistent confusion or stupor associated with characteristic 1- to 4-Hz spike-and-wave or polyspike-and-wave discharges on EEG, usually without other typical clinical manifestations of absence seizures. It may occur in patients with a history of typical or atypical absences with their attendant epilepsy syndromes. This emergency can usually be resolved with intravenous lorazepam or diazepam, or sodium valproate (Depacon).
Management
The mainstays of pharmacotherapy for typical absence seizures are ethosuximide and valproic acid. These drugs appear to be equally effective as monotherapy, controlling more than 80% of patients. Ethosuximide has been considered the first choice because of its lack of the serious, yet rare, side effects associated with valproic acid. By reducing low-threshold T-type calcium currents that play a role in the generation of 3-Hz spike-and-wave rhythms in thalamocortical neurons, ethosuximide is highly effective against absence seizures. However, there is no evidence that it has other common antiepileptic mechanisms of action, and it is not usually effective in monotherapy for generalized tonic-clonic seizures. Its use as monotherapy is therefore largely limited to CAE, but it may be used as an adjunctive
antiepileptic drug in patients with absence seizures in addition to other seizure types. Ethosuximide may also be effective against absence seizures in JME, epilepsy with myoclonic absences, and eyelid myoclonia with absences, as well as atypical absence seizures in Lennox-Gastaut syndrome. The most common doserelated side effects are nausea, drowsiness, and other gastrointestinal complaints, which are usually mild and most prevalent at the onset of therapy. Headaches and behavioral disturbances, including psychosis, can be caused or exacerbated by ethosuximide in rare instances. Valproic acid is effective not only against absence seizures but also against generalized tonic-clonic, myoclonic, and atonic seizures; therefore, it is particularly useful in the treatment of patients with mixed seizure types. It is usually the drug of choice for atypical absence seizures, particularly in patients with LennoxGastaut syndrome. However, valproic acid therapy is frequently associated with weight gain, hair loss, and tremor. These side effects are somewhat dose related and can sometimes be ameliorated with an exercise program, vitamin supplementation, or dose reduction, respectively. Relatively rare but serious idiosyncratic side effects include hepatic failure, bone marrow suppression, and pancreatitis. Valproic acid at higher doses can cause an encephalopathy with hyperammonemia and triphasic waves on EEG. Valproate-induced carnitine deficiency can be addressed with carnitine supplementation (L-carnitine, 50 to 100 mg/kg/day). Valproic acid may also be useful in patients with comorbid conditions for which it is also effective (i.e., migraine headache and bipolar disorder). Lamotrigine may also be considered a potential first-line medication. It has already been shown in a double-blind, placebo-controlled trial to be effective as monotherapy in 64% of children with newly diagnosed typical absence seizures, but a head-to-head comparison with ethosuximide or valproic acid has not been made. Nevertheless, lamotrigine is generally considered to have a low incidence of side effects, and in some studies it has been better tolerated than other antiepileptic drugs. Although there were early concerns about lamotrigines association with serious rash, including Stevens-Johnson syndrome, it has since been learned that the incidence of rash is greatly reduced by initiating this medication at lower dosages and titrating the dosage more slowly (Table 1). Dosage titration must be particularly careful when lamotrigine is given in combination with valproic acid because it inhibits the hepatic metabolism of lamotrigine. The initial and target dosages of lamotrigine (see Table 1) are much lower for patients already taking valproic acid. If given in monotherapy, the dosage of lamotrigine may also require a significant reduction if valproic acid is later added. In contrast, serum lamotrigine levels are reduced by enzyme-inducing antiepileptic drugs, and target dosages of 600 to 1000 mg/day may be required to achieve therapeutic blood levels of lamotrigine. Aside from the risk of rash, the most common dose-related side effects are diplopia, dizziness, and ataxia, which may be worse when lamotrigine is given with drugs that have similar neurotoxic side effects. Because lamotrigine
32
Absence Seizures
TABLE 1 Antiepileptic Drugs for Treatment of Absence Seizures

Medication Ethosuximide (Zarontin) Form Available Capsules: 250 mg Syrup: 50 mg/mL Dosage Initiate slowly at 10-20 mg/ kg/day (bid), increasing q 2 wk according to clinical response; optimal dosage in children is usually 20-40 mg/kg/day (bid) Maintenance dose in adults ranges 500-1500 mg/day (bid) Adverse Effects Usual Target Level 40-100 g/mL
Valproic acid (Depakote)
Depacon Depakene
Tablets: 125, 250, 500 mg; Sprinkles: 125 mg ER (extended release) tablets: 250, 500 mg IV solution: 100 mg/mL Capsules: 250 mg Syrup: 250/mL
Initiate at 10-15 mg/kg/day and increase daily dosage by 5-10 mg/kg/day q wk up to 30-60 mg/kg/day, divided bid-qid Maintenance dose in adults ranges 750-4000 mg/day (bid-qid)
Lamotrigine (Lamictal)
Tablets: 25, 100, 150, 200 mg Chewable dispersible tablets: 2, 5, 25 mg
Children 2-12 yr of age Note: Round all dosages down from recommended mg/kg/day to nearest whole tablet denominations Also taking valproate: Weeks 1 and 2: 0.15 mg/kg/day (bid) Weeks 3 and 4: 0.3 mg/kg/day (bid) Then increase dose by 0.3 mg/kg/day every 1-2 wk up to 1-5 mg/kg/day or maximum of 200 mg/day (bid) Not also taking valproate: Weeks 1 and 2: 0.6 mg/kg/day (bid) Weeks 3 and 4: 1.2 mg/kg/day (bid) Then increase dose by 1.2 mg/kg/day every 1-2 wk up to 5-15 mg/kg/day or maximum of 400 mg/day (bid) Patients > 12 yr of age Also taking valproate: Weeks 1 and 2: 25 mg qod Weeks 3 and 4: 25 mg qd Then increase dose by 25-50 mg every 1-2 wk up to 100-400 mg/day (bid)
Dose-related: nausea, vomiting, anorexia, epigastric pain, diarrhea, headache, drowsiness, dizziness, euphoria, mood and thought disorders Non-dose-related: leukopenia, skin rash, Stevens-Johnson syndrome, systemic lupus erythematosus, aplastic anemia Dose-related: nausea, vomiting, abdominal pain, drowsiness, tremor, increased appetite and weight gain, hair loss, ataxia Non-dose-related: hepatic failure (increased risk with polypharmacy and age <2 years), hyperammonemia, thrombocytopenia, leukopenia, pancreatitis, amenorrhea, polycystic ovarian syndrome (associated with weight gain and insulin resistance) Dose-related: ataxia, dizziness, diplopia, nausea, headache, sedation Non-dose-related: skin rash, StevensJohnson syndrome
50-120 g/mL
4-18 g/mL
33
Seizures
TABLE 1 Antiepileptic Drugs for Treatment of Absence Seizurescontd

Medication Form Available Dosage Adverse Effects Usual Target Level
Methsuximide (Celontin)
Capsules: 150, 300 mg
Not also taking valproate: Weeks 1 and 2: 50 mg/day (bid) Weeks 3 and 4: 100 mg/day (bid) Then increase dose by 100 mg/day every 1-2 wk up to 300-500 mg/day 5-20 mg/kg/day (qd-bid) Usual adult maintenance dosage: 1200-1500 mg/day (qd-tid)
Acetazolamide (Diamox)
Tablets: 125, 250 mg SR (sustainedrelease) capsules: 500 mg
Initiate at 10-25 mg/kg/day (tid) and gradually increase to 1000 mg/day (tid)
Clonazepam (Klonopin)
Tablets: 0.5, 1, 2 mg
Initiate at 0.01-0.03 mg/kg/day and titrate according to seizure control up to 0.1-0.5 mg/kg/day (tid)
Nausea, vomiting, diarrhea, anorexia, abdominal pain, drowsiness, dizziness, mood and thought disorders, rash, Stevens-Johnson syndrome, leukopenia, pancytopenia Acral paresthesias, altered taste, hearing disturbance (tinnitus), lethargy, dizziness, rash, Stevens-Johnson syndrome, nausea, vomiting, fever, leukopenia, aplastic anemia, nephrolithiasis Dose-related: lethargy, sedation, ataxia, behavioral disturbances
10-50 g/mL of N-desmethylmethsuximide
Not established
2
10-50 ng/mL
has exacerbated myoclonic seizures in some patients, its use should be monitored closely in patients with JME and Lennox-Gastaut syndrome, in which it can otherwise serve as a useful adjunctive antiepileptic drug. Methsuximide, chemically related to ethosuximide, is effective against absence seizures, as well as complex partial and generalized tonic-clonic seizures, but tolerance to its anticonvulsant effect is frequent, as are drug-drug interactions with other antiepileptic drugs. It should be considered for patients who are allergic or unresponsive to the first-line agents. Acetazolamide is effective against absence seizures, but tolerance develops rapidly. Its usefulness is therefore limited to intermittent adjunctive therapy, particularly appropriate for brief seizure exacerbations or catamenial epilepsy. Atypical absence seizures are usually more difficult to treat than typical absence seizures because they are associated with more refractory seizure types and have greater neurologic comorbidity. Valproic acid is usually the drug of first choice, but lamotrigine, clonazepam, and topiramate have also been shown to be effective. In medically refractory cases of Lennox-Gastaut syndrome, felbamate and/or the ketogenic diet may be considered, and adrenocorticotropic hormone or prednisone may serve as a last resort. Carbamazepine, vigabatrin, and tiagabine should be avoided because of their potential for exacerbating absence seizures, particularly atypical absence. The prognosis of absence seizures depends largely on the underlying epilepsy syndrome. Seizures spontaneously
remit in up to 90% of patients with CAE, and medication should be withdrawn after the patient has been seizure free for 1 to 2 years. However, the likelihood of remission is much lower in JAE, and JME is usually a lifelong condition. Atypical absence seizures, particularly those associated with Lennox-Gastaut syndrome, are often lifelong and refractory to medication. In these patients the vagus nerve stimulator and/or the ketogenic diet may also be considered.

Susan T. Herman, M.D., and Jacqueline A. French, M.D.
Complex partial seizures (CPSs) are stereotyped episodes characterized by alteration in consciousness and amnesia for some or all of the event. CPSs are often preceded by an aura, or simple partial seizure, which may indicate the ictal onset zone. The clinical manifestations of CPSs are varied, including motionless staring,
33
Seizures
TABLE 1 Antiepileptic Drugs for Treatment of Absence Seizurescontd

Medication Form Available Dosage Adverse Effects Usual Target Level
Methsuximide (Celontin)
Capsules: 150, 300 mg
Not also taking valproate: Weeks 1 and 2: 50 mg/day (bid) Weeks 3 and 4: 100 mg/day (bid) Then increase dose by 100 mg/day every 1-2 wk up to 300-500 mg/day 5-20 mg/kg/day (qd-bid) Usual adult maintenance dosage: 1200-1500 mg/day (qd-tid)
Acetazolamide (Diamox)
Tablets: 125, 250 mg SR (sustainedrelease) capsules: 500 mg
Initiate at 10-25 mg/kg/day (tid) and gradually increase to 1000 mg/day (tid)
Clonazepam (Klonopin)
Tablets: 0.5, 1, 2 mg
Initiate at 0.01-0.03 mg/kg/day and titrate according to seizure control up to 0.1-0.5 mg/kg/day (tid)
Nausea, vomiting, diarrhea, anorexia, abdominal pain, drowsiness, dizziness, mood and thought disorders, rash, Stevens-Johnson syndrome, leukopenia, pancytopenia Acral paresthesias, altered taste, hearing disturbance (tinnitus), lethargy, dizziness, rash, Stevens-Johnson syndrome, nausea, vomiting, fever, leukopenia, aplastic anemia, nephrolithiasis Dose-related: lethargy, sedation, ataxia, behavioral disturbances
10-50 g/mL of N-desmethylmethsuximide
Not established
2
10-50 ng/mL
has exacerbated myoclonic seizures in some patients, its use should be monitored closely in patients with JME and Lennox-Gastaut syndrome, in which it can otherwise serve as a useful adjunctive antiepileptic drug. Methsuximide, chemically related to ethosuximide, is effective against absence seizures, as well as complex partial and generalized tonic-clonic seizures, but tolerance to its anticonvulsant effect is frequent, as are drug-drug interactions with other antiepileptic drugs. It should be considered for patients who are allergic or unresponsive to the first-line agents. Acetazolamide is effective against absence seizures, but tolerance develops rapidly. Its usefulness is therefore limited to intermittent adjunctive therapy, particularly appropriate for brief seizure exacerbations or catamenial epilepsy. Atypical absence seizures are usually more difficult to treat than typical absence seizures because they are associated with more refractory seizure types and have greater neurologic comorbidity. Valproic acid is usually the drug of first choice, but lamotrigine, clonazepam, and topiramate have also been shown to be effective. In medically refractory cases of Lennox-Gastaut syndrome, felbamate and/or the ketogenic diet may be considered, and adrenocorticotropic hormone or prednisone may serve as a last resort. Carbamazepine, vigabatrin, and tiagabine should be avoided because of their potential for exacerbating absence seizures, particularly atypical absence. The prognosis of absence seizures depends largely on the underlying epilepsy syndrome. Seizures spontaneously
remit in up to 90% of patients with CAE, and medication should be withdrawn after the patient has been seizure free for 1 to 2 years. However, the likelihood of remission is much lower in JAE, and JME is usually a lifelong condition. Atypical absence seizures, particularly those associated with Lennox-Gastaut syndrome, are often lifelong and refractory to medication. In these patients the vagus nerve stimulator and/or the ketogenic diet may also be considered.

Susan T. Herman, M.D., and Jacqueline A. French, M.D.
Complex partial seizures (CPSs) are stereotyped episodes characterized by alteration in consciousness and amnesia for some or all of the event. CPSs are often preceded by an aura, or simple partial seizure, which may indicate the ictal onset zone. The clinical manifestations of CPSs are varied, including motionless staring,
34
unresponsiveness, oral or limb automatisms, focal limb posturing or clonus, and postictal confusion or focal neurologic deficits. CPSs typically last less than 2 to 3 minutes. Most patients with CPSs will at some time in their course also experience secondarily generalized tonic-clonic seizures. Most CPSs arise from the temporal lobe. Seizure frequency may range from one per year to many per day. It may be difficult to diagnose a CPS after a single event given the varied clinical manifestations. Most patients have had several CPSs by the time they present to a physician for evaluation. A careful history for previous episodes suggestive of seizures, such as stereotyped auras, episodes of loss of time or confusion, or witnessed staring spells, may help confirm the diagnosis. The differential diagnosis includes syncope, sleep disorders, anxiety and panic disorders, migraine headache, narcolepsy, and nonepileptic psychogenic events. CPSs may be idiopathic (presumed genetic), cryptogenic (no known cause), or remote symptomatic (known prior brain insult). A specific cause can be determined in fewer than 50% of patients. Common etiologic factors include mesial temporal sclerosis, tumor, cortical dysplasia, stroke, complicated febrile seizures, mental retardation, cerebral palsy, central nervous system infections, and traumatic brain injury. Diagnostic evaluation should include complete blood count (CBC), electrolytes, serum glucose, blood urea nitrogen and creatinine, and liver function tests (LFTs) to screen for potential etiologies and establish a baseline prior to initiation of AEDs. Urine toxicology and serum ethanol levels may be useful if substance abuse is suspected. Electroencephalography is an essential part of the work-up. It is most likely to be diagnostic within 24 hours after a suspected seizure. The hallmark abnormality of CPSs is the focal epileptiform discharge (spike or sharp wave), usually over one temporal region. A single electroencephalogram (EEG) shows focal spikes in only approximately 50% of patients, but repeat EEGs and sleep deprivation increase the yield to 70% to 90%. Neuroimaging should be performed for all patients with CPSs. Head computed tomography (CT) may be appropriate in emergency situations, but magnetic resonance imaging (MRI) has greater yield for structural abnormalities. A high-quality 1.5-tesla MRI should be performed. Gadolinium contrast does not increase the yield. Thin T2-weighted and fluid-attenuated inversion recovery (FLAIR) coronal cuts perpendicular to the long axis of the hippocampus are necessary to detect mesial temporal sclerosis, whereas high-resolution spoiled gradient recall images are sensitive for cortical dysplasia. Patients and their families should be fully educated about the risk for seizure recurrence, the potential implications of further seizures, first aid measures for seizures, and common seizure precipitants such as sleep deprivation and alcohol use. Safety precautions include restrictions on swimming alone, working at heights or near open water, operating heavy machinery, participating in contact sports, driving, and other high-risk behaviors. Most states impose driving limitations on patients with episodes of loss of consciousness. Patients usually must be seizure free for 3 to 12 months before
driving privileges are restored. Exceptions may be made for patients with only simple partial seizures (no impairment of consciousness), prolonged stereotyped auras, exclusively nocturnal seizures, or a single seizure with a normal EEG. The physicians responsibility is to instruct the patient about the relevant state laws and to report to the Department of Motor Vehicles when mandated by law. Mortality rates are increased among patients with partial seizures owing to accidents (drowning and motor vehicle accidents), sudden unexplained death, and suicide, particularly in patients with difficult-to-control epilepsy. Treatment should not be initiated unless it is clear that the episode in question was actually an epileptic seizure and only when the recurrence risk is high. Overall, the risk of seizure recurrence after a single seizure is 30% to 40% over 2 years. Patients with no epilepsy risk factors, normal neurologic examinations, normal EEGs, and normal neuroimaging have a recurrence risk of only approximately 20% to 30%. Such patients do not usually require treatment with antiepileptic drugs (AEDs), unless the consequences of a second seizure outweigh the potential adverse effects of the AED. Epileptiform discharges on EEG or a structural abnormality on neuroimaging increases the risk of a second seizure to 60% to 70%. Many epileptologists consider occurrence of a clear-cut CPS in an adult as a strong indication of structural abnormality and treat after a single event. Adults with high likelihood of seizure recurrence require treatment with AEDs because of the potential adverse consequences of a second seizure on driving, independence, and employment. Treatment after a single seizure is not as imperative in children, since the consequences of a second seizure are less problematic. Once a patient has had two or more seizures, a diagnosis of epilepsy can be made. The risk of continued seizures is then greater than 70% to 80%, and most patients should be treated with AEDs. The goal of treatment with AEDs is complete seizure control without side effects. Almost all of the currently available AEDs (Table 1) are effective for the treatment of partial-onset seizures. The choice of the initial AED should be tailored to the individual patient (Table 2). Nearly 50% of patients will achieve complete control of seizures with their first AED and will remain on this therapy for several years to a lifetime. There is no evidence to support efficacy differences among AEDs, so treatment decisions focus on potential adverse effects and other AED characteristics. Patient factors to consider in drug selection include age, gender, concomitant medical disorders, and coadministered medications. AED factors include spectrum of activity, pharmacokinetics, titration rate, drug metabolism and elimination, adverse effect profile, and cost. The longer-established AEDs are less expensive but have more drug interactions and may produce long-term complications. As a group, the newer AEDs have simpler pharmacokinetics, fewer drug interactions, fewer serious idiosyncratic side effects, and less dose-related toxicity. Chronic adverse effects, such as cosmetic changes, bone disease, and teratogenicity, may also be less problematic with the newer AEDs.
TABLE 1 Doses and Adverse Effects of AEDs for Complex Partial Seizures
Total Daily Dose Range Adults 600-2400 mg 15-35 mg/kg bid-qid (bid for XR and Carbatrol) bid-tid Ataxia, dizziness, diplopia, hyponatremia Aplastic anemia, agranulocytosis, rash, SJS, hepatitis Aplastic anemia, hepatotoxicity, rash, SJS Children Dose Schedule Common Adverse Effects Rare or Idiosyncratic Side Effects
Initial Dose and Escalation Children
Agent
Adults
Carbamazepine (Tegretol, Tegretol XR, Carbatrol) 2400-4800 mg 100-125 mg/kg
100 mg bid, increase 100 mg bid q 3-5 days
Felbamate (Felbatol)
300 mg tid, increase 300 mg tid q 7 d 900-6000 mg 20-60 mg/kg tid-qid
Seizures
Gabapentin (Neurontin)
Insomnia, headache, weight loss, nausea, vomiting Weight gain
Lamotrigine monotherapy (Lamictal) 300-800 mg 5-15 mg/kg bid
100-500 mg
1-5 mg/kg
bid
Headache, dizziness, insomnia
Movement disorders, behavioral disturbance (children) Rash, SJS
Lamotrigine + EI-AED 100-300 mg 0.5-2 mg/kg qd-bid
300 mg qd, increase 300 mg daily to 300 mg tid, then 300 mg tid q 7 days 25 mg qd, increase 25-50 mg q 2 wk 50 mg qd, increase 50 mg q 2 wk
Lamotrigine + VPA
25 mg qod, increase 25 mg q 2 wk 1000-4000 mg 30-100 mg/kg
Levetiracetam (Keppra) 900-2400 mg
bid
Irritability, fatigue bid-tid Dizziness, GI disturbance, hyponatremia
Psychosis
Oxcarbazepine (Trileptal) 60-240 mg
20-50 mg/kg
Rash, SJS
Phenobarbital (Luminal)
4-8 mg/kg
qd-bid
Rash, SJS, hepatitis, connective tissue disturbance 200-500 mg 4-8 mg/kg qd-bid Rash, SJS, hepatitis, lupus-like reaction
Phenytoin
250 mg bid, increase 250-500 mg bid q wk 150 mg bid, increase 150-300 mg bid q wk 30-60 mg qd, increase 30-60 mg q 1-2 wk 200-300 mg qd (oral load 6-7 mg/kg q 8 hr for three doses)
5 mg/kg/day divided bid, increase 5 mg/kg/day q 3-5 days 15 mg/kg/day divided tid, increase 15 mg/kg/day q 7 day 5 mg/kg/day divided tid, increase 5 mg/kg/day q 7 days 0.2 mg/kg/day divided bid, increase 0.2 mg/ kg/day q 2 wk 0.6 mg/kg/day divided bid, increase 0.6 mg/ kg/day q 2 wk 0.15 mg/kg/day divided bid, increase 0.15 mg/kg/day q 2 wk 5 mg/kg/day divided bid, increase 5 mg/ kg/day q wk 5 mg/kg/day divided bid, increase 5 mg/ kg/day q wk 1-2 mg/kg/day, increase 1-2 mg/kg/day q 1-2 wk 4 mg/kg/day (oral load 6 mg/kg q 8 hr for three doses) Sedation, somnolence, irritability, depression Ataxia, difficulty concentrating, hirsutism, coarse facial features, gingival hyperplasia
35
Continued
36
TABLE 1 Dosing and Adverse Effects of AEDs for Complex Partial Seizurescontd
Total Daily Dose Range Adults 32-56 mg 0.1-0.4 mg/kg bid-tid Irritability, anxiety, weakness Children Dose Schedule Common Adverse Effects
Initial Dose and Escalation Children
Agent
Adults
Rare or Idiosyncratic Side Effects Spike-wave stupor
Tiagabine (Gabitril) 100-600 mg 5-15 mg/kg bid
Topiramate (Topamax)
4 mg qd, increase 4-8 mg divided bid-tid q wk 25-50 mg qd, increase 25-50 mg divided bid q 1-2 wk
0.1 mg/kg/day divided tid, increase 0.1 mg/ kg/day q wk 0.5 mg/kg/d divided bid, increase 0.5-1 mg/kg/day q 1-2 wk
Acute-angle closure glaucoma, renal calculi
1000-4000 mg
15-60 mg/kg
bid-tid (qd for ER) qd-bid
Hepatotoxicity, pancreatitis, thrombocytopenia Rash, SJS, renal calculi
Valproate (Depakote, Depakene, Depakote ER) Zonisamide (Zonegran) 200-600 mg 8-12 mg/kg
125-250 mg bid, increase 125-250 mg bid q wk 100-200 mg qd, increase 100-200 mg qd q wk
5 mg/kg/day divided bid-tid, increase 5 mg/kg/day 2 mg/kg/day, increase 2 mg/kg/day q wk
Decreased verbal fluency, impaired memory, weight loss, paresthesias, hypohidrosis (mostly children) Tremor, weight gain, hair loss, GI disturbance, diarrhea Headache, GI disturbance, difficulty concentrating, hypohidrosis (mostly children)
AED, Antiepileptic drug; CNS, central nervous system; GI, gastrointestinal; SJS, Stevens-Johnson syndrome. EI-AED, enzyme-inducing antiepileptic drug VPA, valproate QOD, every other day
37
Seizures
TABLE 2 Selection of AEDs for Complex Partial Seizures*

CBZ Monotherapy efficacy established Pediatric efficacy established, good side effect profile in children Oral contraceptives Pregnancy Bone health Taking other AEDs* Taking other medications High cognitive functioning Age > 60 yr Obesity Renal dysfunction Hepatic dysfunction Psychosis, behavior problems, depression Noncompliance Rapid titration possible Patient example (totaled) 1 1 GBP 1 1 LTG 1 1 LVT 2 2 OXC 1 1 PB 1 3 PHT 1 1 PRM 1 3 TPM 1 2 TGB 2 2 VPA 1 1 ZNS 2 2 Example X
3 3 3 3 3 2 2 3 1 3 1 2 3 9
1 2 2 1 1 1 1 3 2 1 2 3 1 7
1 2 2 2 1 1 1 2 1 1 1 2 3 5
1 2 2 1 1 1 1 2 2 1 3 2 1 7
2 2 2 2 1 2 2 2 1 2 2 2 1 7
3 3 3 3 3 3 3 2 2 3 3 1 2 9
3 3 3 3 3 2 3 2 2 3 2 1 1 8
3 3 3 3 3 3 3 2 2 3 3 2 3 9
2 2 2 2 1 3 2 1 2 2 2 2 3 7
1 2 2 2 1 2 2 2 1 2 3 3 2 8
1 3 3 3 1 2 2 3 1 3 1 1 1 9
1 2 2 2 1 2 2 1 2 2 2 X
X X
2
1 1 7
See text for instructions for use and example. 1 = good profile; 2 = neutral or unknown; 3 = adverse profile. CBZ, Carbamazepine; GBP, gabapentin; LTG, lamotrigine; LVT, levetiracetam; OXC, oxcarbazepine; PB, phenobarbital; PHT, phenytoin; PRM, primidone; TPM, topiramate; TGB, tiagabine; VPA, valproate; ZNS, zonisamide. *P-450 enzyme-inducing or -inhibiting AEDs. Relative contraindication in adolescent girls due to teratogenicity. Alter lamotrigine metabolism; OK if dose is stable. Long-acting formulation (Tegretol XR, Carbatrol, Depakote ER). OCP, Oral contraceptive pills
AEDs may be categorized into three broad groups for the initial treatment of CPSs. Group 1 drugs (phenytoin, carbamazepine, valproate, gabapentin, lamotrigine, oxcarbazepine, and topiramate) have demonstrated efficacy as monotherapy in randomized controlled trials in patients with partial-onset or partial and generalized seizures. Carbamazepine and phenytoin have long been considered drugs of first choice, and valproate is also widely used. Chronic adverse effects and complex pharmacokinetics of carbamazepine, phenytoin, and valproate, however, make these less attractive choices. The superior tolerability and adverse effect profiles of gabapentin, lamotrigine, oxcarbazepine and topiramate support the use of these AEDs as initial monotherapy in many patients. Group 2 drugs (tiagabine, levetiracetam, and zonisamide) are effective as adjunctive therapy but have not yet been demonstrated to be efficacious in monotherapy. Such medications can be used as secondline agents or as initial agents in specific patients. Group 3 drugs (phenobarbital, primidone, and felbamate), although equally efficacious, have significant adverse effects that limit their usefulness. These drugs
are not appropriate for use as initial monotherapy of CPSs. Table 1 summarizes initial dosing, titration schedules, and serious adverse effects of currently available AEDs. Therapy should be initiated with a single drug. Using a low dose and slow titration schedule minimizes adverse effects, but frequent seizures necessitate more rapid dose escalations. Polytherapy increases the risk for adverse effects and is not appropriate for new-onset seizures. A reasonable approach is to select two or three appropriate AEDs for presentation to the patient, discuss their potential side effects, and then choose an AED based on patient preference. Avoidance of side effects and use of twice-daily formulations improves compliance with chronic therapy and thereby seizure control. Table 2 presents a tool to select potential best therapies among the wide range of AED options. To determine AED options for an individual patient, choose all relevant patient factors on the left; then add the numbers in the selected rows for each drug. AEDs with the lowest total score may offer a good adverse effect profile for that patient, although the physician must still weigh the
38
relative importance of each factor individually. The last row and column show an example of a 26-year-old woman executive, weighing 200 lb, who is planning her first pregnancy. Lamotrigine (safety in pregnancy, weight neutrality) would be a reasonable first choice for this patient, but several of the other newer AEDs would also be options. The dose of the initial AED should be gradually increased until seizures are completely controlled or until side effects occur. If the first AED fails, a second AED should be substituted and the first AED withdrawn. Combinations of AEDs, the vagus nerve stimulator, and epilepsy surgery are possible options if seizures remain difficult to control (see Chapter 11). Serum AED levels may be useful in assessing compliance, maintaining stable levels during pregnancy or after initiation of a second AED, assessing the presence of drug interactions, or determining the etiology of side effects. Routine monitoring of serum AED levels is not necessary in patients with well-controlled seizures. Many of the newer AEDs do not have well-established therapeutic ranges. CBC, chemistry panel, and LFTs should be checked 1 to 2 months after initiating a new AED. Repeated monitoring of laboratory tests is indicated for some AEDs but not others. For example, more frequent monitoring is indicated early in treatment with valproate due to potential for thrombocytopenia and hepatic failure. CBC and LFTs should be monitored during the first 6 months of carbamazepine and phenytoin use, due to remote risk of aplastic anemia and hepatic failure. Several sodium levels should be drawn for patients receiving carbamazepine/oxcarbazepine to check for hyponatremia. After the first 6 months, serial monitoring rarely detects new clinically significant abnormalities, but annual blood work may still be reasonable. The choice of an AED for women with new-onset CPSs should take into consideration potential effects on contraception, reproductive health, and pregnancy. AEDs that induce the hepatic P-450 enzyme system (phenytoin, carbamazepine, primidone, and, to a lesser extent, topiramate and oxcarbazepine) reduce the efficacy of hormonal contraception, resulting in increased risk of unplanned pregnancy. Oral contraceptive pills, estrogen patches, and depot progesterone all may be affected. Women taking enzyme-inducing AEDs should take an oral contraceptive pill containing at least 50 g of estrogen or use a barrier contraceptive method. Of note, hormonal contraceptives induce the metabolism of lamotrigine. Women should be counseled to report any change in contraception. Both enzyme-inducing and enzyme-inhibiting (e.g., valproate) AEDs may be associated with reproductive dysfunction, such as anovulatory menstrual cycles, infertility, and polycystic ovaries. These effects appear to be most problematic with valproate. Symptoms and signs of reproductive endocrine dysfunction include hirsutism, weight gain, irregular menstrual cycles, and infertility and should trigger a gynecologic evaluation. Many of the AEDs are teratogens. The risk of congenital malformations in children of women with epilepsy taking AEDs is 4% to 8%, compared with 2% to 3% in the general population. The risk is increased with high AED doses and with polytherapy. Malformations can include cardiac, midline facial, neural
tube, genitourinary, and gastrointestinal anomalies. Minor anomalies of the face and digits may be seen in another 10% to 15% of children. Effect of these AEDs on cognitive development is in the early stages of investigation, but there is increasing evidence that some AEDs, valproate in particular, may lead to increased risk of learning disabilities. Because folate administration may protect against some malformations, at least 1 mg of folate daily should be prescribed to all women taking AEDs. Phenytoin, carbamazepine, valproate, phenobarbital, and primidone are pregnancy class D medications, associated with a known teratogenic risk in humans. The newer AEDs are pregnancy class C medications, showing no teratogenicity in animals but unknown safety in humans. Preliminary results from a lamotrigine pregnancy registry suggest low teratogenicity, but final results are pending. Prospective pregnancy registries in the United States and Europe will help to define the risks of the newer AEDs. At this point, we favor the use of the newer AEDs, particularly lamotrigine, in women of reproductive age because of fewer effects on the hormonal milieu and probable lower teratogenicity. Drug interactions are common with AEDs as a class. When initiating AEDs, physicians should consider current concomitant medications as well as potential future needs. One of the most problematic interactions is that of hepatic enzyme induction, which occurs with use of phenytoin, carbamazepine, primidone, and phenobarbital. Hepatic induction increases the clearance of many commonly prescribed medications. Increased clearance of oral contraceptives has already been discussed. Many cholesterol-lowering agents, anticoagulants, antihypertensives, and antiarrhythmics are also subject to induction, as are chemotherapeutic agents. For patients who may require these medications, selection of a noninducing AED may be preferable. Many patients who experience their first seizure are evaluated in the emergency department and may be started on phenytoin. Often, the patient will be referred to a neurologist within the next few weeks. At this visit, it is appropriate to reassess the individual needs of that particular patient and make changes as necessary, including discontinuation if treatment is not indicated or selection of an alterative agent. AED withdrawal may be considered when a patient has been seizure free for at least 2 years. Unfortunately, seizure recurrence rates are relatively high40% to 50%after drug withdrawal. Patients with normal neurologic examinations, neuroimaging, and EEG have a lower recurrence risk. Focal structural lesions or epileptiform abnormalities on EEG, however, indicate a recurrence risk of greater than 70%. Many patients elect to continue AEDs rather than run the risk of a seizure recurrence. If patients decide to discontinue AEDs, the drug should be tapered slowly to avoid withdrawal seizures. Patients should not drive for 3 to 6 months after AED discontinuation. SUGGESTED READING
French JA, Kanner AM, Bautista J, et al: Efficacy and tolerability of the new antiepileptic drugs: I. treatment of new-onset epilepsy. Johnson: Current Therapy in Neurologic Disease (7/E)
First Generalized Seizure Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society, Neurology 62:1252-1260, 2004. Hirtz D, Berg A, Bettis D, et al: Practice parameter: treatment of the child with a first unprovoked seizure. Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society, Neurology 60:166-175, 2003. Kwan P, Brodie MJ: Early identification of refractory epilepsy, N Engl J Med 342:314-319, 2000. Tatum WO, Liporace J, Benbadis SR, Kaplan PW: Updates on the treatment of epilepsy in women, Arch Intern Med 164:137-145, 2004. Zahn CA, Morrell MJ, Collins SD, et al: Management issues for women with epilepsy: a review of the literature, Neurology 51:949-956, 1998.
39
Seizures
The neurologists initial assessment of a patient with an apparent new seizure should systematically address the following questions: Was the event in question truly an epileptic seizure? If the event was a seizure, did it start focally and become secondarily generalized, or was it a manifestation of a primary generalized epilepsy, or secondary generalized epilepsy (typically a question in young children)? Is the risk of recurrence sufficient to justify committing the patient to chronic treatment, and if so, with which agent? Evaluation should include a detailed history, including a personal or telephone interview with any available witness of the event, general and neurologic examination, and typically magnetic resonance (MR) imaging and EEG recording. The goals of this process are to determine the seizure type and the cause of the seizure and to evaluate the risk of recurrence, which will determine the need for ongoing treatment. Additional important goals are to detect systemic conditions that may provoke seizures and to assess the individual with special attention to characteristics that might influence the choice of long-term treatments. Ultimately, the neurologist faces the decision of whether to initiate treatment, or if treatment was already started in the acute setting, whether to continue, change, or discontinue it. Whereas the ED physician was most concerned with acute efficacy and patient safety, the neurologist must be concerned with efficacy, effectiveness (a term encompassing efficacy, tolerability, and compliance), and long-term health consequences of what is likely to be a chronic therapy.
PATIENT RESOURCES
Epilepsy Foundation of America http://www.epilepsyfoundation.org/ American Epilepsy Society http://www.aesnet.org/ The Epilepsy Project www.epilepsy.com

Andrew J. Cole, M.D., F.R.C.P.(C)
Individuals who develop new seizures, especially generalized tonic-clonic attacks, are frequently initially evaluated in an emergency department (ED) setting. When family members are not available, ED physicians obtain historical information from paramedics and from the patient who may still be confused in the postictal state. A general examination and a basic neurologic examination, in combination with computed tomographic (CT) scanning, are typically performed to rule out acute structural processes, whereas standard laboratory testing including electrolytes, blood count, and toxin screens are used to asses potential metabolic etiologies. At the completion of testing, the ED physician faces a two-part treatment decision: Should the patient be treated, and if so, with which antiepileptic drug (AED)? In making these decisions, ED physicians are particularly concerned with the short-term goal of preventing early seizure recurrence and keeping the patient safe until definitive evaluation can be accomplished. Additional factors influencing treatment choices include the time necessary to obtain a therapeutic blood level; ease of drug delivery, including available routes of administration; and their own familiarity and comfort with specific agents. In this context, phenytoin is the most commonly used AED in the ED setting. In the face of the acute issues, less attention is paid to the cognitive and long-term toxicities of potential treatments, which may properly be considered the province of neurologists. On discharge from the ED, referral to the patients internist or to a neurologist is typically suggested.
Evaluation and Diagnosis

The value of a detailed history cannot be overemphasized. Although the initial history might describe a generalized tonic attack, careful questioning might reveal the presence of a warning or evidence of focal onset of motor activity pointing to a focal seizure with secondary generalization. By contrast, a history of absence lasting less than 20 seconds, myoclonic jerks on awakening, and an early morning convulsion without warning suggest the diagnosis of a primary generalized seizure disorder, especially in teenagers and young adults. As a rule, the older the patient, the less likely that the seizure is truly of generalized origin, and for practical purposes new-onset seizures in patients older than 30 years of age should be considered to be focal unless proven otherwise. A careful history may reveal that the event in question was not in fact the first seizure, since the patient had been having minor spells for some time, or that there was a clear provocative factor such as significant sleep deprivation, use of a proconvulsant medication such as tramadol, or withdrawal from an anxiolytic such as alprazolam. In the former case, need for treatment seems clear, whereas in the latter case, many neurologists would attempt to manage the patient with lifestyle modification or avoidance of the offending agents.
First Generalized Seizure Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society, Neurology 62:1252-1260, 2004. Hirtz D, Berg A, Bettis D, et al: Practice parameter: treatment of the child with a first unprovoked seizure. Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society, Neurology 60:166-175, 2003. Kwan P, Brodie MJ: Early identification of refractory epilepsy, N Engl J Med 342:314-319, 2000. Tatum WO, Liporace J, Benbadis SR, Kaplan PW: Updates on the treatment of epilepsy in women, Arch Intern Med 164:137-145, 2004. Zahn CA, Morrell MJ, Collins SD, et al: Management issues for women with epilepsy: a review of the literature, Neurology 51:949-956, 1998.
39
Seizures
The neurologists initial assessment of a patient with an apparent new seizure should systematically address the following questions: Was the event in question truly an epileptic seizure? If the event was a seizure, did it start focally and become secondarily generalized, or was it a manifestation of a primary generalized epilepsy, or secondary generalized epilepsy (typically a question in young children)? Is the risk of recurrence sufficient to justify committing the patient to chronic treatment, and if so, with which agent? Evaluation should include a detailed history, including a personal or telephone interview with any available witness of the event, general and neurologic examination, and typically magnetic resonance (MR) imaging and EEG recording. The goals of this process are to determine the seizure type and the cause of the seizure and to evaluate the risk of recurrence, which will determine the need for ongoing treatment. Additional important goals are to detect systemic conditions that may provoke seizures and to assess the individual with special attention to characteristics that might influence the choice of long-term treatments. Ultimately, the neurologist faces the decision of whether to initiate treatment, or if treatment was already started in the acute setting, whether to continue, change, or discontinue it. Whereas the ED physician was most concerned with acute efficacy and patient safety, the neurologist must be concerned with efficacy, effectiveness (a term encompassing efficacy, tolerability, and compliance), and long-term health consequences of what is likely to be a chronic therapy.
PATIENT RESOURCES
Epilepsy Foundation of America http://www.epilepsyfoundation.org/ American Epilepsy Society http://www.aesnet.org/ The Epilepsy Project www.epilepsy.com

Andrew J. Cole, M.D., F.R.C.P.(C)
Individuals who develop new seizures, especially generalized tonic-clonic attacks, are frequently initially evaluated in an emergency department (ED) setting. When family members are not available, ED physicians obtain historical information from paramedics and from the patient who may still be confused in the postictal state. A general examination and a basic neurologic examination, in combination with computed tomographic (CT) scanning, are typically performed to rule out acute structural processes, whereas standard laboratory testing including electrolytes, blood count, and toxin screens are used to asses potential metabolic etiologies. At the completion of testing, the ED physician faces a two-part treatment decision: Should the patient be treated, and if so, with which antiepileptic drug (AED)? In making these decisions, ED physicians are particularly concerned with the short-term goal of preventing early seizure recurrence and keeping the patient safe until definitive evaluation can be accomplished. Additional factors influencing treatment choices include the time necessary to obtain a therapeutic blood level; ease of drug delivery, including available routes of administration; and their own familiarity and comfort with specific agents. In this context, phenytoin is the most commonly used AED in the ED setting. In the face of the acute issues, less attention is paid to the cognitive and long-term toxicities of potential treatments, which may properly be considered the province of neurologists. On discharge from the ED, referral to the patients internist or to a neurologist is typically suggested.
Evaluation and Diagnosis

The value of a detailed history cannot be overemphasized. Although the initial history might describe a generalized tonic attack, careful questioning might reveal the presence of a warning or evidence of focal onset of motor activity pointing to a focal seizure with secondary generalization. By contrast, a history of absence lasting less than 20 seconds, myoclonic jerks on awakening, and an early morning convulsion without warning suggest the diagnosis of a primary generalized seizure disorder, especially in teenagers and young adults. As a rule, the older the patient, the less likely that the seizure is truly of generalized origin, and for practical purposes new-onset seizures in patients older than 30 years of age should be considered to be focal unless proven otherwise. A careful history may reveal that the event in question was not in fact the first seizure, since the patient had been having minor spells for some time, or that there was a clear provocative factor such as significant sleep deprivation, use of a proconvulsant medication such as tramadol, or withdrawal from an anxiolytic such as alprazolam. In the former case, need for treatment seems clear, whereas in the latter case, many neurologists would attempt to manage the patient with lifestyle modification or avoidance of the offending agents.
40
General and neurologic examinations are focused on searching for coexisting conditions that may cause or predispose the patient to seizures and detecting evidence of focal or diffuse central nervous system dysfunction. Particular attention should be focused on examination of the skin; a search for endocrine or metabolic disturbances; evidence of malignancy; and especially in older patients, evidence of cerebrovascular disease. At the same time, general characteristics of the individual such as body weight, complexion, cognitive function, and even reproductive capacity should be duly noted. We routinely obtain electroencephalographic recordings without sleep deprivation as part of our initial evaluation. The goals are to search for generalized spike-and-wave discharge that is typically frontally predominant at 2.5 4 Hz, supporting a diagnosis of primary generalized epilepsy, or to find focal abnormalities including slowing or epileptiform abnormalities that support the diagnosis of focal epilepsy. This distinction is critical in therapeutic decision making (see later). A negative electroencephalogram (EEG) does not rule out the diagnosis of epilepsy, and positive findings must always be interpreted in the context of available clinical information. All adults with new-onset seizures should have highquality MR imaging, even if a negative CT scan is available. Our protocol includes axial and coronal T2-weighted fast-spin echo (FSE) sequences, axial and coronal fluid-attenuated inversion recovery (FLAIR) sequences, and a T1-weighted coronal volumetric data set with 1.2- to 1.5-mm thick cuts without skip. We do not routinely use gadolinium contrast in the assessment of new seizures, especially in patients younger than 50 years of age, although we do use contrast material to characterize foreign tissue lesions that are discovered on noncontrast scans. In patients with a history of trauma, we frequently obtain gradient echo (susceptibility) sequences as well to search for old blood products. Images should be directly reviewed by the neurologist in the context of all available information, including historical information, findings on examination, and EEG findings. It is not unusual for a neurologist to detect a lesion that had been overlooked by the radiologist, perhaps because the neurologist is in a position to formulate a hypothesis about where to look for the likely causative lesion based on clinical information not readily available to the radiologist.
frequently in this situation, and our practice is supported by considerable published data. General statements about the risk of recurrence can be based on population studies, but their relevance to the specific patient at hand is uncertain. In this context it is difficult to be doctrinaire about the need for treatment, and patient preference should play a substantial role in decision making. Although there are little data to guide patients and physicians with respect to the optimal duration of treatment, experienced neurologists are typically reluctant to discontinue treatment that is well tolerated, even after many years, for fear of seizure recurrence. To the extent that treatment is thus likely to be of long duration, particular attention to the long-term consequences of chronic treatment should be considered at the time of treatment initiation and not, as commonly happens, after some predictable adverse consequence of treatment becomes apparent after months or years (e.g. weight gain, osteoporosis, adverse medication interactions). Treatment of a first generalized seizure is particularly problematic because seizure frequency cannot be used as an endpoint to determine optimal treatment intensity. Dose selection must therefore be determined by an educated guess as to what dose is likely to have a high probability of suppressing recurrent events, even without definitive knowledge of whether seizures will recur in specific patient. The temptation to use a low dose of medication thus seems ill advised. Most drugs should be started at a modest dose and then advanced over weeks to the target dose to avoid undue toxicity. Given the long-term nature of AED treatment, minor differences in the titration rates of available agents should not be a predominant factor in drug selection. After all, the goal is to establish an effective, well-tolerated treatment plan that will continue for years, so whether that takes 6 days or 6 weeks seems of little importance. In situations where the risk of early recurrence is high, patients can be covered with a rapidly titrated agent (often already the case after an ED visit) while titration of the ultimate treatment is underway.
Counseling
The diagnosis of a new seizure disorder raises a series of issues that may be anxiety provoking and psychologically traumatic to consider for patients. Neurologist should have a calm, orderly, and systematic approach to discussing these issues with patients and their families. We begin by emphasizing that the goal of treatment is to allow the patient to live a normal life without undue restrictions. For example, unless there is a history of excessive alcohol consumption and abuse, we do not routinely prohibit the consumption of an occasional beer, glass of wine, or cocktail, although we do counsel moderation. We emphasize the importance of regular sleep habits and compliance with treatment schedules. Rules on driving and reporting vary by state. We advise patients of the rules in their home state and document that information has been provided and that the patient appears to understand. Driving laws in each state can
Treatment Initiation
Treatment decisions should be undertaken largely independent of previous decisions made by non-neurologists. Our algorithm for whether or not to initiate or continue treatment and specific agents to be used is shown in the accompanying diagram (Figure 1). Treatment agents are numbered according to whether they constitute first-line, second-line, or third-line choices. Within groups, agents are listed alphabetically, and choices should be made according to the characteristics of the individual patient. While many of the newer agents do not have a U.S. Food and Drug Administrationapproved indication for use as initial monotherapy, we use them
41
Seizures
Grand mal tonic clonic seizure
History Examination EEG MRI
Epileptic
Non-epileptic
Classification Cardiac Unknown Primary (idiopathic) generalized epilepsy Partial seizure with secondary generalization Yes
Vasovagal/ neurocardiogenic
Psychiatric/ behavioral
Refer/treat as appropriate
Age > 30 and no previous history? No
Review history, sleep-deprived EEG Identifiable provocative factors? Yes No Rx: conservative management
No
Risk/benefit analysis for Rx: EEG or MRI or exam abnl? Patient unwilling to accept 2040% risk of recurrence?
No
No Rx: observe
Yes
Partial seizures with or without secondary generalization: 1. Lamotrigine 300500 mg/d 1. Levetiracetam 20003000 mg/d 1. Oxcarbazepine 6001200 mg/d 2. Carbamazepine 400800 mg/d 2. Phenytoin 30000 mg/d 2. Topiramate 200400 mg/d 2. Valproate 10001500 mg/d 3. Gabapentin 15002400 mg/d 3. Zonisamide 300400 mg/d 4. Mysoline 500750 mg/d 4. Phenobarbital 60120 mg/d
Consider patient characteristics: Age Sex Reproductive status Body habitus Medical co-morbidities Psychiatric co-morbidities Co-medications Cognitive function Financial concerns Select treatment
Primary (idiopathic) generalized epilepsy: 1. Lamotrigine 300500 mg/d 1. Valproate 750500 mg/d 2. Topiramate 200400 mg/d 3. ?Levetiracetam 15003000 mg/d 3. ?Zonisamide 200400 mg/d
FIGURE 1. Flowchart illustrating our approach to the evaluation and treatment of a first convulsion. Drugs are numbered as first-line, second-line, third-line, or fourth-line choices. Within category, drugs are listed alphabetically without implying a specific order of preference. Specific selections should be made based on individual patient characteristics. Dose ranges shown are approximate. All drugs should be titrated no faster than the manufacturers recommendations to avoid excessive initial toxicity. Johnson: Current Therapy in Neurologic Disease (7/E)
42
be accessed at http://epilepsyfoundation.org/answerplace/ Social/driving/statedrivinglaws.cfm. We discuss the effects of medications on the efficacy of oral contraceptives when appropriate, and we recommend supplemental folic acid, 1 mg daily, to all women of childbearing age, although the optimal dose has not been determined.
Treatment Monitoring
We routinely see patients 2 to 3 months after treatment initiation or sooner if problems arise. Although there is little information available on optimal drug levels for many of the newer agents, we measure levels after a stable dose has been achieved to have an individual baseline against which comparisons can be made in the event problems arise in the future. We check routine laboratory tests (complete blood count, electrolytes, liver function tests, clotting parameters) at the initiation of treatment if recent values are unavailable, but we recheck these parameters only in specific cases (e.g., serum sodium in patients on oxcarbazepine, electrolytes in patients on topiramate, platelets and liver function tests in patients on valproate) unless there is a clinical indication. Some authors recommend measuring bone density at the initiation of treatment, but definitive studies supporting the value of this measurement are presently lacking. SUGGESTED READING
French JA, Kanner AM, Bautista J, et al: Efficacy and tolerability of the new antiepileptic drugs: I. Treatment of new-onset epilepsy. Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society, Neurology 62:1252-1260, 2004.
abnormality or focal slowing the probability of a second seizure is 40% to 60%. The EEG may not be a good predictor of pharmacoresistant epilepsy, and additional clinical biomarkers of treatment resistance are needed to improve the care of persons with recurrent seizures. Epilepsy is a chronic condition that requires years, if not lifelong, of treatment for most affected persons. The disability commonly associated with epilepsy begins on the day of the first seizure, because most adult and adolescent patients will receive a driving restriction. Work restrictions, social limitations, and public stigma significantly increase the disability experienced by many persons with epilepsy. Serious injuries such as fractures or burns may occur in up to 10% of patients with recurrent seizures per year. In addition, adverse antiepileptic drug (AED) side effects and the presence of comorbid depression have emerged as important predictors of poor quality of life with epilepsy.
Initial Treatment Considerations

Based on available data from the Centers for Disease Control and Prevention and pharmacy registries, epilepsy care has changed very little during the past 30 years. Phenytoin remains the most frequently prescribed AED, and with carbamazepine, valproate, and phenobarbital, accounts for the large majority of prescriptions for epilepsy in the United States. The eight AEDs approved by the U.S. Food and Drug Administration (FDA) during the past 11 years account for less than 20% of prescriptions for epilepsy treatment in the United States. This may be considered surprising by some clinicians caring for persons with epilepsy, considering that the investigators in the largest randomized double-blind comparison of carbamazepine, phenobarbital, phenytoin, and primidone concluded:
The outcome of this project underscores the unsatisfactory status of antiepileptic therapy with the medications currently available. Most patients whose epilepsy is reasonably controlled must tolerate some side effects. These observations emphasize the need for new AEDs and other approaches to treatment.

Epilepsy is defined as two or more unprovoked seizures and has been described as a tendency toward recurrent seizures. The factors that determine whether a single seizure recurs, or whether recurrent seizures are preventable by medications, have not been clearly established. Understanding of both the genetic predisposition related to specific receptor/neurotransmitter system defects and characteristics of the acquired injury or dysfunction in a particular brain is required to explain a unique individuals risk of epilepsy or pharmacoresistance. Although electroencephalography was developed in the 1930s, it remains the most accurate predictor of the probability of seizure recurrence, as well as epilepsy classification. After a single seizure, less than 30% of patients with a normal electroencephalogram (EEG) will have a second seizure. If the EEG shows an epileptiform
The characteristics of an optimal AED may be described based on pharmacokinetic properties, tolerability, and cost, as presented in Table 1. Considering that newer AEDs tend to have less hepatic enzyme induction and fewer drug interactions, but are generally more
TABLE 1 Optimal Attributes of an Antiepileptic Drug

Simple, linear kinetics Minimal adverse side effects No drug-drug interactions (minimal hepatic enzyme induction and serum protein binding) Long half-life for once-a-day dosing and potential for extended seizure protection after a missed dose (>24-hour elimination half-life) Inexpensive
42
be accessed at http://epilepsyfoundation.org/answerplace/ Social/driving/statedrivinglaws.cfm. We discuss the effects of medications on the efficacy of oral contraceptives when appropriate, and we recommend supplemental folic acid, 1 mg daily, to all women of childbearing age, although the optimal dose has not been determined.
Treatment Monitoring
We routinely see patients 2 to 3 months after treatment initiation or sooner if problems arise. Although there is little information available on optimal drug levels for many of the newer agents, we measure levels after a stable dose has been achieved to have an individual baseline against which comparisons can be made in the event problems arise in the future. We check routine laboratory tests (complete blood count, electrolytes, liver function tests, clotting parameters) at the initiation of treatment if recent values are unavailable, but we recheck these parameters only in specific cases (e.g., serum sodium in patients on oxcarbazepine, electrolytes in patients on topiramate, platelets and liver function tests in patients on valproate) unless there is a clinical indication. Some authors recommend measuring bone density at the initiation of treatment, but definitive studies supporting the value of this measurement are presently lacking. SUGGESTED READING
French JA, Kanner AM, Bautista J, et al: Efficacy and tolerability of the new antiepileptic drugs: I. Treatment of new-onset epilepsy. Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society, Neurology 62:1252-1260, 2004.
abnormality or focal slowing the probability of a second seizure is 40% to 60%. The EEG may not be a good predictor of pharmacoresistant epilepsy, and additional clinical biomarkers of treatment resistance are needed to improve the care of persons with recurrent seizures. Epilepsy is a chronic condition that requires years, if not lifelong, of treatment for most affected persons. The disability commonly associated with epilepsy begins on the day of the first seizure, because most adult and adolescent patients will receive a driving restriction. Work restrictions, social limitations, and public stigma significantly increase the disability experienced by many persons with epilepsy. Serious injuries such as fractures or burns may occur in up to 10% of patients with recurrent seizures per year. In addition, adverse antiepileptic drug (AED) side effects and the presence of comorbid depression have emerged as important predictors of poor quality of life with epilepsy.
Initial Treatment Considerations

Based on available data from the Centers for Disease Control and Prevention and pharmacy registries, epilepsy care has changed very little during the past 30 years. Phenytoin remains the most frequently prescribed AED, and with carbamazepine, valproate, and phenobarbital, accounts for the large majority of prescriptions for epilepsy in the United States. The eight AEDs approved by the U.S. Food and Drug Administration (FDA) during the past 11 years account for less than 20% of prescriptions for epilepsy treatment in the United States. This may be considered surprising by some clinicians caring for persons with epilepsy, considering that the investigators in the largest randomized double-blind comparison of carbamazepine, phenobarbital, phenytoin, and primidone concluded:
The outcome of this project underscores the unsatisfactory status of antiepileptic therapy with the medications currently available. Most patients whose epilepsy is reasonably controlled must tolerate some side effects. These observations emphasize the need for new AEDs and other approaches to treatment.

Epilepsy is defined as two or more unprovoked seizures and has been described as a tendency toward recurrent seizures. The factors that determine whether a single seizure recurs, or whether recurrent seizures are preventable by medications, have not been clearly established. Understanding of both the genetic predisposition related to specific receptor/neurotransmitter system defects and characteristics of the acquired injury or dysfunction in a particular brain is required to explain a unique individuals risk of epilepsy or pharmacoresistance. Although electroencephalography was developed in the 1930s, it remains the most accurate predictor of the probability of seizure recurrence, as well as epilepsy classification. After a single seizure, less than 30% of patients with a normal electroencephalogram (EEG) will have a second seizure. If the EEG shows an epileptiform
The characteristics of an optimal AED may be described based on pharmacokinetic properties, tolerability, and cost, as presented in Table 1. Considering that newer AEDs tend to have less hepatic enzyme induction and fewer drug interactions, but are generally more
TABLE 1 Optimal Attributes of an Antiepileptic Drug

Simple, linear kinetics Minimal adverse side effects No drug-drug interactions (minimal hepatic enzyme induction and serum protein binding) Long half-life for once-a-day dosing and potential for extended seizure protection after a missed dose (>24-hour elimination half-life) Inexpensive
43
Seizures
expensive, the benefits of better pharmacokinetic properties and potential for improved tolerability must be weighed against greater monetary costs. In addition to pharmacokinetic properties, tolerability, and costs, the epilepsy syndrome being treated and clinically important comorbid conditions should be considered in the decision for initial AED treatment. As presented in Figure 1, partial seizures (with or without secondary generalizations), idiopathic generalized seizures, and symptomatic generalized seizures (secondary to prior brain injury) are the major categories that guide AED selection. Some drugs appear to have a broad spectrum of efficacy across multiple seizure categories and might be considered when the classification is not certain. Emerging evidence from clinical trials and aggregate clinical experience suggest that certain AEDs have efficacy for common comorbid conditions. For example,
migraine is more common in persons with epilepsy than the general population; valproate and topiramate have received indications for migraine prophylaxis from the FDA and may be particularly useful in persons with both diagnoses. Lamotrigine at low to moderate doses has been found to have fewer adverse cognitive and fatigue effects compared with carbamazepine and may be advantageous to students and for people in professions requiring sustained concentration or mental vigilance. Valproate and lamotrigine are approved by the FDA for the treatment of bipolar disorder, and carbamazepine and oxcarbazepine may be effective as well. Some clinical trial data suggest that topiramate and zonisamide may facilitate weight loss, as opposed to a tendency toward weight gain with valproate. The lack of hepatic enzyme induction by gabapentin, levetiracetam, and lamotrigine is a consideration for women on
Recurrent seizures (epilepsy)
Thorough history (including witness) + EEG
Seizure (epilepsy) classification
Generalized seizures
Partial seizures (localization-related epilepsy)
Symptomatic or cryptogenic
Idiopathic (e.g., childhood absence, juvenile myoclonic epilepsy, etc.)
Consider patient preferences and comorbidity
1. valproate 2. lamotrigine 3. topiramate 4. levetiracetam 5. zonisamide 6. phenobarbital 7. felbamate
Absence only
Absence + GTC; or GTC only
Absence + GTC + myoclonic
1. ethosuxamide 2. valproate 3. lamotrigine 4. levetiracetam
1. valproate 2. topiramate 3. lamotrigine 4. levetiracetam
Pregnancy
Headaches Oral contraception
Cognition/fatigue Overweight 1. lamotrigine 2. oxcarbazepine 1. topiramate 2. zonisamide
Cost
Avoid valproate and phenobarbital; consider lamotrigine
1. topiramate 2. valproate 1. gabapentin 2. levetiracetam 3. lamotrigine
Generic carbamazepine valproate phenobarbital phenytoin
FIGURE 1. Suggested sequence of medications for recurrent unprovoked seizures (i.e., epilepsy). EEG, Electroencephalogram; GTC, generalized tonic-clonic. Johnson: Current Therapy in Neurologic Disease (7/E)
44
hormonal birth control. However, recent study data indicate that lamotrigine metabolism is significantly affected by hormonal birth control. Early results of systematic birth registries indicate that valproate and phenobarbital should be avoided in women who are considering pregnancy if medically feasible. The long half-life of zonisamide and phenobarbital may provide benefit to persons whose schedule or motivation limit compliance. The recommended maintenance doses of most AEDs are derived from clinical studies performed before optimal dosing strategies were determined. Recent evidence suggests that most people whose seizures can be controlled by AEDs will require doses in the lower end of a recommended range. For example, most persons with epilepsy will require less than 1000 mg/day of carbamazepine, 2000 mg/day of valproate, 400 mg/day of lamotrigine, or 300 mg/day of topiramate. Most AEDs require two- or three-times-a-day dosing, and the package insert should be consulted for specific recommendations. Fewer daily doses improve compliance, but multiple doses during the day may reduce peak serum concentrations and subsequent adverse effects. In general, the starting dose should be approximately one fourth of the initial target dose
with increases every 1 to 2 weeks by one fourth of the target dose. Lamotrigine has a slower titration rate due to the risk of rash, and topiramate has a slower rate to improve tolerability of adverse cognitive effects; the FDA-approved dosing information should be consulted for both of these AEDs. Systematic screening with a reliable and valid instrument, such as the Adverse Events Profile, may be necessary after each dosage adjustment to accurately identify significant side effects.
Treatment of Pharmacoresistant Epilepsy

Most patients will be controlled by moderate doses of their first AED, but approximately 40% will not be controlled or will relapse after an initial response. There is no clear consensus in the epilepsy community about the treatment approach after failure of the initial AED, and as previously emphasized, the treatment decisions should be made in consideration of the individual patients unique situation. A suggested stepwise approach to epilepsy care is shown in Figure 2.
Two or three failed optimal antiepileptic drug (AED) regimens
1. Video/EEG 2. High-resolution MRI
Localized EEG or MRI abnormality
Yes
No
Consider presurgical evaluation: 1. Neuropsychological testing. 2. Functional neuroimaging?
Sensitivity to AED side effects
Yes
No
Good surgical candidate
Consider vagus nerve stimulator
Additional AEDs as mono or dual therapy
Yes
No
Seizure-free without adverse AED effects
Surgical resection* * Some patients may need additional testing such as intracarotid amobarbital test or intracranial EEG monitoring No Yes
Consider vagus nerve stimulator or If injurious tonic or atonic seizures: Consider corpus callosotomy or Additional testing to attempt to localize a focal epileptogenic region
Continue AEDs
FIGURE 2. Comprehensive approach to epilepsy care. EEG, Electroencephalogram. Johnson: Current Therapy in Neurologic Disease (7/E)
Status Epilepticus
45
Seizures
If seizures recur after the initial target dose of an AED is achieved, the dose should be increased at a tolerable rate to the most effective dose. The decision to increase to the next dosage increment, versus titrating to the highest tolerated dose, should be made in consultation with the patient. If seizures recur on the highest tolerated dose, then a second AED should be added in a similar approach to the initial drug. Frequently the dose of the initial AED will need to be reduced to improve tolerability of increased doses of the adjunctive AED. If seizures do not occur on the combination of two AEDs, the option to wean the first AED for convenience and cost should be reviewed with the patient. The decision to wean to monotherapy versus continuing effective combination therapy can be made only by weighing the overall risks and benefits to the specific patients situation. Similarly, the decision to consider a third medication after two have failed, versus proceeding to a presurgical evaluation, can be made only in consultation with the patient. Some patients may want to know if they have unilateral mesial temporal sclerosis, which may have a 75% chance for surgical success, whereas other patients will want to consider additional AEDs regardless of their surgical candidacy. The most important consideration to ensure optimal epilepsy care is that the patient be fully informed regarding the details of their options at each stage of treatment. Available evidence indicates that after three medications have failed due to lack of efficacy, as opposed to tolerability, the probability of achieving long-term remission is less than 10%. Alternative treatments, such as resective surgery or the vagus nerve stimulator, should be discussed in detail with the patient at this juncture. Although most patients who have a potential for complete seizure control, and the subsequent opportunity to drive a car and return to a more normal lifestyle, will elect to proceed with a presurgical evaluation as outlined in Figure 2, some patients may elect to try additional AEDs or the vagus nerve stimulator (VNS). Patients who have not tolerated three or more AEDs due to adverse effects may find the option of the VNS appealing, although less than 10% of patients will have complete seizure control after VNS implantation. Evaluation of patients at a comprehensive epilepsy center with epilepsy surgery capability is required for all patients with pharmacoresistant epilepsy and disabling seizures, as recommended by the published practice guidelines of the American Academy of Neurology. SUGGESTED READING
Engel J Jr, Wiebe S, French J, et al: Quality Standards Subcommittee of the American Academy of Neurology; American Epilepsy Society; American Association of Neurological Surgeons, Neurology 4:53847, 2003. Gilliam F: Optimizing health outcomes in active epilepsy, Neurology 58(Suppl 5):S9-S19, 2002. Kwan P, Brodie MJ: Early identification of refractory epilepsy, N Engl J Med 342:314-319, 2000. Mattson RH, Cramer JA, Collins JF, et al: Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures, N Engl J Med 313:145-151, 1985. Johnson: Current Therapy in Neurologic Disease (7/E)
Status Epilepticus
Status epilepticus (SE) is a common neurologic emergency. There are approximately 100,000 to 200,000 episodes of SE in the United States annually. The term status epilepticus generally refers to the occurrence of a single unremitting seizure or frequent clinical seizures without an interictal return to normal consciousness. An operational definition as proposed by Lowenstein and Alldredge accords the diagnosis after 5 minutes of continuous seizure activity or 2 or more seizures without full recovery of awareness between seizures. Older definitions considered 30 minutes as the time criterion, based on experimental animal data suggesting that seizure activity of this length is associated with significant neuronal damage. The sooner treatment is initiated, the better the outcome; however, the treatment for prolonged seizures versus SE is essentially the same initially anyway, so that the exact definition is less important practically, as long as preparations for the worst-case scenario are carried out early. SE can cause injury due to the intense neuronal activity within the central nervous system (CNS) and due to the metabolic stress of repeated muscular convulsions. Respiratory failure, aspiration pneumonitis, neurogenic pulmonary edema, rhabdomyolysis, and lactic acidosis may complicate convulsions, and neuronal death can occur after 30 to 60 minutes of continuous seizure activity. Classification of the type of SE is crucial because it is a major factor in determining morbidity and therefore the aggressiveness of the required treatment; generalized tonic-clonic or partial-complex SE poses the greatest risk. The most common forms of SE are the following: Simple partial: characterized by repeated or continuous focal seizures that could be motor (twitching of one extremity), sensory (the sensation of numbness and tingling of one extremity), or cognitive (aphasia, dyslexia, and so forth) without impaired consciousness Complex partial: characterized by repeated or continuous episodes of focal motor, sensory, or cognitive symptoms as earlier, but with impaired consciousness, and can be associated with automatisms like swallowing, licking lips, staring, and so forth; could be difficult occasionally to differentiate from other acute confusional states Generalized tonic-clonic: always associated with impaired consciousness; tonic-clonic seizures may be the initial manifestation of SE or may represent secondary generalization from a partial seizure The following are a number of less common but important forms that need to be recognized: Absence: characterized by altered awareness, but not necessarily unconsciousness. Patients are typically confused or stuporous, and there may be associated eye blinking, perseveration, small automatism,
Status Epilepticus
45
Seizures
If seizures recur after the initial target dose of an AED is achieved, the dose should be increased at a tolerable rate to the most effective dose. The decision to increase to the next dosage increment, versus titrating to the highest tolerated dose, should be made in consultation with the patient. If seizures recur on the highest tolerated dose, then a second AED should be added in a similar approach to the initial drug. Frequently the dose of the initial AED will need to be reduced to improve tolerability of increased doses of the adjunctive AED. If seizures do not occur on the combination of two AEDs, the option to wean the first AED for convenience and cost should be reviewed with the patient. The decision to wean to monotherapy versus continuing effective combination therapy can be made only by weighing the overall risks and benefits to the specific patients situation. Similarly, the decision to consider a third medication after two have failed, versus proceeding to a presurgical evaluation, can be made only in consultation with the patient. Some patients may want to know if they have unilateral mesial temporal sclerosis, which may have a 75% chance for surgical success, whereas other patients will want to consider additional AEDs regardless of their surgical candidacy. The most important consideration to ensure optimal epilepsy care is that the patient be fully informed regarding the details of their options at each stage of treatment. Available evidence indicates that after three medications have failed due to lack of efficacy, as opposed to tolerability, the probability of achieving long-term remission is less than 10%. Alternative treatments, such as resective surgery or the vagus nerve stimulator, should be discussed in detail with the patient at this juncture. Although most patients who have a potential for complete seizure control, and the subsequent opportunity to drive a car and return to a more normal lifestyle, will elect to proceed with a presurgical evaluation as outlined in Figure 2, some patients may elect to try additional AEDs or the vagus nerve stimulator (VNS). Patients who have not tolerated three or more AEDs due to adverse effects may find the option of the VNS appealing, although less than 10% of patients will have complete seizure control after VNS implantation. Evaluation of patients at a comprehensive epilepsy center with epilepsy surgery capability is required for all patients with pharmacoresistant epilepsy and disabling seizures, as recommended by the published practice guidelines of the American Academy of Neurology. SUGGESTED READING
Engel J Jr, Wiebe S, French J, et al: Quality Standards Subcommittee of the American Academy of Neurology; American Epilepsy Society; American Association of Neurological Surgeons, Neurology 4:53847, 2003. Gilliam F: Optimizing health outcomes in active epilepsy, Neurology 58(Suppl 5):S9-S19, 2002. Kwan P, Brodie MJ: Early identification of refractory epilepsy, N Engl J Med 342:314-319, 2000. Mattson RH, Cramer JA, Collins JF, et al: Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures, N Engl J Med 313:145-151, 1985. Johnson: Current Therapy in Neurologic Disease (7/E)
Status Epilepticus
Status epilepticus (SE) is a common neurologic emergency. There are approximately 100,000 to 200,000 episodes of SE in the United States annually. The term status epilepticus generally refers to the occurrence of a single unremitting seizure or frequent clinical seizures without an interictal return to normal consciousness. An operational definition as proposed by Lowenstein and Alldredge accords the diagnosis after 5 minutes of continuous seizure activity or 2 or more seizures without full recovery of awareness between seizures. Older definitions considered 30 minutes as the time criterion, based on experimental animal data suggesting that seizure activity of this length is associated with significant neuronal damage. The sooner treatment is initiated, the better the outcome; however, the treatment for prolonged seizures versus SE is essentially the same initially anyway, so that the exact definition is less important practically, as long as preparations for the worst-case scenario are carried out early. SE can cause injury due to the intense neuronal activity within the central nervous system (CNS) and due to the metabolic stress of repeated muscular convulsions. Respiratory failure, aspiration pneumonitis, neurogenic pulmonary edema, rhabdomyolysis, and lactic acidosis may complicate convulsions, and neuronal death can occur after 30 to 60 minutes of continuous seizure activity. Classification of the type of SE is crucial because it is a major factor in determining morbidity and therefore the aggressiveness of the required treatment; generalized tonic-clonic or partial-complex SE poses the greatest risk. The most common forms of SE are the following: Simple partial: characterized by repeated or continuous focal seizures that could be motor (twitching of one extremity), sensory (the sensation of numbness and tingling of one extremity), or cognitive (aphasia, dyslexia, and so forth) without impaired consciousness Complex partial: characterized by repeated or continuous episodes of focal motor, sensory, or cognitive symptoms as earlier, but with impaired consciousness, and can be associated with automatisms like swallowing, licking lips, staring, and so forth; could be difficult occasionally to differentiate from other acute confusional states Generalized tonic-clonic: always associated with impaired consciousness; tonic-clonic seizures may be the initial manifestation of SE or may represent secondary generalization from a partial seizure The following are a number of less common but important forms that need to be recognized: Absence: characterized by altered awareness, but not necessarily unconsciousness. Patients are typically confused or stuporous, and there may be associated eye blinking, perseveration, small automatism,
46
Status Epilepticus
or other symptoms. Absence SE typically occurs in patients with chronic epilepsy and frequently requires electroencephalogram (EEG) for confirmation Myoclonic: characterized by frequent myoclonic jerks in the setting of altered mental status. This typically occurs in patients with one of the generalized epilepsies, such as juvenile myoclonic epilepsy. This condition needs to be differentiated from the patient who has metabolic encephalopathy (particularly uremic or hepatic encephalopathy) and may have also some myoclonic activity. EEG recordings can differentiate the two Psychogenic: should be considered in situations where there are bilateral motor movements with preserved consciousness or side-to-side head movements as part of the convulsion. An EEG recording without seizure activity during motor events can help establish this diagnosis, although the EEG may also appear relatively normal during simple partial SE. It is important to refrain from the whole SE protocol, which has inherent iatrogenic risks, if there is a clinical suspicion for this diagnosis. The nonconvulsive types of SE may pose a greater clinical problem: Patients with complex partial or absence SE may exhibit confusional states that are not easily recognized as seizures. Also, patients who have had recurrent seizures may be considered postictal rather than in nonconvulsive SE; in this situation, subtle signs of ongoing seizures such as rhythmic papillary dilation or breathing may be the only evidence of seizure activity. The patient with possible SE requires rapid evaluation and treatment. Although there are differences in efficacy and side effect profile among effective agents, it is important to become familiar with one reasonable treatment method and use it. In general, more convulsive activity is associated with more systemic complications. Neither focal nor nonconvulsive SE should be considered non-life threatening, because they can progress to full convulsive SE, but they can be treated somewhat slower to minimize iatrogenic side effects. I divide the initial management into three phases: assessment and supportive treatment, initial pharmacotherapy, and pharmacotherapy for refractory seizures.
on medications for chronic epilepsy. A rapid fingerstick glucose should confirm hypoglycemia. Measurement of arterial blood gases is often valuable and may suggest a need for intubation and mechanical ventilatory support. Cardiac monitoring, frequent measurement of blood pressure, and pulse oximetry should be instituted. Before the administration of pharmacologic treatment, administer thiamine, 100 mg, followed by 50 mL of 50% dextrose by direct push into the IV line. This phase usually lasts approximately 5 to 10 minutes (see our suggested protocol in Figure 1).
Initial Pharmacologic Therapy

Lorazepam, 0.02 to 0.03 mg/kg, should be administered IV, and its effect should be assessed after a minute. If seizures continue, additional doses of lorazepam (up to a cumulative dose of 0.1 mg/kg) should be infused at a maximum rate of 2 mg/min, and a second IV catheter should be placed (if not in yet) to begin a concomitant phenytoin (or fosphenytoin) loading infusion.* Even if seizures terminate after the initial lorazepam dose (which happens in more than half of the patients presenting with SE), therapy with phenytoin or fosphenytoin is generally indicated to prevent the recurrence of seizures. As many as half of cases of treated generalized convulsive SE show evidence of persistent seizures on continuous EEG monitoring performed after clinically detectable seizures were abolished. Thus, continuing with administration of a standard anticonvulsant agent such as phenytoin is indicated even if overt seizures stopped with lorazepam. Also, follow-up EEG should be obtained as soon as possible to rule out the presence of nonconvulsive SE. A phenytoin infusion of 20 mg/kg (or 20 mg/kg phenytoin equivalents [PE] for fosphenytoin) should be started at 50 mg/min (or 100 to 150 mg PE/minute for fosphenytoin) and reduced if significant adverse effects of the infusion are seen. Heart rate and blood pressure must be watched closely because phenytoin can cause cardiac arrhythmias and hypotension. Another possible complication is local phlebitis resulting from the sclerotic effect of extravasated phenytoin. Phenytoin must be administered in saline because fluids containing glucose can cause the precipitation of phenytoin. This phase of treatment usually lasts approximately 30 minutes. In specific cases where IV access is not immediately obtained, rectal diazepam in children and intramuscular (IM) fosphenytoin injection in adults is indicated as a first step till an IV access is available. The option of IM administration of fosphenytoin is one of the three major differences between fosphenytoin and phenytoin, the other two being the option of two or three times faster administration compared with phenytoin and the reduced likelihood of causing local vein irritation. The major obstacle to the use of fosphenytoin is the high cost.
Assessment and Support

Once a situation of a prolonged seizure is encountered, it is important to begin with performing a rapid neurologic examination to establish a preliminary classification of the type of SE and its probable etiology. The patient should also undergo a rapid systemic evaluation, with particular attention to circulatory and respiratory status and the possible need for supportive therapy (oxygen, mechanical ventilation). During this time, intravenous (IV) catheters should be placed and blood obtained for electrolytes, serum calcium, magnesium, phosphorus, glucose, toxicology studies, a complete blood count with differential, liver and kidney function studies, prothrombin time, and partial thromboplastin time. Anticonvulsant levels should be obtained if the patient is
*Phenytoin and any of the benzodiazepines are incompatible and will precipitate if infused through the same IV line. Johnson: Current Therapy in Neurologic Disease (7/E)
Status Epilepticus
47
Seizures
Ongoing seizure activity
05 min.
History while watching seizure
Basic ABCs
Examination while placing intravenous lines
530 min.
Consider the diagnosis of SE and draw the necessary bloods. Initial pharmacologic therapy. Consider EEG if possible without delaying treatment unless necessary to verify diagnosis.
Lorazepam 0.1 mg/kg IV at 12 mg/min
Ongoing seizure activity?
Yes
No
Phenytoin 20 mg/kg IV (or 20 mg/kg phenytoin equivalents (PE) for fosphenytoin) at 50 mg/min (or 100150 PE/min for fosphenytoin) and reduced if significant adverse effects of infusion seen.
Phenytoin 20 mg/kg IV (or 20 mg/kg phenytoin equivalents (PE) for fosphenytoin) over 23 hours then end of protocol
Ongoing seizure activity?
2
3060 min. Yes: treatment of refractory seizures (definite SE) No
End of protocol Phenytoin: additional 10 mg/kg IV (or 10 mg/kg phenytoin equivalents (PE) of fosphenytoin) and consider another 0.05 mg/kg of lorazepam if pt. is stable. Correct metabolic derangements, intubate and get continuous EEG recording if possible.
Ongoing SE?
Yes
No
Phenobarbital 20 mg/kg IV at 50 mg/min
End of protocol
Ongoing SE? 60120 min. Yes No
If the patient is hemodynamically very unstable you may consider midazolam 0.2 mg/kg bolus, then 0.050.5 mg/kg per hour for 45 minutes trial prior to pentobarbital. If the patient is at high risk for prolonged mechanical ventilation you may consider propofol 2 mg/kg IV over 10 min. If seizure stops, discontinue bolus and continue infusion at 412 mg/kg/hour while closely monitoring EEG and blood pressure. If seizures do not stop within 45 minutes, stop and start pentobarbital 515 mg/kg rapid IV bolus, then 16 mg/kg/min IV. Continuous EEG monitoring until pattern is isoelectric.
End of protocol
Proceed with further evaluation
FIGURE 1. Evaluation and pharmacologic treatment of status epilepticus (SE). ABC, Airway, breathing, circulation; IV, intravenous; EEG, electroencephalogram. Johnson: Current Therapy in Neurologic Disease (7/E)
48
Status Epilepticus
Treatment of Refractory Seizures

Infuse another 10 mg/kg of phenytoin (or 10 mg/kg PE of fosphenytoin) and consider another 0.05 mg/kg of lorazepam if the patient is stable. Metabolic abnormalities from initial laboratory studies should be appropriately addressed. It is critical to provide adequate ventilatory and hemodynamic support: Patients with refractory seizures should be endotracheally intubated because the combination of benzodiazepines and barbiturates is likely to cause respiratory failure. The primary drugs used in this setting are pentobarbital, midazolam, and propofol; a systematic review of drug therapy for refractory SE assessed data on 193 patients from 28 trials in an attempt to clarify this issue. Overall mortality was 48%, but there was no association between drug selection and the risk of death. Pentobarbital was more effective than either propofol or midazolam in preventing breakthrough seizures (12% vs. 42%), but was associated with a significantly increased incidence of hypotension, defined as a systolic blood pressure below 100 mm Hg (77% vs. 34%). I select further pharmacologic therapy at this point according to the old school (phenobarbital followed by pentobarbital) but may modify treatment if the patient is very unstable hemodynamically or at great risk for prolonged mechanical ventilation (see Figure 1). Treatment with high-dose barbiturates remains the treatment of choice because of the greatest experience with its use. Continuous EEG monitoring should be instituted if possible, along with continuous pulse oximetry and blood pressure monitoring via an arterial catheter. Vasopressors should be available at the bedside. An initial dose of 20 mg/kg of phenobarbital should be infused at a maximum rate of 100 mg/min. If seizure activity continues, pentobarbital coma should be induced. A dose of 10 mg/kg of pentobarbital should be infused while careful attention is paid to the EEG and hemodynamic status. Additional doses of pentobarbital at rates of 1 to 6 mg/kg/min should be infused until seizures stop (and the EEG shows isoelectric pattern). Almost all patients at this point require vasopressor support (typically phenylephrine or dopamine) as well as crystalloid infusions. The mortality rate associated with barbiturate coma reaches 80% in patients older than 70 years of age because of adverse hemodynamic effects and the severity of the underlying neurologic process. If seizures are terminated with pentobarbital, then an infusion at 1 to 4 mg/kg/hr should be maintained for 48 to 96 hours and tapered over the following 24 hours. During this time therapeutic phenytoin and phenobarbital concentrations must be maintained. If EEG is not available emergently, the maintenance dose of pentobarbital should be increased until all visible evidence of seizure activity has been abolished, including subtle signs such as pupillary dilation. Recent studies on the use of pentobarbital coma for treatment of SE shows that patients treated with sufficient dosing to produce isoelectric EEG did better than those whose EEG pattern showed burst suppression only. Also, continuation of the barbiturate anesthesia for longer time, namely 4 days, resulted in better outcome.
HEMODYNAMICALLY UNSTABLE PATIENTS Treatment with barbiturates or propofol may significantly worsen the unstable patients. Therefore, in extreme cases of hemodynamic instability one may proceed with a midazolam infusion because it is the besttolerated treatment in this setting. Generally, therapy is initiated with a 0.2 mg/kg bolus, followed by a continuous infusion of 0.05 to 0.5 mg/kg/hr. If this is unsuccessful within 45 to 60 minutes, a pentobarbital infusion should be started. PATIENTS AT HIGH RISK FOR PROLONGED MECHANICAL VENTILATION Patients who are at high risk for prolonged mechanical ventilation (e.g., with chronic obstructive pulmonary disease, severe debilitation, or cancer) could be treated with propofol in an attempt to minimize the duration of sedation. Blood pressure and EEG should be monitored closely, and pressors should be ready at the bedside, while 2 mg/kg of propofol is administered over 10 minutes. If the seizures stop prior to the infusion of the entire bolus, the bolus should be discontinued and a continuous infusion begun at 4 to 12 mg/kg per hour. This infusion should be titrated over the next 20 to 60 minutes to maintain burst suppression on the EEG and a seizurefree state. If seizures are controlled with propofol, the effective infusion rate should be maintained for 24 hours and then tapered at a rate of 5 percent per hour. This prevents rebound seizures that commonly occur with too fast propofol taper. It is critical that high therapeutic levels of anticonvulsants are obtained prior to tapering the propofol to reduce the risk of seizure recurrence. If seizure activity does not stop within 45 minutes, then the treatment with propofol should be considered unsuccessful. In this case, pentobarbital coma should be considered. Propofol infusions for refractory SE are relatively new in comparison with midazolam or high-dose barbiturates. However, as clinical experience with propofol sedation in the intensive care setting grows, this agent is increasingly used in patients with refractory status persisting after intubation. It remains critical that propofol be employed cautiously and by individuals familiar with its use in this context.
Further Evaluation after Controlling Seizures

Once seizures are under control, other causes of SE should be excluded. Noncontrast brain computed tomography (CT) scan should be obtained to rule out acute CNS hemorrhage and a subsequent lumbar puncture should be done if the CT scan is negative to rule out acute infection. Urinalysis, urine culture, and blood cultures should be obtained in all patients because it may be impossible to discern the cause of existing fever as infection versus seizure related. The cause of a given episode of SE is important to determine for prognosis as well as for acute management. The most common causes for SE in adults are stroke, low anticonvulsant levels in
49
Seizures
chronic epilepsy patients, toxic or metabolic derangements, anoxia or hypoxia, infection, tumor, trauma, or drug withdrawal. These causes can be identified relatively by simple tests, and treatment of the underlying cause can shorten the duration of SE, thereby improving outcome. While the patient is in barbiturate coma, systemic metabolic abnormalities should be managed aggressively. In particular, blood pressure fluctuations require pressors for control, and maintenance of normoglycemia is vital. In addition, as mentioned before, blood levels of phenytoin and phenobarbital should be kept in the high therapeutic ranges before gradual withdrawal of phenobarbital. After several days of barbiturate anesthesia, of which at least 2 days should be free of epileptiform activity on EEG, a gradual pentobarbital taper should be initiated by decreasing 1 mg/min every 6 hours with continuous EEG monitoring. If at any point epileptiform activity is seen, the infusion should be increased back to achieving isoelectric pattern. If, however, infusion can be tapered to zero, EEG monitoring should be continued continuously or intermittently for at least 4 more days to monitor for possible relapse. Good prognostic factors in recovery from SE are history of epilepsy, infectious etiology, lack of multiorgan system failure, and age younger than 40 years. Anoxia, stroke, and tumor are less favorable prognostic factors. SUGGESTED READING
Chapman MG, Smith M, Hirsch NP: Status epilepticus, Anaesthesia 56:648, 2001. Claassen J, Hirsch LJ, Emerson RG, Mayer SA: Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review, Epilepsia 43:146, 2002. DeLorenzo RJ, Hauser WA, Towne AR, et al: A prospective populationbased epidemiologic study of status epilepticus in Richmond, Virginia, Neurology 46:1029-1035, 1996. Krishnamurthy KB, Drislane FW: Relapse and survival after barbiturate anesthetic treatment of refractory status epilepticus, Epilepsia 37:863-867, 1996. Lowenstein DH: Status epilepticus: an overview of the clinical problem, Epilepsia 40(Suppl 1):53-58, 1999. Lowenstein DH, Alldredge BK: Status epilepticus, N Engl J Med 338:970, 1998. Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of Americas Working Group on Status Epilepticus, JAMA 270:854, 1993. Treiman DM: Status epilepticus. In Resor SR Jr, Kutt H, editors: The medical treatment of epilepsy, New York, 1992, Marcel Dekker.

Allan Krumholz, M.D., and Tricia Ting, M.D.
Psychogenic nonepileptic seizures (PNESs) are among the most common and serious of all psychogenic neurologic disorders. They account for approximately 20% of all intractable seizure disorders referred to comprehensive epilepsy centers and present with a reported annual incidence of about 4% of true epilepsy. Moreover, patients with PNESs are seriously ill. PNESs may not be real epilepsy, but their adverse consequences are very real, resulting in severe disability and even death. Compared with patients with real epilepsy, patients with PNES exhibit more frequent, severe, and disabling seizures and a poorer quality of life. Although advances in video-electroencephalogram (EEG) monitoring have much improved our ability to correctly diagnose PNESs, diagnosis and management remain major problems. Consequently, here we emphasize strategies for both correct diagnosis and proper therapy in the management of patients with PNES.
Terminology
There is no uniform standardized definition or classification for psychogenic disorders such as PNESs. We prefer the currently popular term psychogenic nonepileptic seizures. The more general term nonepileptic seizures (NESs) is used to encompass both physiologic and psychological causes for disorders that are mistaken for epilepsy (Table 1). NESs are operationally defined as disorders that mimic epilepsy but are not due to abnormal electrical discharges in the brain; and there are two types, physiologic and psychogenic. Physiologic NESs are physical disorders that are confused or mistaken for epilepsy. The specific causes vary
TABLE 1 Classification of Nonepileptic Seizures
I. Physiologic Nonepileptic Seizures or Events* A. Pure B. Mixed (with psychological exaggeration or embellishment) II. Psychogenic Nonepileptic Seizures A. Somatoform disorders 1. Somatization disorders 2. Conversion disorder or reactions B. Dissociative disorders C. Factitious disorder (e.g., Munchausens syndrome) D. Malingering
*Age dependent, e.g., night terrors or breath-holding spells in children; other syncopes, complicated migraine, and transient ischemic attacks in adults.
PATIENT RESOURCE
Epilepsy Foundation of America 4351 Garden City Drive Landover, Maryland 20785-7223 Phone: 800-332-1000 http://www.epilepsyfoundation.org/
49
Seizures
chronic epilepsy patients, toxic or metabolic derangements, anoxia or hypoxia, infection, tumor, trauma, or drug withdrawal. These causes can be identified relatively by simple tests, and treatment of the underlying cause can shorten the duration of SE, thereby improving outcome. While the patient is in barbiturate coma, systemic metabolic abnormalities should be managed aggressively. In particular, blood pressure fluctuations require pressors for control, and maintenance of normoglycemia is vital. In addition, as mentioned before, blood levels of phenytoin and phenobarbital should be kept in the high therapeutic ranges before gradual withdrawal of phenobarbital. After several days of barbiturate anesthesia, of which at least 2 days should be free of epileptiform activity on EEG, a gradual pentobarbital taper should be initiated by decreasing 1 mg/min every 6 hours with continuous EEG monitoring. If at any point epileptiform activity is seen, the infusion should be increased back to achieving isoelectric pattern. If, however, infusion can be tapered to zero, EEG monitoring should be continued continuously or intermittently for at least 4 more days to monitor for possible relapse. Good prognostic factors in recovery from SE are history of epilepsy, infectious etiology, lack of multiorgan system failure, and age younger than 40 years. Anoxia, stroke, and tumor are less favorable prognostic factors. SUGGESTED READING
Chapman MG, Smith M, Hirsch NP: Status epilepticus, Anaesthesia 56:648, 2001. Claassen J, Hirsch LJ, Emerson RG, Mayer SA: Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review, Epilepsia 43:146, 2002. DeLorenzo RJ, Hauser WA, Towne AR, et al: A prospective populationbased epidemiologic study of status epilepticus in Richmond, Virginia, Neurology 46:1029-1035, 1996. Krishnamurthy KB, Drislane FW: Relapse and survival after barbiturate anesthetic treatment of refractory status epilepticus, Epilepsia 37:863-867, 1996. Lowenstein DH: Status epilepticus: an overview of the clinical problem, Epilepsia 40(Suppl 1):53-58, 1999. Lowenstein DH, Alldredge BK: Status epilepticus, N Engl J Med 338:970, 1998. Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of Americas Working Group on Status Epilepticus, JAMA 270:854, 1993. Treiman DM: Status epilepticus. In Resor SR Jr, Kutt H, editors: The medical treatment of epilepsy, New York, 1992, Marcel Dekker.

Allan Krumholz, M.D., and Tricia Ting, M.D.
Psychogenic nonepileptic seizures (PNESs) are among the most common and serious of all psychogenic neurologic disorders. They account for approximately 20% of all intractable seizure disorders referred to comprehensive epilepsy centers and present with a reported annual incidence of about 4% of true epilepsy. Moreover, patients with PNESs are seriously ill. PNESs may not be real epilepsy, but their adverse consequences are very real, resulting in severe disability and even death. Compared with patients with real epilepsy, patients with PNES exhibit more frequent, severe, and disabling seizures and a poorer quality of life. Although advances in video-electroencephalogram (EEG) monitoring have much improved our ability to correctly diagnose PNESs, diagnosis and management remain major problems. Consequently, here we emphasize strategies for both correct diagnosis and proper therapy in the management of patients with PNES.
Terminology
There is no uniform standardized definition or classification for psychogenic disorders such as PNESs. We prefer the currently popular term psychogenic nonepileptic seizures. The more general term nonepileptic seizures (NESs) is used to encompass both physiologic and psychological causes for disorders that are mistaken for epilepsy (Table 1). NESs are operationally defined as disorders that mimic epilepsy but are not due to abnormal electrical discharges in the brain; and there are two types, physiologic and psychogenic. Physiologic NESs are physical disorders that are confused or mistaken for epilepsy. The specific causes vary
TABLE 1 Classification of Nonepileptic Seizures
I. Physiologic Nonepileptic Seizures or Events* A. Pure B. Mixed (with psychological exaggeration or embellishment) II. Psychogenic Nonepileptic Seizures A. Somatoform disorders 1. Somatization disorders 2. Conversion disorder or reactions B. Dissociative disorders C. Factitious disorder (e.g., Munchausens syndrome) D. Malingering
*Age dependent, e.g., night terrors or breath-holding spells in children; other syncopes, complicated migraine, and transient ischemic attacks in adults.
PATIENT RESOURCE
Epilepsy Foundation of America 4351 Garden City Drive Landover, Maryland 20785-7223 Phone: 800-332-1000 http://www.epilepsyfoundation.org/
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depending on age (see Table 1). If these episodes are uncomplicated by psychological or emotional features, they can be called pure physiologic nonepileptic events. However, sometimes a patients physiologic events are psychologically exaggerated, embellished, or misinterpreted and may be thought of as mixed physiologic nonepileptic events (see Table 1). Physiologic NESs account for only a small proportion of all patients with NESs. Most patients with NESs have PNESs (see Table 1). In general any patient with a psychological disorder that causes symptoms that are mistaken for epilepsy can be said to have PNESs. It is useful to classify psychogenic seizure patients into four major psychopathologic categories based on Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-4) system (see Table 1): A. Somatoform disorders B. Dissociative disorders C. Factitious disorders D. Malingering Somatoform disorders account for the great majority of patients and can be further subclassified (see Table 1). Dissociative disorders are increasing recognized as a significant psychopathology in some patients with PNES. Also, these categories are not mutually exclusive and may be associated with other psychological, physical, and sociologic comorbidities.
neuropsychological assessments can be useful complements to video-EEG monitoring. Diagnosis may be particularly complicated in patients with both nonepileptic and epileptic seizures. Approximately 10 to 40 percent of patients diagnosed with PNES also have been reported to have true epileptic seizures. Fortunately, in most patients with coexisting epilepsy and PNES, the epileptic seizures are usually well controlled or of only historical relevance at the time PNES present. CLINICAL OBSERVATIONS Physicians have long noted that certain overt seizure characteristics are more likely associated with PNES, whereas other features appear more indicative of epilepsy. The most commonly reported characteristics include movements and vocalizations during seizures, seizure duration, and other seizure-related associations such as injury, incontinence, and amnesia. Although variability and overlap in PNES and epileptic seizure semiology preclude relying on any single clinical sign to distinguish between the two, some clinical observations can be useful diagnostically (Table 2). PNESs often persist considerably longer than epileptic seizures, which typically last less than 3 minutes, excluding the postictal state. Some prolonged PNESs may present with nonphysiologic waxing and waning convulsive activity, or the activity may appear distractible with external stimuli. In PNES with convulsions, movements may look purposeful or semipurposeful, asymmetrical, or asynchronous (i.e., thrashing or writhing), in contrast to the synchronous tonic-clonic activity of epileptic seizures. However, it may be difficult to distinguish the semipurposeful behaviors of PNES from the automatisms of complex partial epileptic seizures, particularly frontal lobe seizures. Other distinguishing features of PNES include preservation of consciousness and responsiveness, which are frequently altered in epileptic seizures. Crying and weeping are more common to PNES, as is having the
Diagnosis
Historically, physicians have resorted to clinical observation, seizure semiology, and history for distinguishing NES from epileptic seizures. Today, clinical observation has been buttressed by video-EEG monitoring, now considered the gold standard in the differential diagnosis of seizures. Additional diagnostic techniques including seizure provocation, serum prolactin levels, single photon emission computed tomography (SPECT), and
TABLE 2 Clinical Characteristics of Epileptic versus Psychogenic Nonepileptic Seizures

Characteristics Age at onset Sex Previous psychiatric history Motor Vocalization Incontinence Duration of seizure Injury Amnesia Suggestion provokes seizure Epileptic All ages; children and adolescents more common Male and female about equal Occasionally present In generalized convulsions, bilateral movements are usually synchronous Cry at onset Frequent Usually < 2-3 min Frequent tongue biting Common, unconcious during seizure No Nonepileptic All ages; 15-35 yr most common Female more common: 3:1 Commonly noted Flailing, thrashing, and asynchronous movements more common, side to side head movements, pelvic thrusting Weeping, crying, or screaming more common Occasional Often prolonged, > 2-3 min Uncommon Variable, sometimes conscious during seizure Often
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Seizures
eyes closed during a seizure. Although patients with PNES may report incontinence and self-injury, they are rarely actually witnessed or documented. Similarly, patients with PNES may report having seizures in sleep or appear to be asleep at seizure onset. However, PNESs arising from true sleep as documented by EEG are exceedingly rare. Additionally, unlike epileptic seizures, PNESs characteristically do not respond well to antiepileptic drug treatment. PNESs are much more likely to be provoked by emotional stimuli and suggestion. Thus, provocation procedures may be particularly useful for reproducing PNES during EEG recording to enable confirmation of the diagnosis. Provoking or suggesting seizures can be done in several ways, such as injecting saline or placing a tuning fork on the body or head. Hypnosis has also been used. These procedures all are accompanied by strong suggestion by the physician that this procedure is likely to bring on a typical seizure. An important diagnostic consideration is whether a provoked event truly represents the patients typical seizure. Conclusions based on an atypical induced event or on only one of a variety of seizure types can lead to a misdiagnosis, particularly in patients with coexisting PNES and epilepsy. Seizure provocation by suggestion does raise some ethical controversies. Misleading and deceiving a patient when provoking a seizure can be harmful to the patient-physician relationship and should be avoided. Nonetheless, provocative testing can be done with honesty and benefit the patient, particularly when it facilitates a correct diagnosis. VIDEO-EEG MONITORING A diagnosis of PNESs is most secure when a typical seizure is captured and shows no epileptic activity on simultaneous EEG and video monitoring. In contrast, generalized convulsive epileptic seizures invariably are associated with clear changes in the background EEG during ictal recordings. Similarly, complex partial seizures, potentially arising from small or deep seizure foci, are associated with significant ictal EEG abnormalities in perhaps 85% to 95% of such seizures. Even simple partial seizures that do not impair consciousness have associated ictal EEG abnormalities up to 60% of the time (or nearly 80% if one records multiple seizures). The ictal EEG recording is particularly important because interictal or routine EEGs occasionally may be misleading. Patients with epilepsy may have normal
interictal EEGs, whereas patients with PNES may have minor EEG abnormalities (Table 3). Clinical seizures may be captured for differential diagnosis with either outpatient or inpatient EEG monitoring. Outpatient ambulatory EEG monitoring with or without simultaneous video recording has become a more readily available option that allows patients to wear the EEG at home for several days. It is particularly useful for patients who have daily events. The advantage of home monitoring is the ability to capture typical events that may be triggered by the patients usual environment. However, physician-directed seizure provocation by suggestion is less feasible. Prolonged inpatient video-EEG monitoring may be more appropriate for patients with less frequent events, especially when antiepileptic drug tapering is considered. Simultaneous video-EEG recording offers the advantage of permitting careful observation and review of the clinical manifestations of seizures. This can be especially useful for distinguishing epileptic discharges from movement and muscle artifact when assessing patients with PNES. PROLACTIN LEVELS Detecting a rise in serum prolactin levels following a seizure can be helpful in differentiating epileptic seizures from PNES. Prolactin levels rise approximately fivefold to tenfold after generalized tonic-clonic seizures and somewhat less so but still significantly (typically at least twofold to threefold) after complex partial seizures. This increase in serum prolactin is maximum in the initial 20 minutes to 1 hour after a seizure. Although measurements of serum prolactin may be useful in distinguishing epileptic from NESs, false-negative and false-positive results do occur. Simple partial seizures or mild complex partial seizures, particularly those with little motor activity or those arising from extratemporal regions, may not significantly raise prolactin levels. In addition, serum prolactin elevations have been reported in rare instances to occur after syncope. Overall, a prolactin level elevation is fairly specific for epilepsy; however, lack of an elevation is not highly predictive of PNES. SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHY Single-photon emission computed tomography (SPECT), though not a first-line choice to differentiate PNES and epileptic seizures, may provide helpful data in difficult diagnostic cases. Typically, patients with epilepsy will
TABLE 3 EEG Characteristics of Epileptic Versus Nonepileptic (Psychogenic) Seizures

EEG Interictal Preictal Ictal Postictal Epileptic Spikes and sharp waves common Spikes, sharp waves, or rhythmic ictal activity Spikes, sharp waves, or rhythmic ictal activity Slow activity Nonepileptic Normal or nonspecific abnormalities, e.g., mild slow activity (possibly medication related) Movement artifact Movement artifact Normal EEG, preserved alpha when apparently unconscious
EEG, Electroencephalogram.
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have increased cerebral blood flow in the area of the seizure focus ictally but focally decreased blood flow interictally. In contrast, patients with PNES should not show such abnormalities. NEUROPSYCHOLOGICAL TESTING The performance of PNES and epilepsy patients on various psychological and neuropsychological tests including the Minnesota Multiphasic Personality Inventory (MMPI and MMPI-2), the Weschler Adult Intelligence Scale (WAIS), and the Halstead-Reitan Test Battery have been studied. As compared to their epilepsy counterparts, PNES patients more frequently demonstrate a conversion V profile on the MMPI. A conversion V profile, defined by an elevated MMPI Scale 1 and 3 with a relative trough on Scale 2, is highly associated with somatoform disorders and conversion symptoms. Studies assessing performance on the WAIS and Halstead-Reitan Test Battery have shown that both PNES patients and epilepsy patients have more cognitive impairment compared to the normal population, but on many neuropsychological measures, there is no significant difference in performance between the two groups. These findings suggest that while neuropsychological testing may not help distinguish between patients with PNES and epilepsy, it may nevertheless provide clinically useful data by highlighting comorbid psychopathology or cognitive difficulties that could benefit from psychological or psychiatric interventions. Formal neuropsychological testing requires referral to mental health professionals who are experienced in psychometric assessment and psychotherapeutic intervention in patients with neurologic disorders. However, the distinction between PNES and epileptic seizures is best made by a neurologist, particularly one who has expertise in epilepsy, and should be based on consideration of both clinical data and neuropsychological assessments.
Treatment
PHYSIOLOGIC NONEPILEPTIC SEIZURES For patients with physiologic causes for their NESs, such as syncope, complicated migraine, or transient ischemic attacks, the treatment, clinical course, and outcome vary depending on the etiology. For example, some patients with cardiac syncope may need placement of a pacemaker, and their prognosis depends on the cardiac disease. PSYCHOGENIC NONEPILEPTIC SEIZURES Even after a diagnosis of PNES is established, neurologists can and should continue to take an active role in the care of such patients (Table 4). It is important to consider the associated psychopathology in such patients, and when appropriate, to refer patients to mental health professionals. However, mental health professionals are often uncomfortable and inexperienced with seizures
and PNES, so neurologists need to maintain an active role in the care of such patients, even if that role is simply to provide support to the mental health professional or psychiatrist. Unfortunately PNES seizure patients often fall in the cracks between psychiatry and neurology. Neurologists can be reassured that they can and should continue to be involved with PNES patients and can follow some simple guidelines for managing these types of patients. Management of patients with PNES is similar to that for patients with other types of so-called abnormal illness behavior (see Table 4). Historically, moral therapy was advocated as recognition that psychological, social, and cultural factors play an important role in these types of disorders. More recently approaches have centered on concepts such as supportive re-education. The first consideration should be the manner in which the diagnosis of psychogenic seizures is presented to the patient and family. It is important to be honest with the patient and to demonstrate a positive approach to the diagnosis. The physician should emphasize as favorable the good news that the patient does not have epilepsy and should also stress that the disorder, although serious and real, does not require treatment with antiepileptic medications and that once stress or emotional issues are resolved, the patient has the potential to gain better control of these events. Nevertheless, not all patients readily accept the diagnosis of PNES or this type of approach. Some may seek other opinions, and this should not be discouraged. An adversarial relationship with the patient should be avoided. In fact, the patient should be encouraged to return as desired, and records should be made available to avoid duplication of services. After a diagnosis of PNES is presented, supportive measures should be initiated. Regular follow-up visits for the patient are useful even if a mental health professional is involved. This allows the patient to get medical attention without demonstrating illness behavior. Moreover, it also offers support to the involved mental health professional. Patient education and support are stressed at these visits. Since family issues are often important contributing factors, family members should be involved.
TABLE 4 Management of Nonepileptic Seizure Patients

Present the diagnosis of nonepileptic seizures positively, emphasizing the potential for better seizure control. After patients are referred to mental health professionals, the diagnosing neurologist should provide some followup and support. Regular follow-up visits should be scheduled that are not contingent on persistent, new, or worsening symptoms. Give patients attention when they do well. Avoid prescribing unnecessary medications, unwarranted tests, and excessive referrals to specialists. Permit the continuation of some symptoms. A patients optimal well-being and function, rather than eradication of seizures, is the goal.
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If symptoms worsen or new ones develop, patients should get appropriate attention. However, it is important to avoid unnecessary testing, uncalled-for medication, or excessive referral to specialists. In addition, we advise that sometimes symptoms, even some PNESs, should be tolerated. Indeed, the goal of therapy should be to maximize the patients function, well-being, and quality of lifenot just to eliminate seizures. It is also important to look beyond the patients physical symptoms and apparent psychopathology. Indeed one needs to consider such factors as personality structure, coping mechanism, related psychosocial stressors, and associated cognitive problems. This approach is supported by current psychiatric theory, as emphasized in the DSM-4 classification system. For patients with coexisting epileptic and nonepileptic seizures, proper treatment is dependent on defining the nature of the seizures that are causing problems. In many patients with coexisting epileptic and nonepileptic seizures, the events are really sequential rather than truly actively coexisting or simultaneous. This means that a patient may have a history of epileptic seizures, often in the distant past or in the case of some adults, in childhood, and may be on antiepileptic medications for these, but then the patient develops different types of events that prove to be PNES. In such cases, the active problem is really not epilepsy, because the patients epileptic seizures are well controlled. Therefore, attention and treatment should be directed to the PNES, and the patient and family reassured that the epileptic seizures are controlled. Patients who present with both epileptic and nonepileptic seizures simultaneously demand more complex management. In such patients, we have found it particularly helpful to focus on the semiology of seizure manifestations as recorded by video-EEG monitoring to distinguish the NESs from the epileptic ones. We then direct our treatment of the patient according to the semiology manifesting at that time. We also have found it useful to show such epileptic or nonepileptic seizures to family members to help them understand how to respond best to a specific patients symptoms when epileptic and nonepileptic seizures coexist as active problems. A history of sexual or physical abuse is often reported among patients diagnosed with PNES. NESs occur with greater frequency in women. The exact incidence varies, but women generally account for about 70% to 80% of all individuals with NESs. In addition head injury, particularly mild head injury, is noted as a potential precipitant in a substantial proportion of these patients. These factors may represent specific psychological risk factors or the more general risk of trauma in a susceptible individual. In regard to sexual and physical abuse, these issues should be investigated and treatment directed as appropriate.
with psychogenic seizures function reasonably well after diagnosis. However, many have poor functional outcomes, and only about 30% completely stop having psychogenic seizures. When the diagnosis of psychogenic seizures is based on reliable criteria such a video-EEG monitoring, misdiagnosis is unlikely, but in patients, particularly those with unusual appearing frontal lobe seizures, it can occur. Instead, the usual cause for a poor outcome is related to a patients chronic psychological and social problems. It is noteworthy that children with psychogenic seizures appear to have a much better prognosis than adults. Children may have psychogenic seizures more related to transient stress and coping disorders, whereas adults are more likely to have psychogenic seizures within the context of more chronic psychological maladjustment, such as personality disorders. Another factor accounting for the better outcomes in children is that they are usually diagnosed earlier. Patients without evidence of serious psychiatric or personality disorders but rather symptoms more suggestive of stress and coping disorders respond relatively well to supportive, educational, or behavioral therapeutic approaches. In contrast, patients with somatoform disorders and factitious disorders more often have associated chronic personality problems and, correspondingly, a poorer prognosis. In addition, recent evidence suggests that patients with PNES may benefit from structured treatment programs and continued support by epilepsy specialists or centers. As knowledge about the nature of psychogenic seizures and their associated psychopathology is gained, better treatment strategies can be developed that will improve the care and prognosis of these difficult and challenging patients. SUGGESTED READING
Barry E, Krumholz A, Bergey C, et al: Nonepileptic posttraumatic seizures, Epilepsia 39:427-431, 1998. Bowman ES: Etiology and clinical course of pseudoseizures: relationship to trauma, depression, and dissociation, Psychosomatics 34:333-342, 1993. Cragar DE, Berry DTR, Fakhoury TA, et al: A review of diagnostic techniques in the differential diagnosis of epileptic and nonepileptic seizures, Neuropsychol Rev 12:31-64, 2002. Krumholz A: Nonepileptic seizures: diagnosis and management, Neurology 53(Suppl):S76-S83, 1999. Rueber M, Pukrop T, Bauer J, et al: Outcome in psychogenic nonepileptic seizures: one- to ten-year follow-up in 164 patients, Ann Neurol 53:305-311, 2003. Wyllie E, Friedman D, Luders H, et al: Outcome of psychogenic seizures in children and adolescents compared to adults, Neurology 41:742-744, 1991.
PATIENT RESOURCE
Epilepsy Foundation of America 4351 Garden City Drive Landover, MD 20785-7223 Phone: 800-332-1000 http://www.epilepsyfoundation.org/
Prognosis
The outcomes of patients with psychogenic seizures vary. Outcome studies show that about half of all patients
SECTION 3
Pain
Charles E. Argoff, M.D.
magnetic resonance imaging (MRI) of the lumbar spine does not routinely correlate with the degree of pain experienced by an individual. Patients with severe low back pain may have little or no structural abnormalities seen by MRI, whereas asymptomatic individuals may be noted to have disk herniations or other obvious structural problems with such imaging tools. Electrophysiologic tests may be normal in patients with severe pain, prompting some to question the legitimacy of the pain as opposed to acknowledging the limitations of the diagnostic test. Psychosocial and other factors often play a role in the chronic pain experience, adding an additional layer of complexity for both assessment and treatment. Despite these challenges, advances in our understanding of the pathophysiology of various chronic pain problems have been made that in turn have led to new pharmacotherapeutic and other treatment options for the management of chronic pain. Numerous therapeutic approaches are available that hold great promise for reducing the amount of pain that an individual has to endure, hopefully leading to functional restoration as well. The purpose of this chapter is to review the general principles of chronic pain management for the practicing neurologist. The success of the assessment and treatment of chronic pain may be enhanced by the recognition of the difference between nociceptive and neuropathic pain. Nociceptors are specialized nerve endings that are able to respond to typical normal pain producing stimuli such as thermal, chemical, mechanical, and other potential causes of tissue damage. An activated nociceptor, through C and A-delta nerve fibers, transmits its pain-producing information from the peripheral to the central nervous system, where it is processed further at spinal cord and brain levels. Nociceptive input does not become experienced by a person as pain unless the nociceptive information reaches appropriate areas of the brain. In the absence of nociceptive input, the normal nervous system does not experience pain. In contrast, neuropathic pain results from injury to the peripheral and/or central nervous system and represents abnormalities in transmission that have developed as the result of the injury. Ongoing injury is not required for these abnormalities to be expressed. There is clear evidence that neuropathic pain appears to result from the manner in which the nervous system is reorganized following injury. Peripheral and central sensitization are 55
Nearly 80 million Americans suffer from one or more types of chronic painful disorders, including chronic headache, chronic neuropathic pain, pain secondary to degenerative spinal disorders, pain secondary to nonspinal degenerative joint disease, fibromyalgia, soft tissue pain disorders such as chronic myofascial pain, cancer-related pain, and others. The pain experienced by millions of Americans is frequently associated with profound restrictions of vocational as well as nonvocational activities with devastating effects on ones quality of life. Chronic pain disables more people and adds more costs to our health care economy on an annual basis than do heart disease and cancer combined. Unlike in acute painful states such as postoperative pain or pain associated with an ankle sprain, in which the cause of the pain may be relatively easily determined, for patients with chronic pain, the exact cause of the pain may be difficult to identify even many years after the original acute injury or painful event. The term chronic pain is often defined as pain that lasts 3 months or more; however, in reality, chronic pain is pain that persists beyond the time of normal healing. By this definition, patients in certain settings might begin to experience chronic pain 1 month after the initial onset of acute pain. This is important to recognize for early treatment intervention and for the prevention of lifelong pain for the affected individual. Evaluating chronic pain poses numerous challenges to the neurologist. Although many pain assessment tools exist (see later) and new ones are being developed, the lack of a specific pain measurement tool that can prove or disprove the presence and/or the intensity of the pain may allow some practitioners to dismiss a persons complaint of pain as subjective. There are also limitations in the interpretation of available test results such as imaging and electrophysiologic tests. For example, it is well known that the degree of abnormality seen on
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key mechanisms that many lead in a neuropathic state to this reorganization such that lowered threshold to nociceptive processing that may now occur. Stimuli that may normally not be painful are, in neuropathic pain states, experienced as painful (allodynia). Stimuli that are normally painful may be more painful than usual (hyperalgesia). Any sensory stimuli, painful or otherwise, may be perceived in a more exaggerated manner (hyperesthesia). These clinical findings are the hallmark of neuropathic pain and reflect a nervous system that is now able to facilitate pain production because it is more easily excited than in a normal state. It must be emphasized that neuropathic pain may therefore be experienced even when the affected individual is not subjected to a tissue-damaging stimulus. It is important as well to recognize that a persistent nociceptive pain state may, through peripheral and central sensitization, develop into a neuropathic pain state. Although certainly not all chronic pain states are neuropathic, central nervous system changes that facilitate pain transmission have been postulated in chronic pain as well. Factors underlying this transformation are being actively studied and hold the key to the treatment and hopefully the prevention of many different chronic pain states, including postherpetic neuralgia, complex regional pain syndrome, chronic headache, chronic pain related to degenerative joint disease, chronic low back pain, and fibromyalgia, to name a few. To minimize the effect of the chronic pain on ones quality of life, it is imperative that a patient with chronic pain be assessed as early as possible. I must emphasize that chronic pain may have significant negative impact on a patients ability to function from both a physical as well as cognitive viewpoint. Work, recreational, and normal activities of daily living all may be adversely affected. Patients with chronic pain frequently develop or have exacerbation of depression, anxiety, sleep disturbances, and loss of self-esteem as the result of the pain. Lost workdays, impaired job performance, and frank absence/disability are some of the ways in which employment is often limited by the presence of chronic pain. The goals of chronic pain management must be realistic: (1) reduce pain and (2) improve quality of life and functioningeach to the fullest extent possible. The evaluation and treatment of chronic pain are not only about finding the proper medicine, nerve block, or new exercise to cure the pain: this is not likely to happen in most cases. Rather, the management of chronic pain involves a detailed assessment of the problem, including both medical and nonmedical aspects, and the development of a comprehensive treatment plan. Medical, physical rehabilitative, and psychosocial treatment strategies all are appropriate to consider in this plan. The clinical assessment is the first step in the management of any neurologic disorder, including chronic pain. The goals of the clinical assessment include not only making the diagnosis of chronic pain but also attempting to make as specific a diagnosis as possible. The clinical assessment includes obtaining the following information: When did the pain start? Was the specific onset of the pain remembered (as for example, with postherpetic
neuralgia or trauma)? Was there a specific cause to the pain (e.g., injury, surgery)? Are there already known medical or surgical conditions for the patient (e.g., diabetes, osteoarthritis, osteoporosis, connective tissue disease) that can provide clues regarding the cause of the chronic pain? For how long has the pain existed? Where is the pain? What does the pain feel like? Is it sharp, stabbing, dull, throbbing, aching, burning, knifelike, or a combination of these? What impact on physical function is associated with the pain? What makes it better? What makes it worse? Are there past medical, neurologic, or psychosocial factors that help you, the treatment provider, to understand the pain better? What diagnostic testing is required to assist in the assessment?
The clear purpose of diagnostic testing is to help make as specific a diagnosis as possible. It is not to be used nor can it be used to validate or invalidate the complaint of pain. A normal result does not suggest there is not a chronic pain problem. In my experience, I have encountered too many instances in which a negative test result, particularly a normal electrophysiologic examination (e.g., electromyography, nerve conduction velocity) or MRI was equated to the absence of legitimate pain. This practice is not only scientifically invalid but also ethically inappropriate. The assessment of pain is aided by the use of several pain questionnaires currently available. Individual patients with chronic pain often report widely different pain levels even for similar conditions and similar degrees of functional impairment. It is, therefore, important to always assess pain intensity levels as well as the degree of functional impairment in a person with chronic pain. The Brief Pain Inventory addresses not only the pain level but also the impact of that pain on various functional domains. It is a validated tool, takes only minutes to complete, and is a practical way to assess chronic pain as well as the results of treatment in a busy practice. Use of other tools, such as the Visual Analogue Scale or the Pain Intensity Scale, assess pain solely and not function. Use of the Faces scale may be appropriate for patients who are cognitively impaired or speak a foreign language that you are not conversant in. Longer and more detailed tools also are available but are not as practical or easy to use. Other tools are being developed for specific conditions such as neuropathic pain. After completing a comprehensive assessment of the chronic pain problem, an effective treatment plan needs to be developed that provides acceptable analgesia with an acceptable side effect profile. This may include pharmacologic, interventional, rehabilitative, and cognitivebehavioral approaches singly or in combination. With respect to pharmacotherapy, there is growing empirical evidence that rational polypharmacy may be most successful for patients with chronic pain. No matter how effective a single agent may be, it rarely if ever reduces pain completely; therefore, various medications
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Pain
most often based on complementary mechanisms of action may need to be combined in a rational fashion. As in other areas of medical care (e.g., cancer, hypertension, and coronary artery disease management), combinations of therapies are often believed to be more effective than a single agent. As an example, a recent open label study demonstrated that for three painful conditions (low back pain, postherpetic neuralgia, and painful diabetic neuropathy), the addition of the lidocaine 5% patch to a treatment regimen that already included gabapentin reduced pain further in all three conditions. A randomized, controlled study examining the potential benefit of combining the lidocaine 5% patch with gabapentin for postherpetic neuralgia compared with each alone is being completed. So how do you start to develop a comprehensive treatment plan? Ideally you would consider established and accepted guidelines, based on consensus unbiased expert opinion, for the condition(s) that you are treating. Regrettably, such guidelines are not uniformly available; for example, an international panel has just published guidelines for the treatment of neuropathic pain, but similar guidelines do not exist for the treatment of chronic low back pain, an even more common set of disorders. Truly whole-istic care means integrating medical care with appropriate interventional, physical rehabilitative, and behavioral pain management approaches. When considering any type of pharmacologic therapy, treatment goals need to balance efficacy, tolerability, cost, and safety. Choose among agents that have efficacy established through a variety of means, including published multicenter, randomized, controlled studies as well as significant clinical experience. Assess the tolerability of initiating and maintaining treatment, short- and long-term side effects, the likelihood of drug-drug interactions, the ease of dosage timing, and other medication use. Consider also the severity of the side effects. For example, the nonsteroidal antiinflammatory (NSAID) agent, piroxicam, although effective in reducing symptoms associated with inflammation, is also associated with potentially fatal gastrointestinal complications, thereby making it less than ideal for conditions in which an NSAID would be appropriate. Wherever possible, you should choose the approach (assuming equal efficacy and toxicities) that requires the least laboratory monitoring (e.g., to check drug levels, monitor for hepatic, renal, or bone marrow effects). Using one agent at a time, titrate for therapeutic efficacy versus side effect(s) in a manner consistent with the pharmacokinetics of the agent.* Increase the dose of the agent until acceptable analgesia is experienced or adverse effects limit further use of the agent. Remember that each patient is different. Even if both have similar radiologic findings and the same pain level, one patient with chronic low back pain may benefit from 10 mg
of valdecoxib daily, whereas another may require a 30-mg dose. Each treatment that you offer a patient (medical or otherwise) should be considered a trial therapy. Even if you just read the latest article stating that drug X is the best choice for diabetic neuropathy, you must individually assess and reassess the effect of that drug on each individual patient. If, after a period of treatment, you and the patient believe that it is both safe and effective, then continue. If not, then either amend how the treatment is offered (increase the dose, change the route of delivery) or change the treatment. Treatment goals need to be shared between you and your patient, and they need to include understanding that your patients may need to be titrated and managed with more than one agent and one type of treatment. Patients need to know that you are not married to the same treatment forever even if it does not work. They need to expect that the treatment will be altered if it is not effective. For this reason, you must have, even as you begin treatment, a plan for treatment discontinuation or an exit strategy. Whatever you are treating your patient with: an antidepressant, anticonvulsant, muscle relaxant, opiate analgesic, NSAID, topical analgesic, or any other agent, the patient and you both should have a rational sense of what treatment success or treatment failure are. A complete lack of any pain relief or functional improvement clearly constitutes treatment failure, and the patients report following treatment of minimal pain and return to work certainly suggests treatment success. Most of what we experience with our patients lies somewhere in between. In fact, this matter has been carefully studied recently in patients with postherpetic neuralgia treated with gabapentin. Substantial improvement, as reported by patients, was associated with not 100%, or even 50%, pain reduction, but with only 30% pain reduction. These data emphasize that successful treatment outcomes as defined by the patients experiences occur without absolute pain cessation and, perhaps even more important, that in chronic pain treatment it is not realistic to expect total or even 50% pain reduction.
Conclusions
The management of chronic pain should be viewed in the same way as any other chronic disease. Determine the cause to the fullest extent possible, and institute a treatment plan that has established efficacy and acceptable side effects. Assess and reassess not only the benefit of the treatment but also the possibility of adverse effects. Do not continue treatments that are ineffective or have unacceptable side effects; always be ready to exit one treatment and begin another if needed. Reduce pain and improve function as much as possible. Finally, NEVER GIVE UP. There are numerous options for the treatment of chronic pain. If you believe that all treatment strategies have been exhausted, it is
*For example, doubling the dose of the transdermal fentanyl patch daily until comfort is achieved is likely to be associated with significant side effects, because it takes far longer than 1 day to determine the effect of the patch on the patient. Johnson: Current Therapy in Neurologic Disease (7/E)
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almost certain that one of your colleagues may be able to help with a new approach. Therefore, referral to a specialized center should be considered for the difficultto-manage patientthere is always something more to be done in controlling chronic pain. PATIENT RESOURCES
American Pain Society 4700 W. Lake Avenue Glenview, IL 60025 Phone: 847-375-4715 http://www.ampainsoc.org/ American Academy of Pain Medicine 4700 W. Lake Avenue Glenview, IL 60025 Phone: 847-375-4731 http://www.painmed.org/ International Association for the Study of Pain 909 NE 43rd Street, Suite 306 Seattle, WA 98105 Phone: 206-547-6409 http://www.iasp-pain.org/

Jacob P. Schwarz, M.D., and Neal J. Naff, M.D.
The imprecise term failed back syndrome refers broadly to the pain and disability experienced by patients whose back and/or leg pain remains refractory to surgical therapy. The frustration that these patients and their physicians experience when therapy fails can sour the patient-physician relationship and discourages many physicians from accepting the therapeutic challenge that these patients present. In every case, it is essential to determine the following about the patients prior surgical treatment: (1) Was surgical intervention indicated? and (2) Did the surgical intervention adequately treat the offending pathology? The answers to these questions will direct the appropriate work-up and treatment (Figure 1). We present here our therapeutic strategy for patients with failed back syndrome.
Initial Evaluation
Many patients who suffer from failed back syndrome have not received the diagnosis or treatment most appropriate for their constellation of symptoms. A thorough review of the patients initial history, physical examination, past imaging studies, and previous therapeutic interventions are crucial to developing the most effective treatment plan for these patients. The physical examination should include observation of muscle bulk and tone; symmetry of strength; sensation to light touch, pain, temperature, and joint position; reflexes; gait; posture; tension signs; and the range of motion of the back and legs. Perineal sensation,
a postvoid residual, and rectal tone should be examined if the history suggests injury to the sacral roots. Data regarding the onset of the pain, the circumstances provoking it, its distribution, any patterns of radiation, the effect of various postures, and ameliorating factors are particularly important aspects of the history. Pain originating in the hip joint may radiate to the low back, buttock, and groin. Hip pathology is a frequent mimic of low back pain associated with leg pain. An assessment of hip motion and tenderness should be part of every examination to evaluate back and leg pain. In the case of hip pathology, the examiner can usually provoke the patients pain with abduction, flexion, and external rotation of the hip. Tenderness over the trochanteric bursa should also be evaluated. Pain in the legs that occurs at a reproducible duration of leg activity and disappears immediately on rest is indicative of vascular disease. Neurogenic claudication from lumbar stenosis occurs at a less reproducible duration of leg activity in an erect posture. The pain may not occur at all if the patient is in a flexed posture. Typically patients with neurogenic claudication report they can walk for much longer distance if they are pushing a grocery cart. Less frequently, they may report that stationary biking does not cause the leg pain they experience when walking. Peripheral neuropathy occurs frequently in the same patient population susceptible to neurogenic claudication but is not activity dependent. Appropriate consultations should be made for those patients suspected of having vascular claudication, peripheral neuropathy, or hip pathology. These are the most frequently missed diagnosis in patients with failed back syndrome. If the commonly missed diagnoses are ruled out by history and physical examination, then sources of pain other than might not have been addressed by the patients surgical intervention should be sought. A commonly misapplied surgical intervention is lumbar laminectomy for the treatment of back pain. Patients with lumbar facet arthritis, by definition, have some radiographic evidence of lumbar stenosis. Many of those patients, however, do not have any leg pain consistent with neurogenic claudication. All too frequently, those patients may have a lumbar laminectomy for their back pain in spite of the fact that there is no anatomic reason to expect that decompressing asymptomatic compressed nerve roots will reduce the back pain associated with inflamed and degenerative facet joints. Weight loss and physical therapy, particularly water aerobics, may relieve the inciting stress on the affected facets. Failing these, more appropriate therapy for facet arthropathy would be facet joint injections with cortisone and facet median nerve rhizotomy. Psychological evaluation is critical to successful therapy in many cases. The use of psychotherapy must be introduced carefully and with sensitivity. Certainly there are patients with underlying psychopathology who develop back pain. In these circumstances, awareness of certain psychiatric vulnerabilities, such as drug dependency, may help tailor an appropriate treatment plan for each patient. The sequelae of failed back syndrome can have devastating results to the patients psyche. Appropriate psychotherapy can improve the chances
58
almost certain that one of your colleagues may be able to help with a new approach. Therefore, referral to a specialized center should be considered for the difficultto-manage patientthere is always something more to be done in controlling chronic pain. PATIENT RESOURCES
American Pain Society 4700 W. Lake Avenue Glenview, IL 60025 Phone: 847-375-4715 http://www.ampainsoc.org/ American Academy of Pain Medicine 4700 W. Lake Avenue Glenview, IL 60025 Phone: 847-375-4731 http://www.painmed.org/ International Association for the Study of Pain 909 NE 43rd Street, Suite 306 Seattle, WA 98105 Phone: 206-547-6409 http://www.iasp-pain.org/

Jacob P. Schwarz, M.D., and Neal J. Naff, M.D.
The imprecise term failed back syndrome refers broadly to the pain and disability experienced by patients whose back and/or leg pain remains refractory to surgical therapy. The frustration that these patients and their physicians experience when therapy fails can sour the patient-physician relationship and discourages many physicians from accepting the therapeutic challenge that these patients present. In every case, it is essential to determine the following about the patients prior surgical treatment: (1) Was surgical intervention indicated? and (2) Did the surgical intervention adequately treat the offending pathology? The answers to these questions will direct the appropriate work-up and treatment (Figure 1). We present here our therapeutic strategy for patients with failed back syndrome.
Initial Evaluation
Many patients who suffer from failed back syndrome have not received the diagnosis or treatment most appropriate for their constellation of symptoms. A thorough review of the patients initial history, physical examination, past imaging studies, and previous therapeutic interventions are crucial to developing the most effective treatment plan for these patients. The physical examination should include observation of muscle bulk and tone; symmetry of strength; sensation to light touch, pain, temperature, and joint position; reflexes; gait; posture; tension signs; and the range of motion of the back and legs. Perineal sensation,
a postvoid residual, and rectal tone should be examined if the history suggests injury to the sacral roots. Data regarding the onset of the pain, the circumstances provoking it, its distribution, any patterns of radiation, the effect of various postures, and ameliorating factors are particularly important aspects of the history. Pain originating in the hip joint may radiate to the low back, buttock, and groin. Hip pathology is a frequent mimic of low back pain associated with leg pain. An assessment of hip motion and tenderness should be part of every examination to evaluate back and leg pain. In the case of hip pathology, the examiner can usually provoke the patients pain with abduction, flexion, and external rotation of the hip. Tenderness over the trochanteric bursa should also be evaluated. Pain in the legs that occurs at a reproducible duration of leg activity and disappears immediately on rest is indicative of vascular disease. Neurogenic claudication from lumbar stenosis occurs at a less reproducible duration of leg activity in an erect posture. The pain may not occur at all if the patient is in a flexed posture. Typically patients with neurogenic claudication report they can walk for much longer distance if they are pushing a grocery cart. Less frequently, they may report that stationary biking does not cause the leg pain they experience when walking. Peripheral neuropathy occurs frequently in the same patient population susceptible to neurogenic claudication but is not activity dependent. Appropriate consultations should be made for those patients suspected of having vascular claudication, peripheral neuropathy, or hip pathology. These are the most frequently missed diagnosis in patients with failed back syndrome. If the commonly missed diagnoses are ruled out by history and physical examination, then sources of pain other than might not have been addressed by the patients surgical intervention should be sought. A commonly misapplied surgical intervention is lumbar laminectomy for the treatment of back pain. Patients with lumbar facet arthritis, by definition, have some radiographic evidence of lumbar stenosis. Many of those patients, however, do not have any leg pain consistent with neurogenic claudication. All too frequently, those patients may have a lumbar laminectomy for their back pain in spite of the fact that there is no anatomic reason to expect that decompressing asymptomatic compressed nerve roots will reduce the back pain associated with inflamed and degenerative facet joints. Weight loss and physical therapy, particularly water aerobics, may relieve the inciting stress on the affected facets. Failing these, more appropriate therapy for facet arthropathy would be facet joint injections with cortisone and facet median nerve rhizotomy. Psychological evaluation is critical to successful therapy in many cases. The use of psychotherapy must be introduced carefully and with sensitivity. Certainly there are patients with underlying psychopathology who develop back pain. In these circumstances, awareness of certain psychiatric vulnerabilities, such as drug dependency, may help tailor an appropriate treatment plan for each patient. The sequelae of failed back syndrome can have devastating results to the patients psyche. Appropriate psychotherapy can improve the chances
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Pain
Review initial history and diagnostic imaging
Yes
Was the initial surgery indicated?
No
Did the surgery adequately address the pathology?
Is there lumbar pathology that was not addressed?
Yes
No Re-operate
Yes Address pathology: Facet arthropathy blocks, rhizotomy Lumbar instability spinal fusion Lumbar stenosis spinal decompression
No
Is there additional pathology?
Is extra-spinal pathology present? No Nonoperative pain management Yes Address pathology: Hip arthritis Vascular disease Peripheral neuropathy No Nonoperative pain management
Yes Address pathology: Arachnoiditis spinal cord stimulator Lumbar instability spinal fusion
Consider: Nerve/nerve root injury Spinal cord stimulator Implantable drug pump FIGURE 1. Flowsheet synopsis of our approach to the work-up of failed back surgery syndrome.
that this patient will successfully comply with other treatment strategies and learn the coping mechanisms necessary to regain a reasonable quality of life. A careful review of the initial and most recent diagnostic imaging is also necessary. Plain radiographs provide important information about bone density, spinal alignment, and fractures. Standing, sitting, supine, standing flexion, and standing in extension radiographs provide invaluable information about the spine and how it changes in response to stress that is not available from any other studies. A spine that appears to have a normal radiographic appearance when the patient is standing erect may move out of alignment on flexion or extension. Disk spaces may collapse under different stresses evoked by differences in posture. In such cases mechanical instability may be provoking pain that would respond to surgical intervention. Computed tomography (CT) scans provide similar information to plain radiographs but allow for three-dimensional reconstruction and investigation. This illuminates problems related to joint hypertrophy, calcified ligaments, and osteophytes in the spinal canal or foramen that cannot be seen on plain radiograph. Finally, magnetic resonance imaging (MRI) captures data about connective tissues such as disk material, ligaments, and abnormal masses that
might change the architecture of the spinal column and provoke pain. It is important that all patients with failed back syndrome have an MRI with and without contrast. The contrast component of the imaging is necessary to distinguish between recurrent disk herniation and postsurgical scarring. Contrast administration is also important for the thorough evaluation for arachnoiditis.
Treatment Options
SURGICAL INTERVENTION: OPERATION AND REOPERATION Was the Surgical Intervention Indicated? To determine if the patients initial surgery was indicated, the following factors should be present. First, the patient should have had a complaint that is reliably attributable to a structural problem. Second, there should be a structural abnormality on the initial diagnostic imaging that explained the patients complaint. Third, the surgical procedure performed must have been appropriate to treat the responsible structural abnormality. In the absence of these criteria, the patients surgical intervention was misguided and was destined
60
to fail. It is also a near certainty that a repeat of the same operation in this situation will also be destined to fail. If Surgery Was Indicated, Did the Surgical Intervention Adequately Treat the Pathology? It might be the case that the previous surgery failed in the presence of a surgically correctable abnormality because the wrong surgery was performed or because the appropriate surgical procedure failed or partly failed to treat the offending pathology. Common examples of the latter are residual herniated lumbar disk material or foraminal stenosis that continues to compress one or more nerve roots. In these situations the most reasonable intervention would be another operative attempt to correct the offending pathology. In these cases, repeat surgery, when properly directed at specific findings and complaints, is often successful. Success rates for reoperation vary with each report. Large series report success rates in the range of 30% to 50%. Certain features predict better outcomes. Females do better than males. Those with fewer prior surgeries are more likely to benefit from reoperation than those with multiple unsuccessful attempts. Those who have evidence of epidural scarring from previous operations are more likely to encounter bad outcomes as are those involved in litigation related to their back pain. The patient must be made aware that the risk of perioperative complications increases with reoperation and the efficacy slightly decreases. A more complicated situation is persistent lumbar instability after a lumbar fusion operation. Lumbar fusions have a mixed history of success. Most wellconducted clinical studies demonstrate no better than a 60% success rate. Therefore, 4 of 10 patients that have that operation will not benefit regardless of the technical success of the procedure. Reoperation for persisting back pain following a fusion procedure should be cautiously considered, particularly if there is no clear technical problem with the fusion construct. NO SURGICALLY CORRECTABLE PATHOLOGY PRESENT: OPTIONS WHEN NO SURGERY IS INDICATED If the determination is made that surgical intervention was not indicated, the etiology of the patients initial complaint must be determined through a careful history and physical examination. The history should reveal the specific features about the original pain that the patient had suffered and the pain that the patient experienced subsequent to each surgical intervention. This information will give important insights to the original etiology of the back pain and help to direct nonoperative therapies that might be of benefit. Physical Therapy and Rehabilitation All patients with chronic disabling back pain should be referred for physical therapy and rehabilitation regardless of other concordant therapies. Physical therapy is
important for strengthening, increasing flexibility, and helping patients learn strategies to more efficiently and safely increase their activity. Reasonable exercise has been shown not only to be safe for patients with chronic back pain but to lead to reduction in pain magnitude of 10% to 50%. Lumbar Facet Denervation Among patients whose pain is consistent with lumbar facet joint disease, facet denervation can provide measurable relief. As facet joints degenerate with time, arthritis, or instability, they gradually endure more stress and wear. This is often noticeable on diagnostic imaging where one or both facet joints demonstrate hypertrophy. These enlarged facets may cause stenosis of the lateral recess of the spinal canal and the neural foramen that contributes to radiculopathy from nerve root compression. In other cases, no radiculopathy is present, but instead severe axial back pain with radiation to the flank and hip. If this pain is worst with standing and lumbar extension, it may be that irritation of the nerves of the affected facet joints is responsible for the offending pain. When appropriately used, radiofrequency ablation of the median nerve of the facet can provide 45% to 50% of patients at least a 50% reduction in pain. Spinal Cord Stimulation Spinal cord stimulation provides pain relief by confusing the pain signaling pathways. A stimulator electrode placed over the dorsal columns of the spinal cord causes a mild vibratory sense over the dermatomes it stimulates. When targeted to the region afflicted by pain, a discomforting sensation can be overwhelmed by the vibrating sensation triggered by the stimulator. In this fashion, a constant unbearable sensation is replaced by a pleasing tingling sensation. Stimulator electrodes are designed in such a fashion that selected contact points along the electrode surface may have varying intensity. This allows the effect of the stimulator to be targeted to specific regions of the spinal cord and for the intensity of that effect to be modulated selectively. To ensure that a spinal cord stimulator will be worthwhile and to identify the ideal settings for the stimulator, surgeons conduct a temporary trial of stimulation prior to implanting it permanently. The trial uses a percutaneously placed epidural electrode that is then attached to an external computer. Over the course of the next few days, the patient is able to modulate the stimulator intensities and stimulation pattern. If an efficacious and tolerable combination arises, the surgeon then implants a permanent system. If the patient does not experience any benefit from the temporary stimulator, the electrode is simply removed and no surgery is necessary. Although this technique works best for lower extremity pain, there are many clinical series that report success with the treatment of axial back pain. Again, with careful selection, most patients receive significant pain relief from spinal cord stimulation, and as many as 78% would have the procedure again and recommend it
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Pain
to another patient. Spinal cord stimulation is an increasingly valuable long-term solution for chronic low back pain. Implantable Drug Pumps Intrathecal or epidural administration of opioids and other pharmaceuticals has been used in the treatment of chronic low back pain with mixed success. Although the use of intrathecal drug therapy has been shown to be cost effective in the long term, patient satisfaction has been erratic from one study to the next. Most studies of implantable drug delivery are retrospective and most success has been anecdotal. Further investigation is necessary to establish which patients with failed back syndrome are most likely to benefit from this therapy.
neurosurgeons, a thoughtful methodical evaluation and treatment plan may provide benefit and ensure that all that can be done is offered for these patients. SUGGESTED READING
Kumar K, Hunter G, Demeria DD: Treatment of chronic pain by using intrathecal drug therapy compared with conventional pain therapies: a cost-effectiveness analysis, J Neurosurg 97:803-810, 2002. Loubser PG, Akman NM: Effects of intrathecal baclofen on chronic spinal cord injury pain, J Pain Symptom Manage 12:241-247, 1996. North RB, Han M, Zahurak M, Kidd DH: Radiofrequency lumbar facet denervation: analysis of prognostic factors, Pain 57:77-83, 1994. North RB, Wetzel FT: Spinal cord stimulation for chronic pain of spinal origin: a valuable long-term solution, Spine 27:2584-2591, 2002. Ohnmeiss DD, Rashbaum RF: Patient satisfaction with spinal cord stimulation for predominant complaints of chronic, intractable low back pain, Spine J 1:358-363, 2001. Rainville J, Hartigan C, Martinez E, et al: Exercise as a treatment for chronic low back pain, Spine J 4:106-115, 2004. Royal M, Wienecke G, Movva V, et al: Retrospective study of efficacy of radiofrequency neurolysis for facet arthropathy, Pain Med 2:249-250, 2001. Schwarz J, Naff N: The management of neuropathic pain, Neurosurg Clin North Am 15:231-239, 2004. van Kleef M, Barendse GA, Kessels A, et al: Randomized trial of radiofrequency lumbar facet denervation for chronic low back pain, Spine 24:1937-1942, 1999. Yoshida GM, Nelson RW, Capen DA, et al: Evaluation of continuous intraspinal narcotic analgesia for chronic pain from benign causes, Am J Orthop 25:693-694, 1996.
Conclusions
Failed back syndrome is an all-too-common problem that is disabling, demoralizing, and disruptive to a patients quality of life. A careful history of the patients initial presentation and review of the initial diagnostic studies are necessary to determine the pathology that led to the initial symptoms. Every attempt should be made to identify the initial source of the pain, and if it is determined that the initial intervention was not indicated, appropriate treatment should be offered. This may require investigation and treatment for hip pathology, vascular disease, or peripheral neuropathy. If it is determined that the patient did have a surgically remediable problem, then it must be determined if the surgical intervention adequately treated that problem. If the wrong surgical intervention was chosen initially, the best course would be to offer the patient the appropriate surgical intervention. A frequent example of this situation is the use of lumbar laminectomy for back pain when facet joint injections or median facet nerve rhizotomy would be more appropriate. If the correct surgical intervention was performed initially, then it must be determined if that intervention adequately treated the offending pathology. If the initial procedure did not adequately treat the offending pathology, then a second attempt at the same procedure would likely be the most appropriate treatment. A frequent example of this situation would be residual disk herniation or foraminal stenosis compressing a nerve root. A repeat diskectomy or foraminotomy in this situation has a high likelihood of success. If it is determined that the initial operation was indicated and that there is no residual pathology that is surgically remediable, it is then advisable that the patient pursue a comprehensive pain management program under the direction of a physician with experience in chronic pain management. A frequent example of this last situation is patients with radiculitis from pathologic or iatrogenic intrinsic nerve root injury. If these patients are inadequately treated by pharmaceutical pain management strategies, they may be ideal candidates for spinal cord stimulation or implantable morphine pumps. Although failed back syndrome is one of the more frustrating problems that confronts neurologists and
CERVICAL SPONDYLOSIS
Erick Scott, M.D., and Douglas Kerr, M.D., Ph.D.
Cervical spondylosis is defined as a degenerative condition compromising the spinal canal. It is an inevitable consequence of aging and is present in more than 90% of individuals older than 65 years of age. As such, it is a natural consequence of a bipedal existence and is not a disease state. However, this degenerative process may cause symptoms in up to 10% to 15% of the population and therefore is among the most common causes of patient visits to health care providers. Cervical spondylosis may cause symptoms of neck pain and restricted movement due to mechanical limitation, radicular pain and paresthesias due to compression of nerve roots, or myelopathic symptoms due to compression of the spinal cord itself. This chapter reviews the most recent advances in the diagnosis and treatment of cervical spondylosis.
Definition and Clinical Manifestations

Cervical spondylosis may cause one of three syndromes: radiculopathy, myelopathy, or mechanical neck pain. Radiculopathy is due to nerve root compression, usually from the progressive narrowing of a neural foramen, caused by hypertrophic bony changes in the anterior
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Pain
to another patient. Spinal cord stimulation is an increasingly valuable long-term solution for chronic low back pain. Implantable Drug Pumps Intrathecal or epidural administration of opioids and other pharmaceuticals has been used in the treatment of chronic low back pain with mixed success. Although the use of intrathecal drug therapy has been shown to be cost effective in the long term, patient satisfaction has been erratic from one study to the next. Most studies of implantable drug delivery are retrospective and most success has been anecdotal. Further investigation is necessary to establish which patients with failed back syndrome are most likely to benefit from this therapy.
neurosurgeons, a thoughtful methodical evaluation and treatment plan may provide benefit and ensure that all that can be done is offered for these patients. SUGGESTED READING
Kumar K, Hunter G, Demeria DD: Treatment of chronic pain by using intrathecal drug therapy compared with conventional pain therapies: a cost-effectiveness analysis, J Neurosurg 97:803-810, 2002. Loubser PG, Akman NM: Effects of intrathecal baclofen on chronic spinal cord injury pain, J Pain Symptom Manage 12:241-247, 1996. North RB, Han M, Zahurak M, Kidd DH: Radiofrequency lumbar facet denervation: analysis of prognostic factors, Pain 57:77-83, 1994. North RB, Wetzel FT: Spinal cord stimulation for chronic pain of spinal origin: a valuable long-term solution, Spine 27:2584-2591, 2002. Ohnmeiss DD, Rashbaum RF: Patient satisfaction with spinal cord stimulation for predominant complaints of chronic, intractable low back pain, Spine J 1:358-363, 2001. Rainville J, Hartigan C, Martinez E, et al: Exercise as a treatment for chronic low back pain, Spine J 4:106-115, 2004. Royal M, Wienecke G, Movva V, et al: Retrospective study of efficacy of radiofrequency neurolysis for facet arthropathy, Pain Med 2:249-250, 2001. Schwarz J, Naff N: The management of neuropathic pain, Neurosurg Clin North Am 15:231-239, 2004. van Kleef M, Barendse GA, Kessels A, et al: Randomized trial of radiofrequency lumbar facet denervation for chronic low back pain, Spine 24:1937-1942, 1999. Yoshida GM, Nelson RW, Capen DA, et al: Evaluation of continuous intraspinal narcotic analgesia for chronic pain from benign causes, Am J Orthop 25:693-694, 1996.
Conclusions
Failed back syndrome is an all-too-common problem that is disabling, demoralizing, and disruptive to a patients quality of life. A careful history of the patients initial presentation and review of the initial diagnostic studies are necessary to determine the pathology that led to the initial symptoms. Every attempt should be made to identify the initial source of the pain, and if it is determined that the initial intervention was not indicated, appropriate treatment should be offered. This may require investigation and treatment for hip pathology, vascular disease, or peripheral neuropathy. If it is determined that the patient did have a surgically remediable problem, then it must be determined if the surgical intervention adequately treated that problem. If the wrong surgical intervention was chosen initially, the best course would be to offer the patient the appropriate surgical intervention. A frequent example of this situation is the use of lumbar laminectomy for back pain when facet joint injections or median facet nerve rhizotomy would be more appropriate. If the correct surgical intervention was performed initially, then it must be determined if that intervention adequately treated the offending pathology. If the initial procedure did not adequately treat the offending pathology, then a second attempt at the same procedure would likely be the most appropriate treatment. A frequent example of this situation would be residual disk herniation or foraminal stenosis compressing a nerve root. A repeat diskectomy or foraminotomy in this situation has a high likelihood of success. If it is determined that the initial operation was indicated and that there is no residual pathology that is surgically remediable, it is then advisable that the patient pursue a comprehensive pain management program under the direction of a physician with experience in chronic pain management. A frequent example of this last situation is patients with radiculitis from pathologic or iatrogenic intrinsic nerve root injury. If these patients are inadequately treated by pharmaceutical pain management strategies, they may be ideal candidates for spinal cord stimulation or implantable morphine pumps. Although failed back syndrome is one of the more frustrating problems that confronts neurologists and
CERVICAL SPONDYLOSIS
Erick Scott, M.D., and Douglas Kerr, M.D., Ph.D.
Cervical spondylosis is defined as a degenerative condition compromising the spinal canal. It is an inevitable consequence of aging and is present in more than 90% of individuals older than 65 years of age. As such, it is a natural consequence of a bipedal existence and is not a disease state. However, this degenerative process may cause symptoms in up to 10% to 15% of the population and therefore is among the most common causes of patient visits to health care providers. Cervical spondylosis may cause symptoms of neck pain and restricted movement due to mechanical limitation, radicular pain and paresthesias due to compression of nerve roots, or myelopathic symptoms due to compression of the spinal cord itself. This chapter reviews the most recent advances in the diagnosis and treatment of cervical spondylosis.
Definition and Clinical Manifestations

Cervical spondylosis may cause one of three syndromes: radiculopathy, myelopathy, or mechanical neck pain. Radiculopathy is due to nerve root compression, usually from the progressive narrowing of a neural foramen, caused by hypertrophic bony changes in the anterior
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wall. Although the foraminal compromise is gradual, symptoms may be of sudden onset, often precipitated by a particular event such as a motor vehicle accident, a fall, or an exercise-induced injury. It is likely that the sudden nature of symptom onset is due to microtrauma, stretching or tethering of a nerve root, or inflammation within an already compromised neural foramina. Symptoms usually consist of neck pain and stiffness that evolve to include pain, paresthesias, numbness, and weakness in one arm. Neurologic examination usually reveals sensory loss and weakness in a nerve root distribution and may reveal an accompanying decrease in a deep tendon reflex (biceps reflex for C6 radiculopathy, triceps reflex for C7 radiculopathy). Cervical spondylitic myelopathy results from compression of the spinal cord, anteriorly by bony structures of the vertebral body and facets, or posteriorly by ligamentum flavum hypertrophy. Symptoms usually progress insidiously and can often be present for years prior to seeking medical attention. Occasionally, a relatively minor trauma, such as a hyperextension injury from a fall or a motor vehicle accident, precipitates sudden and severe myelopathic symptoms. Symptoms usually consist of gait difficulty and stiffness. Gait dysfunction may result from abnormal proprioceptive input due to compression of ascending sensory pathways or may be due to evolving spasticity due to compression of descending motor pathways. Bowel and bladder involvement, usually consisting of urgency, is associated with inconsistent symptoms and, if present, suggests a more advanced myelopathy. Examination findings usually consist of spasticity, hyperreflexia, and Babinskis response. Since cervical spondylitic myelopathy typically affects C6 or C7, there may be relative sparing of arm function and there may be a discord between the reflexes and tone of the upper and lower extremities. Mechanical pain due to cervical spondylosis is the most common of the three syndromes, though it is the least clearly understood and defined. In part, this is because there is poor correlation between radiologically defined spondylosis and neck pain. Also, there is no examination finding (e.g., paraspinalis spasm, limitation of neck motion or reflex asymmetry) that defines this syndrome. Typically, patients describe localized pain in the neck without radiation and often limitation in range of motion of the neck or clicks during neck movement. The pain itself likely comes from a variety of sources: new bone generation in the facets or vertebral bodies, myofascial changes, muscular spasm or the degenerating disk (diskogenic pain).
Stage 3: bridging osteophytes with immobilization of the involved segment Stage 4: compression of the spinal cord Recent studies have suggested that the dynamic nature of the cervical spinal cord is an important predictor of disability and that flexion and extension studies must be incorporated into this scheme. Magnetic resonance imaging (MRI) studies and plain radiographs done in the neutral position often do not effectively define spinal canal compromise in either the flexed or extended positions. In this study, 27% of patients in the extended position and 5% of patients in the flexed position experienced worsened spinal canal compromise compared to a neutral-position MRI. Therefore, we recommend a dynamic MRI or computed tomography (CT) myelogram to accurately evaluate cervical spondylosis.
Pathophysiology of Cervical Spondylosis

Cervical spondylosis occurs in response to dehydration or degeneration of intervertebral disks that begins in young adulthood. As a result of this degeneration, adjacent bony structures acquire new stresses as the spinal column is subjected to the dynamic movement of normal life. The disks themselves become less capable of load bearing and transfer this load to facet joints and vertebral bodies. In places where the degeneration is most advanced, adjacent bony structures contact each other, generating new bone. This results in osteophytes, bony ridges, and spurs. Additionally, the ligamentum flavum hypertrophies posterior to the spinal cord. The consequence is narrowing of the spinal canal with impingement of nerve roots or the spinal cord. If the spinal cord is compressed, myelopathic symptoms develop. If nerve roots are compressed, radicular symptoms develop. Pain may be a prominent symptom of cervical spondylosis even in the absence of neural compromise due to mechanical dysfunction.
Pathophysiology of Spondylitic Myelopathy

In some cases of spondylitic myelopathy, a dynamic compression of the spinal cord occurs. During flexion or extension of the spinal cord, a spondylitic spur compresses the spinal cord, resulting either in a direct contusion or in impaired venous drainage out of the spinal cord. Many patients demonstrate a central, high T2-weighted signal intensity on MRI. Recent studies have demonstrated that this central spinal cord abnormality represents cystic necrosis resulting from venous hypertension. Venous drainage of the spinal cord occurs via both intrinsic and extrinsic spinal cord veins. The intrinsic spinal cord veins consist of an anterior median group and a radial group. Blood in the anterior third of the spinal cord drains to the segmental central vein, then to the longitudinally oriented anterior median spinal vein, which lies on the pial surface of the spinal
Classification
Several classification schemes exist to quantify the degree of cervical spondylosis. These stages are defined as follows: Stage 1: diskogenic phase without osteophyte formation Stage 2: spondylosis with disk degeneration and osteophyte formation
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cord in the midline. The radial veins form in the peripheral gray matter or white matter and drain radially to the coronal plexus of veins on the pial surface. The anterior median spinal vein and the coronal plexus (termed the extrinsic venous drainage) are drained by the medullary veins that travel with nerve roots. Anterior medullary veins travel with the ventral roots, while posterior medullary veins travel with the dorsal roots. In the intervertebral foramen, a number of veins, including the anterior and posterior medullary veins, veins from the vertebral plexus, and the radicular veins, coalesce to form a plexus surrounding the spinal nerve. Appreciation of this anatomy is critical to understand how spondylitic myelopathy develops.
Diagnosis
The diagnosis of cervical spondylitic myelopathy or radiculopathy is dependent on the clinical symptoms confirmed by a detailed neurologic examination. The diagnosis of spondylitic radiculopathy can be confirmed by cervical spine radiographs. Oblique views, which are aimed to look down the neural foramina, demonstrate the encroachment by osteophytes from the anterior wall. Spiral CT scanning, especially with two-dimensional sagittal reconstructions, can also confirm foraminal stenosis. MRI images are less helpful in spondylitic radiculopathies. For spondylitic myelopathy, an MRI of the neck in neutral, extended, and flexed position is recommended (no gadolinium needed). If the anterior and posterior cerebrospinal fluid (CSF) spaces remain patent in all sequences, then conservative management is likely warranted. If the anterior and/or the posterior CSF space is impinged, especially if there is a pincer effect (anterior and posterior compression at nearby levels), then neurosurgical consultation is warranted. Cord signal change necessitates urgent neurosurgical referral.
symptoms. In a recent study, only 20% of patients experienced significant relief of symptoms. Mechanical pain from cervical spondylosis should be treated by heating pads and by stretching range-ofmotion exercises. Most patients respond well to no-no stretching of the neck for five seconds at each limit; yes-yes stretching of the neck for 5 seconds at each limit; and ear-to shoulder stretching of the neck for 5 seconds at each limit. Chiropractic therapy is often used by patients with cervical spondylosis, though there are no controlled studies that warrant this approach. Recent uncontrolled reports suggest that chiropractic manipulations may be beneficial. However, though chiropractic manipulation may be appropriate for uncomplicated mechanical pain associated with cervical spondylosis, chiropractic manipulations are not recommended for either radicular or myelopathic symptoms and may cause adverse outcomes in such patients. Shiatsu (deep massage) and acupuncture therapies are often employed by patients with anecdotally excellent response and little risk. SURGICAL APPROACH Patients with spondylitic myelopathy or radiculopathy are often offered surgical treatment that typically consists of either anterior cervical decompressions with fusion and/or instrumentation or posterior cervical laminectomy or laminoplasty. The data to support surgical intervention remain mixed. In a nonrandomized, prospective study of patients with cervical spondylitic myelopathy, surgically treated patients had a significant improvement in functional status and pain, whereas medically treated patients were worse in these areas. In a separate report, cervical laminectomy or laminoplasty was successfully used to decrease symptoms in patients with spondylitic myelopathy. Although patients younger than 65 years of age did well in the short term, they had significant deterioration between 3 and 10 years after surgery. A randomized study designed to define whether patients with mild-to-moderate spondylitic myelopathy did better with conservative or surgical treatment revealed no clear difference between the groups at 3 years follow-up. A recent Cochrane review suggested that there was not sufficient evidence from controlled trials to support surgical treatment of patients with spondylitic radiculopathy or myelopathy. Patients with persistent cord signal change after surgery had worse outcomes. T1-weighted hypointensities predicted a worse outcome.
Treatment
CONSERVATIVE MANAGEMENT For spondylitic radiculopathy, conservative measures should be attempted first. Simple soft collar immobilization often is helpful because it decreases repetitive motion and microtrauma that have precipitated the symptoms. The most effective method is the use of over-the-door cervical traction. Patients can do this at home with the use of a head halter attached to a rope that passes through a pulley set over the top of a door and is connected to a water bag for weight (5 to 10 lb). Patients should sit facing the door (to avoid hyperextension) for 30 minutes twice a day. Nonsteroidal anti-inflammatory agents and localized massage should also be employed in patients with spondylitic radiculopathy. Patients often are offered selective nerve root block for spondylitic radiculopathy. However, this approach usually results in only temporary improvement in
Outcomes
Although the outcomes from cervical spondylosis vary and the treatment of choice remains uncertain, the following guidelines apply: Patients with mechanical pain from spondylosis should have conservative therapy as defined earlier. Patients with spondylitic radiculopathy should be given conservative therapy, including cervical traction and
64
soft collar immobilization, and only later should be offered a surgical treatment. Patients with rapidly progressive spondylitic myelopathy and a clearly defined compressive etiology (either direct compression or impaired venous drainage) should be rapidly offered surgical decompression. The optimal surgical technique (laminectomy, laminoplasty, or anterior decompression with fusion/instrumentation) depends on the dynamic compressive states present. Long-term consequences of surgery remain unknown and depend on the degree of destabilization/compression of other segments of the spinal column. SUGGESTED READING
Epstein NE: Laminectomy for cervical myelopathy, Spinal Cord 41:317-327, 2003. Fouyas IP, Statham PF, Sandercock PA: Cochrane review on the role of surgery in cervical spondylitic radiculomyelopathy, Spine 27:736-747, 2002. Gillilan LA: Veins of the spinal cord: anatomic details, suggested clinical applications, Neurology 20:860-868, 1970. Handal JA, Knapp J Poletti S. The structural degenerative cascade: the cervical spine, 1995. Kirkaldy-Willis WH, Bernard TN, editors: Managing low back pain, ed 4, Philadelphia, 1999, Churchill-Livingstone. Kukurin GW: The amelioration of symptoms in cervical spinal stenosis with spinal cord deformation through specific chiropractic manipulation: a case report with long-term follow-up, J Manipulative Physiol Ther 27:E7, 2004. Mizuno J, Nakagawa H, Inoue T, Hashizume Y: Clinicopathological study of snake-eye appearance in compressive myelopathy of the cervical spinal cord, J Neurosurg 99(Suppl):162-168, 2003. Muhle C, Metzner J, Weinert D, et al: Classification system based on kinematic MR imaging in cervical spondylitic myelopathy, AJNR Am J Neuroradiol 19:1763-1771, 1998. Sampath P, Bendebba M, Davis JD, Ducker TB: Outcome of patients treated for cervical myelopathy: a prospective, multicenter study with independent clinical review, Spine 25:670-676, 2000. Slipman CW, Lipetz JS, DePalma MJ, Jackson HB: Therapeutic selective nerve root block in the nonsurgical treatment of traumatically induced cervical spondylitic radicular pain, Am J Physical Med Rehabil 83:446-454, 2004.
associated with nonspecific symptoms and signs such as altered skin color, temperature, or sudomotor activity, allodynia, disuse atrophy, or edema; and, in contrast with CRPS type 2 (formerly called causalgia), occurs in a distribution different from that resulting from injury to a single peripheral nerve. In many cases CRPS syndromes resolve over weeks or months. Even so, the unexpected finding of persistent, worsening pain, often after seemingly minor trauma or brief limb immobilization, poses a significant psychological challenge that the clinician must keep in mind from the beginning of treatment to avoid a vicious circle of pain, distress, guarding, muscle atrophy, and increased pain susceptibility. At all stages of treatment (Figure 1), effective management of CRPS depends on a threepronged approachrehabilitation, psychological support, and medicinal agentsprobably in descending order of importance. The cornerstone of management of CRPS is physical and occupational therapy. Improvement often requires a closely supervised program of continued and increasing activity of the affected limb, while the patient is under the influence of an analgesic if necessary. In additional to active exercise of the limb, physical therapy approaches can include desensitization, where progressively coarser objects are rubbed across the skin of the affected limb; spinal manipulation; myofascial
CRPS Physical therapy (e.g., active mobilization, desensitization, myofascial release) NSAID Lidocaine patch/capsaicin (local only) Corticosteroids (early only)
Resolved
Unresolved Sympathetically maintained?
Yes Sympatholytic trial e.g., clonidine, terazosin, tizanidine
No Gabapentin Opiate Mexiletine (if acute benefit from i.v. lidocaine)

Resolved
Unresolved
Resolved
Unresolved
Opiate tricyclic
Resolved
Unresolved Spinal cord stimulation trial
Complex regional pain syndromes (CRPSs) come under the classification of neuropathic pain, along with entities such as postherpetic neuralgia and painful diabetic neuropathy. Distinguishing characteristics of CRPS are onset after physical trauma or limb immobilization and spread of involvement. CRPS type 1, formerly called reflex sympathetic dystrophy, refers to post-traumatic pain that spreads from the site of injury; exceeds in magnitude and duration the expected clinical course of the inciting event; progresses variably over time; is
Acute improvement Spinal cord stimulator
Unresolved
FIGURE 1. Treatment algorithm for complex regional pain syndromes. CRPS, Complex regional pain syndrome; NSAID, nonsteroidal anti-inflammatory drug; i.v., intravenous. Johnson: Current Therapy in Neurologic Disease (7/E)
64
soft collar immobilization, and only later should be offered a surgical treatment. Patients with rapidly progressive spondylitic myelopathy and a clearly defined compressive etiology (either direct compression or impaired venous drainage) should be rapidly offered surgical decompression. The optimal surgical technique (laminectomy, laminoplasty, or anterior decompression with fusion/instrumentation) depends on the dynamic compressive states present. Long-term consequences of surgery remain unknown and depend on the degree of destabilization/compression of other segments of the spinal column. SUGGESTED READING
Epstein NE: Laminectomy for cervical myelopathy, Spinal Cord 41:317-327, 2003. Fouyas IP, Statham PF, Sandercock PA: Cochrane review on the role of surgery in cervical spondylitic radiculomyelopathy, Spine 27:736-747, 2002. Gillilan LA: Veins of the spinal cord: anatomic details, suggested clinical applications, Neurology 20:860-868, 1970. Handal JA, Knapp J Poletti S. The structural degenerative cascade: the cervical spine, 1995. Kirkaldy-Willis WH, Bernard TN, editors: Managing low back pain, ed 4, Philadelphia, 1999, Churchill-Livingstone. Kukurin GW: The amelioration of symptoms in cervical spinal stenosis with spinal cord deformation through specific chiropractic manipulation: a case report with long-term follow-up, J Manipulative Physiol Ther 27:E7, 2004. Mizuno J, Nakagawa H, Inoue T, Hashizume Y: Clinicopathological study of snake-eye appearance in compressive myelopathy of the cervical spinal cord, J Neurosurg 99(Suppl):162-168, 2003. Muhle C, Metzner J, Weinert D, et al: Classification system based on kinematic MR imaging in cervical spondylitic myelopathy, AJNR Am J Neuroradiol 19:1763-1771, 1998. Sampath P, Bendebba M, Davis JD, Ducker TB: Outcome of patients treated for cervical myelopathy: a prospective, multicenter study with independent clinical review, Spine 25:670-676, 2000. Slipman CW, Lipetz JS, DePalma MJ, Jackson HB: Therapeutic selective nerve root block in the nonsurgical treatment of traumatically induced cervical spondylitic radicular pain, Am J Physical Med Rehabil 83:446-454, 2004.
associated with nonspecific symptoms and signs such as altered skin color, temperature, or sudomotor activity, allodynia, disuse atrophy, or edema; and, in contrast with CRPS type 2 (formerly called causalgia), occurs in a distribution different from that resulting from injury to a single peripheral nerve. In many cases CRPS syndromes resolve over weeks or months. Even so, the unexpected finding of persistent, worsening pain, often after seemingly minor trauma or brief limb immobilization, poses a significant psychological challenge that the clinician must keep in mind from the beginning of treatment to avoid a vicious circle of pain, distress, guarding, muscle atrophy, and increased pain susceptibility. At all stages of treatment (Figure 1), effective management of CRPS depends on a threepronged approachrehabilitation, psychological support, and medicinal agentsprobably in descending order of importance. The cornerstone of management of CRPS is physical and occupational therapy. Improvement often requires a closely supervised program of continued and increasing activity of the affected limb, while the patient is under the influence of an analgesic if necessary. In additional to active exercise of the limb, physical therapy approaches can include desensitization, where progressively coarser objects are rubbed across the skin of the affected limb; spinal manipulation; myofascial
CRPS Physical therapy (e.g., active mobilization, desensitization, myofascial release) NSAID Lidocaine patch/capsaicin (local only) Corticosteroids (early only)
Resolved
Unresolved Sympathetically maintained?
Yes Sympatholytic trial e.g., clonidine, terazosin, tizanidine
No Gabapentin Opiate Mexiletine (if acute benefit from i.v. lidocaine)

Resolved
Unresolved
Resolved
Unresolved
Opiate tricyclic
Resolved
Unresolved Spinal cord stimulation trial
Complex regional pain syndromes (CRPSs) come under the classification of neuropathic pain, along with entities such as postherpetic neuralgia and painful diabetic neuropathy. Distinguishing characteristics of CRPS are onset after physical trauma or limb immobilization and spread of involvement. CRPS type 1, formerly called reflex sympathetic dystrophy, refers to post-traumatic pain that spreads from the site of injury; exceeds in magnitude and duration the expected clinical course of the inciting event; progresses variably over time; is
Acute improvement Spinal cord stimulator
Unresolved
FIGURE 1. Treatment algorithm for complex regional pain syndromes. CRPS, Complex regional pain syndrome; NSAID, nonsteroidal anti-inflammatory drug; i.v., intravenous. Johnson: Current Therapy in Neurologic Disease (7/E)
65
Pain
release; and massage with moist heat. It is important to emphasize to the patient that physical therapy, while painful, does not worsen the injury. The distress associated with prolonged, painful treatment can exacerbate comorbid depression or anxiety; supportive psychological counseling and psychiatric drug treatments may be essential for the patient to cope with the condition and continue the rehabilitation. Psychological treatments such as relaxation, imagery, self-hypnosis, cognitive behavioral therapy, and biofeedback may help. Throughout treatment the patient should be reassured that the condition does not progress to a neurodegenerative or lethal disease and that most people with CRPS improve if they adhere to the rehabilitation program. For local pain and allodynia, topical lidocaine can be effective. Capsaicin, the alkaloid that makes red chili peppers hot, stimulates transient receptor potential vanilloid (TRPV1)-1 receptors on cutaneous nociceptor C-fibers. It is thought that prolonged stimulation of the TRPV-1 receptors suppresses hyperactive nociceptors to alleviate pain without loss of sensation. Although accepted treatment for other neuropathic painful conditions, capsaicin has not yet been established as effective for CRPS. Patients may find the burning sensation produced by capsaicin to be unacceptable. Mysteriously, the pain in CRPS can spread to the opposite limb or the ipsilateral other limb, which were not traumatized. Spread of pain over a relatively large area at sites distant from that of trauma mitigates benefits of local treatments such as with topical lidocaine or capsaicin. Chronic CRPS syndromes constitute miserable, frustrating disordersfor patients and clinicians. Pathophysiologic bases for the pain remain unclear; and since CRPS is a relatively rare consequence of physical trauma, the trauma itself might interact importantly with as yet unidentified predisposing or reactive factors. Recent reviews have emphasized traumatic sympathetic denervation, followed subacutely or chronically by secondary pathologic responses such as aberrant sprouting of regenerant sympathetic nerves. A variable proportion of patients with CRPS have sympathetically maintained pain, where the pain improves temporarily with local stellate ganglion block for an upper limb or lumbar sympathetic block for a lower limb; intravenous (IV) infusion or local injection of the alpha-adrenoceptor blocker, phentolamine; or IV infusion of the ganglion blocker trimethaphan. The finding of sympathetically maintained pain rationalizes a trial of a sympatholytic drug such as clonidine or tizanidine. These alpha2-adrenoceptor agonists act in the brain to decrease sympathetic nervous system outflows and also act at alpha2-adrenoceptors on sympathetic nerves to inhibit release of the sympathetic neurotransmitter, norepinephrine, for a given amount of sympathetic nerve traffic. The main limitation of treatment with alpha2-adrenoceptor agonists is sedation. Alpha1-adrenoceptor blockers such as terazosin may also be tried; however, these can produce substantial orthostatic intolerance or hypotension, headache, flushing, and reflexive tachycardia.
Even in patients with repeated, temporary improvement with ganglion blocks, surgical sympathectomy does not necessarily guarantee long-term pain relief. On the contrary, patients can fail to obtain relief, the pain can recur months or years later, and the pain can spread to other limbs and body regions. By the time of establishment of chronic CRPS, mechanisms relatively independent of postganglionic sympathetic nerve traffic maintain the pain in most patients. In patients without sympathetically maintained pain, the anticonvulsant gabapentin (Neurontin) has become a first-line drug. Gabapentin can be effective to treat postherpetic neuralgia and painful diabetic neuropathy, and some uncontrolled studies have touted its value to treat CRPS. The drug has a relatively low toxicity profile, but there is a wide range of employed dosages, and no randomized, placebo-controlled trial of gabapentin for CRPS has been published yet. The same lack of controlled trials obtains for retrograde local IV injection of sympatholytic drugs, periganglionic injection of local anesthetics, systemically administered alpha-adrenoceptor antagonists, clonidine, tricyclic antidepressants, selective serotonin reuptake inhibitors, other antiepileptic drugs, ganglion blockers, mexiletine (the oral analog of lidocaine), and surgical sympathectomy; studies of these treatments have yielded disappointingly inconsistent results. Tricyclic antidepressants are often tried in CRPS. They not only can relieve pain but also can exert other beneficial effects, such as improving sleep and inducing sedation. Clinical use of tricyclics is often limited by orthostatic intolerance, dry mouth, constipation, or decreased concentration. There is recent interest in serotonin-norepinephrine reuptake inhibitors such as duloxetine in neuropathic pain, but no data are available for CRPS. Most patients with severe, chronic CRPS receive treatment with some type of opiate. Even with highdose opiate treatment, the pain, while more bearable, rarely disappears. Treatment on a continuous rather than an as-needed basis is preferred, and so long-acting agents are used, such as sustained-release oxycodone (Oxycontin), sustained-release morphine (MS Contin), methadone, and a transdermal fentanyl patch (Duragesic). Most authorities now believe that, in the absence of a history of substance abuse, neither tolerance nor addiction is an issue when opiates are prescribed for CRPS. Calcium channel blockers, beta-adrenoceptor blockers, or classic anticonvulsants are not recommended, because of lack of positive clinical experiences and frequent intolerable side effects. Stimulation of the dorsal spinal cord, via an electrode placed in the epidural space, constitutes a different treatment strategy, based on interference with transmission of impulses from the nociceptors. This approach has been used for many years in other painful conditions. A variety of ascending and descending pain pathways converge in or near the dorsal spinal cord, including a descending inhibitory noradrenergic pathway from the pontine locus ceruleus. Exactly how spinal cord stimulation relieves pain remains unclear,
66
and several possible mechanisms are not mutually exclusive. Previous studies have reported positive results of dorsal spinal cord stimulation in alleviating pain in CRPS, especially in patients with successful trial stimulation. A recent report provides reassuring information about the long-term efficacy of spinal cord stimulation. Briefly, in a 2-year follow-up study of a randomized, controlled trial of spinal cord stimulation with physical therapy versus physical therapy alone in patients in whom conventional treatment had failed but who had had a successful test stimulation, there was long-term improvement in pain and health-related quality of life, although functional status did not change. The results confirmed and extended those from a previously reported trial that lasted 6 months. Spinal cord stimulation, therefore, seems to be an effective long-term treatment for CRPS, in patients in whom a trial stimulation alleviates the pain.
SUGGESTED READING
Backonja MM: Anticonvulsants (antineuropathics) for neuropathic pain syndromes, Clin J Pain 16:S67-S72, 2000. Davis KD, Treede RD, Raja SN, et al: Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain, Pain 47:309-317, 1991. Drummond PD: Mechanism of complex regional pain syndrome: no longer excessive sympathetic outflow? Lancet 358:168-170, 2001. Hord ED, Cohen SP, Cosgrove GR, et al: The predictive value of sympathetic block for the success of spinal cord stimulation, Neurosurgery 53:626-632, 2003; discussion 632-633. Kemler MA, De Vet HC, Barendse GA, et al: The effect of spinal cord stimulation in patients with chronic reflex sympathetic dystrophy: two years follow-up of the randomized controlled trial, Ann Neurol 55:13-18, 2004. Kingery WS: A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes, Pain 73:123-139, 1997. Kumar K, Nath RK, Toth C: Spinal cord stimulation is effective in the management of reflex sympathetic dystrophy, Neurosurgery 40:503-508, 1997; discussion 508-509. Oakley JC, Prager JP: Spinal cord stimulation: mechanisms of action, Spine 27:2574-2583, 2002.
SECTION 4
Headache and Facial Pain

B. Todd Troost, M.D.
effort must be made to reduce the intake of all analgesic medication. I usually start out with a request that there be a 10% reduction each week, up to 6 weeks, when the medication is to be discontinued entirely. During this time, I prescribe a preventive therapy such as that discussed later. If patients have more than two headaches per month or are not responding well to simple analgesics, I begin one of the triptrans (Table 3). The usual dosing of triptans is one as soon as possible during the onset of a migraine attack, followed by a second, if needed, in 2 hours. The nature of the attack also makes a difference. If it is an entirely predictable migraine, a slow-onset triptan, such as frovatriptan, may be appropriate versus a faster occurring attack, when sumatriptan or rizatriptan may be the preferred triptan. Patients respond differently to the triptans, and if one does not work after two or three trials, it is appropriate to shift to another triptan. The triptans that I personally use most often are (1) eletriptan, 40 mg to repeat in 2 hours, and (2) sumatriptan, 100 mg to repeat in 2 hours. As an off-label use, if I find that patients are frequently needing a second dose, I may have them double-up on the initial dose of eletriptan and take 80 mg at the onset of the migraine. It is clear, from recent studies, that the earlier into an attack that a person takes a triptan, the more likely it is that the attack can be abolished along with cutaneous allodynia. Occasionally, patients with status migrainosus may require a variety of outpatient abortive procedures, as follows, and these are listed with doses: Valproate sodium injection (Depacon 500 mg and 50 mL saline) given intravenously (IV) over 5 minutes and repeated a single time in 1 hour. Dihydroergotamine (DHE) protocol in which patients are given, first, 10 mg of metoclopramide by slow IV push followed in 15 minutes by 0.5 mg of DHE, and this can be repeated in 1 hour. If this does not break the headache, the patient may need to be admitted for the standard IV DHE protocol. Another possibility that patients can try at home, before coming to the outpatient clinic or emergency department, is subcutaneous sumatriptan in a stat dose pack such as listed in Table 3. PREVENTIVE THERAPY The decision to use preventive therapy depends on the degree of disability and the frequency and the intensity 67
The classification of migraine and cluster headache is presented in the second edition of the International Headache Classification published in 2004 (see Suggested Reading).
Treatment of Migraine
ACUTE THERAPY A variety of acute medications may be prescribed for migraine, including the triptans, ergotamines, and analgesic medication. I avoid, as much as possible, the use of class II narcotics or excessive dependence on acetaminophen or nonsteroidal anti-inflammatory drugs. If a patient just has one headache per month that readily responds to an NSAID or two extra-strength acetaminophen, that may be sufficient. However, for more frequent acute migraine headaches, up to three per month, acute therapies may be used such as listed in Tables 1 and 2. The choice of acute treatment depends on the severity and frequency of headaches, the pattern of associated symptoms, comorbid illness, and the patient treatment response profile. The most simple treatment is with nonprescription or prescription analgesics. Most of the patients I see, however, are beyond the stage of one or two headaches per month and frequently present with chronic daily headache. I take a detailed history and attempt to verify it with a significant other of the number of analgesic medications the patient is taking. If patients are using analgesic medication more than twice a week, they tend to get rebound headache and transform their migraine into chronic daily headache. Therefore, it is imperative to determine how many extra-strength acetaminophen tablets, NSAIDs, or barbiturate-containing compounds the patient is actually consuming. Frequently, patients are taking more than 200 doses of analgesic medication per week. A determined
68
TABLE 1 Symptomatic Therapy for Migraine

Route of Administration PO PO PO, IM PO Suppository IM/IV PO Suppository PO IM IV PO PO PO
Drug NSAIDs Naproxen Ibuprofen Antiemetics* Promethazine Prochlorperazine Trimethobenzamide Metoclopramide Dimenhydrinate Mixed barbiturate analgesics Butalbital, aspirin or acetaminophen, and caffeine; butalbital and acetaminophen Narcotics (codeine-containing compounds, oxycodone, propoxyphene, meperidine)
*Given 10-20 min before ingestion of oral abortive migraine medication. NSAID, Nonsteroidal anti-inflammatory drug.
Dosage 550-750 mg with repeat in 1-2 hr; limit three times per wk 200-300 mg with repeat in 1-2 hr; limit three times per wk 50-125 mg/day 1-25 mg/day 2.5-25 mg/day 5-10 mg/day 250 mg/day 200 mg/day 5-10 mg/day 10 mg/day 5-10 mg slowly 50 mg 1 or 2 tablets q 4-6 hr; limit 4 tablets per day up to twice per wk Sparingly and infrequently, if at all, in patients with chronic headaches
of headaches in a given patient. My current regimens are listed in Table 4. Anticonvulsants I usually begin with topiramate 25 mg, increasing weekly up to 50 to 100 mg twice a day with careful monitoring of efficacy. The primary side effects are cognitive dysfunction (10% to 15%), weight loss, and paresthesias (usually mild and disappearing within a few weeks).
Rare complications include hair loss, dry eyes, kidney stones, and an idiopathic form of glaucoma occurring in roughly 8 patients per 1 million. The next anticonvulsant I prescribe is levetiracetam (Keppra), and with slow titration, as described in Table 5, the main side effect of drowsiness is avoided. Levetiracetam is an excellent anticonvulsant with no significant drug-drug interactions. It is weight neutral, and in one study we performed, we found that 70% of patients with chronic daily headache had some level of improvement.
TABLE 2 Abortive Therapy for Migraine

Route of Administration IM, SC, IV PO Sublingual Suppository PO PO IM
Drug Serotonin receptor agonists Dihydroergotamine Ergotamine derivatives Ergotamine and caffeine* Ergotamine* Ergotamine and caffeine* Sympathomimetic agents Isometheptene, acetaminophen, dichloralphenazone Corticosteroids Dexamethasone
Dosage 0.5-1 mL 2 tablets, repeat in 1 hr if necessary; limit 4 per attack 1 tablet (let dissolve), may repeat in 30 min; limit 2 per attack 1 /2-1 suppository, repeat in 1 hr if necessary; limit two doses 2 capsules, may repeat in 1 hr; limit three times per wk 2-6 mg; may repeat in 3 hr if necessary
*Wait 3 days between dosing with ergotamine in patients with frequent migraine or daily headache. For protracted migraine.
69
TABLE 3 Triptans
Trade Name Imitrex Amerge Zomig MaxAlt Frova Relpax Axert
TABLE 4 Migraine Preventive Therapy

Anticonvulsants Botulinum toxin type A injections Calcium channel blockers Beta blockers Methysergide Nonsteroidal anti-inflammatory drugs Lithium Antidepressants
Drug Sumatriptan Naratriptan Zolmitriptan Rizatriptan Frovatriptan Eletriptan Almotriptan
Dosage 25, 50, 100 mg PO 25 mg nasal spray and 6 mg SC 2.5 mg PO 2.5, 5 mg PO (oral melting tablet also available) 2.5 mg nasal spray 5, 10 mg PO (oral melting tablet also available) 2.5 mg PO 40 mg PO 12.5 mg PO
I use zonisamide at the dosage described in Table 5, lamotrigine, and gabapentin, in that order. I generally do not use divalproex sodium (Depakote) because of a significant tendency for weight gain, hair loss, and tremor. Botulinum Toxin Type A Mounting clinical evidence supports the use of botulinum type A (BoNT-A) in migraine and tension headache, particularly when there is a history or physical examination finding of neck muscle spasm. The discovery of the efficacy of BoNT-A in headache was serendipitous. Migraineurs who received BoNT-A injections for cosmetic reasons reported significant improvement in headache symptoms, and thereafter, an open-label multicenter trial suggested a high level of migraine relief. In prior studies, when we used a five-point categorical scale based on 1 = no effect to 5 = excellent improvement (90% reduction in headache) when we analyzed 436 patients, we found that most patients, who had previously failed three or more preventive pharmacologic therapies for migraine, had significant improvement after three or four injection cycles. Patients who were administered two treatments noted significantly greater improvement than those who were administered just a single treatment. We have now treated more than 650 patients with 2500 injection cycles and found that 75% to 80% reported improvement as good or excellent. It also
appeared that there was a major reduction of other analgesic medication on BoNT-A therapy. Therefore, we believe BoNT-A is a significantly promising treatment for the management of severe headache. Major placebo-controlled, double-blind studies are required to obtain U.S. Food and Drug Administration approval, and these are the results of the trials currently being analyzed. ADDITIONAL THERAPY Additional preventive therapies include calcium channel blockers and beta blockers (Table 6). For patients who have concurrent comorbidity such as Raynauds phenomenon, a calcium channel blocking drug may be efficacious. The dose can be gradually increased with verapamil or diltiazem as described in Table 6. Patients must be warned about the possibility of constipation (less with diltiazem) and should be evaluated for the possibility of cardiomyopathy or the history of congestive heart failure because these are both contraindications of the use of a calcium channel blocking drug. Beta blockers (see Table 6) such as propranolol and timolol have had the longest trial of preventive use; however, there is a significant incidence of depression in women, and I personally find the efficacy not as good as with the anticonvulsants. 4
Cluster Headache
The characteristics of cluster headache, now classified as one of the autonomic cephalalgias, is discussed in the International Headache Society publication listed in the Suggested Reading. Cluster headache is extremely
TABLE 5 Anticonvulsants for Migraine Therapy

Generic Name Topiramate Levetiracetam Zonisamide Lamotrigine Gabapentin Divalproex sodium Trade Name Topamax Keppra Zonegran Lamictal Neurontin Depakote Dosage 25 mg daily times 1 wk, increasing to 200 mg/day, average 100 mg/day 500 mg,1/2 qhs increased by 1/2 pill each week, to 11/2 pills bid, may increase up to 3000 mg 100 mg daily times 1 wk, then 200 mg/day, to be increased to 300 mg/day in single dose 25 mg, 2 tablets at night for 2 wk, then increase by 25 mg q 1-2 wk to 100-200 mg 100-300 mg, 1-3/day to 1200 mg 250 mg, 1 tablet tid to 1.5 gm/day
70
TABLE 6 Additional Pharmacologic Migraine Therapy

Generic Name Calcium channel blockers Verapamil Diltiazem Beta blockers Propranolol Timolol Trade Name Inderal Cardizem Verelan Blocadren Dosage 120 mg/day, increasing to 600 mg/day 120 mg bid, increasing to 720 mg/day 10 mg tid, increasing to 180 mg/day 5 mg bid, increasing to 40 mg/day
difficult to treat. I use most of the standard preventive therapies such as calcium channel blocking drugs or anticonvulsants as initial starting therapy. Nasal oxygen (8 to 10 L/min) may be helpful at the start of a series of cluster headaches. However, I have found that most patients with recurrent cluster headache do not respond to these therapies and need to be treated with other agents such as methysergide (Sansert). The methysergide dosage should be 2 mg once to three times per day, and the patient should be given a drug-free month once every 6 months to reduce the likelihood of retroperitoneal fibrosis. Rarely, I have also used lithium in the form of Lithobid 300 mg one or two times per day. Patients may experience tremor and should have lithium levels checked at least monthly and not be on concurrent therapy with calcium channel blocking drugs. Finally, in selected patients, I have used BoNT-A with modest success in approximately 25% of the patients. SUGGESTED READING
Headache Classification Subcommittees of the International Headache Society: The international classification of headache disorders: 2nd edition, Cephalalgia 24(Suppl 1):9-160, 2004. Troost BT: Botulinum toxin type A (Botox) in the treatment of migraine and other headaches, Expert Rev Neurother 4:27-31, 2004. Goadsby PJ, Lipton RB, Ferrari MD: Migraine: current understanding and treatment, N Engl J Med 346:257-270, 2002.
Definition
What is CDH? CDH is a symptom rather than a diagnosis. CDH simply refers to the presence of headache on 15 or more days per month for more than 3 months. There are many primary and secondary causes of CDH. The International Headache Society (IHS) classification of headache disorders recently developed operational diagnostic criteria for primary and secondary CDH disorders (see Suggested Reading).
Epidemiology
The population prevalence of CDH is 3% to 5%, whereas the prevalence within U.S. headache centers approaches 80%. The annual incidence of CDH in the general population is approximately 3%. The disability associated with primary forms of CDH is substantial. These patients experience significant impairment in health-related quality of life and in physical and mental health, as well as decreased social and occupational functioning.
Approach to the Patient with Chronic Daily Headache

In most cases, CDH is attributable to primary headache disorders. However, clinicians need to be vigilant in excluding secondary causes of headaches in this population (Table 1). A thorough history is the most critical aspect of the evaluation and provides the diagnosis or guides the evaluation in most cases. Clinical evaluation should always address the possibility of elevated or low intracranial pressure, a chronic infectious or inflammatory disease, a space-occupying lesion, or symptomatic medication overuse. In the absence of red flags in the history or physical examination, a secondary cause can usually be eliminated (Table 2). Next, the question How long do the patients individual headaches last if left untreated? narrows the primary CDH subtypes into two discrete categoriesshort lasting (<4 hours) and long lasting (>4 hours) (Figure 1). By recognizing the distinctive clinical features of the common primary CDH subtypes, a specific diagnosis can be made and appropriate treatment initiated in most patients.
PATIENT RESOURCE
http://www.imigraine.net/

Jonathan P. Gladstone, M.D., and David W. Dodick, M.D.
Chronic daily headache (CDH) is a significant public health problem affecting 3% to 5% of the population worldwide. The treatment of patients with CDH can be both challenging and immensely rewarding. Effective management requires a systematic approach to diagnosis and treatment.
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TABLE 6 Additional Pharmacologic Migraine Therapy

Generic Name Calcium channel blockers Verapamil Diltiazem Beta blockers Propranolol Timolol Trade Name Inderal Cardizem Verelan Blocadren Dosage 120 mg/day, increasing to 600 mg/day 120 mg bid, increasing to 720 mg/day 10 mg tid, increasing to 180 mg/day 5 mg bid, increasing to 40 mg/day
difficult to treat. I use most of the standard preventive therapies such as calcium channel blocking drugs or anticonvulsants as initial starting therapy. Nasal oxygen (8 to 10 L/min) may be helpful at the start of a series of cluster headaches. However, I have found that most patients with recurrent cluster headache do not respond to these therapies and need to be treated with other agents such as methysergide (Sansert). The methysergide dosage should be 2 mg once to three times per day, and the patient should be given a drug-free month once every 6 months to reduce the likelihood of retroperitoneal fibrosis. Rarely, I have also used lithium in the form of Lithobid 300 mg one or two times per day. Patients may experience tremor and should have lithium levels checked at least monthly and not be on concurrent therapy with calcium channel blocking drugs. Finally, in selected patients, I have used BoNT-A with modest success in approximately 25% of the patients. SUGGESTED READING
Headache Classification Subcommittees of the International Headache Society: The international classification of headache disorders: 2nd edition, Cephalalgia 24(Suppl 1):9-160, 2004. Troost BT: Botulinum toxin type A (Botox) in the treatment of migraine and other headaches, Expert Rev Neurother 4:27-31, 2004. Goadsby PJ, Lipton RB, Ferrari MD: Migraine: current understanding and treatment, N Engl J Med 346:257-270, 2002.
Definition
What is CDH? CDH is a symptom rather than a diagnosis. CDH simply refers to the presence of headache on 15 or more days per month for more than 3 months. There are many primary and secondary causes of CDH. The International Headache Society (IHS) classification of headache disorders recently developed operational diagnostic criteria for primary and secondary CDH disorders (see Suggested Reading).
Epidemiology
The population prevalence of CDH is 3% to 5%, whereas the prevalence within U.S. headache centers approaches 80%. The annual incidence of CDH in the general population is approximately 3%. The disability associated with primary forms of CDH is substantial. These patients experience significant impairment in health-related quality of life and in physical and mental health, as well as decreased social and occupational functioning.
Approach to the Patient with Chronic Daily Headache

In most cases, CDH is attributable to primary headache disorders. However, clinicians need to be vigilant in excluding secondary causes of headaches in this population (Table 1). A thorough history is the most critical aspect of the evaluation and provides the diagnosis or guides the evaluation in most cases. Clinical evaluation should always address the possibility of elevated or low intracranial pressure, a chronic infectious or inflammatory disease, a space-occupying lesion, or symptomatic medication overuse. In the absence of red flags in the history or physical examination, a secondary cause can usually be eliminated (Table 2). Next, the question How long do the patients individual headaches last if left untreated? narrows the primary CDH subtypes into two discrete categoriesshort lasting (<4 hours) and long lasting (>4 hours) (Figure 1). By recognizing the distinctive clinical features of the common primary CDH subtypes, a specific diagnosis can be made and appropriate treatment initiated in most patients.
PATIENT RESOURCE
http://www.imigraine.net/

Jonathan P. Gladstone, M.D., and David W. Dodick, M.D.
Chronic daily headache (CDH) is a significant public health problem affecting 3% to 5% of the population worldwide. The treatment of patients with CDH can be both challenging and immensely rewarding. Effective management requires a systematic approach to diagnosis and treatment.
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TABLE 1 Causes of Chronic Daily Headache

Primary Short lasting (<4 hr) Chronic cluster Chronic paroxysmal hemicrania SUNCT Hypnic Long lasting (>4 hr) Chronic migraine Chronic tension type Hemicrania continua New daily persistent type Secondary Medication related Medication overuse Drug side effects Vascular Giant cell arteritis Subdural hematoma Ischemic or hemorrhagic stroke Venous sinus thrombosis Arterial dissection Severe arterial hypertension Infectious Meningitis (viral, bacterial, tubercular, fungal, parasitic) Sinusitis (sphenoid) Disorders of intracranial pressure Increased intracranial pressure (primary or secondary tumor, idiopathic intracranial hypertension, hydrocephalus) Decreased intracranial pressure (spontaneous intracranial hypotension, post-lumbar puncture headache) Structural Attributable to cervical spine disorders Attributable to TMJ/dental pathology Post-traumatic Attributable to head injury Attributable to neck injury or whiplash Metabolic Hypoxia, hypercarbia Obstructive sleep apnea Carbon monoxide Thyroid disease
TMJ, Temporomandibular joint; SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.
TABLE 2 Daily Headache: Red Flags for Secondary Causes

Factor Onset age >50 years Comments Consider giant cell arteritis, brain tumor (primary or secondary), or subdural hematoma Chronic meningitis (tubercular, fungal, or parasitic infection) Sinusitis (sphenoid sinusitis may occur without nasal symptoms) Vasculitis (primary CNS or secondary to other inflammatory/rheumatologic conditions) Giant cell arteritis If worse when standing, consider spontaneous intracranial hypotension If worse when supine, consider increased intracranial pressure and/or posterior fossa pathology Be wary of metastatic disease or intracranial infection Re-evaluate original diagnosis, and consider a secondary cause Always be on the lookout for caffeine or medication overuse headache
Presence of fever or systemic symptoms
Focal neurologic symptoms or signs Precipitated by positional changes, Valsalva maneuver, bending or coughing
History of cancer, immunocompromise, or HIV infection Progressive headache or escalating medication requirements
CNS, Central nervous system; HIV, human immunodeficiency virus.
Primary CDH
SHORT-DURATION (<4 HOURS) PRIMARY CHRONIC DAILY HEADACHE The prototypical short-lasting primary CDH is cluster headache. It is characterized by severe pain in the orbital or temporal region and cranial autonomic features (e.g., lacrimation, rhinorrhea, conjunctival injection, ptosis). Chronic paroxysmal hemicrania and SUNCT syndrome (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing) are classified together with cluster headache as the trigeminal autonomic cephalgias because of the trigeminal
distribution of the pain and the accompanying cranial autonomic features. These syndromes must be differentiated from each other because they are each treated in a different manner (Table 3). The important treatment implications are the exquisite response of chronic paroxysmal hemicrania to indomethacin, and the preferred use of second- or third-generation anticonvulsants (gabapentin, lamotrigine, topiramate) for SUNCT syndrome. Cluster Headache Cluster headache is extremely debilitating and requires thoughtful and aggressive management. Nonpharmacologic management includes eliminating alcohol and tobacco use and directing patients to the helpful support groups available for cluster headache sufferers. The pharmacologic management of cluster headache can be separated into acute, transitional, and prophylactic therapy. Subcutaneous sumatriptan (6 mg) is the fastest acting and most effective medication for the relief of a
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Headache 15 or more days per month
Exclude secondary headaches
Treat secondary headache
Classify based on duration
Short duration (< 4 hours)
Long duration (> 4 hours)
Chronic cluster headache (CCH) Chronic paroxysmal hemicrania (CPH) Hypnic headache (HH) SUNCT syndrome
Chronic migraine (CM) Chronic tension type headache (CTTH) New daily persistent headache (NDPH) Hemicrania continua (HC)
Autonomic
+ Autonomic
Autonomic
+ Autonomic
Hypnic Headache
CCH CPH* SUNCT
CM CTTH NDPH
HC*
Onset < 3 days
Gradual onset
See Table 3
NDPH
* Indomethacin responsive Autonomic cranial autonomic symptoms
CM CTTH
FIGURE 1. Approach to chronic daily headache: narrowing the differential diagnosis based on the duration of individual headaches. SUNCT, Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.
cluster headache. Recently, trials in patients with episodic cluster headache demonstrated good efficacy with intranasal sumatriptan (20 mg) and intranasal zolmitriptan (5 mg). Inhalational oxygen, administered via face mask at 10 to 15 L/min for at least 15 minutes, is effective in up to 70% of patients. Practically, the need for an oxygen canister and regulator makes this modality cumbersome for some patients. Dihydroergotamine (DHE) administered intravenously (IV), subcutaneously, or intranasally is also effective, although there are few data from randomized, controlled trials. For some patients, especially those who cannot use or tolerate
vasoconstrictive drugs such as triptans or DHE, intranasal lidocaine 4% may be effective. Prescription analgesics or opioids are not effective and may lead to medication overuse headache and central nervous system side effects. An effective preventive regimen for patients with cluster headache is crucial because attacks often occur daily for months or years (Table 4). Corticosteroids usually provide swift relief from attacks. Prednisone can be initiated at 60 mg/day for 3 days followed by 10-mg decrements every 3 days. Blockade of the ipsilateral occipital nerve can suppress attacks for up to 2 weeks in as many
TABLE 3 Differentiating Features of the Trigeminal Autonomic Cephalalgias

Feature Gender (male/female) Attack duration Attack frequency Autonomic features Alcohol ppt First-line treatment Cluster 4:1 15-180 min 1-8/day ++ ++ Verapamil CPH 1:3 2-45 min 1-40/day ++ + Indomethacin SUNCT 4:1 5-250 sec 1/day-30/hour ++ + Lamotrigine gabapentin
CPH, Chronic paroxysmal hemicrania; SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.
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TABLE 4 Treatment for Cluster Headache

Transitional (1-2 wk) Prednisone 60 mg qd for 3 days, then 10-mg decrements q 3 days (18 days) Ergotamine tartrate 1-2 mg PO/suppository qd (qhs or divided dosage) D.H.E-45 0.5-1 mg SC/IM q 8-12 hr Occipital nerve blockade (e.g., 3-5 mL 0.5% bupivacaine + 10-20 mg Depo-Medrol) Maintenance (duration of cluster period, usually 2-3 mo) Verapamil 80 mg tid or 240 mg SR; up to 720 mg/day Methysergide 2 mg tid; up to 12 mg/day Lithium carbonate 150-300 mg tid or 450 mg SR Valproic acid 500-2000 mg/day in divided dosages Topiramate 50-150 mg in divided daily dosages Adjunctive Melatonin 10 mg PO qhs Indomethacin 25-50 mg tid Gabapentin 300-1200 mg tid
as two thirds of patients and avoid the potential side effects associated with oral corticosteroids. Occipital nerve blockade can be achieved with 3 mL of 0.5% bupivacaine combined with 10 to 20 mg of methylprednisolone or another long-acting corticosteroid. IV DHE with repetitive infusions every 8 to 12 hours over a 1- to 2-day period can provide significant relief; however inpatient admission or an outpatient infusion center is required. Verapamil should be considered the first-line preventive agent for both episodic and chronic cluster headache. After a baseline electrocardiogram (ECG) the initial starting dose is 80 mg three times a day, or one can titrate to this dose over 3 to 5 days. Titration, as needed, should occur in 80-mg intervals every 3 to 7 days. For doses above 480 mg/day, an ECG is required prior to each dose escalation. If partial benefit is obvious at this dose, some patients may become cluster free at higher dosages (720 mg). If side effects occur (significant constipation, fatigue, gastrointestinal symptoms, hypotension, edema), we recommend decreasing the dose and adding a second-line agent such as melatonin, topiramate, or gabapentin. Although two open-label studies with divalproic acid for chronic cluster headache were encouraging, a recent placebo-controlled study failed to show a significant difference (though the placebo response in this study was unusually high). Beta blockers and tricyclic antidepressants have no role in the treatment of chronic cluster headache. Although quite effective, lithium carbonate and methysergide are typically reserved as third-line agents due to their potential for significant side effects and systemic toxicity, difficulty with dose titration, and access issues (methysergide is no longer available in the United States). Patients on methysergide require a 1-month drug holiday every 6 months and regular screening for retroperitoneal/ pleural/pericardial fibrosis. Testing usually requires an echocardiogram, computed tomographic scan of the chest and abdomen, serum creatinine, erythrocyte sedimentation rate, and urinalysis.
A number of other agents have been reported in small open-label studies or within case reports to have demonstrated efficacy in patients with cluster headache. These include methylphenidate, pizotifen, indomethacin, antispasticity drugs (tizanidine and baclofen), clonidine, diltiazem, flunarizine, histamine, somatostatin, and intranasal capsaicin. There is a paucity of clinical experience with most of these drugs in patients with cluster headache, and because of the lack of data, further evidence is needed before recommendations can be made to support their routine use in cluster headache. However, consideration of all medical options should be given in patients with treatment-resistant cluster headache before an ablative surgical procedure is attempted. For individuals who fail medical management or develop unacceptable side effects and are psychologically stable, surgical options are available. Multiple surgical interventions have been proposed, but the results are best and experience is greatest with those procedures directed at the sensory portion of the trigeminal nerve. These include percutaneous radiofrequency, glycerol or balloon rhizolysis, and trigeminal root sectioning. Each of these procedures is irreversibly destructive with the potential for significant neurologic morbidity. Two emerging surgical options for patients with refractory chronic cluster headache are available in select research centersdeep brain stimulation and occipital nerve stimulation. Ipsilateral posteroinferior hypothalamic stimulation has been found to be relatively safe and effective in patients with medically intractable chronic cluster headache. However, fatal iatrogenic cerebral hemorrhage occurred in one patient, reminding us of the potential for serious neurologic morbidity and mortality associated with this procedure. Occipital nerve stimulation may represent an effective and minimally invasive procedure for patients with chronic cluster headache. Thus far, only two patients with chronic cluster headache have been treated, both with good results, and further investigation into the effectiveness of occipital nerve stimulation for patients with chronic migraine and cluster headache is under way. Chronic Paroxysmal Hemicrania and Hemicrania Continua Chronic paroxysmal hemicrania and hemicrania continua are typically responsive to indomethacin in dosages ranging between 25 and 75 mg three times a day. Hemicrania continua is a continuous exclusively unilateral headache that is punctuated by severe exacerbations lasting hours to days. These patients also experience one or more cranial autonomic symptoms, often during painful exacerbations. Patients typically notice complete relief within 48 hours, and once a stable dose is obtained, patients can be switched to a once-daily dosage with the slow-release formulation. If indomethacin is not effective, the diagnosis should be revisited. If indomethacin is poorly tolerated or contraindicated, alternative treatment options include other nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen, sulindac, diclofenac, aspirin, cyclooxygenase-2 inhibitors, and verapamil, and brief courses of corticosteroids.
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SUNCT Until recently, SUNCT syndrome has been notoriously difficult to treat effectively. An initial trial of indomethacin, especially if there is diagnostic uncertainty, is warranted. Lamotrigine should be considered first-line therapy. Second-line therapies include gabapentin and topiramate. Hypnic Headache Hypnic headache is a unique headache entity occurring mainly in the elderly and exclusively during sleep. The headache is generally bilateral, moderately severe, and lasts between 15 and 120 minutes. Patients generally feel better upright, and there are no cranial autonomic symptomsfeatures that distinguish this disorder from cluster headache, which can also awaken patients from sleep. Paradoxically, caffeine before bed is often effective and should be tried initially either in the form of a caffeinated beverage or tablet. Lithium, melatonin, and indomethacin all have demonstrated benefit in patients with hypnic headache. LONG-DURATION (>4 HOURS) CHRONIC DAILY HEADACHES Chronic Migraine and Transformed Migraine Chronic migraine is characterized by headaches fulfilling the criteria for migraine without aura on more than 15 days per month for more than 3 months in the absence of medication overuse. Most headache specialists in North America use the Silbsertein-Lipton criteria for transformed migraine (TM) since they are more sensitive and relevant to the CDH patients seen in U.S. clinics (Table 5). Patients with transformed migraine usually have a history of episodic migraine that gradually transforms to chronic migraine, although this transformation may be abrupt in up to 15% of patients.
Patients with transformed migraine often require aggressive management with both nonpharmacologic and pharmacologic treatment modalities. Migraineurs are often exquisitely sensitive to internal and external stimuli. Therefore, regulating daily activities (e.g., regular mealtimes and sleep schedules) and avoiding identifiable triggers are important. Anxiety and attention to pain results in inhibition of antinociceptive brainstem structures such as the periaqueductal gray matter. Therefore, training in relaxation, biofeedback, stress management, and cognitive-behavioral therapy allow patients to exert control over physiologic responses that may influence pain modulation. The efficacy of these techniques has been demonstrated in multiple welldesigned clinical trials in patients with episodic migraine and received a grade A recommendation in the U.S. Headache Consortium Guidelines and American Academy of Neurology Practice Parameter. Preventive therapy should be considered for patients with transformed migraine whether or not symptomatic medication overuse is present. Although the most frequently prescribed preventive medications for episodic migraine in North America continue to be the beta blockers and tricyclic antidepressants, evidence has emerged over the last decade for novel formulations of older anticonvulsants (divalproic acid extended-release); for newer, second-generation anticonvulsants (e.g., topiramate, gabapentin); and for botulinum toxin type A (BoNT-A) for the treatment of both episodic and chronic migraine. Although most studies have been with episodic migraine, these agents are, and will continue to be, widely used in practice to treat patients with chronic migraine in the absence of evidence from randomized, controlled data to the contrary. Medication Overuse Headache Medication overuse headache (rebound headache) is a common and disabling headache disorder characterized by the generation, perpetuation, or maintenance of CDH, caused by the frequent and excessive use of immediaterelief (symptomatic) medications. Patients with medication overuse headache frequently have a history of episodic migraine that has been transformed into CDH as a result of symptomatic medication overuse. In susceptible individuals the frequent, neardaily, or daily use of simple analgesics (aspirin or acetaminophen), combination analgesics (containing caffeine, codeine, or barbiturates), opioids, ergotamine, or triptans may transform an episodic pattern of headache into one that occurs daily. Characteristic features of medication overuse headache have been well described (Table 6) and the IHS has developed operational criteria for the diagnosis of medication overuse headache (Table 7). Medication overuse headache is a retrospective diagnosis made when the offending agent is withdrawn and the headache pattern ceases to be daily. This process generally takes weeks to months. However, daily headache is not synonymous with analgesic overuse, and many patients with transformed migraine, chronic tensiontype headache, and new daily persistent headache do not overuse symptomatic medications. It is these patients
TABLE 5 Transformed Migraine: Silberstein-Lipton Criteria

Type A B C Description Daily or almost daily (>15 days/mo) head pain for > 1 mo Average headache duration of > 4 hr/day (if untreated) At least one of the following: (1) History of any form of episodic migraine meeting IHS criteria 1.1-1.6* (2) History of increasing headache frequency with decreasing severity of migrainous features over at least 3 mo (3) Headache at some time meets HIS criteria for migraine other than duration Does not meet criteria for new daily persistent headache or hemicrania continua
*IHS criteria refers to International Headache Society classification (see Suggested Reading).
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TABLE 6 Features of Medication Overuse Headache

Frequency of headaches increases insidiously over time Patients often awake in the early morning with headache A proportion of individual headache attacks may become nondescript (lose the characteristic migrainous features) Lowered threshold for precipitating headache exacerbations (concentration, minimal exertion, anxiety) Escalating doses of symptomatic medications required for headache relief Headaches occur within a predictable period after the last consumption of symptomatic medication, usually with reduced efficacy
who continue to have daily headache even after analgesics are discontinued. Familiarity and comfort with drug withdrawal and detoxification strategies are essential for the treatment of patients with medication overuse headache (Table 8). Patients with CDH who overuse acute symptomatic medications must discontinue or taper the overused medication due to the possibility of tolerance; habituation and dependence; the potential for renal, hepatic, or gastrointestinal side effects; and the possibility that medication overuse may neutralize the effectiveness of prophylactic medications. In the absence of prospective, placebo-controlled, randomized studies evaluating the different treatment modalities for medication overuse headache or the efficacy of medication withdrawal alone, treatment strategies are based on case reports, case series, retrospective chart reviews, and expert opinion. Treatment of medication overuse headache may occur in the outpatient setting or at an infusion center, or it may require hospitalization. Hospitalization is
typically reserved for patients overusing opioids, barbiturates, or benzodiazepines; those with severe psychiatric comorbidity; or those who have failed previous withdrawal attempts as an outpatient (Table 9). Most patients can be managed as outpatients. The first stage of treatment involves headache education, particularly regarding the role of medication overuse in the patients CDH. Comorbid depression and anxiety need to be addressed concurrently. Biobehavioral education with training in relaxation techniques and biofeedback is often helpful to allow patients to achieve an internal locus of control. Modifications of lifestyle habits must be made including, but not limited to, decreasing caffeine consumption, increasing exercise, incorporating stress management strategies, and improving sleep hygiene. Patients should always be provided with support and close follow-up and provided with the realistic expectation that they may feel worse before they feel better. In parallel, simple analgesics, ergotamines, triptans, and most combination analgesics can be abruptly discontinued, whereas opioids and butalbital containing analgesics should be gradually tapered. To alleviate potential side effects from barbiturate withdrawal, a long-acting barbiturate alternative (phenobarbital) may be substituted and tapered; similarly to avoid complications from opioid withdrawal, low doses of clonidine may be considered. Patients should be provided with
TABLE 8 Treatment of Medication Overuse Headache

Education and support with follow-up Encourage healthful behavior (smoking, exercise, meals, sleep, caffeine) Biobehavioral therapy (relaxation therapy, biofeedback) Abrupt withdrawal of overused acute medications except barbiturates, opioids, or benzodiazepines Butalbital overuse (taper over 2-4 wk; if concern for withdrawal syndrome, provide tapering course of phenobarbital 30 mg bid for 2 wk followed by 15 mg bid for 2 wk) Opioid overuse (taper over 2-4 wk; if concern for withdrawal, clonidine transdermal patch for 1-2 wk) Relief of worsening/breakthrough headache Prednisone 60 mg for 3 days; decrease by 10 mg q 3 days NSAIDs (ketoprofen 50-100 mg; naproxen sodium 550 mg; ibuprofen 600-800 mg) Antiemetics (metoclopramide 10-20 mg, prochlorperazine 10 mg or 25 mg suppository) SC or IM DHE 1 mg Triptans (if not drug being overused ) Preventive drug therapy Amitriptyline 25-100 mg qhs Divalproex sodium ER 500-2000 mg Topiramate 50-200 mg Gabapentin 900-3600 mg Botulinum toxin type A Tizanidine 4-16 mg qhs Fluoxetine 20-60 mg
NSAID, Nonsteroidal anti-inflammatory drug; DHE, dihydroergotamine.
TABLE 7 Headache Attributed to Medication Overuse: IHS Criteria*

Type A B Comments Headache present on >15 days/mo, fulfilling criteria C and D Characteristics depend on drug Regular overuse of a medication for > 3 mo Ergotamine, triptans, opioids, and combination analgesics 10 days/mo Simple analgesics 15 days/mo Total exposure to symptomatic medications 10 days/mo Headache has developed or markedly worsened during medication overuse Headache resolves or reverts to its previous pattern within 2 mo after discontinuation of overused medication
C D
*IHS criteria refers to International Headache Society classification (see Suggested Reading).
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TABLE 9 Treatment of Medication Overuse Headache

Indications Failure of outpatient treatment High consumption of opioids, butalbital, or benzodiazepines Significant psychological or behavioral disturbances Significant coexistent medical illnesses Protocols Repetitive IV infusions q 8 hr for 2-4 days Dihydroergotamine 0.5-1 mg plus metaclopramide 10-20 mg or prochlorperazine 10 mg Prochlorperazine 10 mg Divalproex sodium 6.4 mg/kg Methylprednisolone 250-500 mg q 12 hr Initiate taper/withdrawal symptomatic medications overused (clonidine, phenobarbital) Initiate preventive therapy
as well as pharmacologic therapy with tricyclic antidepressants. New Daily Persistent Headache New daily persistent headache is characterized by a constant and unremitting headache of acute onset (developing over <3 days). Clinically, the headache features may be indistinguishable from chronic tension-type headache; however, contrary to the IHS diagnostic criteria, our experience suggests that migrainous symptoms (nausea, vomiting, photophobia) may occur in these patients and the pain can be debilitating. Patients can pinpoint the calendar date of onset, unlike chronic tension-type headache. In these patients, an exhaustive search for secondary causes is mandatory. There is no available evidence on which to base therapeutic decisions for new daily persistent headache; unfortunately, many patients with new daily persistent headache who present for subspecialty consultation are particularly refractory to treatment. In the absence of alternative evidence, treatment strategies should mirror those used for chronic migraine (and for medication overuse headache when applicable).
symptomatic agents in limited doses (e.g., long-acting NSAIDs, DHE, triptans, or steroids) from drug classes other than those which they are overusing to alleviate withdrawal symptoms (headache, nausea, vomiting, arterial hypotension, tachycardia, sleep disturbances, restlessness, and nervousness). Withdrawal symptoms typically last from 2 to 10 days. For patients requiring more aggressive treatment, various strategies have been advocated including parenteral DHE, methylprednisolone, neuroleptics, or divalproex sodium acid. After initial detoxification, alternative acute medications to treat breakthrough attacks are provided in strictly limited doses. Prophylactic pharmacotherapy is initiated from the outset. There is no evidence base on which to make prophylactic therapy decisions in the medication overuse headache population, but reasonable options include amitriptyline, divalproex sodium, topiramate, botulinum toxin type A, fluoxetine, and tizanidine (see Table 4). The goal of withdrawal or detoxification therapy for medication overuse headache is to eliminate daily or neardaily medication use, to restore an episodic pattern of headache, and to establish an effective preventive and acute (symptomatic) treatment strategy. In patients with a long-standing history of near-daily or daily headache, it may be unrealistic to expect restoration of pain-free intervals. In these patients, the objective becomes to reduce the intensity of daily pain, to restore the patients ability to function, and to provide an effective strategy for acute management of severe headaches. Significant relapse rates estimated at 1 (20%) and 5 years (50%) highlights the need for ongoing follow-up care. Chronic Tension-Type Headache Chronic tension-type headache is seen much less commonly in neurologic practice than chronic migraine. Typically the syndrome evolves after years of episodic tension-type headache. First-line treatments for chronic tension-type headache include nonpharmacologic therapy such as relaxation, stress reduction, and biofeedback
Conclusion
Although CDH can be challenging to manage, considerable clinical experience over the past decade has led to the development of operational diagnostic criteria and a better understanding of the clinical features, pathogenesis, and treatment requirements for these patients. Most of these patients can be effectively treated in clinical practice with existing therapies; however, the recidivism rate in those with medication overuse and the unacceptably high number of patients that are refractory to medical management illustrate the importance of further research in this area. As emerging evidence from ongoing randomized, controlled clinical trials becomes available, future improvements in treatment are undoubtedly around the corner. SUGGESTED READING
Bigal ME, Tepper S J, Sheftell FD, et al: Chronic daily headache: correlation between the 2004 and the 1988 International Headache Society diagnostic criteria, Headache 44:684-691, 2004. Dodick DW: Indomethacin-responsive headache syndromes, Curr Pain Headache Rep 8:19-26, 2004. Dodick DW, Mosek AC, Campbell JK: The hypnic (alarm clock) headache syndrome, Cephalalgia 18:152-156, 1998. Dodick D, Rozen T, Goadsby P, Silberstein S: Cluster headache, Cephalalgia 20:787-803, 2000. Evers S, Goadsby PJ: Hypnic headache: clinical features, pathophysiology, and treatment, Neurology 60:905-909, 2003. Gladstone JP, Eross E, Dodick DW: Chronic daily headache: a rational approach to a challenging problem, Semin Neurol 23:265-276, 2003. Headache Classification Subcommittees of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgia, and facial pain: 2nd edition, Cephalalgia 24(Suppl 1):9-160, 2004. Mathew NT: Chronic refractory headache, Neurology 43(Suppl 3): S26-S33, 1993. Rozen TD: Interventional treatment for cluster headache: a review of the options, Curr Pain Headache Rep 6:57-64, 2002. Johnson: Current Therapy in Neurologic Disease (7/E)
Headaches in Children Scher AI, Stewart WF, Liberman J, et al: Prevalence of frequent headache in a population sample, Headache 38:497-506, 1998. Scher AI, Stewart WF, Ricci JA, Lipton RB: Factors associated with the onset and remission of chronic daily headache in a populationbased study, Pain 106:81-89, 2003. Silberstein SD: Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology, Neurology 55:754-762, 2000. Silberstein SD, Lipton RB, Solomon S, Mathew N: Classification of daily and near-daily headaches in the headache clinic: proposed revision to the International Headache Society criteria. In Olesen J, editor: Frontiers in headache research, vol 4: headache classification and epidemiology, New York, 1994, Raven Press, 117-126.
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PATIENT RESOURCES
American Council for Headache Education http://www.ache.org/ National Headache Foundation http://www.headaches.org/ OUCHThe Organization for the Understanding of Cluster Headache http://www.clusterheadaches.org/
Eric H. Kossoff, M.D.
Headaches in the pediatric population are surprisingly common, much to the surprise of parents but not to pediatric neurologists. By 7 years of age, half of all children have experienced a headache at some time. Migraines are also quite common, with a prevalence of 3.2% by age 7, and 11% by age 15. Despite this, children tend to be referred to ear, nose, and throat physicians for sinusitis and ophthalmologists for myopia before seeing a neurologist. Males tend to be more likely to be affected in the prepubertal age group, followed by the more traditional female predominance after age 11. Headaches are a major source of morbidity and can lead to school failure and emotional problems. The accurate diagnosis and swift institution of appropriate therapy can be crucial.
pallor or autonomic symptoms with their headaches, frequent motion sickness, or unexplained vomiting at very young ages. Children with periodic migraines tend to be high functioning and on honor rolls, perhaps indicating the triggering factor of stress in migraines. Typically the mother bringing in the child for evaluation has migraines herself, which are occasionally unrecognized. One quick and convenient method of distinguishing migraine from other headaches in a less verbal child is by the use of drawings of how the child feels during a headache. It is important to distinguish a headache caused by tension or migraine from that of a potentially lifethreatening neurologic condition such as meningitis or malignancy. This can often be difficult in children, especially in those prior to school age. All children complaining of headache should have a careful history obtained, with strong consideration to neuroimaging if the headache severity is increasing rapidly, they are awakening the child from sleep, or are different from a usual pattern. The presence of focal deficits, seizures, or increased intracranial pressure on neurologic examination should lead to an immediate magnetic resonance imaging (MRI). Most neurologists obtain an MRI in patients with complicated migraine (e.g., confusional, hemiplegic) to ensure that no structural abnormalities exist. Neuroimaging should also be considered in those patients with risk factors such as ventriculoperitoneal shunt, head trauma, human immunodeficiency virus, or systemic malignancy. However, when the history is consistent with migraine and the examination is normal, neuroimaging is not required, regardless of age. There is no indication for electroencephalography, lumbar puncture, or routine laboratory studies in children with migraine.
Treatment
BASIC PRINCIPLES It is important for all physicians to be honest and realistic with children and their families as early in the course of treatment as possible. Migraines are typically a lifelong diagnosis with a fluctuating severity over the years. A promise or expectation of migraine freedom is often followed by disappointment and frustration. Setting appropriate goals, such as a 50% to 75% reduction in severity and frequency in combination with advising patience, often leads to better therapeutic success. To fully treat the patient with headaches, both acute (abortive) and preventive (prophylactic) therapies must be provided at the same time (Figure 1). ACUTE THERAPY The role for nonpharmacologic abortive therapies for childhood migraine is limited but should always be advised. Children may occasionally continue activities such as video games or television during the onset of a migraine; this should be discouraged, and the child should rest in a quiet, dark room. Ice packs can be applied to
Diagnosis
Migraine symptoms can be similar between children and adults, but there are distinct differences. The International Headache Society (IHS) criteria from 1988 are not particularly specific for the pediatric patient. Several potential recommendations have been made by experts to alter the diagnostic criteria for children, specifically to reduce the duration of migraine to less than 1 hour, eliminate the requirement for unilaterality (because many childhood migraines are frontal or bilateral), and allow either phonophobia or photophobia (not necessarily both). Many children have a history of facial
Headaches in Children Scher AI, Stewart WF, Liberman J, et al: Prevalence of frequent headache in a population sample, Headache 38:497-506, 1998. Scher AI, Stewart WF, Ricci JA, Lipton RB: Factors associated with the onset and remission of chronic daily headache in a populationbased study, Pain 106:81-89, 2003. Silberstein SD: Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology, Neurology 55:754-762, 2000. Silberstein SD, Lipton RB, Solomon S, Mathew N: Classification of daily and near-daily headaches in the headache clinic: proposed revision to the International Headache Society criteria. In Olesen J, editor: Frontiers in headache research, vol 4: headache classification and epidemiology, New York, 1994, Raven Press, 117-126.
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PATIENT RESOURCES
American Council for Headache Education http://www.ache.org/ National Headache Foundation http://www.headaches.org/ OUCHThe Organization for the Understanding of Cluster Headache http://www.clusterheadaches.org/
Eric H. Kossoff, M.D.
Headaches in the pediatric population are surprisingly common, much to the surprise of parents but not to pediatric neurologists. By 7 years of age, half of all children have experienced a headache at some time. Migraines are also quite common, with a prevalence of 3.2% by age 7, and 11% by age 15. Despite this, children tend to be referred to ear, nose, and throat physicians for sinusitis and ophthalmologists for myopia before seeing a neurologist. Males tend to be more likely to be affected in the prepubertal age group, followed by the more traditional female predominance after age 11. Headaches are a major source of morbidity and can lead to school failure and emotional problems. The accurate diagnosis and swift institution of appropriate therapy can be crucial.
pallor or autonomic symptoms with their headaches, frequent motion sickness, or unexplained vomiting at very young ages. Children with periodic migraines tend to be high functioning and on honor rolls, perhaps indicating the triggering factor of stress in migraines. Typically the mother bringing in the child for evaluation has migraines herself, which are occasionally unrecognized. One quick and convenient method of distinguishing migraine from other headaches in a less verbal child is by the use of drawings of how the child feels during a headache. It is important to distinguish a headache caused by tension or migraine from that of a potentially lifethreatening neurologic condition such as meningitis or malignancy. This can often be difficult in children, especially in those prior to school age. All children complaining of headache should have a careful history obtained, with strong consideration to neuroimaging if the headache severity is increasing rapidly, they are awakening the child from sleep, or are different from a usual pattern. The presence of focal deficits, seizures, or increased intracranial pressure on neurologic examination should lead to an immediate magnetic resonance imaging (MRI). Most neurologists obtain an MRI in patients with complicated migraine (e.g., confusional, hemiplegic) to ensure that no structural abnormalities exist. Neuroimaging should also be considered in those patients with risk factors such as ventriculoperitoneal shunt, head trauma, human immunodeficiency virus, or systemic malignancy. However, when the history is consistent with migraine and the examination is normal, neuroimaging is not required, regardless of age. There is no indication for electroencephalography, lumbar puncture, or routine laboratory studies in children with migraine.
Treatment
BASIC PRINCIPLES It is important for all physicians to be honest and realistic with children and their families as early in the course of treatment as possible. Migraines are typically a lifelong diagnosis with a fluctuating severity over the years. A promise or expectation of migraine freedom is often followed by disappointment and frustration. Setting appropriate goals, such as a 50% to 75% reduction in severity and frequency in combination with advising patience, often leads to better therapeutic success. To fully treat the patient with headaches, both acute (abortive) and preventive (prophylactic) therapies must be provided at the same time (Figure 1). ACUTE THERAPY The role for nonpharmacologic abortive therapies for childhood migraine is limited but should always be advised. Children may occasionally continue activities such as video games or television during the onset of a migraine; this should be discouraged, and the child should rest in a quiet, dark room. Ice packs can be applied to
Diagnosis
Migraine symptoms can be similar between children and adults, but there are distinct differences. The International Headache Society (IHS) criteria from 1988 are not particularly specific for the pediatric patient. Several potential recommendations have been made by experts to alter the diagnostic criteria for children, specifically to reduce the duration of migraine to less than 1 hour, eliminate the requirement for unilaterality (because many childhood migraines are frontal or bilateral), and allow either phonophobia or photophobia (not necessarily both). Many children have a history of facial
78
Child with frequent, debilitating headaches
Obtain history, perform neurologic examination, obtain neuroimaging as necessary
Acute therapy
Preventive therapy
Pharmacologic
Non-pharmacologic
NSAIDs Ibuprofen, naproxen early in migraine, but not more than twice/week
Rest in a dark, quiet room Clear fluids as tolerated Ice pack to forehead and occiput
If abortives are being used more than 23 per week, immediately taper or discontinue
If headache not responsive after several attempts
Triptans Use preparation acceptable to child as early as possible into the headache, but not more than twice/week can be used earlier if child has failed to respond to NSAIDs for previous headaches
Basic lifestyle changes 810 hours sleep/night Exercise 3 times/week Avoid caffeine Avoid food triggers if present No missed meals Stress reduction 30 minutes/day
Evaluate patient in 23 months if headaches are still present, are impacting quality of life, occurring weekly or biweekly, or do not respond to acute therapies
Second-line choices Intranasal DHE (Migranal) Promethazine suppositories Combination agents (Midrin, Excedrin, Fioricet)
Consider pharmacologic therapy for a 68 week time period
If the child is under age 5, begin cyproheptadine 2 mg qhs
If headache not responsive and/or the child is requiring a hospital admission
Intravenous valproate (Depacon)
If not, and the child has comorbid depression or insomnia, begin either amitriptyline 1020 mg qhs or nortriptyline 1020 mg qhs
Tylenol with codeine Intravenous DHE Steroids
If not, and the child has comorbid obesity, begin topiramate 1525 mg qhs or zonisamide 2550 mg qhs
If not, and the child has comorbid bipolar symptoms or is underweight, begin valproate 125 mg qhs or gabapentin 100 mg qhs
If none of the previously mentioned comorbid conditions apply, use propranolol 10 mg qhs or verapamil 40 mg qhs. Can also choose any other agent based on side effect profile and preparations available
FIGURE 1. Algorithm for the diagnosis and treatment of headache in children. NSAIDs, Nonsteroidal anti-inflammatory drugs; DHE, dihydroergotamine.
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the forehead or occipital area. If the child is not nauseated, clear fluids can be provided. First-line therapies for children with headache are nonsteroidal anti-inflammatory drugs, specifically ibuprofen (10 mg/kg) and naproxen sodium (200 mg). Gastric irritation can occur but is unusual if the NSAID is used infrequently. Should these medications prove ineffective, the triptans can be extremely valuable despite the lack of U.S. Food and Drug Administration (FDA) approval for children younger than 18 years of age. Several studies of rizatriptan and sumatriptan in adolescents have shown efficacy without major side effects. These agents are traditionally avoided in complicated migraine. All agents appear equally effective, although individual patients may respond differentially. Zolmitriptan (2.5 and 5 mg) and rizatriptan (5 and 10 mg) exist in dissolvable tablet forms, which are convenient for children who cannot swallow tablets. Sumatriptan (20 mg) and zolmitriptan (5 mg) also have nasal spray preparations, which are better tolerated if the child leans forward during administration to avoid a bitter taste from swallowing the spray. Recent evidence has demonstrated nasal sprays value over placebo in adolescents. Other abortive therapies that can be helpful include promethazine (Phenergan) suppositories or intravenous metoclopramide (Reglan), especially if vomiting is a significant component of the childs migraine. Intranasal dihydroergotamine (DHE) (Migranal) is also a potential option. Combination agents such as Midrin, Fioricet, and agents containing caffeine such as Excedrin, should be used sparingly and provided in limited amounts to avoid dependence. PREVENTIVE THERAPY Nonpharmacologic Approaches Considering the occasionally dramatic improvement seen in patients just from visiting a neurologist, the avoidance of daily preventive medications is justified at least in the initial visit. Most families are willing to allow for nonmedication improvement if the physician realistically explains the disorder, reassures the child, provides abortive options, advises lifestyle alterations, and arranges close telephone and clinic follow-up. Although it is quicker to give a prescription, it is often unnecessary to do so. Basic lifestyle recommendations include adequate sleep (8 to 10 hours per night, including weekends), aerobic exercise (two or three times per week for 30 minutes), avoidance of missed meals and triggers (e.g., aged cheese, nitrites, bright sunlight) if they should exist, elimination of caffeine from the diet, and encouragement of periods of relaxation time after school each day. Pharmacologic Approaches If the child returns in 2 to 3 months with persistent, severe migraines occurring weekly or biweekly, the use of preventive medications should be discussed. Most of these agents in children can be administered nightly to avoid sedation in school and at low doses. All therapies should be given 6 to 8 weeks before they are judged
ineffective and a substitution is made. The risks of polytherapy generally tend to outweigh potential benefits, so a single preventive agent at a time is advised. If effective, medications should be continued for approximately 1 year, with discontinuation during a school vacation. Therapeutic classes include antihistamines, antihypertensives, antidepressants, and anticonvulsants. The choice of therapy is typically based on comorbidity, side effect profile, and preparation (Table 1). If a choice from a therapeutic class is ineffective, it is logical to try another class before using an agent with a similar mechanism of action. Cyproheptadine (Periactin) is used most often in children younger than 5 years of age and has antihistaminergic and antiserotonergic effects. Efficacy is unproved despite years of use in children. It is typically dosed at 0.5 mg/kg and can be provided as a liquid. Allergic symptoms, if present, can be alleviated, but side effects of appetite stimulation and sedation can be limiting. Propranolol and other beta blockers are proven therapies for migraine but are contraindicated in diabetes, depression, and asthma. Verapamil can also be used, but it occasionally leads to sedation, weight gain, and constipation. This may have a particular role for familial hemiplegic migraine, in which genetically defective calcium channels may be involved in the pathophysiologic mechanisms. These medications are available only as tablets. Antidepressants are quite effective, especially when insomnia or depression are comorbid states. Amitriptyline (Elavil) and nortriptyline (Pamelor) are more effective than the newer selective serotoninreuptake inhibitors for migraine prevention. Side effects include sedation, constipation, dry mouth, and cardiac conduction problems (an electrocardiogram should be obtained if the drug is used long term). Doses should be started low and advanced slowly if necessary. Anticonvulsants are perhaps the most rapidly expanding class of migraine therapeutic agents in children, although few of them are studied and approved by the FDA despite widespread use for epilepsy. Many of them can have mood-stabilizing benefits. Because all have some teratogenic risk, folic acid, 400 g, should be recommended to all adolescent female patients. Valproic acid (Depakote) is the most studied agent and is available as sprinkle capsules, liquid, and extendedrelease tablets. It can also be administered intravenously as an abortive agent, to be continued orally on discharge from a hospital setting. Side effects include weight gain, alopecia, and hepatotoxicity. Topiramate (Topamax) has gained significant popularity due to efficacy in adult studies and the side effect of weight loss and can be administered as sprinkle capsules. It is a weak diuretic due to carbonic anhydrase inhibition, so it may have a role in patients with mildly increased intracranial pressure (e.g., pseudotumor or minimal ventriculoperitoneal shunt dysfunction). Other side effects of word finding difficulties, acidosis, and kidney stones can occur and should be discussed. Zonisamide (Zonegran) appears to be similar to topiramate in mechanism of actions as well as weight loss but perhaps
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TABLE 1 Commonly Used Preventive Drugs and Doses

Medication Cyproheptadine Propranolol Verapamil Amitriptyline Nortriptyline Fluoxetine Valproic acid Topiramate Gabapentin Zonisamide Dosages (Pediatric-Friendly Preparations) 2-4 mg qhs (liquid available) 10-40 mg qhs or bid 40-120 mg qhs 10-50 mg qhs 10-50 mg qhs 10-20 mg q AM (liquid) 125-500 mg qhs (liquid, sprinkles) 15-50 mg qhs (sprinkles) 100-600 mg qhs (liquid) 25-100 mg qhs Special Indications Allergies, anorexia Hypertension Hemiplegic migraine Depression, insomnia Depression, insomnia Depression Bipolar, anorexia Obesity, menstrual pattern Bipolar, no drug interactions Obesity Side Effects Sedation, appetite stimulant Avoid in asthma, diabetes, depression Hypotension, constipation Sedation, dry mouth, cardiac conduction Sedation, dry mouth, cardiac conduction Can be activating Weight gain, alopecia, hepatotoxicity Weight loss, renal stones, word finding difficulties Slight weight gain Weight loss, renal stones
may have less risk of cognitive changes. Gabapentin (Neurontin) is available in liquid form and has few side effects and interactions, making it an attractive option for a child with other comorbid conditions requiring many medications (e.g., malignancy). It has clinical experience for pain syndromes such as postherpetic neuralgia and recently for chronic daily headache. Other agents such as lamotrigine and levetiracetam may have a potential role as well. Other Approaches Biofeedback, psychological counseling, massage therapy, stress reduction techniques, yoga, cognitive training, botulinum toxin, and acupuncture all may have some role for individual patients and can be used early in the treatment regimen if indicated. A major benefit to these options involves the de-emphasis on pharmacologic treatments as the sole option, which can lead to rebound headache (discussed later). Chiropractic therapy can occasionally lead to carotid dissection if neck manipulation is aggressively performed; therefore, it should be avoided. REBOUND HEADACHE It is imperative to be aware of the entity of rebound headache, otherwise known as both transformed migraine and medication overuse headache. This disorder has reached epidemic proportions in the community with the increasing availability of products such as Excedrin, ibuprofen, naproxen, and other over-the-counter pain medications. The frequent use, typically two or three or more doses per week for several weeks, of almost any abortive therapies will invariably lead to an increase in headache frequency or even chronic daily headaches. Although opioids and caffeine are traditionally implicated, in my experience ibuprofen is more common. Neither acute nor preventive therapies are effective in this scenario. Despite the adult literature describing this, and television programs such as NBCs Dateline bringing it to public attention, the average pediatrician and parent are unaware of the dangers.
Discontinuation of the offending agent is the only efficacious therapy, with gradual reintroduction after several weeks to a less frequent dosing regimen. Amitriptyline and steroids have been used in some series to help with the transition.
SUMMARY
The quick and accurate diagnosis of migraines as differentiated from a more serious condition causing headache is important for all physicians caring for children. Although relatively common, the diagnosis is often missed. When it is suspected, extensive evaluations including MRI are not required. Realistic treatment strategies using both acute and preventive therapies, while cognizant of the risks of medications used inappropriately, can lead to an extremely gratified child and family. SUGGESTED READING
Lavenstein BA: Comparative study of cyproheptadine, amitriptyline, and propranolol in the treatment of preadolescent migraine, Cephalagia 11(Suppl 11):122-123, 1991. Lewis DW, Ashwal S, Dahl G, et al: Practice parameter: evaluation of children and adolescents with recurrent headaches, Neurology 59:490-498, 2002. Rothner AD, Winner P: Headaches in children and adolescents. In Wolffs headache and other facial pain, ed 7, New York, 2001, Oxford University Press. Stafstrom CE, Rostasy K, Minster A: The usefulness of childrens drawings in the diagnosis of headache, Pediatrics 109:460-472, 2002. Vasconcellos E, Pina-Garza JE, Millan EJ, Warner JS: Analgesic rebound headache in children and adolescents, J Child Neurol 13:443-447, 1998. Winner P, Rothner AD, Saper J, et al: A randomized, double-blind, placebo-controlled study of sumatriptan nasal spray in the treatment of acute migraine in adolescents, Pediatrics 106:989-992, 2000.
PATIENT RESOURCE
American Headache Society: http://www.ahsnet.org/ Johnson: Current Therapy in Neurologic Disease (7/E)
Trigeminal and Glossopharyngeal Neuralgia
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Pharmacologic Options

William P. Cheshire, Jr., M.D.
Trigeminal neuralgia is one of the most severe pain syndromes in human experience. Patients characteristically complain of paroxysmal facial pain that strikes one or more branches of the sensory division of the trigeminal nerve. Most cases involve the maxillary or mandibular territories. Evidence suggests that pulsatile indentation of the trigeminal nerve root by redundant arterial loops leads to focal demyelination and the generation of ectopic neural impulses that conduct ephaptically and spill over into adjacent fibers to yield a painful crescendo. Affected persons report repetitive, momentary attacks of unilateral pain that is typically sharp, lancinating, or electrical in quality. Occasionally more sustained burning or aching pain lasting minutes to hours may also be present. The pain is triggered by light tactile stimulation of a trigger zone usually located in the nasolabial or intraoral region. Daily activities such as washing the face, speaking, smiling, applying facial cosmetics, shaving, brushing the teeth, or exposure to wind can become intolerably painful. Bouts typically continue for weeks to months separated by pain-free remissions lasting months to years. There is a tendency for exacerbations to increase in frequency, although sustained remissions may occur. Glossopharyngeal neuralgia is an infrequent disorder consisting of pain similar in its quality and temporal characteristics, but its location lies at the base of the tongue, the tonsillar fossa, beneath the angle of the jaw, or in the auditory canal, following the distribution of the glossopharyngeal nerve or the auricular or pharyngeal branches of the vagus nerve. Swallowing, speaking, or coughing triggers the painful paroxysms. Spreading of glossopharyngeal impulses via the tractus solitarius into the vagal dorsal motor nucleus often provokes reflex bradycardia, heart block, or asystole resulting in syncope that may require insertion of a cardiac pacemaker.
Diagnosis
In both disorders the diagnosis is reached on the basis of the historical details and normal neurologic and dental examinations. Evaluation should include gadolinium-enhanced cranial magnetic resonance imaging (MRI) with high-resolution axial and coronal sectioning of the posterior fossa to exclude the possibility of a cerebellopontine angle tumor or a central demyelinating disorder. Unambiguous imaging of trigeminal vascular compression and nerve root demyelination are beyond the level of current MRI resolution.
Accurate diagnosis is important because trigeminal and glossopharyngeal neuralgia respond to antiepileptic medications but not to traditional analgesics. The mechanism is believed to be neural membrane stabilization or enhancement of gamma-aminobutyric (GABA)ergic trigeminal segmental inhibition. Nonsteroidal anti-inflammatory drugs, tricyclics, and opioids, for example, produce little if any relief. In most cases I initiate treatment with carbamazepine because of its superior efficacy (Figure 1). A starting dose of 100 mg two or three times daily is increased by 100 mg every other day until adequate pain relief is achieved or until intolerable side effects (usually sedation and ataxia) intervene. Typical effective maintenance doses are 300 to 800 mg daily and need not always be as high as those used to treat epilepsy. Pain can be completely controlled in some patients on 200 to 300 mg daily. Self-limited initial and dose-dependent side effects such as drowsiness, nausea, dizziness, ataxia, or diplopia can often be managed by titrating slowly. Uncommon but potentially serious adverse reactions can include allergic rash, bone marrow suppression, hepatotoxicity, lymphadenopathy, lupus erythematosus, Stevens-Johnson syndrome, and aplastic anemia. A complete blood count, serum sodium, and liver function tests should be checked within several weeks of initiating therapy and at least biannually thereafter. For the patient who, because of advanced age or medical comorbidity, is less able to tolerate carbamazepine, I may initiate treatment with gabapentin (see Figure 1). Although less efficacious than carbamazepine, gabapentin lacks serious adverse effects or drug interactions. A starting dose of 300 mg daily may be increased as tolerated by 300 mg every 3 days, divided three times a day, up to 2700 mg daily. Side effects may include dizziness, drowsiness, or peripheral edema. If pain persists, baclofen administered in combination or alone may be started at 5 to 10 mg three times a day. The daily dose is increased by 10 mg every other day as tolerated up to 60 mg daily. Common side effects are drowsiness, dizziness, asthenia, and gastrointestinal distress. If pain persists, I will promptly move on to oxcarbazepine or lamotrigine, either of which is a reasonable first- or second-line therapy. Oxcarbazepine is started at 150 mg twice daily and the daily dose increased as tolerated by 300 mg every 3 days to a typical maintenance dose of 300 to 600 mg twice daily. Side effects are similar to those of carbamazepine except that hyponatremia is more frequent. Lamotrigine is started at 25 mg twice daily and should be increased slowly by 100 mg/day every 1 to 2 weeks. Daily doses of 100 to 400 mg divided twice daily have been effective. Side effects may include diplopia, ataxia, dizziness, headache, and gastrointestinal distress. Lamotrigine should be promptly discontinued at the first sign of any rash, because serious rashes including Stevens-Johnson syndrome have occurred in approximately 0.1% of patients and usually appear within 2 to 8 weeks of starting treatment.
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Paroxysmal facial pain
Normal neurological exam
Diagnosis of trigeminal neuralgia
Carbamazepine
Pain persists Add baclofen
Not tolerated Gabapentin
Pain persists or drugs not tolerated
Oxcarbazepine or Lamotrigine or Topiramate or Levetiracetam or Phenytoin Retry previously effective then other drugs Pain persists or drugs not tolerated
Surgical referral
Balloon compression or Microvascular decompression or Gamma knife
Pain recurs
FIGURE 1. Suggested scheme for treating trigeminal neuralgia. The same pharmacologic strategy may be applied to the treatment of glossopharyngeal neuralgia. The order of choices differs for individual patients.
I have found the newer anticonvulsants topiramate and levetiracetam also to be effective in occasional patients. Topiramate is started at 25 mg once or twice daily, and the daily dose may be increased by 25 mg every 3 days as tolerated to 100 to 400 mg divided twice daily. Side effects can include anorexia, weight loss, somnolence, anxiety, fatigue, psychomotor slowing, urolithiasis, and glaucoma. Levetiracetam is started at 500 mg twice daily, which can be doubled after 2 weeks. Side effects can include somnolence, asthenia, and dizziness. For the patient with refractory pain, potentially useful further options are phenytoin, clonazepam, and sodium divalproex.
the drug reaches steady state, if pain persists, the dosage should be increased within the limits of safety and tolerability. In contrast, starting at too high a dose or increasing the dose too rapidly could influence the patient to dismiss what might ultimately have proved to be a tolerable and effective drug. In such cases a retrial at a lower dose may be worthwhile. Decreased elimination half-life sometimes results in an apparent loss of efficacy over time and can be corrected by slightly increasing the drug dosage. Tachyphylaxis can develop months to years into treatment such that pain recurs despite increasing the dose of a previously effective drug. It is then time to advance to a second drug. I prefer to continue the first drug during the transition phase into the second drug, tapering the first drug once pain relief is achieved. The first drug may again prove effective if reintroduced months or years later. Since the natural history of trigeminal neuralgia consists of spontaneous remissions, I advise my patients to taper their medication once the pain has remained under control for a month. Incremental decreases on a weekly schedule are aimed at finding the lowest dose necessary to maintain freedom from pain. Medication should not be discontinued abruptly after long-term administration. I will also advise the patient who is pain free off medication to keep a ready standby supply not only at home but also when traveling in case the pain returns suddenly. I will honor the request of the occasional patient who may be in complete remission yet chooses to remain on medication for fear that excruciating pain might otherwise return, while tapering to the lowest possible dose. Neuralgia sometimes escalates to the point of crisis in the patient who presents in a state of desperate pain, losing weight and hydration because attempts to eat or drink set off more attacks. When urgent control of extreme pain is needed, treatment with intravenous fosphenytoin can provide reliable relief and usually requires a full loading dose of 14 mg/kg. Relief typically lasts 2 days and affords a window of opportunity for a simultaneously administered new oral medication to take hold or to prepare for surgical referral. Lidocaine, applied transcutaneously via patch or intraorally via viscous gel, or ophthalmic instillation of 0.5% proxymetacaine drops also may provide temporary relief.
Surgical Referral
Generally I reserve surgical referral for patients whose pain has proved refractory to a sufficient trial of at least three medications including carbamazepine. The most severe cases may warrant expedited medication trials while arranging neurosurgical backup. Some patients with pain very nearly controlled will nevertheless request surgery because they do not wish to endure the subtle cognitive side effects of long-term medication. Surgical intervention is best accomplished by a neurosurgeon who performs trigeminal nerve procedures regularly. Fluoroscopically guided ablative procedures include radiofrequency thermocoagulation and neurolysis using
Management Strategy
When initiating therapy, the clinician must balance the need to achieve rapid relief from pain with the need to avoid troublesome side effects. Increasing the dose too slowly can prolong the agony of neuralgia. As soon as
83
glycerol, phenol, or streptomycin. First-division lesions carry the risk of corneal anesthesia, which can lead to keratitis. Third-division lesions may alter lingual sensation and affect speech. All carry the risk of anesthesia dolorosa, which is an enduring, continuous burning trigeminal pain that tends to respond poorly to medication. Among my patients I have seen the most favorable outcomes following percutaneous balloon compression of the trigeminal ganglion. Results are frequently satisfactory and long lasting, and this procedure seems to carry the least risk of compromising corneal sensation or inducing anesthesia dolorosa. Suboccipital microvascular decompression of the trigeminal nerve root is unique in that it addresses the presumed underlying pathology. Although highly effective and less likely than neurodestructive procedures to impair facial sensation, this procedure carries nontrivial risks of cranial nerve deficits, stroke, cerebellar hemorrhage, and more rarely, meningitis, air embolism, and seizures. Stereotactic gamma knife radiosurgery targeting the trigeminal nerve origin is a minimally invasive intervention that has shown promising initial results. Its main disadvantage is that the time to response is several months. Medically intractable glossopharyngeal neuralgia is likewise amenable to vascular decompression. Also helpful has been surgical sectioning of the glossopharyngeal nerve, which can be complicated by severe hypertension due to baroreflex denervation. Treating patients with trigeminal neuralgia is a rewarding part of the practice of neurology because successful treatments are available. The choice of specific treatment, whether medical or surgical, should be tailored to the individual patients needs. SUGGESTED READING
Cheshire WP: Trigeminal neuralgia: diagnosis and treatment, Curr Neurol Neurosci Rep 5:79-85, 2005. Cheshire WP: Defining the role for gabapentin in the treatment of trigeminal neuralgia: a retrospective study, J Pain 3:137-142, 2002. Cheshire WP: Fosphenytoin: an intravenous option for the management of acute trigeminal neuralgia crisis, J Pain Symptom Manage 21:506-510, 2001. Cheshire WP: Trigeminal neuralgia: a guide to drug choice, CNS Drugs 7:98-110, 1997. Fromm GH, Sessle BJ, editors: Trigeminal neuralgia: current concepts regarding pathogenesis and treatment, Boston, 1991, Butterworth-Heinemann.

Ricardo Cruciani, M.D., Ph.D., and Sallu Jabati, M.D.
Definition
Herpes zoster is an acute, painful sensory mononeuropathy associated with a skin eruption due to a herpesvirus infection. In 90% of the cases it resolves in days to weeks, but 10% of patients progress into a debilitating, chronic, painful condition known as postherpetic neuralgia (PHN).
Etiology
The offending agent is the varicella zoster virus, a member of the herpes virus family that in children causes chickenpox. After the infection resolves, the virus remains dormant in the dorsal root ganglia. Years to decades after the chickenpox infection, for unclear reasons there is a reactivation of the virus in 2% of immunocompetent and 10% of immunocompromised patients. The virus replicates in the dorsal root ganglia, causing an inflammatory response with swelling, hemorrhage, areas of necrosis, and neuronal loss. Subsequently, the virus travels centrifugally along the nerve (producing in its course nerve inflammation and damage), to the skin, forming a self-limited rash known as shingles. This consists of multiple vesicular lesions with a red base from which multinucleated cells can be identified in a Tzanck smear. On occasion, the virus may travel centripetally toward the spinal cord (involving both sensory and motor areas) and the brainstem. In 50% of immunocompromised patients a generalized lifethreatening viral dissemination involving the central nervous system with a 10% to 20% mortality rate (encephalitis, angiitis) may develop, instead of the local reactivation of the virus.
Clinical Presentation
Herpes zoster usually starts with a prodromal phase characterized by pain, paresthesias (numbness/tingling), and dysesthesias (unpleasant sensations) in the affected dermatomes in a beltlike fashion followed a few days later by a maculopapular rash that evolves into vesicles. The vesicles do not cross the midline and can be quite painful, especially in the elderly. The characteristic vesicles usually scab over within 10 days and heal in a month, leaving behind a hypopigmented scar. Infrequently the prodrome is not followed by the skin lesions (zoster sine herpete), and laboratory work may be necessary to identify antibodies to herpes zoster. A fourfold increase has been used to support the
PATIENT RESOURCE
Trigeminal Neuralgia Association: http://www.tna-support.org/
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glycerol, phenol, or streptomycin. First-division lesions carry the risk of corneal anesthesia, which can lead to keratitis. Third-division lesions may alter lingual sensation and affect speech. All carry the risk of anesthesia dolorosa, which is an enduring, continuous burning trigeminal pain that tends to respond poorly to medication. Among my patients I have seen the most favorable outcomes following percutaneous balloon compression of the trigeminal ganglion. Results are frequently satisfactory and long lasting, and this procedure seems to carry the least risk of compromising corneal sensation or inducing anesthesia dolorosa. Suboccipital microvascular decompression of the trigeminal nerve root is unique in that it addresses the presumed underlying pathology. Although highly effective and less likely than neurodestructive procedures to impair facial sensation, this procedure carries nontrivial risks of cranial nerve deficits, stroke, cerebellar hemorrhage, and more rarely, meningitis, air embolism, and seizures. Stereotactic gamma knife radiosurgery targeting the trigeminal nerve origin is a minimally invasive intervention that has shown promising initial results. Its main disadvantage is that the time to response is several months. Medically intractable glossopharyngeal neuralgia is likewise amenable to vascular decompression. Also helpful has been surgical sectioning of the glossopharyngeal nerve, which can be complicated by severe hypertension due to baroreflex denervation. Treating patients with trigeminal neuralgia is a rewarding part of the practice of neurology because successful treatments are available. The choice of specific treatment, whether medical or surgical, should be tailored to the individual patients needs. SUGGESTED READING
Cheshire WP: Trigeminal neuralgia: diagnosis and treatment, Curr Neurol Neurosci Rep 5:79-85, 2005. Cheshire WP: Defining the role for gabapentin in the treatment of trigeminal neuralgia: a retrospective study, J Pain 3:137-142, 2002. Cheshire WP: Fosphenytoin: an intravenous option for the management of acute trigeminal neuralgia crisis, J Pain Symptom Manage 21:506-510, 2001. Cheshire WP: Trigeminal neuralgia: a guide to drug choice, CNS Drugs 7:98-110, 1997. Fromm GH, Sessle BJ, editors: Trigeminal neuralgia: current concepts regarding pathogenesis and treatment, Boston, 1991, Butterworth-Heinemann.

Ricardo Cruciani, M.D., Ph.D., and Sallu Jabati, M.D.
Definition
Herpes zoster is an acute, painful sensory mononeuropathy associated with a skin eruption due to a herpesvirus infection. In 90% of the cases it resolves in days to weeks, but 10% of patients progress into a debilitating, chronic, painful condition known as postherpetic neuralgia (PHN).
Etiology
The offending agent is the varicella zoster virus, a member of the herpes virus family that in children causes chickenpox. After the infection resolves, the virus remains dormant in the dorsal root ganglia. Years to decades after the chickenpox infection, for unclear reasons there is a reactivation of the virus in 2% of immunocompetent and 10% of immunocompromised patients. The virus replicates in the dorsal root ganglia, causing an inflammatory response with swelling, hemorrhage, areas of necrosis, and neuronal loss. Subsequently, the virus travels centrifugally along the nerve (producing in its course nerve inflammation and damage), to the skin, forming a self-limited rash known as shingles. This consists of multiple vesicular lesions with a red base from which multinucleated cells can be identified in a Tzanck smear. On occasion, the virus may travel centripetally toward the spinal cord (involving both sensory and motor areas) and the brainstem. In 50% of immunocompromised patients a generalized lifethreatening viral dissemination involving the central nervous system with a 10% to 20% mortality rate (encephalitis, angiitis) may develop, instead of the local reactivation of the virus.
Herpes zoster usually starts with a prodromal phase characterized by pain, paresthesias (numbness/tingling), and dysesthesias (unpleasant sensations) in the affected dermatomes in a beltlike fashion followed a few days later by a maculopapular rash that evolves into vesicles. The vesicles do not cross the midline and can be quite painful, especially in the elderly. The characteristic vesicles usually scab over within 10 days and heal in a month, leaving behind a hypopigmented scar. Infrequently the prodrome is not followed by the skin lesions (zoster sine herpete), and laboratory work may be necessary to identify antibodies to herpes zoster. A fourfold increase has been used to support the
PATIENT RESOURCE
Trigeminal Neuralgia Association: http://www.tna-support.org/
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diagnosis of subclinical herpes zoster. However, a rising titer secondary to viral exposure rather than reactivation cannot be ruled out. The elderly individual undergoing high levels of stress, and immunocompromised patients (acquired immunodeficiency syndrome, cancer, treatment with steroids, chemotherapy, transplant recipients, or immunosuppressant), are at high for herpes zoster infection. After the scab forms, the lesions are not contagious. The scarred areas are less sensitive and often anesthetic. Paradoxically the skin may exhibit marked superficial pain with light touch (allodynia) or an increased sensitivity to noxious stimulation (hyperalgesia). In most patients the resolution of the skin lesions is accompanied by decreased pain. The reactivation typically affects one thoracic dermatome unilaterally (does not cross midline), but it can affect multiple sites including limbs and cranial nerves. The more commonly affected cranial nerve is the ophthalmic branch of the fifth nerve (V1) and the infection may involve the eye, producing keratitis and/or uveitis. Aggressive treatment is crucial to avoid subsequent scarring and compromised vision. Early consultation with ophthalmology is highly recommended. Palsies of cranial nerves III, IV, and VI can also occur. When shingles affects the geniculate ganglion, it is called Ramsay Hunt syndrome and can cause facial paralysis, hearing loss, and vertigo and pain. Vesicles in the tympanic membrane may be the only observable sign. The most common complication of herpes zoster is PHN. This is usually a self-limited condition defined as pain persisting beyond 3 months of the resolution of the skin lesions. The most well-established risk factors for PHN are older age, greater severity of acute pain during zoster, more severe rash, and a prodrome of dermatomal pain before onset of the rash. Symptoms tend to abate over time. Less than one fourth of the patients still experience pain at 6 months after the herpes zoster eruption, and fewer than one in 20 has pain at 1 year. Patients may complain of a steady burning or aching pain with or without paroxysmal lancinating pain. Both may occur spontaneously and may be aggravated by even the lightest contact. It is not unusual for patients to complain that they cannot tolerate the contact of clothing or the bed sheets at night. Some have to stay away from fans or air conditioning; even the light breeze provoked by fast walking can cause significant discomfort. Physical activity, temperature change, and emotional upsets may cause the exacerbation of the pain. The patients quality of life can become severely affected, and depression may develop.
been speculated that aggressive treatment of the acute infection may prevent plastic changes in the central nervous system that may be responsible for the development of PHN. There is some evidence that the use of antiviral agents (acyclovir, valacyclovir, famciclovir) within the first 72 hours may prevent viral replication and thus reduce the severity of the acute eruption and the incidence of PHN. The use of amitryptiline (a tricyclic antidepressant), 10 to 50 mg/day, may also have a similar preventive effect. Prednisone has been used with a variable degree of success with the same objective. In at least one study, when administered close to the onset of the episode, steroids can decrease pain at 3 and 12 months. Other studies have demonstrated no benefit. However, when used in conjunction with acyclovir it has been shown to reduce the pain associated with herpes zoster. Hence, if there are no contraindications, oral prednisone can be used in the treatment of the herpes zoster episode despite unclear evidence on the prevention of PHN (Figure 1).
Treatment of Postherpetic Neuralgia

A pharmacologic approach is the standard of care. A number of antidepressants and anticonvulsants have been advocated for the treatment of this condition. There are several general concepts that may increase the success rate in the treatment of PHN that could also be applied to other forms of neuropathic pain. They include the following: The results are variable and the selection of the pharmacologic agent has to be customized to the individual patient. It is important to consider that failure to respond to an antidepressant or an anticonvulsant does not preclude response to a different agent from the same pharmacologic family. Be aware that there is a significant degree of variability in the dose range and time before pain relief is seen. Discussion of the treatment plan with the patient may increase compliance. For a trial to be considered negative, it has to cover an extensive dose range and last for at least 4 to 6 weeks. Failure of treatment is commonly associated with inadequate titration of dose and/or short trial duration. There is no correlation between plasma levels and response. It is recommended to start at a low dose to decrease the incidence of side effects, a common cause for abandonment of treatment.
Treatment of Herpes Zoster

ANTICONVULSANTS The acute pain can be treated topically and systemically. Covering the lesions with calamine lotion, petroleum jelly, local anesthetic creams, or an occlusive bandage may give some symptomatic relief. Systemic medications include nonsteroidal anti-inflammatory drugs with or without codeine, but due to the intensity of the pain, more potent opioids may be indicated. It has Gabapentin Gabapentin has been shown to be of benefit in the treatment of PHN in two double-blind, placebo-controlled studies. Owing to its low incidence and severity of side effects, it has been advocated as a first-line drug for the treatment of PHN. Although its mechanism of action
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CNS involvement (myelitis/angiitis)
Herpes zoster (shingles)
Herpes zoster ophthalmicus (keratitis/retinitis) Early referral to ophthalmology IV acyclovir 10 mg/kg every 8 h for 7 to 14 days Prevention of corneal exposure
Acyclovir 10 mg/kg q8h (adults) or 500 mg/m2 body surface (children) for 7 days. Prednisone 6080 mg/day for 35 days Stop treatment if negative zoster PCR in the CSF.
Skin lesions
No lesions (zoster sine herpete)
Topical
Acute pain
Systemic
Cover area Calamine After scab forms may use lidocaine cream or patch
Persistent pain >13 months after resolution of skin lesions
Acyclovir: PO: 800 mg five times daily for 7 to 10 days IV: 10 mg/kg every 8 hours for 7 to 10 days or Famciclovir: 500 mg orally three times daily for 7 days or Valacyclovir: 1,000 mg orally three times daily for 7 days Prednisone: 30 mg orally twice daily for 7 days then 15 mg twice daily for 7 days then 7.5 mg twice daily for 7 days Amitriptyline: elderly: 10 mg qhs, others 20 mg qhs. Titrate up to 100150 mg/day qd if needed and tolerated
Topical
Chronic pain postherpetic neuralgia (PHN)
Systemic
Lidocaine patch 5%, 12h on, 12h off; up to 3 patches at a time (minimum of 2 weeks trial) Capsaicin 0.075%. Initial exacerbation of pain limits its use.
NSAIDs + adjuvants: Gabapentin: 300 mg/day for 3 days, then b.i.d. for 3 days, then t.i.d., then double. If additional benefit then continue titration up to 3600 mg/day. If side effects Tiagabine: 150300 mg/day If no effect Amitriptyline (if already on it, titrate) elderly: 10 mg qhs, others 20 mg qhs. Titrate up to 100150 mg/day q.d. if needed and tolerated If no effect or side effects Newer anticonvulsants (topiramate, levetiracetam, lamotrigine, oxcarbazepine) or other antidepressants (desipramine, nortriptyline) Opioids: May use at initiation of treatment for intense pain. Oxycodone 5 mg tabs q 4h. Once taking >20 mg q.d. introduce long-acting form.
No response or intolerable side effects
Nerve blocks Spinal cord stimulation Intrathecal methylprednisolone
FIGURE 1. Algorithm for approach to the treatment of herpes zoster. PCR, Polymerase chain reaction; CSF, cerebrospinal fluid; CNS, central nervous system; NSAIDs, nonsteroidal anti-inflammatory drugs.
has been elusive for many years, recently it has been shown to bind to the alpha2-delta subunits of the voltage-sensitive calcium channels. Its pharmacokinetic profile (with renal excretion) makes it safe in patients taking a variety of medications. Since only 10% binds to plasma proteins, the drug has little effect on the
international normalized ratio in patients on warfarin (Coumadin) anticoagulation. The liver does not metabolize gabapentin; hence, it does not compete for the P-450 with the selective serotonin receptor inhibitors. The dose may need to be reduced in patients with elevated creatinine.
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Pregabalin In a double-blind, placebo-controlled clinical trial, pregabalin in doses ranging from 150 to 300 mg/day reduced pain scores by more than 50% in patients with PHN. The mechanism of action and side effect profile are similar to those of gabapentin. However, since it has a linear pharmacokinetic profile, there is less interindividual variability and the dose range is more narrow and predictable. It also may have fewer side effects than gabapentin. Other Anticonvulsants When an adequate response is not achieved or in the presence of unacceptable side effects, trials with other anticonvulsants can be attempted. Topiramate, lamotrigine, levetiracetam, zonegram, and tiagabine have been shown to be of help in certain forms of neuropathic pain, and they may be helpful in the treatment of PHN. Both carbamazepine and phenytoin have been used in the past with some degree of success, but their use has been relegated to second- or third-line agents due to the high incidence and severity of side effects. ANTIDEPRESSANTS Amitriptyline Among the tricyclic antidepressants, amitriptyline is the most extensively studied. In a double-blind, placebocontrolled clinical study, amitriptyline showed significant pain relief in patients with PHN. Unfortunately the tricyclics may cause dose-limiting side effects due to their anticholinergic activity. Side effects (dry mouth, impotence, constipation, urinary retention, tachycardia, confusion) may be ameliorated by starting at low doses, slow titration, and night administration when possible. Side effects are more prominent in the elderly. The starting dose is 10 to 20 mg and because of potential somnolence and sedation, it should be given at bedtime. This side effect may be of help in patients with insomnia, a common comorbidity in chronic pain patients. On occasion, doses of 100 to 150 mg a day may be necessary. When dosing above 75 to 100 mg a day (or lower if side effects are observed), blood levels should be determined to avoid toxicity. Desipramine, a tricyclic with less severe anticholinergic effects, and nortriptyline have also been shown to be effective in controlled studies for the treatment of PHN. OPIOIDS Depending on the intensity of the pain, opioids may need to be introduced early in the treatment plan for both herpes zoster and PHN. A placebo-controlled clinical study with the extended form of oxycodone has shown significant pain relief in patients with PHN. The opioids, when used in the right context, can be a valuable tool. The patient must be warned of the potential side effects, which include physical dependence, constipation, nausea/vomiting, sedation, and the potential for addiction. If certain guidelines are followed (patient
cannot change dosing on his or her own, only one practitioner writes the prescriptions, utilization of only one pharmacy, frequent assessments), they are safe to use. Patients with a history of drug abuse can represent a unique challenge. When treating patients who are attending a methadone program, it is advisable to discuss the plan with the methadone maintenance treatment program clinic counselor and use methadone for the treatment of pain. Methadone is an interesting drug that, due to its low cost and long half-life, has been advocated for the treatment of chronic pain. The formulation available in the United States is a racemic form. While the L-enantiomer activates mu opioid receptors inducing analgesia, the D-enantiomer blocks (weakly) N-methyl-D-aspartatemediated excitatory responses, believed to be exacerbated in neuropathic pain. Urine toxicology, pill counting, and contracts are useful tools that have to be tailored to the patient. LOCAL ANESTHETICS Topical Lidocaine Double-blind, placebo-controlled trials with lidocaine 5% in a patch form have been shown to alleviate pain in PHN. Up to three patches can be used at a given time. The patches should be used 12 hours on and 12 hours off. No significant side effects have been observed with this regimen. The patch can be used alone or in combination with other adjuvants (e.g., gabapentin). The combination of the lidocaine patch with gabapentin has proved to be more effective than the two agents separately. Intravenous Lidocaine The pain crisis may be managed with intravenous (IV) administration of lidocaine. This procedure can be done on an outpatient basis. When pain scores improve more than 50%, oral mexiletine can be initiated. The IV dose is converted into an equivalent oral dose, and the titration up can be continued by 150 mg at a time every 3 to 4 days if tolerated. Patients may require up to 400 to 500 mg a day to experience relief. Capsaicin Capsaicin 0.075% cream has been shown to decrease pain. The initial application may temporarily exacerbate pain possibly due to depletion of substance P or activation of nociceptors, which frequently results in abandonment of treatment.
Conclusion
Although the literature is not conclusive, it is recommended to treat herpes zoster infection aggressively to decrease PHN. No single best treatment for PHN is known. Both topical and systemic therapies can be initiated simultaneously. If the pain is very intense, opioids can be initiated early into the regimen.
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SUGGESTED READING
Davis PS, Gailor BS: Review of lidocaine patch 5% studies in the treatment of postherpetic neuralgia, Drugs 64:937-947, 2004. Dworkin RH, Schmader KE: Epidemiology and natural history of herpes zoster and postherpetic neuralgia. In Watson CPN, Gershon AA, editors: Herpes zoster and postherpetic neuralgia, ed 2, New York, 2001, Elsevier, 39-64. Helgason S, Petursson G, Gudmundsson S, et al: Prevalence of postherpetic neuralgia after a first episode of herpes zoster: prospective study with long-term follow-up, BMJ 321:794-796, 2000. Raja SN, Haythornthwaite JA, Pappagallo M, et al: Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebocontrolled trial, Neurology 59:1015-1021, 2002. Rowbotham M, Harden N, Stacey B: Gabapentin for the treatment of postherpetic neuralgia: a randomized, controlled trial, JAMA 280:1837-1842, 1998.
Sabatowski R, Galvez R, Cherry DA, et al, and the 1008-045 Study Group: Pregabalin reduces pain and improves sleep and mood disturbances in patients with postherpetic neuralgia: results of a randomized, placebo-controlled clinical trial, Pain 109:26-35, 2004. Tyring S, Barbarash RA, Nasklik JE: Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo-controlled trial. Collaborative Famciclovir Herpes Zoster Study Group, Ann Intern Med 123:89-96, 1995. Watson CP, Vernich L, Chipman M: Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial, Neurology 51:1166-1171, 1998. Whitley RJ, Shukla S, Crooks RJ: The identification of risk factors associated with persistent pain following herpes zoster, J Infect Dis 178(Suppl 1):S71-S75, 1998.
SECTION 5
Developmental Disorders
Steven P. Miller, M.D., C.M., F.R.C.P.C.
hypocalcemia, hyponatremia, hypoxemia, and acidosis are frequently seen and should be identified and treated. Lumbar puncture should be performed if the history is not typical for hypoxic-ischemic encephalopathy to rule out intracranial infections. Neuroimaging has become increasingly important for the accurate diagnosis of neonatal encephalopathy in the term newborn. The American Academy of Neurology practice parameter suggests that a noncontrast computed tomography (CT) scan should be performed to detect hemorrhagic lesions with a history of birth trauma, low hematocrit, or coagulopathy. If CT findings are inconclusive, magnetic resonance (MR) imaging should then be performed (on days 2 and 8 of life) to establish the pattern of injury and predict neurologic outcome. Other observations suggest that CT scan is not often helpful in making a diagnosis since it is relatively insensitive to changes in water content and because injury in the posterior fossa can be obscured by bony artifact. Given this, CT is best used to determine the extent of bleeding in an emergency situation where MR imaging is not available. MR imaging has proved to be a sensitive technique to determine injury in term neonatal encephalopathy and can help establish the diagnosis of hypoxic-ischemic injury. MR imaging helps to narrow the differential diagnosis in the evaluation of an encephalopathic neonate who might have an underlying metabolic, neurogenetic, neurovascular, or inflammatory disease requiring intervention. As the first step in caring for an encephalopathic newborn is establishing the diagnosis, MR imaging should be performed in the first week of life as the diagnostic test of choice. Additionally, MR imaging, particularly in combination with MR spectroscopy, can provide important prognostic information. Regardless of the specific etiology, the importance of the immediate management of neonatal encephalopathy cannot be overestimated. The management of moderate or severe encephalopathy should occur in a neonatal intensive care unit in close collaboration with a neonatologist. Immediate management requires securing an appropriate airway and maintaining adequate ventilation and circulation. As discussed earlier, an important component of the diagnostic work-up is to identify treatable conditions causing neonatal encephalopathy that require specific therapy. Blood tests obtained routinely are serum glucose, arterial or capillary blood gas, 89
Neonatal encephalopathy is a major cause of neurodevelopmental disability in term infants, occurring in 1 to 6 per 1000 live term births. Neonatal encephalopathy is a serious condition: 15% to 20% of affected infants will die during the newborn period, and an additional 25% will sustain permanent clinical deficits. Hypoxic-ischemic encephalopathy certainly accounts for a substantial proportion of these patients, yet many cases of neonatal encephalopathy have no documented hypoxic-ischemic insult. Furthermore, there is continuing controversy as to whether neonatal encephalopathy is primarily related to insults sustained in the antepartum or intrapartum period. For the purpose of this article, the term neonatal encephalopathy is used instead of hypoxic-ischemic encephalopathy, in recognition of the many variables in the etiology and timing of this syndrome. As many causes of neonatal encephalopathy have specific therapies, a critical part of management is to determine the diagnosis. The diagnosis is made through careful history taking and neurologic examination, with laboratory studies to exclude conditions with specific therapy. Metabolic abnormalities (including inborn errors of metabolism), infection, trauma, and malformations of cerebral development all can result in neonatal encephalopathy. The history should elicit indicators of intrauterine distress: fetal heart tracing abnormalities, passage of meconium, or difficulty in labor or delivery that may have contributed to decreased placental or fetal blood flow. Hypoxicischemic brain injury is frequently accompanied by a history of difficult resuscitation including cardiopulmonary resuscitation, medications in the delivery room, intubation, and assisted ventilation at birth. Seizures, apneic episodes, jitteriness, and abnormal cry all are indicators of brain injury but do not identify the etiology of the injury. Because the clinical signs are often not specific for an etiology, laboratory tests are critical to exclude reversible causes of neonatal encephalopathy. Metabolic complications such as hypoglycemia,
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electrolytes (including calcium and magnesium), and a complete blood count with differential. Determinations of liver enzymes and serum creatinine are performed to detect injury in other end organs. If the history or examination is atypical for hypoxic-ischemic injury, a lumbar puncture is performed to rule out intracranial infections, and serum ammonia and lactate levels are obtained to expedite the investigation of an inborn error of metabolism. If infection is suspected, ampicillin and gentamicin are empirically started in addition to acyclovir if herpes simplex virus infection is suspected. If an inborn error of metabolism is suspected based on the history, examination, and the initial laboratory investigations, early treatment is crucial. Management in this situation, in consultation with a biochemical geneticist, includes stopping feeds, correcting acidosis and hypoglycemia, and considering hemodialysis based on the specific metabolic disorder. Additional diagnostic tests such as serum amino acids and urine organic acids are required to identify the specific disorder. The diagnosis of a severe intracranial hemorrhage on neuroimaging should prompt consultation with a neurosurgeon to manage raised intracranial pressure from mass effect or hydrocephalus and confirmation of platelet levels and coagulation function. In cases where neonatal encephalopathy is caused by hypoxic-ischemic injury, it is important to point out that at this time there is no specific treatment for the injury. The specific management of neonatal hypoxic-ischemic brain injury, therefore, focuses on preventing secondary brain injury. Since the clinical syndrome evolves considerably over the first 72 hours of life, management of specific complications can often be anticipated. As the clinical signs and symptoms depend on the severity, timing, and duration of the insult, it is extremely helpful to perform serial neurologic examinations. The severity of the encephalopathy can be measured daily for the first 3 days of life using a simple bedside encephalopathy score (Table 1). Not only is this score helpful in determining prognosis but it allows the management team to monitor the evolution of the clinical syndrome. The evolution of the clinical syndrome associated with hypoxic-ischemic injury is described in detail by Volpe (see Suggested Reading). The first 12 hours after birth are dominated by a depressed level of consciousness and
breathing abnormalities, including apnea. Ventilatory support with mechanical ventilation or continuous positive airway pressure is often required. Significant bradycardia and hypotension may require treatment with agents such as dopamine. Cerebral cortical involvement may present as hypotonia with decreased movement or as jitteriness. Seizures are seen in 50% of severely affected infants by 6 to 12 hours after birth. Seizures at this stage are often subtle, manifesting as ocular movements such as tonic horizontal eye deviation, tongue or lip smacking, bicycling movements of the extremities or as recurrent apnea. It is therefore important to alert the nursing staff to identify and document paroxysmal behaviors. Multifocal or focal clonic seizures may also occur, and they often indicate focal cerebral infarction. The management of neonatal seizures is outlined later. During the 12- to 24-hour period after the injury there is an apparent increase in the level of alertness that is not accompanied by other signs of improvement in neurologic function. This should not be falsely reassuring because it is frequently accompanied by more seizures and apneic episodes. An electroencephalogram (EEG) is helpful on the first day to assess background activity and determine the presence of electrographic seizures. After 24 to 72 hours following severe brain injury the infants level of consciousness deteriorates again, often accompanied by brainstem and respiratory depression requiring ventilatory support. During this period cerebral edema resulting from hypoxia-ischemia is maximal and can further impair cerebral blood flow secondary to increased vascular pressure. Most investigators avoid treatment of cerebral edema in this setting, because many interventions such as corticosteroids, hyperventilation (PaCO2 of 20 to 25 mm Hg), furosemide, or mannitol may be harmful. Follow-up EEG during this period is used primarily to determine the progression of background activity. Infants surviving beyond 72 hours often have an improvement in level of consciousness, needing less intensive care but requiring attention to feeding because suck and swallow often remain impaired. Neonatal seizures require treatment to prevent secondary brain injury, either from the seizures themselves or from the associated impairments in respiration and hemodynamics. Anticonvulsant medication should be
TABLE 1 Neonatal Encephalopathy Score*

Encephalopathy Feature Feeding Alertness Tone Respiratory status Reflexes Seizure Total Abnormal Signs Gavage feeds, gastrostomy tube, or not tolerating oral feeds Irritable, poorly responsive, or comatose Hypotonia or hypertonia Respiratory distress (need for CPAP or mechanical ventilation) Hyperreflexia, hyporeflexia, or absent reflexes Suspected or confirmed clinical seizure Score if Abnormal 1 1 1 1 1 2 0 -7
*Because the duration of an abnormal neurologic examination is usually helpful in predicting long-term neurologic disability, newborns are scored daily for the first 3 days of life and the maximum score is considered. CPAP, Continuous positive airway pressure.
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initiated only after adequate ventilation and perfusion have been established and the blood glucose concentration has been measured. The following guidelines are presented for the treatment of neonatal encephalopathy with seizures: Ensure adequate ventilation and perfusion. Correct metabolic disturbances, in particular hypoglycemia, hyponatremia, hypocalcemia, and hypomagnesemia. Begin anticonvulsant therapy. The three main anticonvulsants for use in the newborn are the following: Phenobarbital: 20 mg/kg intravenously (IV); if necessary, administer additional 10 to 20 mg/kg IV in 10 mg/kg aliquots. Monitor blood pressure and respiration. A therapeutic drug level of 40 microgram/ml or greater is targeted. Maintenance dose is 4 to 6 mg/kg per 24 hours IV or orally (PO). Lorazepam: 0.05 to 0.1 mg/kg IV over several minutes. Again, monitor closely for respiratory depression. The half-life of lorazepam in asphyxiated newborns can be as long as 40 hours, with duration of action from 6 to 24 hours. Lorazepam can be repeated at this dose (0.05 to 0.1 mg/kg IV) every 6 to 8 hours as short-term maintenance if necessary. Phenytoin: 20 mg/kg IV (diluted in 0.9% NaCl); maximal rate is 1 mg/kg/min. Monitor cardiac rate and rhythm. Maintenance dose is 5 mg/kg IV per 24 hours. Note that phenytoin is poorly absorbed orally in the newborn and is not recommended as oral maintenance therapy. Pyridoxine deficiency is a rare cause of neonatal seizures and should be considered in any newborn with intractable seizures. The diagnosis is made by pyridoxine IV with concurrent EEG. The literature supports the use of phenobarbital as the first-line agent and phenytoin as a second-line agent for seizures associated with neonatal encephalopathy. These medications, especially phenobarbital, are frequently associated with electroclinical dissociation, with control of clinical seizures but not electrographic ones. Lorazepam may be more effective in the acute setting, particularly for control of both clinical and electrographic seizures. Lorazepam can often be used as a single agent because seizures associated with neonatal encephalopathy are often limited to the first 3 days of life. If seizures are not controlled by lorazepam, phenobarbital can be added. If seizures are not controlled after the addition of phenobarbital, phenytoin can be started. Before giving a second dose or a second medication, it is important to consider the following: Is the diagnosis correct? Are ventilation and perfusion optimal? Are metabolic disturbances recognized and corrected? The optimal duration of therapy for neonatal seizures is controversial, given the potential detrimental effects of these medicines on longer-term brain development.
If phenytoin is started, attempts to stop this medication are best done prior to the childs advancing to full oral feeds because this medication is not reliably absorbed orally. Discontinuing phenobarbital is considered when the neurologic examination is normal or, if the neurologic examination does not normalize, when the EEG is normal. Phenobarbital is discontinued as a slow taper over 6 weeks. The continued need for anticonvulsant medication should be evaluated prior to discharge and at each follow-up visit as an outpatient, in an attempt to treat for the shortest duration possible. Considerable advances continue to be made in understanding the mechanisms of neonatal encephalopathy. Preventing the conditions that underlie neonatal encephalopathy is ultimately the best treatment strategy. Several approaches, such as selective cerebral hypothermia, are now actively being evaluated to treat neonatal encephalopathy resulting from hypoxic-ischemic brain injury. The results of these forthcoming studies may substantially alter the management of affected infants. Until such strategies are proved effective and implemented, child neurologists will continue to follow survivors of neonatal encephalopathy. At follow-up, these infants and children require specific attention to language and cognitive function, motor function, feeding skills, and epilepsy. Acknowledgment The author thanks Drs. Donna Ferriero, Shannon Hamrick, and William Weiss for critical review of this chapter. SUGGESTED READING
Badawi N, Kurinczuk JJ, Keogh JM, et al: Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study, BMJ 317:1549-1553, 1998. Badawi N, Kurinczuk JJ, Keogh JM, et al: Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study, BMJ 317:1554-1558, 1998. Cowan F, Rutherford M, Groenendaal F, et al: Origin and timing of brain lesions in term infants with neonatal encephalopathy, Lancet 361:736-742, 2003. Finer NN, Robertson CM, Richards RT, et al: Hypoxic-ischemic encephalopathy in term neonates: perinatal factors and outcome, J Pediatr 98:112-117, 1981. Ment LR, Bada HS, Barnes P, et al: Neuroimaging of the neonate: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society, Neurology 58:1726-1738, 2002. Miller S, Newton N, Ferriero D, et al: MRS predictors of 30-month outcome following perinatal depression: role of socio-economic factors, Pediatr Res 52:71-77, 2002. Miller SP, Latal B, Clark H, et al: Clinical signs predict 30-month neurodevelopmental outcome after neonatal encephalopathy, Am J Obstet Gynecol 190:93-99, 2004. Nelson KB, Ellenberg JH: The asymptomatic newborn and risk of cerebral palsy, Am J Dis Child 141:1333-1335, 1987. Vannucci RC, Perlman JM: Interventions for perinatal hypoxicischemic encephalopathy, Pediatrics 100:1004-1014, 1997. Volpe J: Neurology of the newborn, ed 4, Philadelphia, 2001, WB Saunders.
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Roger W. Kula, M.D.
TABLE 1 Major Causes of Syringomyelia

Chiari I malformation Spine/spinal cord trauma Meningitis and other infections including intraspinal abscess Subarachnoid hemorrhage Tumors of spinal column or cord Diastomatomyelia Developmentally persistent central canal
Chiari malformations were traditionally known to include a complex group of disorders characterized by herniation of the cerebellum through the foramen magnum into the spinal canal. Chiari malformation type I (CMIs) was first described by the pathologist Hans von Chiari in the late 1800s and constituted the simplest and most prevalent example of this continuum of hindbrain malformations. The easily recognized Chiari II malformation was associated with spinal myelomeningocele and hydrocephalus. The much rarer Chiari III/IV malformations were associated with cervical spina bifida and encephalocele or severe cerebellar hypoplasia. These more severe congenital malformations were apparent at birth and associated with complex abnormalities of the brain and spinal cord. CMI, which forms the focus of this chapter, is now properly considered to be a malformation of the mesoderm in which a hypoplastic posterior fossa results in neural compression within the posterior fossa. Herniated cerebellar tonsillar tissue, furthermore, blocks the circulation of cerebrospinal fluid between the posterior fossa and spinal canal and results in a 20% to 70% incidence of syrinx cavity formation within the spinal cord. Likewise, CMI defined as tonsillar herniation of at least 3 to 5 mm below the foramen magnum, accounts for the predominant overall etiology of syringomyelia (SM) (70%).
diagnosis. Older characterizations based on pathologic case reviews can be seen to fall short of current clinical understanding.
Clinical Presentations
CHIARI MALFORMATION I Patients with CMI may experience no symptoms. When symptoms are present, they usually do not appear until adolescence or early adulthood. Most patients complain of severe pressure-like occipital headache and neck pain. Other common symptoms are listed in Table 2. Because of this complex symptomatology, patients with CMI are frequently misdiagnosed. At least one fourth of patients manifest symptoms following relatively minor head injury or neck injury, again frequently complicating the understanding of their underlying disorder and raising issues of malingering or secondary litigious gain. Symptoms can occasionally be seen in young children who are more likely to present with oropharyngeal dysfunction and scoliosis. A number of children younger than 3 years of age have undergone fundoplication and/or gastrostomy because of vomiting and reflux before a neurologic diagnosis was entertained. The typical posterior fossa or Chiari headache requires clearer definition. Patients describe a suboccipital pain in the head that is pressure like and more often continuous but variable rather than episodic. It is more likely to be exaggerated by bearing down with bowel movements or with laughter, crying, or orgasm than cough or sneeze, the fact of which many patients are reluctant to volunteer. The pain radiates most prominently to the retro-orbital regions and the vertex. It is explosive in character rather than throbbing or pounding. Although visual sparkles and scotomas may occur, these punctuate the peaks of headache rather than occurring as a prodrome, and the headache is almost never hemicranial. Many patients languish in headache clinics as medication-resistant or narcoticdependent chronic daily headache patients. Many, because of a longstanding history, chronic depression, and multiple symptomatic complaints in the absence of abnormal neurologic findings, have never been properly imaged. The frequent presence of neck pain without radicular features, except for evanescent hand numbness and tingling, and other generalized musculoskeletal complaints with negative rheumatologic evaluations have led to their frequent labeling as chronic fatigue or
Epidemiology
Having so set the stage, it is appropriate to shift focus from the early pathologic characterization of these disorders to their increasingly frequent clinical presentations. Until the advent of more easily obtainable magnetic resonance (MR) scanning and more sophisticated sagittal imaging, CMI was regarded as a rare condition. Current estimates range from 200,000 to 2 million Americans affected with this condition. New genetic studies support a hereditary tendency with a transmissibility rate approaching 12%. Women are affected three times more often than men. Not surprisingly, MR imaging technology has led to the recognition of syrinx cavities that previously might have escaped even postmortem identification. A recent estimate suggests the prevalence of SM in the U.S. population to be between 140,000 to 210,000 individuals, or about 1 in 1300 to 1900 Americans, considering all causes (Table 1). Since increasingly well-defined strategies now exist to investigate, diagnose, and medically and surgically manage these patients, it is of ever greater importance to understand their clinical presentations and redefine the place of these lesions in the neurologic differential
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TABLE 2 Chiari Malformation Type I (CMI) Symptoms
From Milhorat TM, Chou MW, Trinidad EM, et al: Chiari I malformation redefined: clinical and radiographic findings in 364 symptomatic patients, Neurosurgery, 44:1005-1017, 1999.
fibromyalgia patients. Many patients may be simultaneously affected by migraine headache because of its prevalence and both may be exacerbated premenstrually, but the Chiari headache responds little or not at all to common migraine treatments with antidepressants, beta blockers, and triptans. Commonly used non-narcotic medications (e.g., Fiorinal, Esgic, Midrin, and nonsteroidal anti-inflammatory drugs) may give some relief, and topiramate (Topamax) with its cerebrospinal fluid (CSF) pressure-lowering carbonic anhydrase activity may offer some falsely reassuring benefit. The patients neurologic examination is rarely objectively abnormal. The most typical finding is a vestibular-like dysequilibrium and difficulty in tandem standing and walking. Nystagmus is difficult to appreciate even with Fresnel lens examination. Objective findings frequently elude sophisticated vestibular testing, which only occasionally reveals nystagmus of possible central or peripheral etiology but which routinely fails treatment with vestibular rehabilitation. Classic downbeat nystagmus is rarely seen even with tonsillar descent as striking as 20 mm. SYRINGOMYELIA SM occurs when a tubular cavity or syrinx develops within the spinal cord resulting from an obstruction of spinal fluid circulatory pathways. In CMI, most (80%) of these occur within the cervical cord. The thoracic cord can, however, be affected in isolation, and more rarely a lumbosacral syrinx may appear associated with spinal cord tethering secondary to a thickened and restrictive filum terminale. Approximately 70% of SM cases result from CMI, with an additional small percentage associated with a hypoplastic posterior fossa as suggested by recent studies. The remaining occurrences are listed in Table 1. The syrinx cavities can give rise to painful sensory disturbances and both lower motor neuron and upper motor neuron paralytic signs. Painful neuropathic dysesthesias are most likely to occur at or adjacent to the caudal extent of the syrinx cavity.
Symptoms are more related to the pace of evolution of the syrinx than to its absolute size. Otherwise healthy patients with slitlike syrinx cavities may present with severe localized spinal and radicular pain. Other patients with syrinx cavities displacing as much as 90% of the spinal cord mass may be virtually asymptomatic. The classic dissociated sensory loss (preserved touch sensation in the face of absent pain sensation) considered indicative of SM is rarely identifiable. The importance of identifying Chiari headache and associated CMI or its other causes (Table 3) and SM lies in the availability of sound medical and surgical approaches to treatment and the invaluable provision to these patients of an understandable explanation for their misery. The secret to their identification lies in elevating them to a level of consideration through a clear appreciation of their often insidious and subtle manifestations.
Initial Diagnostic Evaluation

In the initial evaluation of these patients, an extensive clinical history and physical examination are appropriate with an open mind toward multisymptomatic
TABLE 3 Secondary Causes of Tonsillar Descent and Chiari Headache

Hydrocephalus, obstructive Pseudotumor syndrome Arachnoid cyst of posterior fossa Basilar invagination Craniosynostosis Achondroplasia Hypophosphatemic rickets Pagets disease or other hyperostotic bone disease Chronic spinal cerebrospinal fluid leak Spinal cord tethering either congenital or secondary to trauma
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presentations (see Table 2). Once either of these conditions rises to a suspicion in differential diagnosis, appropriate imaging studies are a paramount consideration (Table 4). The diagnosis of CMI has traditionally been left in the hands of neuroradiologists identifying a threshold level of tonsillar descent usually greater than 3 to 5 mm. Although sagittal imaging of the craniocervical junction has revolutionized the detection of CMI, tonsillar structure and its radiological representation with volume averaging techniques frequently underestimate the anatomic degree of tonsillar descent. Specific radiologic criteria for the identification of tonsillar ectopia and CMI are fuzzy. Recent analyses of posterior fossa dimensions and subtle abnormalities of CSF flow at the craniocervical junction may make it possible to more easily identify a hypoplastic posterior fossa (with only minimal or no tonsillar descent) sometimes referred to as Chiari zero. This may increase diagnostic sensitivity but complicate an already controversial diagnosis. The average position of the cerebellar tonsils in normal series is approximately 3 mm above the foramen magnum. The most constant feature of CMI is a volumetrically small posterior fossa, which predisposes patients to hindbrain overcrowding. The goal of the diagnostic work-up is to establish a correct diagnosis, separate possibly concurrent or associated clinical problems (Table 5), provide a course of management, and clearly lay out the risks, benefits, and expectations of possible operative intervention. Patients with CMI frequently experience chronic fatigue (72%) or fibromyalgia-like (12%) symptoms, although only a small percentage of patients with such symptoms (<5%) actually have CMI. On the other hand, significant numbers of patients with radiographically confirmed CMI are misdiagnosed for years as suffering from conditions such as migraine, multiple sclerosis, and psychiatric disorders. A gradually developing Chiari headache exacerbated with activity and straining may have propelled the patient into a progressively sedentary lifestyle with weight gain and other attendant clinical problems including depression, central and obstructive
TABLE 5 Ancillary Conditions Frequently Complicating Management

Concurrent Conditions Migraine Cluster headache Chronic daily headache Rebound headache Occipital neuralgia Multiple sclerosis Chronic fatigue syndrome Fibromyalgia syndrome CSF leak Joint hypermobility Cervical spondylosis and stenosis Depression Lyme disease Associated Conditions Pseudotumor syndrome Hydrocephalus Sleep apnea, central and obstructive Arachnoid cysts Craniocervical instability Empty sella syndrome Klippel-Feil syndrome Dysphagia Achondroplasia Hadju-Cheney syndrome Temporomandibular joint disease Eagles syndrome Sinus arrhythmia Paroxysmal orthostatic tachycardia Neurally mediated hypotension
CSF, Cerebrospinal fluid.
sleep apnea, and neck and shoulder pain frequently mistaken for cervical spondylosis or fibromyalgia. A frequent failure to find objective causes by way of electromyographic abnormalities or responses to chronic migraine treatments frequently results in patients being labeled as drug seeking, psychosomatic, and chronically depressed. Sensitivity to the clinical aspects of this disorder should significantly increase the accuracy of its identification and the exclusion of other disorders through appropriate screening laboratory investigations (Table 6).
TABLE 6 Laboratory Studies and Other Testing

CBC, ESR, ANA, SPEP, IFE T3, T4, TSH AM and PM cortisol, prolactin, IGF-1, ACTH, FSH/LH CK, Lyme titers Lying and standing blood pressure Tilt-table testing Holter monitor Echocardiogram Vestibular testing: calorics, ENG, vestibulo-optic reflex testing Lumbar puncture: CSF pressure studies (deferred with significant tonsillar descent) ICP monitoring Noninvasive or invasive cervical traction Sleep studies Barium swallow testing
CBC, Complete blood count; ESR, erythrocyte sedimentation rate; ANA, antinuclear antibody; SPEP, serum protein electrophoresis; IFE, immunofixation electrophoresis; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone; IGF-1, insulin growth factor 1; ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; CK, creatine kinase; ENG, electronystagmography; CSF, cerebrospinal fluid; ICP, intracranial pressure.
TABLE 4 Imaging Studies

Mandatory MRI Brain: T1-, T2-weighted; FLAIR (transverse, coronal, sagittal) Cervical, thoracic, lumbar spine with T2-weighted sagittal views Cine CSF flow study Three-dimensional CT with contrast: posterior fossa and cervical spine Cervical spine radiographs in flexion and extension Optional Thin-slice T2-weighted axial section of posterior fossa through C3 Flexion/extension cervical spine MRI CT myelography Isotope cisternography
FLAIR, Fluid-attenuated inversion recovery; CSF, cerebrospinal fluid.
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Management
Effective patient management frequently requires a multidimensional, if not multidisciplinary, approach. Given that the Chiari headache results from CSF flow restriction and consequent pressure differential across the craniocervical junction, strategies to decrease CSF production are frequently helpful. In practice, we prescribe acetazolamide (Diamox) in doses gradually increasing to 250 mg three times a day and, in the absence of significant side effects, progressing to maximum doses of 1500 to 2000 mg daily. (Alternately, we prescribe methazolamide [Neptazane], 50 mg three times a day, increasing to 200 to 300 mg daily.) About 15% to 20% of the time, however, the use of carbonic anhydrase inhibitors such as acetazolamide and methazolamide is frequently limited by a history of allergy to sulfa-like medications, nausea, a history of renal stone disease, or annoying perioral and limb dysesthesias associated with the mild metabolic acidosis resulting from treatment. Many patients require significant oral potassium supplements of up to 20 to 60 mEq of potassium per day. In early administration, measurements of serum potassium and electrolytes are necessary. A small but nonetheless gratifying percentage of successfully treated patients (perhaps 10% to 15% of patients) derive significant relief. As alternatives, topiramate (Topamax), zonisamide (Zonegran), tizanidine (Zanaflex), and clonidine (Catapres) as well as marijuana use may have less well-defined effects on reducing CSF pressure along with more standard loop diuretics. Both topiramate and zonisamide have cross-reacting allergy profiles with sulfa drugs. Sleeping somewhat upright with a wedge pillow or in an adjustable bed may limit early-morning headache symptoms associated with lying supine. Some female patients may successfully limit such strategies and medication use to their premenstrual period. A component of pain in most patients is related to secondary cervical muscle spasm, which can often be relieved with physical massage, ultrasound, and physical therapy in addition to the use of muscle relaxants like cyclobenzoprine (Flexeril), tizanidine (Zanaflex), carisoprodol (Soma), baclofen (Lioresal), or, in extreme cases, botulinum toxin type A (Botox). Antidepressants are also frequently helpful in managing pain in general and the secondary depressive aspects of the disorder. Amitriptyline (Elavil), nortriptyline (Pamelor), and duloxetine (Cymbalta) are most frequently used. Aside from some occasional benefit from vasoactive medications such as Midrin, pharmacologic approaches to the treatment of migraine are notoriously unproductive, including beta blockers, calcium channel blockers, and triptans. This is not to say that some thought should be given to patients who may have associated migraine simply by virtue of its frequent occurrence. Patients generally quite clearly distinguish the difference between these types of headaches, often more clearly than their physicians. Because of the frequent association (25%) of even minor traumatic events aggravating or initiating CMI symptoms, patients are appropriately cautioned to refrain from high-risk behaviors such as the recreational use of
roller coasters, skiing, physically competitive sports, and other activities that risk head and neck injury. In patients whose clinical symptoms remain unclear in the face of borderline tonsillar descent, a detailed analysis of CSF pressures and other CSF analyses are appropriately reviewed. Occasional patients with pseudotumorlike syndromes may be thus identified and a possible CSF shunting procedure contemplated. Ventriculoperitoneal shunting with the use of a Medtronic Strata programmable valve is preferred. Pregnancy is not contraindicated, although it is suggested that patients be delivered somewhat preterm and without the use of epidural anesthesia. In the case of pregnant women with SM, a cesarean section delivery is advised to avoid long hours of intrathoracic and abdominal pressure elevations consequent to pushing. Patients with SM are additionally restricted from lifting activities involving more than 15 pounds. Activities such as lifting and severe coughing have been known to result in rupture or dissection of syrinx cavities in some patients. In the case of patients without SM, an overwhelming majority are driven to surgical treatments because of intractable pressure-like posterior fossa or Chiari headache. Approximately 3500 posterior fossa decompressions in the treatment of CMI are performed each year in the United States. In the case of patients with clearly significant tonsillar descent and with obstructed CSF pathways demonstrated by cine CSF flow studies, a surgical option is largely determined by the degree of their functional incapacity. In practice, an assessment of functional disability is provided by a Modified Karnofsky Scale score (Table 7). Surgical management is not offered to patients with scores of 70 or higher. This translates into identifying those patients whose life has been significantly altered toward a dependency on others for at least some activities of daily living. These patients can frequently not sustain fulltime employment or participation in the normal demands of everyday life. Surgery is not considered for nuisance or only moderately troublesome symptoms. Surgery is not recommended as a prophylactic measure to prevent the expectation of worsening headache or fear of syrinx progression, because the natural history of SM in Chiari malformation is incompletely understood. Surgery is recommended when one or more of the following conditions are met: MR imaging evidence of syrinx propagation Clinical evidence of neurologic progression (e.g., sleep apnea, dysphagia, vertigo, sensory loss, or paralysis) Intractable symptoms, primarily Chiari headache, which have become unbearable or utterly disabling Surgery should be in the hands of an expert team with familiarity in the management of Chiari patients. The requirements for successful surgery are (1) optimal decompression of nervous tissue; (2) reconstruction of normal-sized CSF spaces at the cisterna magna and behind the cerebellum (8- to 10-mL volume); and (3) restoration of normal CSF flow between the intracranial and spinal compartments. The recent application of real-time color Doppler monitoring has helped to tailor the extent of surgical intervention
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TABLE 7 Functional Disability Assessment Tool: Modified Karnofsky Scale*

Please circle the score that best describes your current level of functioning I I I I I I I I I feel normal. carry on normal activity. carry on most normal activity. can manage all of my needs. can manage most of my needs. can manage only some of my personal needs. am disabled. am severely disabled. am totally disabled or very ill. No complaints; no evidence of illness . . . with minor symptoms. . . . with effort and some symptoms. . . . but normal activities are limited. . . . but I require occasional assistance excluding personal care. I require considerable assistance including some personal care. I require frequent assistance for most personal care. I require full assistance for most personal care. I require full assistance for all personal care; home bound in bed or chair. I have fatal processes that are rapidly progressing; I am near death. Score 100 90 80 70 60 50 40 30 20 10
I am critically ill.
See Figure 1 where this table appears in the algorithm.
and provide maximal intraoperative confirmation of the goals of surgery. Relief of the severe pressure-like Chiari headache is the most consistent surgical benefit. All other aspects of clinical symptomatology such as vestibular disturbances, chronic fatigue, brain fog, and musculoskeletal pain are not as consistently relieved. The management of SM in association with CMI most importantly benefits from the surgical release of craniocervical pressure differentials bringing about syrinx collapse. Consideration of syringosubarachnoid or syringoperitoneal shunting should be implemented only as a last resort following unsuccessful posterior fossa decompression. The extent of posterior fossa decompression is tailored to re-establish normal CSF flow characteristics at the craniocervical junction using color Doppler ultrasonography. Tonsillar shrinkage with bipolar cautery is frequently required and a dural patch typically fashioned from locally harvested pericranium, which is an excellent autologous dural substitute. The fashioning of a protective cranioplasty plate from titanium mesh and methyl-methacrylate is determined by surgical judgment based on the size of the craniotomy defect and contraindicated only in children because of anticipated cranial growth or by the presence of a very thin and porous underlying dura, which might contribute to postoperative pseudomeningocele formation. Cranioplasty frequently limits the development of later cerebellar ptosis into the craniotomy defect and scarring of muscle and subcutaneous tissue to subjacent dural membranes later contributing to a painful local surgical site. Overall, about 85% of patients experience some significant relief of severe pressure-like Chiari headache. Nevertheless, a small percentage of patients experience a return of prior symptoms 4 to 6 months or longer postoperatively (Table 8). Under these circumstances, careful attention is paid to the documentation of CSF pressure, which in many patients is moderately elevated though rarely in excess of 250 mm H2O. Such patients who generally have small ventricular size may benefit from ventriculoperitoneal shunting. These patients tend to be extremely sensitive to CSF pressure
fluctuations, even with the advent of the more sophisticated programmable valves such as the Medtronic Strata. These patients are managed with pressure readjustments and continued attention to pain management strategies, which frequently include but are not limited to muscle relaxants, physical measures, carbonic anhydrase inhibitors, gabapentin (Neurontin), and narcotic as well as nonsteroidal analgesics. In patients with SM in the absence of CMI or hypoplastic posterior fossa, contrast MR imaging studies to rule out intramedullary tumor are necessary. In addition, CT myelographic studies may be necessary to exclude a subarachnoid block resulting from possible occult arachnoiditis, which could be related to surface spinal cord bruising or extravasated blood as the result of prior impact chest or abdominal injuries, to subarachnoid hemorrhage, or to inflammatory disorders. In such cases, surgical establishment of CSF flow around such obstructions by way of laminectomy and expansile duroplasty are attempted prior to any attempt to relieve syrinx pressure with catheter placement either within the subarachnoid space or to adjacent pleural or peritoneal cavities. Shunting of syrinx cavities is a consideration of last resort and is usually associated with some degree of surgically related sensory or motor deficit. Figure 1 provides an overall management algorithm for the treatment of symptomatic CMI and SM.
TABLE 8 Conditions Constituting Failed Posterior Fossa Decompression

Intractable or progressive symptoms from inadequate decompression Persistent or enlarging syrinx Pseudomeningocele Chronically raised cerebrospinal fluid pressure Cranial settling/basilar invagination Craniocervical instability Hydrocephalus
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Posterior fossa headache?
Laboratory studies and other testing Imaging studies
Atypical/unexplained back pain and/or limb dysesthesias?
Brain, C-, T-, LS-spine MR imaging
Cine CSF flow study
3D-CT with contrast
Cervical spine films: Flex/Ext Re-image with contrast Re-image in 612 mo
Syringomyelia
Hypoplastic posterior fossa with <5mm tonsil descent? Yes
No
CMI with >5mm tonsil descent?
No
Idiopathic syringomyelia?
Yes
Conservative/ medical treatment
No Yes
Score 100 90 Modified Karnofsky Scale: Please circle the score that best describes your current level of functioning. I feel normal. I carry on normal activity. No complaints. No evidence of illness. ...with minor symptoms.
MKS score =/> 70 No
Yes No
I carry on ...with effort and some symptoms. most normal activity. I can manage all of my needs. I can manage most of my needs. ...but normal activities are limited. ...but I require occasional assistance excluding personal care.
80 70 60 50
Progression?
I require considerable assistance I can manage only some of my personal including some personal care. needs. I am disabled. I am severely disabled. I am totally disabled or very ill. I am critically ill. I require frequent assistance for most personal care. I require full assistance for most personal care. I require full assistance for all personal care. Home bound in bed or chair. I have fatal processes that are rapidly progressing. I am near death.
MKS score < 70 Yes Syrinx propagation? Yes
5
Yes CT myelography
40 30
20
10
P r i m a r y s u r g i c a l c r i t e r i a No
No
Posterior fossa decompression Failed? Yes Continuing Chiari headache? Yes Yes Repeat complete imaging
Tethering? CSF flow obstruction?
Yes Expansile spinal duroplasty Failed?
Empty sella? Yes Pituitary function studies Continued conservative medical management (Chronic fatigue, musculoskeletal pain, and vertigo are not considered reliable indicators for surgical management)
Progressive neurological deficit? No
Intractable Chiari headache?
Continuing syrinx progression?
Yes Posterior fossa revision No Good surgical result? Yes Syringoperitoneal shunt
No
High CSF pressure >200mm and headache relief with fluid removal Yes
Lumbar puncture: CSF pressure studies
VP shunt
FIGURE 1. Management algorithm for Chiari malformation type I (CMI) and syringomyelia. C-, T-, LS=, Cervical, thoracic, lumbosacral; CSF, cerebrospinal fluid; 3D, three-dimensional; MKS, Modified Karnofsky Scale; VP, ventriculoperitoneal. Johnson: Current Therapy in Neurologic Disease (7/E)
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Neurofibromatosis
SUGGESTED READING
Cohen AR, Gaskill S J, topic editors: Chiari I malformation, Neurosurg Focus 11(1), 2001. http://www.aans.org/education/ journal/neurosurgical/july01/11-1-nsf-toc.asp Greenlee JDW, Donovan KA, Hasan DM, Menezes AH: Chiari I malformation in the very young child: the spectrum of presentations and experience in 31 children under the age 6 years, Pediatrics 110:1212-1219, 2002. Milhorat TH, Bolognese PA: Tailored operative technique for Chiari type I malformation using intraoperative color Doppler ultrasonography, Neurosurgery 53:899-906, 2003. Milhorat TH, Chou MW, Trinidad EM, et al: Chiari I malformation redefined: clinical and radiographic findings for 364 symptomatic patients, Neurosurgery 44:1005-1017, 1999. Milhorat TH, topic editor: Syringomyelia, Neurosurg Focus 8(3), 2000. http://www.aans.org/education/journal/neurosurgical/mar00/ 8-3-NSF-toc.asp Mueller DM, Oro JJ: Prospective analysis of presenting symptoms among 265 patients with radiographic evidence of Chiari malformation type I with or without syringomyelia, J Am Acad Nurse Pract 16:134-138, 2004. Tamaki N, Batzdorf U, Nagashima T, editors: Syringomyelia: current concepts in pathogenesis and management, Tokyo, 2001, Springer-Verlag.
the clinical result of mosaicism for NF-1 gene mutations. Other types are either allelic to NF-1 or are of unclear significance. We discuss NF-1 and NF-2 in this chapter.
Neurofibromatosis Type 1 (von Recklinghausens Disease)

NF-1 is the most common form of NF and accounts for nearly 90% of NF cases. The incidence of NF-1 is 1 per 3500 individuals. It is inherited as an autosomal dominant disorder, but 50% of cases represent new mutations. Penetrance is nearly 100%, but expression varies widely. Mutational analysis of the gene encoding neurofibromin on 17q11.2 is available commercially. Although this test enjoys high sensitivity (95%), it is expensive, and diagnosis still rests on demonstration of clinical criteria. Two of seven age-dependent clinical criteria are required to make a clinical diagnosis (Table 1). In familial cases, clinical diagnostic criteria are present in 70% of 12-month-old children with NF-1 and 100% of affected 8-year-old children. In the sporadic cases, 97% of the patients display at least two diagnostic criteria by age 8 years; 100% do so by age 20 years. Other clinical manifestations, not part of the diagnostic criteria, are listed in Table 2. DIAGNOSIS Criteria as listed in Table 1 should be used as a guide for diagnostic purposes. Young infants do not always meet the criteria, especially when the disease is sporadic. However, the characteristic features develop over time, and careful and close follow-up is necessary, especially in children who have multiple caf au lait spots (CALSs) but do not meet other criteria for the diagnosis for NF-1. They should be followed until the diagnosis can be confirmed or excluded. The usual order of appearance of the clinical features is CALSs, axillary freckles, Lisch nodules, and neurofibromas. Thorough physical, ophthalmologic, audiologic, and radiologic examinations and a team approach are essential. Subsequent investigations are determined by clinical necessity. Diagnostic criteria for NF-1 provide the clinician with a highly specific tool for clinical diagnosis. In individuals with only one criterion (usually skin lesions, parenchymal tumors, or bony changes), a differential diagnosis may be generated (Table 3). These diagnoses usually are easy to differentiate from NF-1. MANAGEMENT About 45% of individuals affected with NF-1 suffer a significant medical or neurodevelopmental complication of the disorder. Management consists of screening for treatable complications, subsequent interventions that may reduce morbidity and mortality, and patient and family education and genetic counseling. We discuss management of specific features and complications of NF-1 in the following sections.
PATIENT RESOURCES
American Syringomyelia Alliance Project, Inc. P.O. Box 1586 Longview, TX 75606-1586 Phone: 903-236-7079 Toll-free phone: 800-ASAP-282 Fax: 903-757-7456 E-mail: info@ASAP.org http://www.asap.org/ World Arnold-Chiari Malformation Association Contact: Bernard H. Meyer 31 Newtown Woods Road Newtown Square, PA 19073 Phone: 610-353-4737 E-mail: internautbhm2@comcast.net http://www.wacma.com/ Chiari and Syringomyelia Patient Education Foundation Contact: Chiari and Syringomyelia News 346 Valerie Drive Cranberry Township, PA 16066 E-mail: editor@chiari-syringo-news.com http://www.chiari-syringo-news.com
Neurofibromatosis
Laurence Walsh, M.D., and Bhuwan P. Garg, M.D.
Neurofibromatosis (NF) is not a single disease. The term subsumes at least two distinct disorders that share some common features. The two distinct types of NF most commonly recognized are NF-1 and NF-2. NF-1 is a single gene disorder with protean manifestations. The nervous system, blood vessels, bones, and skin all may be involved in NF-1. NF-2 likewise is a single gene disorder, with variable but more circumscribed clinical features. There are other types of NF: segmental NF usually is
98
Neurofibromatosis
SUGGESTED READING
Cohen AR, Gaskill S J, topic editors: Chiari I malformation, Neurosurg Focus 11(1), 2001. http://www.aans.org/education/ journal/neurosurgical/july01/11-1-nsf-toc.asp Greenlee JDW, Donovan KA, Hasan DM, Menezes AH: Chiari I malformation in the very young child: the spectrum of presentations and experience in 31 children under the age 6 years, Pediatrics 110:1212-1219, 2002. Milhorat TH, Bolognese PA: Tailored operative technique for Chiari type I malformation using intraoperative color Doppler ultrasonography, Neurosurgery 53:899-906, 2003. Milhorat TH, Chou MW, Trinidad EM, et al: Chiari I malformation redefined: clinical and radiographic findings for 364 symptomatic patients, Neurosurgery 44:1005-1017, 1999. Milhorat TH, topic editor: Syringomyelia, Neurosurg Focus 8(3), 2000. http://www.aans.org/education/journal/neurosurgical/mar00/ 8-3-NSF-toc.asp Mueller DM, Oro JJ: Prospective analysis of presenting symptoms among 265 patients with radiographic evidence of Chiari malformation type I with or without syringomyelia, J Am Acad Nurse Pract 16:134-138, 2004. Tamaki N, Batzdorf U, Nagashima T, editors: Syringomyelia: current concepts in pathogenesis and management, Tokyo, 2001, Springer-Verlag.
the clinical result of mosaicism for NF-1 gene mutations. Other types are either allelic to NF-1 or are of unclear significance. We discuss NF-1 and NF-2 in this chapter.
Neurofibromatosis Type 1 (von Recklinghausens Disease)

NF-1 is the most common form of NF and accounts for nearly 90% of NF cases. The incidence of NF-1 is 1 per 3500 individuals. It is inherited as an autosomal dominant disorder, but 50% of cases represent new mutations. Penetrance is nearly 100%, but expression varies widely. Mutational analysis of the gene encoding neurofibromin on 17q11.2 is available commercially. Although this test enjoys high sensitivity (95%), it is expensive, and diagnosis still rests on demonstration of clinical criteria. Two of seven age-dependent clinical criteria are required to make a clinical diagnosis (Table 1). In familial cases, clinical diagnostic criteria are present in 70% of 12-month-old children with NF-1 and 100% of affected 8-year-old children. In the sporadic cases, 97% of the patients display at least two diagnostic criteria by age 8 years; 100% do so by age 20 years. Other clinical manifestations, not part of the diagnostic criteria, are listed in Table 2. DIAGNOSIS Criteria as listed in Table 1 should be used as a guide for diagnostic purposes. Young infants do not always meet the criteria, especially when the disease is sporadic. However, the characteristic features develop over time, and careful and close follow-up is necessary, especially in children who have multiple caf au lait spots (CALSs) but do not meet other criteria for the diagnosis for NF-1. They should be followed until the diagnosis can be confirmed or excluded. The usual order of appearance of the clinical features is CALSs, axillary freckles, Lisch nodules, and neurofibromas. Thorough physical, ophthalmologic, audiologic, and radiologic examinations and a team approach are essential. Subsequent investigations are determined by clinical necessity. Diagnostic criteria for NF-1 provide the clinician with a highly specific tool for clinical diagnosis. In individuals with only one criterion (usually skin lesions, parenchymal tumors, or bony changes), a differential diagnosis may be generated (Table 3). These diagnoses usually are easy to differentiate from NF-1. MANAGEMENT About 45% of individuals affected with NF-1 suffer a significant medical or neurodevelopmental complication of the disorder. Management consists of screening for treatable complications, subsequent interventions that may reduce morbidity and mortality, and patient and family education and genetic counseling. We discuss management of specific features and complications of NF-1 in the following sections.
PATIENT RESOURCES
American Syringomyelia Alliance Project, Inc. P.O. Box 1586 Longview, TX 75606-1586 Phone: 903-236-7079 Toll-free phone: 800-ASAP-282 Fax: 903-757-7456 E-mail: info@ASAP.org http://www.asap.org/ World Arnold-Chiari Malformation Association Contact: Bernard H. Meyer 31 Newtown Woods Road Newtown Square, PA 19073 Phone: 610-353-4737 E-mail: internautbhm2@comcast.net http://www.wacma.com/ Chiari and Syringomyelia Patient Education Foundation Contact: Chiari and Syringomyelia News 346 Valerie Drive Cranberry Township, PA 16066 E-mail: editor@chiari-syringo-news.com http://www.chiari-syringo-news.com
Neurofibromatosis
Laurence Walsh, M.D., and Bhuwan P. Garg, M.D.
Neurofibromatosis (NF) is not a single disease. The term subsumes at least two distinct disorders that share some common features. The two distinct types of NF most commonly recognized are NF-1 and NF-2. NF-1 is a single gene disorder with protean manifestations. The nervous system, blood vessels, bones, and skin all may be involved in NF-1. NF-2 likewise is a single gene disorder, with variable but more circumscribed clinical features. There are other types of NF: segmental NF usually is
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TABLE 1 Diagnostic Criteria for Neurofibromatosis (NF)-1

Clinical Criteria* 6 caf au lait macules > 0.5 mm in diameter in prepubertal patients and > 15 mm in postpubertal patients 2 neurofibromas of any type (intracutaneous or subcutaneous) or 1 plexiform neurofibroma Freckling in the axillary or inguinal regions (3 freckles) Optic pathway glioma 2 iris hamartomas (Lisch nodules) Distinctive osseous lesion, e.g., sphenoid wing hypoplasia or thinning of long bone cortex with or without pseudoarthrosis 1 first-degree relative with NF-1 according to the above criteria
*A diagnosis of NF-1 requires 2 of these criteria.
Usual Age of Occurrence Birth 8-12 yr Congenital 3-5 yr 3-4 yr 5-12 yr Birth
Prevalence (%) by 18 Years of Age >99 (99 by 12 mo) 84 (48 by age 10 yr) >44 (25-30 apparent in infancy, 44 by age 5 yr) >90 (by age 7 yr) 15 >70 (by age 10 yr) 7-14 50
Skin Lesions Skin lesions are the most common manifestations of NF-1. The earliest and most common cutaneous lesions are CALSs. Of infants with multiple (6) CALSs, more than 80% will develop NF-1. Cosmetic concerns may occur with multiple or very large CALSs, but they do not require medical intervention otherwise. Vitamin D analogs and laser therapy have been tried with initial success, but results await confirmation. CALSs often fade by middle age, if not earlier. Isolated CALSs (usually 3) occur in 10% to 20% of the population. They are slightly more common and are slightly more likely to be multiple in individuals of Mediterranean, African, or South Asian ancestry. Some families (with and without NF-1 gene mutations) transmit multiple CALSs as an isolated autosomal dominant trait. Multiple CALSs are also reported in children with tuberous sclerosis complex, Russell-Silver syndrome, and ataxia-telangiectasia, although there is argument concerning their specific association with those disorders. Intertriginous freckling is the second most common manifestation of NF-1. Axillary freckling is twice as common as inguinal freckling. This freckling has no medical significance other than as a criterion for diagnosis. More irregular or diffuse hyperpigmentation occurs
as well; large hyperpigmented areas, sometimes with hemangiomatous changes, may overlie an often palpable plexiform neuroma. Neurofibromas occur in 84% of people with NF-1. They are discrete and are either cutaneous or subcutaneous in location. Cutaneous neurofibromas may be violaceous or tan, and they feel soft or fleshy to palpation. Subcutaneous neurofibromas are not visibly pigmented, are firmer, and are more readily associated with peripheral nerve trunks. Either may be up to 3 to 4 cm in diameter. They usually appear in late school age or adolescence but may be present in toddlers. Although puberty may be associated with the appearance of multiple new neurofibromas, they occur throughout life. They may cause local itching and cosmetic problems and may be susceptible to repeated incidental trauma (e.g., from shaving). Angiomas and xanthomas are less commonly seen. Xanthogranulomas, rare in children with NF-1, may be associated with an increased risk of lymphoproliferative disorders; however, there currently is no specific recommendation regarding additional screening.
TABLE 3 Differential Diagnosis for Neurofibromatosis Type 1

Neurofibromatosis type 2 LEOPARD syndrome Multiple intradermal nevi Multiple lipomatosis Proteus syndrome Noonans syndrome Multiple caf au lait spots McCune-Albright syndrome Multiple endocrine neoplasia type 2B Bannayan-Riley-Ruvalcaba syndrome
LEOPARD, Lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, deafness.
TABLE 2 Other Significant Features of Neurofibromatosis Type 1

Learning disabilities Macrocephaly Aqueductal stenosis Epilepsy Scoliosis Hypertension Ungual neurofibromas Interstitial pulmonary disease
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Pruritus is common in NF-1. The itching may be severe, but the patient may not volunteer its presence. It occurs in association with neurofibromas but also diffusely, unattached to a specific cutaneous or subcutaneous lesion. Antihistamines have been tried with mixed results. Plexiform Neuromas Plexiform neurofibromas (plexiform neuromas) are larger than neurofibromas and may cause more serious problems. They occur equally on the trunk or head and neck (40% to 45% each) and less commonly on the limbs. They are congenital but may not be apparent until they enlarge with age. Plexiform neuromas start in nerve sheaths anywhere between the spinal roots and distal nerves in the extremities and appear as either nodular or diffuse lesions. Thirty percent of people with NF-1 have plexiform neuromas; malignant change to a malignant peripheral nerve sheath tumor (MPNST) occurs in 5% of cases. Deep nodular or diffuse plexiform neuromas are most likely to degenerate to MPNSTs. Even without transformation to an MPNST, plexiform neuromas may grow to compress nerves and other vital structures. Periorbital plexiform neurofibromas not only may have cosmetic consequences but may also cause ptosis, exophthalmos, and vision loss. Intraoral tumors may cause airway obstruction. Lesions in the neck may compress nearby arteries or veins with sometimes life-threatening consequences. Cephalic or paraspinous plexiform neurofibromas may extend intracranially or intraspinally. Intra-abdominal tumors also may encase important structures such as the renal artery or aorta, causing secondary hypertension or more serious complications. Plexiform neuromas that are visible on physical examination are measured during each annual or semiannual visit. Although not routinely included as part of a screening protocol, magnetic resonance (MR) imaging reveals the extent of larger tumors and allows follow-up of noncutaneous plexiform neuromas. Indications for therapeutic intervention include indications of possible malignant degeneration (rapid growth in a previously stable tumor or pain, especially associated with new growth), and impending compromise in patient function or important structures. Therapy is limited. Radiation therapy has no role in the treatment of plexiform neuromas. Chemotherapy has shown little efficacy to date. Complete surgical excision is optimal but often difficult to achieve. Incomplete resection risks recurrence but may be necessary if the tumor is especially large or if complete resection threatens vital structures. Therapy of MPNST consists of resection and chemotherapy in consultation with oncologists. Forty percent recur within 2 years. Five-year survival with MPNST is 35%; median survival is 36 months. Ophthalmic Lesions Lisch nodules in the iris are the most common eye signs in NF-1, appearing as brown nodules. These are melanocytic hamartomas. The presence of two nodules is required to meet the diagnostic criterion. They are
age dependent, and the incidence increases with age; only about 6% of children younger than 6 years of age have them, but more than 70% patients have them by teenage years. Pulsating exophthalmos due to sphenoid wing hypoplasia is seen in some children. Buphthalmos and congenital glaucoma have also been reported. These may be associated with an underlying plexiform neuroma. Optic nerve glioma is discussed in the following section. Neurologic Complications Macrocephaly (head size greater than 2 SD above mean) occurs in nearly half of the NF-1 patients. It usually is due to megalencephaly. Signs of increased intracranial pressure require exclusion of other causes such as obstructive hydrocephalus, posterior fossa tumors, aqueductal stenosis, tectal plate gliomas, and hypothalamic tumors. In some children a cause for ventriculomegaly is not found. Epilepsy occurs in 5% to 7% of affected individuals with NF-1. Seizures occur more frequently in children with NF-1 and severe neurodevelopmental disabilities than in children with NF-1 and normal development. Appropriate anticonvulsants are used for seizure control. Attention deficit with or without hyperactivity is seen often in children with NF-1, and learning disabilities (LDs) occur in about 50% (30% to 62%) of individuals with NF-1. The IQ score of patients with NF-1 averages 10 points lower than that of their siblings. Verbal scores exceed performance scores. Common, specific NF-1associated LDs include poor visuospatial skills and specific reading and language disabilities. Mental retardation occurs less commonly in NF-1 patients and may be mutation specific. Management of children with NF-1 should include specific inquiry into learning or school difficulties. Psychoeducational testing should be sought aggressively if there is any hint of cognitive delay or school difficulty. MR imaging of the brain currently is not part of recommended screening protocols for NF-1 in otherwise asymptomatic children. However, our threshold for obtaining an MR scan in a child with NF-1 is extremely low. Indications include absolute macrocephaly (>2 SD above the mean), headaches (new or worsening), decreasing vision or unexplained nystagmus in a young child, funduscopic changes suggestive of an optic nerve glioma, developmental delay or LDs, decline in school performance, cephalic plexiform neuroma that may have intracranial extension, and abnormal neurologic examination that is not explained otherwise. Precocious puberty is an absolute indication for MR scan of the brain to include detailed study of the hypothalamus and sella. Headaches occur in one half of patients with NF-1; 10% are caused by an intracranial structural lesion. Intracranial tumors require management as discussed in the following section. Optic Pathway Glioma Optic pathway gliomas have been reported in 15% of children with NF-1. The tumor may involve the
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optic nerve, optic chiasm, and/or the optic tracts. Sometimes the tumor spreads posteriorly along the optic radiations. Optic gliomas may present with decreased visual acuity, visual field defects, ptosis, proptosis, and signs and symptoms of increased intracranial pressure, or they may be asymptomatic and found on MR scans or ophthalmologic examinations. Diencephalic syndrome and precocious puberty in patients with NF-1 require exclusion of optic chiasm or hypothalamic gliomas. Most symptomatic gliomas present by 6 years of age and often do so by 2 years of age, but only about 30% to 50% of patients with optic gliomas have symptoms. Optic gliomas may remain static and behave as hamartomas, or they may grow actively. Periodic MR scans following initial detection are helpful in determining whether the tumor is progressive or static. One suggested protocol is MR scans (including optic nerve views) and ophthalmologic examinations every 3 months for 1 year, followed by MR imaging and ophthalmologic examinations every 6 months for 2 years and yearly scans and every-6-month ophthalmologic examinations thereafter. Some protocols relax surveillance even further after 36 months, but this decision rests on the age of the child and the behavior of the tumor on previous surveillance studies. Progression of optic gliomas after 10 years of age is rare. Static tumors should be watched and need no treatment. Actively growing tumors may be treated with chemotherapy, or surgery when possible. Radiation therapy may result in serious complications in NF-1 patients. These complications, including moyamoya disease, stroke, and secondary malignant glioma formation, make radiation therapy an unappealing last choice. About 25% of patients with optic gliomas require treatment for them, whereas the tumors may spontaneously regress in some patients. Routine screening for optic gliomas in a healthy asymptomatic child with NF-1 consists of yearly eye examinations by an ophthalmologist. This said, such examinations carry only about 50% to 60% sensitivity. Astrocytomas of the cerebellum, cerebrum, and brainstem are other common intracranial tumors in NF-1. Symptoms depend on location. Brainstem gliomas in patients with NF-1 may be indolent, with very slow growth and better outcome than brainstem gliomas in children without NF-1. Most (80%) occur in the medulla; 15% to 20% require intervention beyond shunt for hydrocephalus. Meningiomas and primitive neural-ectodermal tumors occur as well. Presence of symptomatic optic nerve glioma increases the likelihood of these other central nervous system tumors by a factor of nine. Intraspinal tumors may be single or multiple. Cervical neuromas may occur in 25% of children with NF-1. They may be extradural or intradural. Intramedullary spinal tumors are rare in NF-1. Intraspinal tumors may extend through the intervertebral foramen and assume a dumbbell shape. In some patients these intraspinal tumors may be in continuity with a subcutaneous plexiform neurofibroma. A 2% to 7% risk of sarcomatous change in these tumors has been reported. Appropriate treatment is necessary in symptomatic patients (e.g., with intractable pain or focal neurologic deficits).
Vasculopathy Vasculopathy is an under-recognized aspect of NF-1. Renal artery stenosis is the best known, but the vasculopathy of NF-1 really is a generalized disorder. Carotid artery stenosis with moyamoya disease has been reported. Coarctation of aorta has been reported by several investigators. Other, less common associations include pheochromocytoma. Hypertension is a common complication of NF-1, occurring in at least 40% of adults and up to 20% of children with NF-1. It requires thorough evaluation and treatment. Renal artery stenosis and compression of the artery from a tumor should be excluded using abdominal MR or computed tomography (CT) scan. Hypertension caused by such structural lesions may be relatively refractory to medical management and may require surgery. Pheochromocytoma, usually after the age of 15 years, is a rare cause of hypertension in NF-1. It occurs in 0.1% to 1.5% of reported NF-1 patients and presents with initial episodic hypertension and other vasomotor phenomena. Appropriate consultation is advisable for evaluation of suspected pheochromocytoma. Data for vasculopathy-related morbidity in NF-1 are sketchy. People affected with NF-1 who die prior to age 30 years have an odds ratio of 2 to 3 of having vascular disease compared with non-NF individuals who die before 30 years of age. It has been suggested that the vasculopathy is a result of alteration of the function of neurofibromin (the NF-1 gene product) in the vascular endothelium and smooth muscle cells. Skeletal Lesions Multiple bony abnormalities have been reported in NF-1. Dysplasia of the greater wing of the sphenoid bone may cause pulsating exophthalmos and marked facial disfigurement. Dural ectasias may produce enlargement of various bony (cranial nerve) foramina and need to be distinguished from enlargement due to neurofibroma involving the nerve. Cranial CT with thin slices or MR scan is useful in evaluation. Scoliosis occurs in 12% of children with NF-1. Scoliosis in NF-1 is bimodal in onset and severity. Its presence is an indication for plain films and MR imaging of the complete spine. Scoliosis due to vertebral dysplasia begins in preschool- and school-age children; this tends to be progressive and severe. Teenage-onset scoliosis in NF-1 usually is less severe. Either age group may have scoliosis due to paraspinal or intraspinal tumors with symptoms specifically referable to the tumor site. Scalloping of the vertebral body is a common radiologic finding. Dural ectasia also occurs in the spine. Bowing of the tibia and fibula and secondary pseudoarthrosis of the tibia are other bony abnormalities in NF-1. The latter may result in significant disability and may necessitate amputation of the affected leg. Short stature is common and occurs in 25% to 43% of patients with NF-1. NF-1 patients on average are reported to fall short of their siblings height and their own predicted mid-parental height.
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Additional MR Imaging Findings In addition to the abnormalities due to tumors, there are many other unusual findings in the cranial MR scans of patients with NF-1. Hyperintense foci occur on T2-weighted images in 43% to 77%. These usually are found incidentally, and most commonly occur in the globus pallidus, followed by the cerebellum, brainstem, thalamus, and periventricular white matter. Histologic verification is lacking, though they were described in the past as hamartomas. They more likely represent transient abnormalities of myelin structure. They are age dependent and usually vanish by age 12 years. Their clinical significance is unknown. Their presence is associated with LDs and may predict other NF-1related morbidities. Genetic Considerations All families affected by NF-1 require genetic counseling. The disorder is autosomal dominant. One half of cases are sporadic and suggest a new (noninherited) mutation. This may have occurred before or after conception. A mutation before conception raises the possibility of germline mosaicism in a parent. Although a presumed new mutation might suggest sibling recurrence risk of less than 1%, the possibility of a preexisting mutation limited to a parental germ cell line slightly raises the sibling recurrence risk in de novo cases. The clinically affected individual then has a 50% risk of passing the mutation to his or her offspring, with essentially 100% penetrance. In families with a clinically affected parent, offspring recurrence is 50%. There is some evidence that there is less intrafamilial than interfamilial variability in manifestations, but many exceptions exist. Thus, although the presence of only CALSs, freckling, and Lisch nodules in a given family may be reassuring, vigilance for more serious sequelae still is required. There are several specific variant clinical subtypes (Noonan-NF syndrome, Watson syndrome, a microdeletion syndrome, familial CALSs, and spinal NF with MPNST). Medical genetic consultation may be advisable in some instances, and even in cases requiring only genetic counseling, genetic counselors often are far more effective than physicians in conveying this information to affected families.
TABLE 4 Diagnostic Criteria for Neurofibromatosis (NF)-2

Bilateral vestibular schwannomas Unilateral vestibular schwannoma and first-degree relative with NF-2 First-degree relative with NF-2 and any two of the following: Glioma Meningioma Neurofibroma Schwannoma Juvenile posterior subcapsular contract Unilateral vestibular schwannoma with any two of the following*: Meningioma Schwannoma Gliomas Neurofibroma Juvenile posterior subcapsular lenticular opacities Multiple meningiomas and one of the following*: Unilateral vestibular schwannoma Any two of schwannoma, glioma, neurofibroma, cataract
*The presence of any one of these criteria is sufficient for the diagnosis of NF-2 except as noted with the asterisk. Any one of criteria with the asterisk is sufficient for probable or presumptive diagnosis.
Neurofibromatosis Type 2
NF-2 is less common than NF-1. The major hallmark of NF-2 is the development of bilateral acoustic neuromas. Occasionally there are also other brain and spinal cord tumors. The clinical mnemonic for NF-2 is MISME (multiple inherited schwannomas, meningiomas, ependymomas). NF-2 is transmitted as an autosomal dominant trait. As with NF-1, 50% of cases are sporadic and represent new mutations. Diagnostic criteria are presented in Table 4. Most patients have few or no CALSs; Lisch nodules are generally not seen. Peripheral neurofibromas are not present. Patients have a high frequency of presenile
posterior subcapsular and nuclear cataracts. These predate the symptoms of bilateral acoustic neuromas and sometimes require surgery. Acoustic neuromas or schwannomas are the hallmark of NF-2 and usually appear in late adolescence or early adulthood. They are often bilateral. Hearing loss is the first symptom. Facial weakness is a late complication. Schwannomas of other cranial nerves may also occur and are often multiple. Meningiomas are other intracranial tumors in NF-2. Optic gliomas do not occur. Spinal schwannomas may be multiple and present management difficulties. There may be two types of NF-2: one with early onset, rapid course, and multiple other tumors in addition to bilateral vestibular schwannomas, and the second with late onset, more benign course, and usually only bilateral vestibular schwannomas. As mentioned earlier, age of presentation is late teens to mid twenties. Prognosis is worse overall than in NF-1, with historical survival usually into middle age. This likely has improved with improvement in therapy for the various tumors. The NF-2 gene has been mapped to chromosome 22. NF-2 gene product is schwannomin. This protein shows a close relationship to the family of ERM (ezrin-radixinmoesin) proteins, which serve as linkers of cytoskeleton to membrane proteins. This may be a novel class of tumor suppressor genes. Audiologic evaluation is essential. BAER is often helpful. CT scan and especially MR imaging with gadolinium enhancement are helpful in visualizing even small vestibular schwannomas or acoustic neuromas. Management is symptomatic, with surgery and radiation therapy as appropriate.
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SUGGESTED READING
DeBella K, Szudek J, Friedman JM: Use of the National Institutes of Health criteria for diagnosis of neurofibromatosis 1 in children, Pediatrics 105:608-614, 2000. Friedman JM, Gutmann DH, MacCollin M, Riccardi VM, editors: Neurofibromatosis: phenotype, natural history, and pathogenesis, ed 3, Baltimore, 1999, Johns Hopkins University Press. http://www.genetests.org/ (search term: neurofibromatosis) North KN, Riccardi V, Samango-Sprouse C, et al: Cognitive function and academic performance in neurofibromatosis 1: Consensus statement from the NF-1 Cognitive Disorders Task Force, Neurology 48:1121-1127, 1997. Nunes F, MacCollin M: Neurofibromatosis 2 in the pediatric population, J Child Neurol 18:718-724, 2003. Ruggieri M, Husom SM: The clinical and diagnostic implications of mosaicism in the neurofibromatosis, Neurology 56:1433-1443, 2001.
the diagnosis remains difficult in individuals with subtle disease manifestations. The clinical diagnostic criteria established for TSC are highly reliable, and patients who meet the clinical diagnostic criteria for definite TSC do not require genetic testing for diagnostic purposes. It is likely that gene testing might be more useful in less obvious cases depending on the clinical situation and the age of the patient in question.
Clinical Aspects
The clinical features of TSC may involve neurologic, psychiatric, behavioral, and cognitive features including epilepsy (especially infantile spasms), mental retardation, pervasive developmental disorder and autism, renal disease and tumors, cardiac tumors, ocular lesions, and pulmonary disease. The characteristic brain lesions are unique enough to be considered part of the diagnostic criteria and include cortical tubers, subependymal glial nodules (SGNs), and subependymal giant cell astrocytomas (SEGAs). Almost any other organ system can be involved with the disease complex in some patients, though any individual usually has only a relatively limited number of organs with significant involvement. We address the most commonly encountered clinical manifestations of TSC. DERMATOLOGIC The dermatologic manifestations of TSC, which are characteristic enough to be considered major features in the diagnostic criteria, include hypomelanotic macules (ash leaf spots), ungual or periungual fibroma, facial angiofibroma (sebaceous adenomas), forehead plaques, and the shagreen patch. The confetti skin lesion is less specific and is considered only a minor feature. The hypomelanotic macules are found on the skin in more than 90% of patients with TSC. The lesions are usually present on the trunk, abdomen, back, or extremities at birth and are more easily seen on a pigmented background or with the use of an ultraviolet light in fair-skinned individuals. Because hypomelanotic macules are often present as single lesions in the normal population, the diagnostic criteria require more than three lesions. The confetti lesions may develop later, after the newborn period, and are usually on the extremities. Facial angiofibromata are fibrovascular lesions that are present in about 75% of patients. They are not present at birth and begin to develop after 2 to 4 years of age. Frequently they are mistaken for acne even though they are noted well before the usual age at which acne is seen. Beginning as small red papules, the lesions increase in number and perhaps size also as the patient ages. Puberty seems to produce the most rapid changes in the number and distribution of the lesions. The angiofibromata are generally distributed over the malar region of the face and may spread over the nasolabial folds on to the chin (frequently sparing the angle of the mouth). Although they are considered specific for TSC, the fact that they are not reliably present limits their use as a
PATIENT RESOURCES
National Neurofibromatosis Foundation 95 Pine Street, 16th Floor New York, NY 10005 Phone: 212-344-NNFF Toll-free phone: 800-323-7938 Fax: 212-747-0004 E-mail: NNFF@aol.com or NNFF@nf.org http://www.nf.org/ Neurofibromatosis, Inc. 8855 Annapolis Road, Suite 110 Lanham, MD 20706-2924 Phone: 301-577-8984 Toll-free phone: 800-942-6825 Fax: 301-577-0016 E-mail: nfinc1@aol.com http://www.nfinc.org/

John B. Bodensteiner, M.D., and Vinodh Narayanan, M.D.
Tuberous sclerosis complex (TSC) is a disorder that affects many tissues in the body including brain, heart, lungs, kidneys, skin, eyes, and bone. The disease complex is a disorder of cellular differentiation and proliferation resulting in hamartomata and true neoplasms, most prominently in the brain, kidney, and heart. The disease complex results from deletion/mutation abnormalities in either of two genes that work in concert in cell growth control pathways and produce indistinguishable disease manifestations although on average, the patients with TSC2 have a somewhat greater severity of manifest disease than those with TSC1. TSC1 is found on 9q34 (hamartin) and TSC2 on 16p13 (tuberin). Abnormal migration of cerebral neurons plays a central role in the neurologic manifestations of the disease. The prevalence of TSC is estimated at 1 in 6000 to 9000 individuals. Because of the striking variability of the clinical manifestations and severity of the disease,
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SUGGESTED READING
DeBella K, Szudek J, Friedman JM: Use of the National Institutes of Health criteria for diagnosis of neurofibromatosis 1 in children, Pediatrics 105:608-614, 2000. Friedman JM, Gutmann DH, MacCollin M, Riccardi VM, editors: Neurofibromatosis: phenotype, natural history, and pathogenesis, ed 3, Baltimore, 1999, Johns Hopkins University Press. http://www.genetests.org/ (search term: neurofibromatosis) North KN, Riccardi V, Samango-Sprouse C, et al: Cognitive function and academic performance in neurofibromatosis 1: Consensus statement from the NF-1 Cognitive Disorders Task Force, Neurology 48:1121-1127, 1997. Nunes F, MacCollin M: Neurofibromatosis 2 in the pediatric population, J Child Neurol 18:718-724, 2003. Ruggieri M, Husom SM: The clinical and diagnostic implications of mosaicism in the neurofibromatosis, Neurology 56:1433-1443, 2001.
the diagnosis remains difficult in individuals with subtle disease manifestations. The clinical diagnostic criteria established for TSC are highly reliable, and patients who meet the clinical diagnostic criteria for definite TSC do not require genetic testing for diagnostic purposes. It is likely that gene testing might be more useful in less obvious cases depending on the clinical situation and the age of the patient in question.
Clinical Aspects
The clinical features of TSC may involve neurologic, psychiatric, behavioral, and cognitive features including epilepsy (especially infantile spasms), mental retardation, pervasive developmental disorder and autism, renal disease and tumors, cardiac tumors, ocular lesions, and pulmonary disease. The characteristic brain lesions are unique enough to be considered part of the diagnostic criteria and include cortical tubers, subependymal glial nodules (SGNs), and subependymal giant cell astrocytomas (SEGAs). Almost any other organ system can be involved with the disease complex in some patients, though any individual usually has only a relatively limited number of organs with significant involvement. We address the most commonly encountered clinical manifestations of TSC. DERMATOLOGIC The dermatologic manifestations of TSC, which are characteristic enough to be considered major features in the diagnostic criteria, include hypomelanotic macules (ash leaf spots), ungual or periungual fibroma, facial angiofibroma (sebaceous adenomas), forehead plaques, and the shagreen patch. The confetti skin lesion is less specific and is considered only a minor feature. The hypomelanotic macules are found on the skin in more than 90% of patients with TSC. The lesions are usually present on the trunk, abdomen, back, or extremities at birth and are more easily seen on a pigmented background or with the use of an ultraviolet light in fair-skinned individuals. Because hypomelanotic macules are often present as single lesions in the normal population, the diagnostic criteria require more than three lesions. The confetti lesions may develop later, after the newborn period, and are usually on the extremities. Facial angiofibromata are fibrovascular lesions that are present in about 75% of patients. They are not present at birth and begin to develop after 2 to 4 years of age. Frequently they are mistaken for acne even though they are noted well before the usual age at which acne is seen. Beginning as small red papules, the lesions increase in number and perhaps size also as the patient ages. Puberty seems to produce the most rapid changes in the number and distribution of the lesions. The angiofibromata are generally distributed over the malar region of the face and may spread over the nasolabial folds on to the chin (frequently sparing the angle of the mouth). Although they are considered specific for TSC, the fact that they are not reliably present limits their use as a
PATIENT RESOURCES
National Neurofibromatosis Foundation 95 Pine Street, 16th Floor New York, NY 10005 Phone: 212-344-NNFF Toll-free phone: 800-323-7938 Fax: 212-747-0004 E-mail: NNFF@aol.com or NNFF@nf.org http://www.nf.org/ Neurofibromatosis, Inc. 8855 Annapolis Road, Suite 110 Lanham, MD 20706-2924 Phone: 301-577-8984 Toll-free phone: 800-942-6825 Fax: 301-577-0016 E-mail: nfinc1@aol.com http://www.nfinc.org/

John B. Bodensteiner, M.D., and Vinodh Narayanan, M.D.
Tuberous sclerosis complex (TSC) is a disorder that affects many tissues in the body including brain, heart, lungs, kidneys, skin, eyes, and bone. The disease complex is a disorder of cellular differentiation and proliferation resulting in hamartomata and true neoplasms, most prominently in the brain, kidney, and heart. The disease complex results from deletion/mutation abnormalities in either of two genes that work in concert in cell growth control pathways and produce indistinguishable disease manifestations although on average, the patients with TSC2 have a somewhat greater severity of manifest disease than those with TSC1. TSC1 is found on 9q34 (hamartin) and TSC2 on 16p13 (tuberin). Abnormal migration of cerebral neurons plays a central role in the neurologic manifestations of the disease. The prevalence of TSC is estimated at 1 in 6000 to 9000 individuals. Because of the striking variability of the clinical manifestations and severity of the disease,
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diagnostic feature. Furthermore, though they are of no functional significance and have no malignant potential, attempted removal is commonly undertaken for cosmetic reasons. The shagreen patch can be found on the back or flank most commonly. It is an irregularly shaped, slightly raised patch of skin that has a texture resembling the surface of a football. This lesion is also found infrequently in younger patients and in only 20% to 30% of patients overall. Ungual fibromas are nodular or fleshy lesions arising at the nail bed. Not usually seen in preadolescent patients with TSC, they occur in only 15% to 20% of the patients with TSC, and though they are considered by many as specific for the disease, similar lesions can result from trauma to the nail beds. We have seen several patients who have undergone procedures to remove the lesions that have been mistaken for warts. RENAL Renal lesions occur in 75% to 80% of patients with TSC. There are two types of renal lesions: cysts (single or multiple) and tumors (angiomyolipomata). Cysts tend to appear early and may be solitary, in which case they may disappear, or the cysts may be so numerous or large as to be symptomatic. Most often the solitary cysts are only an incidental feature. The presence of multiple cysts and multiple angiomyolipomata is characteristic of TSC. Bilateral tumors with many angiomyolipomata per kidney are typical. The prevalence and size of the renal tumors increase with age, so they must be followed serially with ultrasonography. Lesions that reach more than 4 cm in diameter are more likely to become symptomatic than are the smaller ones (hemorrhage into the tumor causing pain, hematuria, or acute renal failure), and the lesions that attain that size usually are treated with embolization or surgical intervention. There is a small but definite risk (<5%) of renal cell carcinoma that may arise from an angiomyolipoma or from another source. CARDIAC Rhabdomyomata, hamartomata involving the heart, are present in almost two thirds of patients with TSC and are usually multiple. They are most often located within the muscular walls of the cardiac chambers but can also be found within the papillary muscles or attached to the valve leaflets. Often the lesions are seen on prenatal fetal ultrasound, and because they usually regress with age, if they are not symptomatic early in life they usually do not become symptomatic later in life. The most common clinical manifestation is early in life with congestive heart failure that may be due to obstruction of flow by the hamartomata within the ventricle. Congestive heart failure resistant to medical management or location such as to interfere with the normal function of one of the major heart valve leaflets is the primary indication for surgical removal of the lesion. Cerebral embolism from a cardiac rhabdomyoma can occur but appears to be quite uncommon.
PULMONARY Although lung disease develops in only 1% of patients with TSC, the clinician needs to be aware of the possibility. Pulmonary lymphangiomatosis with chylothorax, spontaneous pneumothorax, dyspnea, cough, and hemoptysis are the most frequent symptoms. Pulmonary involvement is five times as common in females and may not develop till the 3rd or 4th decade. The prognosis with pulmonary involvement in TSC is not good, since two thirds of the patients die within 5 years of the onset of the symptoms. OPHTHALMOLOGIC The likelihood of finding one of the ophthalmologic features of TSC depends on the intensity of the search. Up to 87% of patients have ocular involvement but a considerably smaller number have one or more lesions identified. The retinal astrocytoma may be detected funduscopically, as can depigmented retinal lesions that represent hamartomata in the retina. Clinically significant lesions are rare, but the astrocytomata and the hamartomata may enlarge slowly and have the potential to limit vision due to their size. Occasional patients may have visual loss from vitreous hemorrhage or retinal detachment. NEUROLOGIC The classic neurologic manifestations of TSC are seizures, mental retardation, and behavioral abnormalities. A number of mildly affected individuals may have no neurologic impairment, though the proportion of patients so affected is unknown at present. The neurologic symptoms result from the disrupted neuronal migration along radial glial fibers and abnormal proliferation of glial elements. Pathologically, the lesions include the subependymal nodules (SGN and SEGA), cortical hamartomata (tubers), areas of focal cortical hypoplasia, and gray matter heterotopias. These lesions may be demonstrated by neuroimaging. SGNs frequently are calcified when they are seen best on computed tomography (CT) scans of the brain. SEGA, cortical hamartomata, and heterotopic gray matter are most easily seen on brain magnetic resonance (MR) imaging. Seizures occur in 80% to 90% of patients with TSC and may include a variety of types. Most mentally retarded patients with TSC have seizures, but there are exceptions. There is a particular tendency for infants with TSC to develop infantile spasms with hypsarrhythmia on electroencephalogram (EEG). The children with TSC who have infantile spasms are likely to have more lesions on neuroimaging and are likely to be more impaired than others with the disease complex. Other seizures, generalized and partial or partial complex, may also occur in these patients. Although many patients with TSC respond well to standard antiepileptic drug therapy, there is clearly an increased risk of refractory epilepsy in these patients. It is not surprising that a cortical tuber can frequently be identified as an epileptic focus in some patients, but perhaps more commonly the
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seizures are multifocal or generalized and a single epileptic focus cannot be identified. Most patients with seizures and TSC are retarded, but many patients with TSC and mental retardation do not have seizures. There is a rough correlation between the severity of cognitive impairment and the number and size of the cortical tubers. There is also a rough correlation between the number and size of the cortical lesions and the likelihood of behavioral disorders including autism, hyperkinesis, frank psychosis, and particularly aggressiveness, which is likely to worsen about puberty. The percentage of patients with TSC who will manifest severe behavior disturbances is not well established, but the onset of aggressive behavior near the time of puberty is characteristic of TSC in our experience. The intracranial tubers are well-localized hamartomata and do not enlarge over time. The SGNs have the potential to enlarge as the patient ages. Most SGNs are less than 2 cm in size; however, the most common location is at the level of the foramen of Monro, which can be obstructed, leading to unilateral or bilateral ventricular obstruction and hydrocephalus, which may produce acute of subacute changes in neurologic function of the affected patient. Some people believe the SEGAs represent enlarged SGNs, but there is some evidence that they are different lesions histologically. In either case, this subependymal lesion may have the potential to enlarge, and lesions larger than 1 cm are the ones most likely to do so. The frequency of this event is not well established but is sufficient to justify longitudinal evaluation of these patients. Once a SEGA begins to grow, it can be locally invasive. Because surgical removal is curative, the identification of an enlarging SEGA before the onset of symptoms has therapeutic implications.
TABLE 1 Diagnostic Criteria for Tuberous Sclerosis Complex (TSC)

Major Features Facial angiofibromata or forehead plaque Nontraumatic ungula or periungual angiofibromata Hypomelanotic macules (>3) Shagreen patch (connective tissue nevus) Subependymal nodule Cortical tuber* Subependymal giant cell astrocytoma Multiple retinal nodular hamartomata Cardiac rhabdomyomata, single or multiple Lymphangiomyomatosis Renal angiomyolipomata Minor Features Multiple, randomly distributed dental enamel pits Hamartomatous rectal polyps Bone cysts Cerebral white matter migration tracts*, Gingival angiofibromata Nonrenal hamartomata Retinal achromic patch Confetti skin lesions Multiple renal cysts Definite TSC Either 2 major features or 1 major feature and 2 minor features Probable TSC One major feature plus 1 minor feature Suspect TSC Either 1 major feature or 2 or more minor features
*When cerebral cortical dysplasia and cerebral white matter migration tracts occur together, they should be counted as one rather than two features of TSC. When both lymphangiomyomatosis and renal angiomyolipomas are present, other features of TSC should be present before a definite diagnosis is assigned. Histologic confirmation is suggested but not required. Radiographic confirmation is sufficient. Modified from Roach ES, Gomez MR, Northrup H: Tuberous Sclerosis Complex Consensus Conference: revised clinical diagnostic criteria, J Child Neurol 13:624-628, 1998.
Clinical Evaluation
Any patient suspected of having TSC should undergo a complete history and physical examination in an effort to match the findings to the established diagnostic criteria (Tables 1 to 4). Since the diagnosis frequently requires the documentation of lesions in the brain by neuroimaging, CT or MR imaging is generally considered part of the initial evaluation. In addition to the neuroimaging, cardiac and renal ultrasonography is also part of the initial evaluation. If the patient meets the criteria for definite TSC, one need not confirm with genetic testing. If one is unable to make a definite diagnosis at this point, ophthalmologic and dental evaluations are considered useful. We do not usually evaluate the colon for polyps unless other factors point in that direction. Genetic testing may be useful in establishing the diagnosis if the diagnosis must be made now rather than waiting for new features to develop over time. There are four clinical presentations that account for the vast majority of patients with TSC: (1) infantile spasms in the infant; (2) seizures at any age, but typically early childhood; (3) the evaluation of a mentally retarded child; and (4) the consult from the renal clinic for seizures or the dermatology clinic due to the skin lesions.
Infantile spasms are so characteristic of TSC that they were part of the diagnostic criteria in the past. The evaluation of patients with infantile spasms always includes a careful evaluation of the integument of the patient and parents as well as family history. In this setting it is important to remember the ultraviolet light because at 4 to 6 months of age, when infantile spasms most frequently begin, the depigmented macules may not be readily apparent without the Woods light. EEG is necessary to make the diagnosis of infantile spasms but is not useful in the diagnosis otherwise. Neuroimaging is considered part of the evaluation of these seizures and generally MR imaging is considered the study of choice because a good-quality study will identify even the small uncalcified SGNs. Though vigabatrin is touted as the drug of choice for infantile spasms associated with TSC, the recently published practice parameter concluded that there was insufficient evidence to conclude
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TABLE 2 Important Aspects of the Evaluation of the Patient with TSC

Presenting Signs and Symptoms Infantile spasms Seizures in childhood Mental retardation Seizures in a renal patient Skin abnormalities: white patches, acne-like lesions, shagreen patch, wartlike lesions under nails Important History Features Family history: epilepsy, mental retardation, skin lesions, consanguinity Autistic features Cardiac tumor in infancy Renal cysts or tumors Skin lesions Seizures Important Examination Features Integument Funduscopic Nail beds Malar rash Gingival angiofibromata Diagnostic Tests EEG if appropriate for seizures MR imaging or, if necessary, CT Renal ultrasound examination Cardiac ultrasound examination, if indicated Woods lamp (ultraviolet) examination of the integument Ophthalmologic examination
TSC, Tuberous sclerosis complex; EEG, electroencephalogram.
that vigabatrin is effective in these seizures. We use adrenocorticotropic hormone (ACTH), 150 units/m2, as a once-daily injection as the primary therapy for infantile spasms. A 4-week course of everyday therapy is completed if possible. Then the patient is switched to every other day, and a taper is begun that lasts over 6 to 8 weeks. When ACTH is changed to every other day,
valproate is started with the intent that it will be used as the maintenance drug when the steroid is stopped. We do an echocardiogram at the onset of therapy and follow blood pressures weekly, and if the patient develops hypertension we repeat the echo. If the repeat echo shows thickening of the myocardium, we begin the taper of the ACTH at that point. About two thirds of the patients develop hypertension and myocardial hypertrophy, which is transient and therapy related. The child who presents with seizures may already be suspected of having TSC. Stereotypic, focal seizures in a small infant should prompt the search for focal cortical dysplasias, including the cortical tubers of TSC. The evaluation includes EEG, MR imaging, and a search for other characteristic features. The choice of AED is made on the same basis as with any other seizure patient, that is, the seizure type and the EEG findings. Diagnosis in this context frequently has a major impact on prognosis and also frequently necessitates genetic counseling. Once the diagnosis is suspected, cardiac and renal ultrasound examinations are appropriate. Features that suggest the need for further or more intensive follow-up include SGN or SEGA larger than 1 cm in diameter or located precisely at the foramen of Monro on MR imaging. Renal ultrasound revealing an angiomyolipoma greater than 4 cm in size requires intervention, but smaller lesions require periodic evaluations to follow their growth. The discovery of TSC in a patient being evaluated for mental retardation or delayed acquisition of motor milestones is a relatively frequent event in practice. The principal components of the evaluation would include a careful history and physical examination, including a search of the integument and examination of the family members. MR imaging is the imaging study most likely to provide diagnostic information. On several occasions, we have made the diagnosis in a parent who was unaware of this condition. MR is the imaging study most likely to provide diagnostic information. Cardiac and renal ultrasound studies provide a baseline and help design the serial examination schedule. The patient referred from the renal or dermatology clinic for the possible diagnosis of TSC should be
TABLE 3 Suggested Serial Examinations for Various Abnormalities in Patients with TSC
Lesion Location
Abnormal Finding MRI Identification SGN or SEGA
Size
Recommendation
Lesion < 1 cm in diameter Lesion > 1 cm in diameter
Lesion at foramen of Monro Lesion elsewhere on ependymal surface Lesion at foramen of Monro Lesion elsewhere on ependymal surface
MRI q 1-2 yr if asymptomatic MRI q 3-5 yr MRI q yr MRI q 1-2 yr if asymptomatic
Ultrasonographic Identification Renal cysts or renal angiomyolipoma
Lesion < 4 cm in diameter Lesion > 4 cm in diameter
Repeat renal ultrasound q yr Treatment advised
TSC, Tuberous sclerosis complex; SGN, subependymal glial nodule; SEGA, subependymal giant cell astrocytoma.
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approached just like the patient with seizures or mental retardation with signs of TSC. Frequently, though they may have been identified as possibly having TSC, the patients referred from other medical clinics have not had the disease, its genetics, and implications explained to them or the family. The long-term management of patients with TSC includes treatment of active neurologic problems (seizures, behavior problems, mental retardation), as well as surveillance testing to prevent complications from known hamartomata. Surveillance testing usually consists of brain MR imaging, renal ultrasonography, and ophthalmologic examination. Serial brain imaging is aimed at identifying enlarging SGNs (which might actually be astrocytomas) and SEGAs, as well as detecting ventricular obstruction at the foramen of Monro. Serial renal ultrosonography is aimed at identifying renal cysts that are at risk for rupture or renal angiomyolipamas that are larger than 4 cm and are at risk for hemorrhage and other complications (see Table 3).
TABLE 4 Genetic Testing in Tuberous Sclerosis Complex

Indications Diagnostic confirmation in a suspected case Prenatal testing in an unaffected mother with a single affected child Testing for germinal mosaicism in unaffected parents with more than one affected child Testing in familial cases for genetic counseling Current Methods Amplification of exons and screening by DHPLC Direct sequencing of selected exons Future Methods Direct sequencing of TSC1 and TSC2 genes by microarray hybridization
Resources: http://www.genetests.org/ DHPLC, Denaturing high-performance liquid chromatography.
Genetics, Genetic Testing, and Genetic Counseling

About two thirds of the cases of TSC are sporadic, and the remaining cases are familial. The inheritance pattern is autosomal dominant. In most patients, the diagnosis can be made by clinical examination and radiologic studies. Genetic testing is not a part of the routine diagnostic evaluation. More than 300 distinct mutations in the TSC1 and TSC2 genes have been identified, and these are scattered over all the exons of the two genes. This makes the job of mutation detection difficult. Research studies looking for mutations in either TSC1 or TSC2 among sporadic patients with TSC report an identification rate of between 60% and 80%. The question of looking for a mutation in one of the two TSC genes comes up in certain special circumstances, and most of these deal with genetic counseling. One of these comes about because of the phenomenon of germinal mosaicism. This might be suspected when there are two or more affected children in a family, without any evidence of the disorder in either parent or other family members. Knowing the genetic mutation in the children allows us to define the carrier status of the parents, as well as to differentiate between germinal mosaicism in a parent and different spontaneous mutations in the children. A second scenario in which genetic testing may be useful is when the diagnosis is made in the child of a young unaffected couple. Again, the problem in providing accurate genetic risk information is because of the phenomenon of germinal mosaicism in a parent. Identification of the mutation in the affected child will permit prenatal testing in future pregnancies. A third setting in which genetic testing is done is when clinical and radiologic testing is not conclusive, and early diagnosis is important (e.g., when the mother is pregnant). In this situation, identification of a genetic mutation (as distinct from a polymorphism) is helpful,
but failure to define a gene mutation should not be interpreted as ruling out the diagnosis. This is because of the limitations of the methods used to screen for mutations, and the fact the known mutations in TSC1 and TSC2 are scattered over the entire extent of the genes. SUGGESTED READING
Kandt RS: Tuberous sclerosis complex and neurofibromatosis type 1: the two most common neurocutaneous diseases, Neurol Clin North Am 20:941-964, 2002. Mackay MT, Weiss SK, Adams-Webber T, et al: Medical treatment of infantile spasms, Neurology 62:1668-1681, 2004. Roach ES, DiMario FJ, Kandt RS, Northrup H: Tuberous Sclerosis Consensus Conference: recommendations for diagnostic testing, J Child Neurol 14:401-407, 1999. Roach ES, Gomez MR, Northrup H: Tuberous Sclerosis Complex Consensus Conference: revised clinical diagnostic criteria, J Child Neurol 13:624-628, 1998. Shevell M, Ashwal S, Donley D, et al: Evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology; Committee of the Child Neurology Society, Neurology 60:367-380, 2003.
PATIENT RESOURCE
Tuberous Sclerosis Alliance 801 Roeder Road, Suite 750 Silver Spring, MD 20910 Phone: 301-562-9890 Toll-free phone: 800-225-6872 http://www.tsalliance.org info@tsalliance.org/
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Anne Comi, M.D.
port-wine stain and new onset of complex partial seizures and a strokelike episode with hemiparesis following the event. In each case, a thorough assessment of involvement is needed so that the patient and family can be appropriately counseled and treatment initiated.
Sturge-Weber syndrome (SWS) is the third most common neurocutaneous disorder and occurs sporadically. There is typicallya facial port-wine stain in the ophthalmic distribution of the trigeminal nerve, glaucoma and vascular eye abnormalities, and a parieto-occipital leptomeningeal angioma ipsilateral to the cutaneous and ocular anomalies. The usual presentation is in infancy; however, presentation with first seizure and subsequent diagnosis is known to occur in adulthood. Somatic mutation has been proposed as a possible etiology; however, the putative gene is unknown. Patients with SWS often develop neurologic problems including seizures, migraines, strokelike episodes, learning difficulties or mental retardation, visual field cuts, and hemiparesis. These problems frequently persist into adulthood and can be further complicated by psychological problems and difficulty establishing independence from the family of origin. Multiple specialists, including a neurologist, ophthalmologist, dermatologist, medical rehabilitation specialist, occupational and physical therapists, speech and language pathologist, psychiatrist, and behavioral psychologist, are therefore often involved in the care of individuals with SWS (Figure 1).
Diagnosis and Evaluation

Any child with a facial port-wine stain in the cranial nerve V1 distribution, or an adult presenting with this and neurologic symptoms, should have a head computed tomography (CT) scan to image the calcification and magnetic resonance (MR) imaging of the brain with and without contrast to detect the angioma. The typical CT findings are cortical calcifications often in a gyral pattern and atrophy, although these findings may not be present in neonates or infants. The brain MR scan demonstrates increased T2-weighted signal in the white matter and focal meningeal enhancement. When possible, we also ask for postcontrast fluid-attenuated inversion recovery (FLAIR) imaging because this appears to have greater sensitivity for visualizing the angioma. Imaging with technetium-99m hexamethylpropyleneamine oxime single-photon emission CT (SPECT) or perfusion MR imaging is useful for assessing the extent and localization of the perfusion defects and metabolic imaging with fluorodeoxyglucose positron emission tomography (FDG-PET) or MR spectroscopy may also be helpful in characterizing the extent of brain disease in SWS. If MR imaging is negative in infancy, one may need to repeat it by the first birthday or with the onset of neurologic symptoms. Close neurologic and developmental follow-up is essential for children with SWS to diagnose and treat developmental delays, seizures, headaches, hemiparesis, learning difficulties, and behavioral issues as they arise. Most children with SWS require occupational and physical therapy for their hemiparesis and visual field cut. Developmental and neuropsychological assessments can be quite helpful for addressing attentional issues and learning difficulties. Attention deficit disorder occurs in about 20% and mental retardation in about 50% of children and adults with SWS. Screening for glaucoma should be done at birth, under anesthesia if necessary, and then at least every 3 to 4 months in the first year, every 6 months in the second year, and yearly thereafter. The peak time for diagnosis of glaucoma is in infancy, but a second smaller peak occurs in young adulthood. Ophthalmologic evaluations can determine the extent of abnormal vessel involvement with the eye. Patients with port-wine stains involving both the upper and the lower eyelids are at the greatest risk for glaucoma. Glaucoma in the young child can present with eye enlargement (buphthalmos) or with corneal clouding and vision loss at any time, and these signs and symptoms need urgent evaluation. Patients with a port-wine stain are also referred for dermatologic assessment. In infancy the port-wine stain is often pink and flat. The port-wine stain generally grows commensurate with growth and often darkens or
Presentations
The diagnosis of SWS can frequently be suspected when an individual is noted to have a facial port-wine stain. The diagnosis of SWS means that the cutaneous port-wine stain is associated with either brain or eye involvement. The risk of an associated underlying leptomeningeal angioma and/or glaucoma is about 8% with a port-wine stain anywhere on the face. Thus, most patients with a facial port-wine stain do not have SWS. This risk increases to about 25% when the skin angioma is in the cranial nerve V1 ophthalmic distribution on the face. A careful examination of the upper eyelid may reveal cutaneous involvement of just a few millimeters in some cases. The risk of intracranial involvement increases to 33% with bilateral facial port-wine stains. In approximately 85% of individuals with SWS, the involvement is unilateral with the brain and eye involvement on the same side as the port-wine stain. However, a unilateral port-wine stain can be paired with bilateral leptomeningeal angioma involvement or vice versa. The most frequent presentation for the neurologic manifestations in SWS is focal and complex partial seizures in an infant with a facial port-wine stain. Onset of seizures is usually in the first 2 years of life but occasionally can start later in childhood or even adulthood. Other presentations for SWS include a visual field cut presenting as an infant that neglects a hemivisual space or the early onset of handedness in a child with a facial port-wine stain. An adult can present with a facial
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FIGURE 1. Evaluating a patient with facial cutaneous capillovascular malformation (port-wine stain). SPECT, Single-photon emission computed tomography; FDG-PET, fluorodeoxyglucose positron emission tomography; AED, antiepileptic drug; EEG, electroencephalogram.
Patient with facial port-wine stain including the V1 trigeminal nerve distribution
Dermatologic and ophthalmologic evaluations
Obtain MRI of the brain with and without contrast Normal Consider reimaging and metabolic imaging with perfusion MRI, SPECT or FDG-PET Abnormal Provide Diastat, anticipatory guidance for seizures, daily multivitamin, screen for iron deficiency anemia, anticipatory guidance for illness and avoidance of dehydration and close neurodevelopmental follow-up
Have seizures occurred? No Close neurologic follow-up Yes Aggressive seizure management: First line AED: Carbamazepine Second line AED: Valproic acid or topiramate Maintain high-normal blood levels of AED Diastat for seizure >5 minutes If unsuccessful, consider video EEG Monitoring and PET imaging for surgery
Have focal weakness or stroke-like episodes? No Close neurologic follow-up Yes Occupational/physical therapy Low dose aspirin 35 mg/kg/day if stroke-like episodes present
may become raised with time. It is recommended that port-wine stains be treated in infancy, before hypertrophy and blebbing develop and make treatment more difficult. Later in childhood, plastic surgery may be judiciously considered to deal with the tissue hypertrophy that can occur in the region of the port-wine stain. Presenting the diagnosis of SWS to patients and parents is complex and requires the coordinated input of multiple specialists to address the different organ systems involved in this disorder. It is essential that time is spent answering questions so that seizures, strokelike episodes, and other complications are recognized and appropriately managed to minimize brain injury.
SEIZURES Infants with SWS typically develop complex partial seizures in the first 3 years of life, most in the first year. It is essential that family members receive counseling regarding what seizures look like and how to obtain help rapidly for a first seizure. Seizures are managed acutely with benzodiazepines, phosphenytoin, and, if necessary, phenobarbital. A prolonged hemiparesis, lasting days, weeks, or months is common after a seizure episode, and a permanent hemiparesis frequently develops over time. Although controversial, there is evidence that seizures, particularly if they are frequent or prolonged, may result in increased brain injury resulting from the impairments in blood flow. Therefore, chronic anticonvulsants should be initiated after the first seizure, whether febrile or afebrile, in a patient with SWS and brain involvement. Vigorous efforts should be made to gain control of seizures. I recommend medication levels (when applicable) at least in the high-therapeutic range and regular adjustments of dose for weight gain to best maintain seizure control. Generally the first-choice anticonvulsant is carbamazepine, or phenobarbital transitioning to carbamazepine, depending on the age of the child, because
Therapy
In all patients with SWS and intracranial involvement, I advise the empirical use of a daily multivitamin. Patients with SWS should be screened for iron deficiency anemia, which is relatively common in young children and some adults and, if present, could exacerbate ischemic brain injury and should be treated.
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most seizures in SWS are complex partial. Oxcarbazine (Trileptal) may also be used. Second-line choices include topiramate and valproic acid. Rectal or oral diazepam is given to the family for use with seizures lasting longer than 5 minutes or with clusters of seizures. Seizures in SWS, as in other settings, commonly occur during illness. I advise family members and patients to treat fevers and maintain good hydration during illness, even if intravenous fluids are needed. I advise continuing the anticonvulsant for a few years, until the fifth birthday if possible, because older children appear to be less susceptible to permanent neurologic decline that may be exacerbated by seizures in the younger children. If seizures are not controlled with anticonvulsants, are occurring frequently so as to interfere with development, or deterioration in neurologic status is occurring, then children should be considered for surgical resections. Surgery may include focal resections or hemispherectomies. Most candidates for surgery have significant developmental delay and hemiparesis. Timing of surgery should be carefully weighed for risks and benefits; however, in the appropriate situation surgery can result in cessation of seizures and resumption in development. There is no evidence that surgical resection of the affected cortex is the proper course of action in the absence of intractable epilepsy. STROKELIKE EPISODES Strokelike episodes can occur in SWS and present as episodes of transient visual field cuts or weakness that can occur independent of seizures or may precede or follow seizures. It is not entirely clear what these episodes represent; however, thrombosis, hypoxia-seizure, complicated migraine, and/or seizure activity all may have some role in these episodes. Minor head trauma can trigger these events as well. I recommend prophylactic use of aspirin when strokelike episodes have occurred. Experience with its use in the prevention of pediatric stroke, and anecdotal evidence in SWS, suggest that low-dose aspirin at 3 to 5 mg/kg/day is safe and effective; however no randomized, placebo-controlled trial has been done. Children on aspirin therapy should receive varicella immunization and the yearly influenza vaccine because of the association between these illnesses, aspirin use, and Reyes syndrome in children. The international experience with low-dose aspirin use for stroke prophylaxis in children, however, suggests that this therapy is safe. Preventing severe illness with these vaccinations is probably a good idea anyway because episodes of deterioration in SWS often occur in the setting of illness. Occupational and physical therapies are prescribed when weakness is persistent to maximize function and prevent contractures. HEADACHES Headaches and migraines are also common in SWS. Acutely, antimigraine medications such as ibuprofen are used; however, the safety of triptans has not been studied in SWS. In older children and adults, it seems that seizures can provoke headaches, and headaches can
precede the onset of seizures or strokelike episodes. When frequent, valproic acid may provide prophylaxis for both seizures and recurrent headaches. Alternatively, a combination of an anticonvulsant, such as carbamazepine, and a calcium channel blocker or beta blocker may be required. COGNITIVE AND PSYCHOLOGICAL ISSUES Learning disabilities and mental retardation frequently develop in SWS and need to be evaluated and addressed educationally. Attention deficit disorder is common in SWS and should be addressed with a combination of behavioral and pharmacologic approaches. When behavioral approaches are insufficient, then treatment with either a stimulant or atomoxetine should be initiated and response closely monitored. Depression and anxiety are also common in SWS. Older children and adolescents can demonstrate a decline in function or new behavioral issues, and psychological factors should be evaluated when this occurs. Treatment with a selective serotonin reuptake inhibitor or tricyclic may be helpful. However, the safety and efficacy of these approaches have not been studied specifically in SWS.
Treatment of Ophthalmologic and Dermatologic Complications

Treatment of the port-wine stain requires a series of laser treatments. Pulsed-dye laser can improve the appearance of the vascular malformation in about 10 treatments. Without treatment, the port-wine stains often develop blebbing and hypertrophy of underlying soft tissue and bone that can lead to significant psychological and functional issues depending on the location and extent of involvement. It is unknown if infancy is the best time for treatment of SWS, given the other systems involved; however, the current practice in SWS is to treat the port-wine stain early. Laser treatments are painful and can occasionally result in scarring, and older children should therefore be included in discussions for timing for treatment. Glaucoma may occur at any age, although two peaks exist in infancy and in early adulthood. The goal of treatment is to reduce intraocular pressure to protect vision. Medical and surgical approaches are used and concentrate on either reducing the production of aqueous fluid or promoting its drainage. Medications include beta-agonist eye drops, adrenergic eye drops, and carbonic anhydrase inhibitors. Trabeculectomy and goniotomy are common surgical options. SUGGESTED READING
Bodensteiner JB, Roach ES, editors: Sturge-Weber syndrome, Mt. Freedom, NJ, 1999, Sturge-Weber Foundation. Chapieski L, Friedman A, Lachar D: Psychological functioning in children and adolescents with Sturge-Weber syndrome, J Child Neurol 15:660-665, 2000. Comi AM: Pathophysiology of Sturge-Weber syndrome, J Child Neurol 18:509-516, 2000. Johnson: Current Therapy in Neurologic Disease (7/E)
Autism Kossoff EH, Buck C, Freeman JM: Outcomes of 32 hemispherectomies for Sturge-Weber syndrome worldwide, Neurology 59: 1735-1738, 2002. Maria BL, Neufeld JA, Rosainz LC, et al: Central nervous system structure and function in Sturge-Weber syndrome: evidence of neurologic and radiologic progression, J Child Neurol 13:606-618, 1998. Rothfleisch JE, Kosann MK, Levine VJ, Ashinoff R: Laser treatment of congenital and acquired vascular lesions, Dermatol Clin 20:1-18, 2002.
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PATIENT RESOURCES
Sturge-Weber Foundation P.O. Box 418 Mt. Freedom, NJ 07970 Phone: 800-627-5482 Fax: 973-895-4846 http://www.sturge-weber.com/ The Kennedy Krieger Institute and Johns Hopkins Medicine Sturge-Weber Syndrome Center 707 N Broadway Baltimore, MD 21205 Phone: 443-923-9128 Fax: 443-923-9160 http://www.sturge-weberkennedy krieger.org
Neuropathologic findings in autism postmortem brain tissue include altered neuronal populations in the limbic system, decreased Purkinje cells, altered cortical minicolumns, increased white matter, and neuroglial activation. Most of the findings are consistent with abnormal developmental programs of prenatal onset. These altered programs could result in observations of altered neuropeptides at birth, accelerated brain growth during infancy, and increased platelet serotonin. In addition to genetic influences, epigenetic and environmental factors may affect selectively vulnerable neural networks through multiple mechanisms. Several neurobiologic processes have been implicated in the pathogenesis of autism, including abnormal neurotransmitters, experience-dependent synaptic plasticity, glutamate excitotoxicity, and neuroimmune mechanisms.

Early detection of autism is important because early intensive intervention improves outcome for most children. An effective screening tool for autism is the Modified Checklist for Autism in Toddlers (M-CHAT) (available at http://www.firstsigns.org/). Clinical indicators for a more structured evaluation include (1) failure to point at objects to get anothers attention (normally present at 12 months of age); (2) impaired receptive and expressive language (e.g., failure to use single words by 18 months, 2-word phrases by 2 years, answer what, where, and who questions by 3 years); and (3) the use of sustained high-pitched sounds (eeeee) or echolalia. An exception is Aspergers syndrome, in which semantics are usually spared. Early signs of abnormal social relatedness may include difficulty engaging in peek-aboo games, making and maintaining eye contact, and showing reciprocal emotion. The child may be affectionate on his or her own terms or relate to older children and adults rather than peers. Children and adults with ASDs lack theory of mind: they are unable to perceive the thoughts and feeling states of others. Repetitive and stereotypic behaviors may include waving the hands in the lateral visual fields, flapping the hands, and ordering objects. Persons with autism exhibit an insistence on sameness without apparent meaning. Certain autistic behaviors, such as covering the ears, scratching the skin, and repeating visual patterns, may result from abnormal neurophysiologic processing of sensory inputs. A preliminary impression of ASD in preschool children, based on observation and screening tests (e.g., M-CHAT or Childhood Autism Rating Scale [CARS]), should be followed by a coordinated team evaluation (physician, speech and language pathologist, and psychologist). The diagnosis is confirmed and further defined using the Autism Diagnostic Observation Schedule (ADOS) or Autism Diagnostic Interview-Revised (ADI-R), both of which are administered by specially trained testers. Evaluations should also include assessments of cognitive functions and adaptive skills. All children should have audiologic, speech and language therapy (SLT), and occupational therapy (OT) evaluations. It is important to rule out hearing loss using age-appropriate
Autism
Autism is a heterogeneous group of lifelong neurobehavioral syndromes, now referred to as autism spectrum disorders (ASDs), that result from abnormal early neural development with appearance of initial symptoms by the age of 3 years. Known etiologies are detectable in up to 10% of patients, although the causes in most are still unknown. Patients typically present with delayed or disordered language development, abnormal social relatedness, and repetitive, odd behaviors. Autistic symptoms and cognitive deficits vary widely among patients in their age at onset, severity, and clinical course. Regression in previously acquired language and social skills occurs in approximately 30%, usually between 18 and 21 months. Classic, or Kanner-type, autism is grouped with other ASDs (or pervasive developmental disorders [PDDs] in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), including Aspergers syndrome and PDD/NOS (not otherwise specified). Idiopathic autism is genetic; concordance for the broad autism spectrum in monozygotic twins is 90% and in dizygotic twins, 10%. The recurrence risk for a family with one child with autism is up to 9%. The disorders typically affect boys more than girls (4:1) and occur in all cultural and racial groups. The estimated prevalence of ASDs is 1:250 to 500 and appears to be increasing. However, this may result in part from broader definition and improved recognition in recent years. In any case, autism is now the most common neurodevelopmental disorder.
Autism Kossoff EH, Buck C, Freeman JM: Outcomes of 32 hemispherectomies for Sturge-Weber syndrome worldwide, Neurology 59: 1735-1738, 2002. Maria BL, Neufeld JA, Rosainz LC, et al: Central nervous system structure and function in Sturge-Weber syndrome: evidence of neurologic and radiologic progression, J Child Neurol 13:606-618, 1998. Rothfleisch JE, Kosann MK, Levine VJ, Ashinoff R: Laser treatment of congenital and acquired vascular lesions, Dermatol Clin 20:1-18, 2002.
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PATIENT RESOURCES
Sturge-Weber Foundation P.O. Box 418 Mt. Freedom, NJ 07970 Phone: 800-627-5482 Fax: 973-895-4846 http://www.sturge-weber.com/ The Kennedy Krieger Institute and Johns Hopkins Medicine Sturge-Weber Syndrome Center 707 N Broadway Baltimore, MD 21205 Phone: 443-923-9128 Fax: 443-923-9160 http://www.sturge-weberkennedy krieger.org
Neuropathologic findings in autism postmortem brain tissue include altered neuronal populations in the limbic system, decreased Purkinje cells, altered cortical minicolumns, increased white matter, and neuroglial activation. Most of the findings are consistent with abnormal developmental programs of prenatal onset. These altered programs could result in observations of altered neuropeptides at birth, accelerated brain growth during infancy, and increased platelet serotonin. In addition to genetic influences, epigenetic and environmental factors may affect selectively vulnerable neural networks through multiple mechanisms. Several neurobiologic processes have been implicated in the pathogenesis of autism, including abnormal neurotransmitters, experience-dependent synaptic plasticity, glutamate excitotoxicity, and neuroimmune mechanisms.

Early detection of autism is important because early intensive intervention improves outcome for most children. An effective screening tool for autism is the Modified Checklist for Autism in Toddlers (M-CHAT) (available at http://www.firstsigns.org/). Clinical indicators for a more structured evaluation include (1) failure to point at objects to get anothers attention (normally present at 12 months of age); (2) impaired receptive and expressive language (e.g., failure to use single words by 18 months, 2-word phrases by 2 years, answer what, where, and who questions by 3 years); and (3) the use of sustained high-pitched sounds (eeeee) or echolalia. An exception is Aspergers syndrome, in which semantics are usually spared. Early signs of abnormal social relatedness may include difficulty engaging in peek-aboo games, making and maintaining eye contact, and showing reciprocal emotion. The child may be affectionate on his or her own terms or relate to older children and adults rather than peers. Children and adults with ASDs lack theory of mind: they are unable to perceive the thoughts and feeling states of others. Repetitive and stereotypic behaviors may include waving the hands in the lateral visual fields, flapping the hands, and ordering objects. Persons with autism exhibit an insistence on sameness without apparent meaning. Certain autistic behaviors, such as covering the ears, scratching the skin, and repeating visual patterns, may result from abnormal neurophysiologic processing of sensory inputs. A preliminary impression of ASD in preschool children, based on observation and screening tests (e.g., M-CHAT or Childhood Autism Rating Scale [CARS]), should be followed by a coordinated team evaluation (physician, speech and language pathologist, and psychologist). The diagnosis is confirmed and further defined using the Autism Diagnostic Observation Schedule (ADOS) or Autism Diagnostic Interview-Revised (ADI-R), both of which are administered by specially trained testers. Evaluations should also include assessments of cognitive functions and adaptive skills. All children should have audiologic, speech and language therapy (SLT), and occupational therapy (OT) evaluations. It is important to rule out hearing loss using age-appropriate
Autism
Autism is a heterogeneous group of lifelong neurobehavioral syndromes, now referred to as autism spectrum disorders (ASDs), that result from abnormal early neural development with appearance of initial symptoms by the age of 3 years. Known etiologies are detectable in up to 10% of patients, although the causes in most are still unknown. Patients typically present with delayed or disordered language development, abnormal social relatedness, and repetitive, odd behaviors. Autistic symptoms and cognitive deficits vary widely among patients in their age at onset, severity, and clinical course. Regression in previously acquired language and social skills occurs in approximately 30%, usually between 18 and 21 months. Classic, or Kanner-type, autism is grouped with other ASDs (or pervasive developmental disorders [PDDs] in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), including Aspergers syndrome and PDD/NOS (not otherwise specified). Idiopathic autism is genetic; concordance for the broad autism spectrum in monozygotic twins is 90% and in dizygotic twins, 10%. The recurrence risk for a family with one child with autism is up to 9%. The disorders typically affect boys more than girls (4:1) and occur in all cultural and racial groups. The estimated prevalence of ASDs is 1:250 to 500 and appears to be increasing. However, this may result in part from broader definition and improved recognition in recent years. In any case, autism is now the most common neurodevelopmental disorder.
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Autism
audiometric techniques or, if necessary, brainstem auditory evoked responses. Structured behavioral therapies (e.g., applied behavioral analysis) should be considered for young children, with assisted programming based on psychological and educational testing in school-age children. Additional help with play or social skills groups may be needed. The differential diagnosis of ASD includes more than 100 conditions that show autistic behaviors. Many of these include double syndromes, in which the phenotype of autism is associated with another disorder of known cause, such as Rett, Down, and fragile X syndromes, and tuberous sclerosis. Rett syndrome results from defects in the methyl-CpG-binding protein 2 (MeCP2) gene and affects mainly females, who regress after the first year of life and often develop seizures and typical hand-wringing movements. Fragile X syndrome, due to expansion of trinucleotide repeats within the FMR1 gene, is a major cause of mental retardation and may present with autism in boys, as well as learning disabilities in girls. Autism, by itself, in most cases does not have an identifiable cause. Identification of a specific etiology can have important implications for prognosis and treatment, such as for seizures and mitochondrial dysfunction. Neurologic evaluations for ASDs should include histories of the prenatal and perinatal periods, early development, infections, gastrointestinal (GI) and immune functions, and seizures. The family history may reveal conditions concurrent with autism or elements of ASDs (e.g., difficulties with social or pragmatic language skills). The neurologic examination, often a challenge to perform, should include direct observation of the childs communication and play behaviors; evaluation of receptive, expressive, and social aspects of language; measurements of growth; notation of dysmorphic features; and Woods lamp examination.
seizure activity (atypical Landau-Kleffner syndrome). Other tests may be indicated for specific syndromes, such as 7-dehydrocholesterol for Smith-Lemli-Opitz syndrome, FISH for velocardiofacial and Angelmans syndrome, transferrin electrophoresis for congenital disorders of glycosylation, 24-hour urinary uric acid for purine autism, and serum ammonia levels. Cranial computed tomography (CT), single-photon emission CT, and magnetic resonance (MR) scans are generally not performed routinely and should be reserved for those with special indications based on the history and neurologic examination. Other imaging methods, such as positron emission tomography, functional MR imaging, and MR spectroscopy, are strictly research tools.
Treatment
Established therapies for autism include individualized special school programs and speech/language and behavioral therapies in a setting that is coordinated, structured, and predictable and contains visual supports and high degrees of reinforcement. Beginning therapies early takes advantage of potential synaptic plasticity. Although most children improve, an individual childs trajectory for improvement varies over time. Outcomes for independent functioning correlate with attainment of functional language and adaptive skills by school age. Periodic, regular assessments should include cognitive, social skills and educational testing, in additional to SLT, OT, and occasionally physical therapy. Drug therapies for ASDs (Figure 1) are symptomatic and are chosen to improve short-term function and behavior such as calming, improving attention, or reducing aggression to enable the child to remain in the classroom. There is no evidence to suggest pharmacotherapy affects long-term outcomes. In individual cases, therapy targeted to the treatment of concurrent medical disorders, such as mitochondrial dysfunction, allergy, or hypothyroidism, can be beneficial. Children with GI symptoms (recurrent loose stools or constipation in 24%) may benefit from GI evaluation and elimination diets (e.g., gluten- and casein free). Sleep is disordered in 60% of ASD patients (more in young children), and abnormal rapid eye movement arousals can be observed on sleep studies. Treatment with melatonin, up to 3 mg/day, or clonidine, 0.025 to 0.1 mg, at bedtime may help to initiate but not maintainsleep, whereas trazodone, 25 to 75 mg, may benefit both. The following steps are suggestions for drug treatment and may be selected in any order, depending on the patients symptoms. The goal is to improve function with as few agents as possible, allowing adequate time between trials to assess their efficacy. Step 1. Selective serotonin reuptake inhibitors (SSRIs) SSRIs improve function in most children with ASDs. Multiple clinical and experimental studies over 30 years have shown that altered serotonin (increased in platelets; decreased synthesis in the central nervous system [CNS]) is a critical component of ASDs in many patients and suggest that treatment may
Laboratory Testing
Recommendations for laboratory testing in children with autism range from no studies to a comprehensive evaluation. In my opinion basic laboratory studies in children with ASDs should include complete blood count, serum chemistries (including aspartate aminotransferase [AST]/amino alanine transferase [ALT] and creatine kinase), red blood cell lead levels, and thyroid function. Marginal or low hemoglobin levels occur frequently, especially in children with restricted food preferences. Genetic testing should include a karyotype with subtelomere screening by fluorescence in situ hybridization (FISH), and fragile X by DNA (in girls as well as boys). If there has been regression of language and other skills, further testing of mitochondrial function is indicated, including fasting lactic acid, serum carnitine, plasma amino and urinary organic acids; the ratios of plasma alanine-to-lysine should normally be less than 3:1 and serum AST/ALT less than 2:1. An overnight or extended electroencephalographic (EEG) study including deep natural sleep is also suggested, to evaluate for
Autism
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FIGURE 1. Suggested drug treatment plan over 1 year for 4- to 8-year-old children with autistic spectrum disorders. Successive treatment trials for clinical symptoms should start with smallest doses and increase slowly to assess responses and to avoid overstimulation, due to sensitivity to serotonergic agents (buspirone, selective serotonin reuptake inhibitors [SSRIs]). Regimens should be limited to one or two drugs if possible.
Anxiolytic: buspirone 2.55 mg t.i.d. 1st
(or)
(Treat anxiety, mood, attention, repetitive behaviors)
SSRI: e.g., citalopram 0.5 mg q.a.m.; increase weekly by 0.5 mg, up to 45 mg; avoid overstimulation Alpha-2 adrenergic agonists: e.g., clonidine 0.050.1 mg q.h.s.; up to 0.1 mg t.i.d.
2nd
(Sleep, calming)
(usually not together)
3rd
(Focus, attention)
Stimulants: e.g., methylphenidate 2.510 mg q.a.m. and afternoon Antiepileptics/mood stabilizers: e.g., divalproex sprinkles, 1015 mg/kg; up to 30 mg/kg; monitor labs Atypical antipsychotics: e.g., risperidone 0.25 mg q.h.s., up to 1 mg b.i.d. 9 12
4th
(Seizure activity, mood)
5th
(Mood, aggressive behaviors)
6 Months
improve outcomes. Unfortunately, currently available clinical assays of circulating serotonin are not useful to guide treatment. SSRIs decrease anxiety and repetitive behaviors and improve attention and mood. Experience shows that most children with ASDs have increased sensitivity to SSRIs and respond to small doses; a few children show decreased sensitivity and require high doses. I prefer to begin therapy with very small doses of citalopram (using liquid preparations of 0.5 to 1 mg daily, usually in the morning) and to increase weekly by a similar amount, being cautious to avoid overstimulation as the dose is increased. This may occur when the dose exceeds the individuals therapeutic window, usually in doses from 1 to 5 mg in young children. Individual responses to different SSRIs vary, so repeated trials of different medications may be needed, each over 2 to 3 months. Full therapeutic benefits may not become apparent for 6 to 8 weeks and may be superseded by side effects if the dose is increased too rapidly. Treatment should continue for 6 to 12 months and then be tapered slowly over 6 to 8 weeks. Most young children maintain their gains after the SSRI is discontinued, although loss of function may dictate restoration of drug therapy. Step 2. Sleep, calming, and attentionAlpha2-adrenergic agonists (e.g., clonidine, guanfacine) are useful agents; clonidine helps induce sleep and can be used during the day for calming and to improve focus and attention but may also induce drowsiness. Guanfacine produces less sedation and calming but may be more effective for focus and attention. Step 3. Stimulants for attentionAlthough symptoms of attention deficit hyperactivity disorder (ADHD) occur frequently, children with ASDs are less likely than typical children with ADHD to respond favorably to stimulant medications. Children with ASDs overfocus and have selective attention. Brief medication
trials with stimulants (e.g., methylphenidate) are indicated but may lead to irritability and increased hyperactivity. Imipramine and atomoxetine are often good alternatives. Step 4. AnticonvulsantsEEGs following language regression or seizures may reinforce a decision to treat with anticonvulsant medications, such as divalproex or carbamazepine. Although guidelines for the evaluation, treatment, and prognosis of children with abnormal EEGs (but without clinical seizures) have not been determined, experience suggests that approximately one half of these patients will improve in their behavior and language when treated with anticonvulsants. Such improvements, however, likely result from the effect of these medications as mood stabilizers and suggest that epileptiform activity on EEGs reflects, rather than causes, underlying CNS dysfunction. Approximately 30% of persons with autism develop generalized tonic-clonic epilepsy, usually during adolescence. Step 5. Atypical antipsychoticsThese medications are helpful for aggression and adverse behaviors in ASDs. Despite their demonstrated efficacy in short-term trals, risperidone and related drugs deserve cautious follow-up for side effects that include extrapyramidal movements, weight gain, and hyperprolactinemia. Olanzapine and other atypical antipsychotics may induce diabetic changes requiring glucose monitoring.
Summary
Current therapies for ASDs may take advantage of inherent CNS plasticity and lead to improved outcomes. Basic and clinical research in autism is evolving rapidly and should provide approaches based on new knowledge of the underlying pathogenesis of ASDs.
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Attention Deficit Hyperactivity Disorder and Learning Disabilities
Acknowledgment The author thanks Dr. Susan Connors for her review and helpful suggestions. SUGGESTED READING
Bauman, ML, Kemper TL, editors: The neurobiology of autism, ed 2, Baltimore, 2005, Johns Hopkins University Press. Palermo MT, Curatolo P: Pharmacologic treatment of autism, J Child Neurol 19:155-164, 2004. Tuchman R: Autism, Neurol Clin North Am 21:915-932, 2003. Zimmerman AW: Autism spectrum disorders. In Singer HS, Kossoff EH, Hartman AL, Crawford TO, editors: Treatment of pediatric neurologic disorders, New York, 2005, Marcel Dekker, pages 489-494.
EVALUATION The evaluation of an individual with suspected ADHD includes the following: 1. Identification of ADHD features that continue to impair function and fulfill diagnostic criteria. This should include information from multiple sources (individual, family member, educators, job colleagues, and friends) and from preexisting documents (report cards, school assessments, psychological testing). Rating scales can be helpful as part of the assessment of individuals with ADHD, with results interpreted in conjunction with other information. Common tools include Conners Parent and Teacher Rating Scales, ADHD Rating Scale, and Vanderbilt Assessment Scale (available as part of an ADHD Toolkit at http:// www.nichq.org/). Adult scales include Adult ADHD Self-Report Scale Wender Utah Rating Scale, Conners Adult ADHD Rating Scales, and Brown Adult ADD Scale. 2. Confirmation that the individual manifested features of ADHD during childhood, especially during or prior to the early school-age years. 3. Review of prenatal, birth, and developmental history for factors that can cause ADHD and for timing and severity of presentation. These include in utero ethanol exposure, prematurity, encephalitis and meningitis, and traumatic brain injury. Individuals with neurodevelopmental disabilities can have an increased risk for ADHD. 4. Delineation of possible alternative diagnoses (psychiatric and medical) and comorbid conditions (Figure 1). Neuropsychological testing (either through a schoolbased multifactorial evaluation or an independent evaluator) should be done when there is a question about the diagnosis or the presence of other learning problems. 5. Family history of psychiatric and neurologic conditions, including ADHD, bipolar disorder, and Tourette syndrome. ADHD may be the first feature of Tourette syndrome or chronic tic disorder, which usually presents during the school-age years in 10% to 12% of this population. Children with bipolar disorder may initially have features of ADHD with excessive mood lability prior to the overt presentation of bipolar features. 6. Physical examination for possible underlying medical condition that may mimic ADHD or impact on treatment (sleep disturbance, hypertension, endocrinopathy, medication side effect from anticonvulsant or beta adrenergic drugs) or neurologic abnormalities (dyspraxia, cerebral palsy, movement disorder).
PATIENT RESOURCES
Autism Society of America http://www.autism-society.org/ Cure Autism Now Foundation http://www.cureautismnow.org/ National Alliance for Autism Research http://www.naar.org/ Kennedy Krieger Institute http://www.kennedykrieger.org/

Max Wiznitzer, M.D.
Attention Deficit Hyperactivity Disorder

Attention deficit hyperactivity disorder (ADHD) is a common reason for consultation with primary care providers and pediatric specialists. The prevalence for this biologically based disorder is 5% to 10% in children and 2% to 4% in adults. The core symptoms of ADHD are short attention span for mental age, impulsivity (acting without thinking of consequences), easy distractibility (inability to maintain focus on a needed task), and motor overactivity (which may range from fidgetiness to continuous movement). These core features have been organized into two major groupings (inattentiveness and hyperactivity-impulsivity) in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and are listed in Table 1. Features can vary by age at presentationdisruptive behavior in the preschool years; academic struggles in the school-age years; and disorganization, impulsive risk taking, social difficulties, and educational and employment challenges in adolescence and adulthood.
TREATMENT The management of ADHD requires an approach that combines behavioral and educational techniques with judicious use of medication. This conclusion is supported by the findings in the Multimodal Treatment Study of Children with ADHD, which showed that the core features of ADHD were best managed with
114
Acknowledgment The author thanks Dr. Susan Connors for her review and helpful suggestions. SUGGESTED READING
Bauman, ML, Kemper TL, editors: The neurobiology of autism, ed 2, Baltimore, 2005, Johns Hopkins University Press. Palermo MT, Curatolo P: Pharmacologic treatment of autism, J Child Neurol 19:155-164, 2004. Tuchman R: Autism, Neurol Clin North Am 21:915-932, 2003. Zimmerman AW: Autism spectrum disorders. In Singer HS, Kossoff EH, Hartman AL, Crawford TO, editors: Treatment of pediatric neurologic disorders, New York, 2005, Marcel Dekker, pages 489-494.
EVALUATION The evaluation of an individual with suspected ADHD includes the following: 1. Identification of ADHD features that continue to impair function and fulfill diagnostic criteria. This should include information from multiple sources (individual, family member, educators, job colleagues, and friends) and from preexisting documents (report cards, school assessments, psychological testing). Rating scales can be helpful as part of the assessment of individuals with ADHD, with results interpreted in conjunction with other information. Common tools include Conners Parent and Teacher Rating Scales, ADHD Rating Scale, and Vanderbilt Assessment Scale (available as part of an ADHD Toolkit at http:// www.nichq.org/). Adult scales include Adult ADHD Self-Report Scale Wender Utah Rating Scale, Conners Adult ADHD Rating Scales, and Brown Adult ADD Scale. 2. Confirmation that the individual manifested features of ADHD during childhood, especially during or prior to the early school-age years. 3. Review of prenatal, birth, and developmental history for factors that can cause ADHD and for timing and severity of presentation. These include in utero ethanol exposure, prematurity, encephalitis and meningitis, and traumatic brain injury. Individuals with neurodevelopmental disabilities can have an increased risk for ADHD. 4. Delineation of possible alternative diagnoses (psychiatric and medical) and comorbid conditions (Figure 1). Neuropsychological testing (either through a schoolbased multifactorial evaluation or an independent evaluator) should be done when there is a question about the diagnosis or the presence of other learning problems. 5. Family history of psychiatric and neurologic conditions, including ADHD, bipolar disorder, and Tourette syndrome. ADHD may be the first feature of Tourette syndrome or chronic tic disorder, which usually presents during the school-age years in 10% to 12% of this population. Children with bipolar disorder may initially have features of ADHD with excessive mood lability prior to the overt presentation of bipolar features. 6. Physical examination for possible underlying medical condition that may mimic ADHD or impact on treatment (sleep disturbance, hypertension, endocrinopathy, medication side effect from anticonvulsant or beta adrenergic drugs) or neurologic abnormalities (dyspraxia, cerebral palsy, movement disorder).
PATIENT RESOURCES
Autism Society of America http://www.autism-society.org/ Cure Autism Now Foundation http://www.cureautismnow.org/ National Alliance for Autism Research http://www.naar.org/ Kennedy Krieger Institute http://www.kennedykrieger.org/

Max Wiznitzer, M.D.
Attention Deficit Hyperactivity Disorder

Attention deficit hyperactivity disorder (ADHD) is a common reason for consultation with primary care providers and pediatric specialists. The prevalence for this biologically based disorder is 5% to 10% in children and 2% to 4% in adults. The core symptoms of ADHD are short attention span for mental age, impulsivity (acting without thinking of consequences), easy distractibility (inability to maintain focus on a needed task), and motor overactivity (which may range from fidgetiness to continuous movement). These core features have been organized into two major groupings (inattentiveness and hyperactivity-impulsivity) in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and are listed in Table 1. Features can vary by age at presentationdisruptive behavior in the preschool years; academic struggles in the school-age years; and disorganization, impulsive risk taking, social difficulties, and educational and employment challenges in adolescence and adulthood.
TREATMENT The management of ADHD requires an approach that combines behavioral and educational techniques with judicious use of medication. This conclusion is supported by the findings in the Multimodal Treatment Study of Children with ADHD, which showed that the core features of ADHD were best managed with
115
TABLE 1 Diagnostic Criteria for Attention Deficit Hyperactivity Disorder

A. Either (1) or (2): (1) six (or more) of the following symptoms of inattention have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level: Inattention (a) often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities (b) often has difficulty sustaining attention in tasks or play activities (c) often does not seem to listen when spoken to directly (d) often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions) (e) often has difficulty organizing tasks and activities (f) often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort (such as schoolwork or homework) (g) often loses things necessary for tasks or activities (e.g., toys, school assignments, pencils, books, or tools) (h) is often easily distracted by extraneous stimuli (i) is often forgetful in daily activities (2) six (or more) of the following symptoms of hyperactivity-impulsivity have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level: Hyperactivity (a) often fidgets with hands or feet or squirms in seat (b) often leaves seat in classroom or in other situations in which remaining seated is expected (c) often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or adults, may be limited to subjective feelings of restlessness) (d) often has difficulty playing or engaging in leisure activities quietly (e) is often on the go or often acts as if driven by a motor (f) often talks excessively Impulsivity (g) often blurts out answers before questions have been completed (h) often has difficulty awaiting turn (i) often interrupts or intrudes on others (e.g., butts into conversations or games) B. Symptoms that caused impairment were present before 7 years C. Impairment from the symptoms is present in two or more settings (e.g., at school, work, and home) D. Clinically significant impairment in social, academic, or occupational functioning E. The symptoms do not occur exclusively during the course of a Pervasive Developmental Disorder, Schizophrenia, or other Psychotic Disorder and are not better accounted for by another mental disorder (e.g., Mood Disorder, Anxiety Disorder, Dissociative Disorder, or a Personality Disorder) Attention-Deficit/Hyperactivity Disorder, Combined Type: if both Criteria A1 and A2 are met for the past 6 months Attention Deficit/Hyperactivity Disorder, Predominantly Inattentive Type: if Criterion A1 is met but Criterion A2 is not met for the past 6 months Attention Deficit/Hyperactivity Disorder, Predominantly Hyperactive-Impulsive Type: if Criterion A2 is met but Criterion A1 is not met for the past 6 months
From American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC, 1994, American Psychiatric Association.
appropriate dosing of medication, whereas the consequences of ADHD (school performance, peer and family relations, self-esteem) best improved with combined pharmacologic and behavioral/educational intervention. For individuals with mild to moderate ADHD (especially the inattentive type), nonpharmacologic intervention may be sufficient. For those with moderate to severe symptomatology, medication is necessary to improve attention and reduce impulsivity before they can learn new learning and behavioral habits. Recommendations for nonpharmacologic intervention include: Behavioral interventions with psychosocial interventions that focus on family, school, and child; teach parenting skills; and provide support in multiple environments. Involvement with a parent support
group can be useful. Intervention should focus on the encouragement of wanted behaviors using verbal or tangible reward techniques rather than the sole use of extinction of unwanted behaviors. Frequent changes in rewards and positive approach methods may be needed in this population. Social skills training is frequently necessary because of the social immaturity present in many children with ADHD (especially the combined type). Behavioral intervention should also focus on aggressive intervention for any comorbid condition such as oppositional-defiant disorder, anxiety, or depression. This management is usually done by a psychologist or counselor/therapist with consultation with a psychiatrist for significant psychiatric comorbidities. Academic intervention requires an organized environment, a well-trained educational staff that understands
116
Referral for suspected inattention, hyperactivity and/or impulsivity presenting as: disruptive behavior, academic difficulties, social issues, work difficulties History from: family, other caregivers; school/camp personnel and reports; employers and work evaluations Physical and neurological examination Confirmation with parent and teacher rating scales Neuropsychological assessment Diagnosis of ADHD Yes No Cognitive deficiency Learning disability/style Peripheral sensory deficit Epilepsy Sleep disorder Medication effect Oppositional-defiant disorder Conduct disorder Anxiety disorder Mood disorder Autism spectrum disorder Environmental/social stressors Difficult child Medical illness
FIGURE 1. Referral for suspected inattention, hyperactivity, and/or impulsivity presenting as disruptive behavior, academic difficulties, social issues, and work difficulties. ADHD, Attention deficit hyperactivity disorder.
Behavioral Parent training (positive reinforcement) Social skills training Educational Family education School accommodations
Medication (see Table 2) Stimulant (methylphenidate or amphetamine) as first choice. Try the other if first not effective or has side effects. Extended release preparation is preferred. Atomoxetine as a first line choice: Need early AM or late PM effect History of substance abuse Stimulant nonresponder/side effects
Comorbidity monitoring Oppositional-defiant disorder Dyspraxia Learning/language disability Temperament dysregulation Anxiety disorder Mood disorder Conduct disorder Substance use disorder Tic disorder
Preschool years Mixed amphetamine salt D-Methylphenidate Clonidine
School age years 8 hour effect (methylphenidate) Only needed for school Need 16 hour effect (bid dose) 12 hour effect (stimulant, atomoxetine) Homework, behavior problems Desire once daily dosing Lower abuse potential
Adult years Long-acting stimulant Atomoxetine
Incomplete response, consider: Stimulant + Atomoxetine Stimulant + Clonidine or Guanfacine Nortriptyline
the need for structure and routine, and a defined educational approach to children with a short attention span. This can include more time for lessons and tests, smaller work units, and a decrease in external distractions. Use of a schedule, daily teacher feedback, and a positive reward mechanism can be successful. Medications can successfully improve attention span and, consequently, decrease distractibility and overactivity in more than 80% to 90% of children with ADHD. The primary medications and recommended initial starting doses are listed in Table 2. Medication use is indicated when ADHD causes a risk of physical injury, impaired family and social relationships or academic failure, and nonpharmacologic intervention has an
inadequate effect. General usage rules include to start at a low dose and increase slowly (usually every 4 to 7 days) and to titrate to maximal efficacy without undue side effects. Whether medication is needed on a daily basis or only for in-school use needs to be determined on an individual basis. Children with comorbid behavioral problems and difficulties with peer interactions should take medication on a daily basis. Medication choice is influenced by age and ability to swallow pills. Stimulants (methylphenidate and amphetamine) are first-line treatment and appear to be equally effective. If the child does not show a good response to one, another should be tried since responses can be idiosyncratic. When possible, long-acting preparations should
TABLE 2 Medications Used in the Treatment of Attention Deficit Hyperactivity Disorders

Generic Class Stimulants Methylphenidate Daily Dose Frequency Duration Dosing*
0.3-2 mg/kg
MethylphenidateStart with 0.3 mg/kg/dose for immediate release and 0.5-1 mg/kg/day for extended-release preparation. Increase dose every 4-7 days as tolerated by 0.15-0.3 mg/kg up to 2 mg/kg/day. Although maximum recommended dose is 60 mg/day, adolescents and adults may require higher daily doses. Monitor blood pressure, height, and weight. Side effects include insomnia, appetite suppression, headache, and nausea bid-qid q AM 3-4 hr 8 hr 8 hr 12 hr
IR ER Metadate CD Ritalin LA Concerta Amphetamine
0.15-1.5 mg/kg
AmphetamineStart with 0.15 mg/kg/dose for immediate release and 0.2-0.3 mg/kg/day for extended release preparation. Increase dose every 4-7 days as tolerated by 0.15-0.3 mg/kg up to 1.5 mg/kg/day. While maximum recommended dose is 40 mg/day, adolescents and adults may require higher daily doses. Monitor blood pressure, height and weight. Side effects include insomnia, appetite suppression, headache and nausea q q
AM-bid AM
IR ER Dexedrine Spansule Adderall XR Antidepressants Atomoxetine 1-2 mg/kg
4-6 hr 6-8 hr 12 hr
qd or bid
AtomoxetineStart with 0.5-0.7 mg/kg/day as a qd or bid dose. Increase after 4-7 days to 1-1.4 mg/ kg/day as qd or bid dose. It may take 4-6 weeks to observe the full effect. Although the maximum recommended dose is 100 mg/day, adolescents and adults may require higher doses. Slow metabolizers through CYP2D6 require lower doses. Side effects include tiredness, decreased appetite, GI upset and nausea, urinary retention, and liver dysfunction NortriptylineStart 0.5-1 mg/kg day qhs or bid and increase weekly by 0.5-1 mg/day increments to 1-3 mg/kg/day bid or tid. Electrocardiogram at baseline and with dose changes (especially at final dose) to monitor QTc. Side effects include fatigue, dizziness, constipation, tachycardia, and irritability
Imipramine Nortriptyline
2-5 mg/kg 1-3 mg/kg
bid bid-tid
Bupropion Venlafaxine Others Clonidine
2-6 mg/kg 1-3 mg/kg 3-10 g/kg
qd-tid bid-tid bid-qid 2-4 hr ClonidineStart with 0.1 mg tablets at a dose of 1/41/ 2 tablet qhs and increase by 1/4-1/2-tablet increments q wk to a tid or qid regimen with maximum dose of 10 g/kg/day. If effective, consider use of transdermal patch. Monitor blood pressure. Side effects include lethargy and irritability GuanfacineStart with 1-mg tablets at a dose of 0.25-0.5 mg qhs and increase weekly by 0.25-0.5 mg increments to a bid or tid regimen with maximum of about 100 g/kg/day. Monitor blood pressure. Side effects include lethargy and irritability
Guanfacine
30-100 g/kg
bid-tid
4-8 hr
*Goal is maximal efficacy without undue side effects. IR, Immediate release; ER, extended release; GI, gastrointestinal; QTc, QT correction.
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be used since they minimize the number of daily doses and provide more even effect throughout the day. Although atomoxetine may not be as effective as the stimulants, it should be considered as a first-line therapy in individuals who need early-morning or late-evening treatment, have a history of substance use, have failed or do not tolerate stimulants, or require combined therapy with stimulants. Stimulant side effects include transient headache and upset stomach that can be ameliorated with medication administration after a meal, a sleep disturbance that may need additional treatment, and a worsening in mood that disappears with discontinuation. As the medication effect diminishes, rebound hyperactive behavior lasting 35 to 40 minutes may occur and probably represents a return to baseline ADHD. This effect can be lessened by changing from a shorter- to longer-acting stimulant medication. Tics may occur during use of stimulant medication, although research does not suggest that de novo causation or exacerbation of tics occurs. Most children with tics have little change in tic frequency or severity over time. If tics occur within 2 weeks of stimulant initiation, a decrease in dose or change to another medication should be considered. Children with well-controlled epilepsy do not have a seizure exacerbation when placed on methylphenidate. Children on stimulants should have periodic measurement of height and weight because of potential appetite suppression and reports of possible slowing of growth, especially in children at the higher height percentile who are on daily therapy. Whether this effect is transient and will disappear during the pubertal growth spurt or whether it will produce a small but permanent blunting of growth has not been determined. Blood pressure and pulse should be checked. Effective treatment of ADHD with stimulants reduces the risk of substance use to the age-matched peer level and does not contribute to illicit drug use in this population. Diversion and use by non-ADHD individuals can occur but is not a prominent problem. Atomoxetine, a selective norepinephrine reuptake inhibitor, has become available and is useful in the management of ADHD. Its side effects include tiredness, gastrointestinal complaints, and decreased appetite. In adults, modest blood pressure and heart rate elevation, urinary retention, and sexual dysfunction can occur. Liver dysfunction with elevated aspartate aminotransferase, alanine aminotransferase, and bilirubin has been rarely reported. Since it is metabolized through CYP2D6, dosing reduction may be warranted in slow metabolizers and those on medications that inhibit CYP2D6 (such as paroxetine, fluoxetine, or quinidine). It should be considered as first-line therapy in the nonstimulant category, especially for those who do not tolerate or want a stimulant or whose history precludes use of a stimulant. Clonidine and guanfacine are alpha-adrenergic agonists that have shown some efficacy in the treatment of children with ADHD. Most frequently, they are used in conjunction with stimulant medications and for stabilization of mood and decrease in aggression and overarousal. Abrupt discontinuation is not recommended.
Learning Disabilities
Learning disabilities are a severe discrepancy between achievement and intellectual ability in one or more areas that include reading, mathematics, written language, oral expression, or listening comprehension. The prevalence is 10% to 15%, with dyslexia (reading disability) being most common. The physician is frequently the first professional who is asked to address family concerns about the childs developmental progress. The assessment includes the following: 1. History that investigates potential risk factors such as family history of learning disability, prematurity, past central nervous system insult (toxin, infection, trauma), epilepsy, or congenital syndrome and examines developmental milestones (language delay/disorder, difficulties learning letters), present academic progress (isolated difficulty in one or more academic areas with otherwise normal development), and available school records and teacher reports 2. Medical examination that identifies a syndrome that can be associated with learning disabilities (e.g., neurofibromatosis, Turners syndrome, velocardiofacial syndrome) and motor difficulties (dyspraxia) that can aggravate learning problems; office-based screening should include hearing and vision (if not yet done) and samples of reading, writing, and math skills 3. Screening for comorbid disorders such as ADHD, anxiety disorder, depression, and social skills impairment 4. No specific medical testing (e.g., electroencephalogram or other electrophysiologic tests, magnetic resonance imaging, positron emission tomography or singlephoton emission computed tomography scan) without clinical indications 5. Referral for psychoeducational testing through the school system or neuropsychological evaluation for diagnosis of a learning disability; other assessments for motor or language problems should be obtained as necessary, with the physician maintaining a position within the multidisciplinary team After identification of and intervention for the learning disability, the physicians input may be requested. Educating the child and family about the diagnosis and available resources, planning a referral for counseling, prescribing medication for comorbid conditions, and addressing questions about alternative/complementary therapies may be needed. The remaining part of the management team helps with advocacy issues and monitoring of the childs clinical course. SUGGESTED READING
American Academy of Child and Adolescent Psychiatry: Practice parameters of the use of stimulant medications in the treatment of children, adolescents and adults with attention-deficit/hyperactivity disorder, J Am Acad Child Adolesc Psychiatry 41(2 Suppl):26S-49S, 2002. American Academy of Pediatrics: Clinical practice guideline: diagnosis and evaluation of the child with attention-deficit/hyperactivity disorder, Pediatrics 105:1158-1170, 2000.
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PATIENT RESOURCES
International Dyslexia Society Chester Building, Suite 382 8600 LaSalle Road Baltimore, MD 21286 Phone: 800-ABC-D123 http://www.interdys.org/ Learning Disabilities Association of America 4156 Library Road Pittsburgh, PA 15234 Phone: 412-341-1515 http://www.ldanatl.org/
Children and Adults with Attention Deficit Hyperactivity Disorder (CHADD) 8181 Professional Place, Suite 150 Landover, MD 20785 Phone: 800-233-4050 http://www.chadd.org/ American Academy of Pediatrics: ADHD: A Complete and Authoritative Guide, Elk Grove Village, IL, 2003, AAP. National Institute for Child Health Quality (NICHQ) ADHD Practitioners Toolkit (http://www.nichq.org/resources/toolkit/) contains assessment and management documents for ADHD, including the Vanderbilt Assessment Scale.
SECTION 6
Viral Infections
Micheline McCarthy, M.D., Ph.D.
although inhibition of viral DNA polymerase is less efficient. Penciclovir achieves a much longer intracellular half-life than acyclovir, allowing for two- or three-timesa-day dosing. Ganciclovir has relatively greater potency against CMV and HHV-6, good activity against HSV, and less activity against VZV and EBV. Intravenous (IV) ganciclovir has been the first-line therapy for CMV infection in immunocompromised patients. But oral ganciclovir has poor bioavailability, making it ineffective for long-term prophylactic suppressive regimens. Valganciclovir provides an oral bioavailability for ganciclovir of 60% and is replacing IV ganciclovir as the first choice for anti-CMV maintenance. Two additional, clinically effective drugs, foscarnet and cidofovir, directly inhibit herpesvirus DNA polymerases. Both have broad-spectrum antiherpesvirus activity but require IV administration. Herpesvirus resistance to acyclovir or ganciclovir can arise through mutations in viral thymidine kinase or DNA polymerase enzymes. Drug-resistant mutants occur rarely among herpesvirus isolates from immunocompetent patients; however, among immunocompromised patients, including those treated with prophylactic courses of antiviral drugs, drug-resistant mutants are more likely to be clinically significant and occur more than ten times more frequently. Foscarnet and cidofovir are used to treat herpesvirus infections that are resistant to first-line antiviral therapy. The antiherpesvirus drugs all have varying degrees of nephrotoxic potential. Ganciclovir is also myelosuppressive. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are rare but life-threatening complications reported with high-dose (8 gm/day) valacyclovir therapy in severely immunocompromised patients. The antiherpesvirus drugs must be administered with careful attention to detailed, current prescribing information. Dosages must be adjusted for renal function. Patients should be well hydrated, and IV infusions should be administered slowly with an infusion pump. There are no standards for the use of prophylactic valacyclovir or famciclovir in children.
Human herpesviruses (HHVs) constitute a diverse group of ubiquitous viral pathogens capable of both acute and persistent infection in the host. These complex DNAcontaining viruses typically infect humans early in life and establish latent infection at the cellular level. Latent infection is clinically dormant, but reactivation of viral replication can lead to recurrent clinical illness. Primary (initial) or reactivated infection by these viruses can also cause severe neurologic illness. Neurologic complications are especially prominent in aging or immunocompromised patients, and these pose an increasing diagnostic and treatment challenge to the neurologist.
Antiherpesvirus Therapy
Among human viral infections of the nervous system, herpesvirus infections are probably the most amenable to antiviral therapy. This is largely due to the growing drug family of purine nucleoside analogs that are activated by virus-specific kinases and then interfere with herpes viral DNA replication. The prototype drug, acyclovir (acycloguanosine), was identified about 30 years ago, followed by penciclovir and ganciclovir a decade or more later. Now available are oral prodrugs of acyclovir (valacyclovir, the L-valyl ester of acyclovir), penciclovir (famciclovir, the diacetate ester of 6-deoxy-penciclovir), and ganciclovir (valganciclovir, the L-valyl ester of ganciclovir). The oral prodrug provides greater bioavailability and higher plasma levels of the active antiviral drug. Acyclovir is most active against herpes simplex viruses (HSVs), then varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus (HHV-6), in decreasing order of antiviral potency. Valacyclovir, with its greater bioavailability, allows a simpler dosing regimen than oral acyclovir. It is likely to eventually replace oral acyclovir, but currently generic oral acyclovir is much less expensive. The antiviral spectrum of penciclovir is similar to that of acyclovir,
Herpes Simplex Viruses

Two human HSVsHSV-1 and HSV-2have similar molecular structures but tend to cause different neurologic illnesses. HSV-1 is most frequently associated with 121
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recurrent orolabial mucocutaneous lesions (cold sores), whereas HSV-2 is associated with recurrent genital mucocutaneous lesions. These viruses establish latency in the sensory ganglia subserving these anatomic locations. Either primary or reactivated HSV infection can cause neurologic illness. HERPES SIMPLEX ENCEPHALITIS (HSE) HSV-1 is the most common cause of fatal sporadic viral encephalitis in adults and children. Beyond the neonatal period, most cases of fatal encephalitis are due to HSV-1 and are more commonly reactivated rather than primary infection. The classic clinical presentation is necrotic, hemorrhagic, frontal-temporal lobe encephalitis, but the distribution of lesions can be diffuse and may involve the brainstem. HSV-2 accounts for less than 10% of frontal-temporal encephalitis in immunocompetent patients. Milder or atypical cases of HSE can also occur, particularly in immunocompromised patients. Diagnostic evaluation and treatment should be instituted speedily since delayed onset of therapy, along with coma and older age, are poor prognostic indicators. Mortality among untreated patients exceeds 70%. Polymerase chain reaction (PCR) testing for HSV DNA in the cerebrospinal fluid (CSF) is the diagnostic test of choice for herpes simplex encephalitis (HSE). Treatment should be with IV acyclovir for 14 to 21 days (Table 1). Follow-up PCR determination of HSV DNA in the CSF may be useful to monitor the adequacy of therapy. Patients treated with IV acyclovir for 14 days should have a negative CSF PCR test for HSV DNA. If not, treat an additional 14 days. Acyclovir-resistant HSE occurs almost exclusively in immunocompromised patients, particularly those with recurrent HSV infections requiring repeated courses of antiviral therapy. Treatment of acyclovir-resistant HSE is with foscarnet for 14 to 21 days (see Table 1). If HSE is resistant to both acyclovir and foscarnet, treat with cidofovir (see Table 1). When treating any HSV infection that appears resistant to acyclovir, isolate virus from CSF, if possible, or from a peripheral source (e.g., mucocutaneous lesion), and test the isolates for antiviral drug susceptibility. Even with clinical improvement after treatment of HSE, relapse or progressive neurologic impairment may occur. This may be due to reactivation of latent virus in the brain. The efficacy of long-term oral antiviral therapy to suppress viral reactivation, increase survival, and/or decrease sequelae after HSE has not been demonstrated. However, this issue is being addressed in randomized, placebo-controlled, double-blind trials of oral valacyclovir given for 3 months after IV acyclovir. These trials are being conducted by the Collaborative Antiviral Study Group (CASG), a multi-institutional collaborative network funded by the National Institute of Allergy and Infectious Diseases. NEONATAL ENCEPHALITIS Neonatal HSE is due to HSV-2 in approximately two thirds of cases and to HSV-1 in the remainder. The virus
is acquired from the female genital tract in the intrapartum interval. Neonatal HSE can be a devastating disease, associated with serious neurologic sequelae even with aggressive antiviral treatment. Neonates with HSE should receive IV acyclovir for 21 days (see Table 1). The CASG is conducting trials of oral acyclovir given for 6 months after IV acyclovir to prevent relapse in neonatal HSE. BELLS PALSY Idiopathic peripheral seventh cranial nerve palsy, or Bells palsy, is the most common cause of unilateral facial paralysis. VZV infection is known to cause Bells palsy as part of the Ramsay Hunt syndrome. More recently, studies using PCR have linked HSV-1 with Bells palsy through detection of viral DNA sequences in endoneural fluids or auricular muscle. Since HSV-1 typically establishes latency in peripheral sensory ganglia, not motor neurons, the role of HSV-1 in the pathogenesis of Bells palsy remains controversial. Appropriate diagnostic evaluation is essential. Addition of oral acyclovir to standard prednisone treatment for Bells palsy has been demonstrated to produce a moderate clinical improvement in volitional facial muscle action. Combination therapy should be started within 3 days of symptom onset and should continue for 10 days (see Table 1). To date no conclusive benefit has been demonstrated with antiviral therapy alone. HSV MENINGITIS AND MYELITIS HSV infection can cause aseptic meningitis, including benign recurrent lymphocytic meningitis. These clinical presentations are usually due to HSV-2 infection in immunocompetent patients. HSV-2 is likely the major viral agent responsible for recurrent meningitis, including many or most cases of Mollarets meningitis. Aseptic HSV-2 meningitis occurs concomitant with or after primary HSV-2 genital infection but may also occur in the absence of recent genital lesions. Rarely necrotizing meningitis has been reported in association with immunosuppression (e.g., corticosteroid treatment). The treatment of single or recurrent episodes of HSV meningitis has not been defined by clinical trials. In practice, patients presenting with acute aseptic meningitis are often treated empirically with IV acyclovir until CSF test results are available. Confirmed HSV meningitis may be treated with IV acyclovir for 5 to 7 days, followed by oral valacyclovir to complete a total 14-day course of therapy (see Table 1). With recurrent lymphocytic meningitis due to HSV-2, there is limited evidence for the efficacy of oral antiviral therapy for recurrent episodes or for continuous prophylaxis (see Table 1). Myelitis or radiculomyelitis can result from HSV infection of immunocompetent patients, with most reported cases resulting from HSV-2. In immunocompromised patients, HSV-2 central nervous system (CNS) infection may result in ascending necrotizing myelitis or myelopathy. These clinical presentations should be treated with IV acyclovir for 14 days or longer with more extensive illness (see Table 1).
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TABLE 1 Human Herpesvirus Infections: Antiviral Therapy for Neurologic Illness

Viral Infection Herpes simplex: Immunocompetent Clinical Presentation Encephalitis Adult and adolescent (12 yr) Pediatric (3 months to 12 years) Neonatal (birth to 3 months) Postencephalitis (clinical trials) HSV Neonatal Bells palsy Drug*, Acyclovir Acyclovir Acyclovir Dosage* 10-15 mg/kg IV q 8 hr for 14-21 days 500 mg/m2 or 20 mg/kg IV q 8 hr for 14-21 days 20 mg/kg IV q 8 hr for 21 days Comments These antiviral drugs are nephrotoxic; adjust dose for renal function, infuse over 1 hr Consider serial CSF PCR for HSV DNA to monitor adequacy of therapy Acyclovir-resistant HSE is rare in immunocompetent patients but is more likely to occur in patients with prior recurrent or chronic anti-HSV therapy Postencephalitis regimens are in clinical trials to evaluate efficacy Do appropriate diagnostic evaluation Role of HSV in Bells palsy etiology is controversial; more data needed to support antiviral therapy Drug therapy should be started within 3 days of symptom onset
Valacyclovir Acyclovir Prednisone plus
PO, 3-mo course PO, 6-mo course 1 mg/kg PO qd divided bid for 3-5 days, then tapered over total 10-day course 400 mg PO 5 times/ day for 10 days
Acyclovir Meningitis Single episode Acyclovir then
Recurrent episode Continuous prophylaxis Myelitis, radiculomyelitis Chronic suppression
Herpes simplex: Immunocompromised
Acyclovir resistant Acyclovir and foscarnet resistant
Varicella zoster: Immunocompetent
Zoster (shingles); herpes zoster ophthalmicus; varicella in adults, adolescents
HSV-2 is major cause of meningitis 5-10 mg/kg IV No controlled trials have established q 8 hr for 5-7 days treatment of single or recurrent then episodes of HSV meningitis Valacyclovir 1000 mg PO bid for 7-9 days to complete a 14-day course Valacyclovir 1000 mg PO tid for 10 days Valacyclovir 1000 mg PO qd Only anecdotal evidence for efficacy or of antiviral prophylaxis Acyclovir 400 mg PO bid Acyclovir 10-15 mg/kg IV q Use a longer course for more serious 8 hr for 14 days illness Valacyclovir 500 mg PO bid TTP and HUS have been reported in or severely immunocompromised patients treated with high doses Famciclovir 500 mg PO bid of valacyclovir (8 mg/day) for or extended periods Acyclovir 400-800 mg PO No standards available for bid or tid valacyclovir or famciclovir in children Foscarnet 40 mg/kg IV q 8 hr Isolate virus for antiviral susceptibility for 14-21 days testing Cidofovir 5 mg/kg IV once/wk Isolate virus for antiviral susceptibility twice, then 5 mg/ testing kg IV q 2 wk; coadminister cidofovir with probenecid (2 gm PO 3 hr prior to cidofovir; 1 gm 2 hr after cidofovir; 1 gm 8 hr after cidofovir) Valacyclovir 1000 mg PO tid for Valacyclovir preferable (higher or 5-7 days bioavailability of active drug) Start antiviral therapy within 3 days of rash
continued
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TABLE 1 Human Herpesvirus Infections: Antiviral Therapy for Neurologic Illnesscontd

Viral Infection Clinical Presentation Drug*, Acyclovir or Famciclovir Herpes zoster in patients > 50 yr of age; Ramsay Hunt syndrome (zoster oticus) Valacyclovir or Dosage* 800 mg PO 5 times/ day for 7-10 days 500 mg PO tid for 7 days 1000 mg PO tid for 7 days Comments Hospitalized zoster patients should be isolated to prevent transmission of VZV to other patients
Acyclovir therapy plus prednisone CNS complications of zoster Aseptic meningitis with rash Myelitis or myelopathy VZV vasculopathy Stroke (contralateral to zoster) Encephalomyelitis (immunemediated demyelination) Zoster sine herpete (dermatomal pain without rash) Varicella with cerebellar ataxia (postvaricella cerebellitis) Varicella (primary infection) Shingles >1 dermatome Disseminated herpes zoster Acyclovir-resistant zoster Progressive encephalitis, ventriculitis, meningoencephalitis Retinitis (systemic therapy) Valacyclovir Acyclovir Acyclovir plus prednisone Methylprednisolone Acyclovir
800 mg PO 5 times/ day for 7-10 days; prednisone, 1 mg/ kg/day, tapered over 10 days Diagnostics should include CSF for antiviral antibody and viral DNA (PCR) testing 1000 mg PO tid for 7 days 10-15 mg/kg IV q 8 hr for 7-10 days 10-15 mg/kg IV q 8 hr for 7-10 days; prednisone, 60-80 mg for 3-5 days 1000 mg IV qd divided qid or bid for 5 days, then oral steroid taper 10-15 mg/kg IV q 8 hr for 7-10 days 20 mg/kg (800 mg max) PO qid for 5 days 10 mg/kg IV q 8 hr for 7 days 10 mg/kg IV q 8 hr for 7-14 days 15 mg/kg IV q 8 hr for 7 days 40 mg/kg IV q 8 hr for 14-21 days 10 mg/kg IV q 8 hr for 10 days or longer in severely immunocompromised patients 5 mg/kg IV q 12 hr for 14-21 days 900 mg PO bid for 21 days 5 mg/kg IV once per wk twice (give 1 L normal saline IV Stroke usually delayed complication of herpes zoster ophthalmicus Postinfectious neurologic complication of VZV infection Confirm rising titers of VZV-specific antibody and VZV DNA in the CSF Efficacy of antiviral therapy reported but not established Usual course is self-limited without sequelae Antiviral therapy not proven to alter course
Acyclovir
Varicella zoster: Immunocompromised
Acyclovir Acyclovir Acyclovir Foscarnet Acyclovir
Isolate virus for antiviral susceptibility testing
Cytomegalovirus: Immunocompromised
Induction therapy Ganciclovir or Valganciclovir or Cidofovir
These antiviral drugs are nephrotoxic. Use with caution in combination with immunosuppressive drug regimens Dosages must be adjusted for renal function CMV retinitis should be diagnosed and monitored by ophthalmologic specialists
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Viral Infections

Viral Infection Clinical Presentation Drug*, Dosage* before cidofovir); give with probenecid (2 gm PO 3 hr prior to cidofovir, 1 gm 2 hr after cidofovir, 1 gm 8 hr after cidofovir) Comments Systemic therapy as adjunct to intraocular antiviral therapy can prevent CMV disease in contralateral eye and other organs Immune recovery inflammatory vitreitis may occur with inactive CMV retinitis in HIV-infected patients recovering CD4+ cell counts on HAART; this may require steroid treatment Consider discontinuing maintenance therapy with CD4+ count >100 cells/mm3 after 6 mo HAART and retinitis is inactive
Maintenance therapy Valganciclovir or Ganciclovir or

Cidofovir Ganciclovir resistant Foscarnet Induction
900 mg PO qd 5 mg/kg IV qd or 6 mg/kg IV qd 5 days per wk 5 mg/kg IV q 2 wk; give with probenecid
Monotherapy resistant Nervous system complications Lumbosacral polyradiculitis, myelitis
60 mg/kg IV q 8 hr or 90 mg/kg IV q 12 hr for 14-21 days Maintenance 90-120 mg/kg IV qd Ganciclovir 5 mg/kg IV qd plus Foscarnet 90-125 mg/kg IV qd
Induction therapy Ganciclovir Maintenance therapy Valganciclovir or Ganciclovir
5 mg/kg IV q 12 hr for 14-21 days 900 mg PO qd 5 mg/kg IV qd or 6 mg/kg IV qd 5 days/wk 5 mg/kg IV q 12 hr for 14-21 days 60 mg/kg IV q 8 hr for 14-21 days 5 mg/kg IV qd or 6 mg/kg IV qd 5 days/wk 90-120 mg/kg IV qd
Polyradiculitis most likely to be seen in AIDS patients Consider combination ganciclovir and foscarnet if patient develops symptoms despite prior anti-CMV therapy
Encephalitis, ventriculoencephalitis
Induction therapy Ganciclovir plus (?) Foscarnet Maintenance therapy Ganciclovir plus (?)
Foscarnet
Serial CSF PCR for CMV DNA may be useful to monitor response to anti-CMV therapy Long-term maintenance therapy may be necessary in patients who remain profoundly immunosuppressed Consider combined therapy in HIV-infected patients with low CD4+ counts (<100 cells/mm3) and/or in immunocompromised patients with poor response to monotherapy In most reports, HHV-6 encephalitis occurs in the setting of severe immunosuppression, particularly bone marrow transplantation Several published reports find successful treatment in this setting, but no clinical trial data setting, but no clinical trial data are available
continued
Human herpesvirus 6 (HHV-6, B variant)
Encephalitis: focal features and/or demyelination
Foscarnet
60 mg/kg IV q 8 hr for 14 days Maintenance 90 mg/kg IV qd for or 1-4 wk
Induction
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Viral Infection Clinical Presentation Drug*, Ganciclovir Induction Dosage* 5 mg/kg IV q 12 hr for 3 wk 5 mg/kg IV qd 900 mg PO qd Acyclovir significantly reduced oropharyngeal Epstein-Barr virus shedding in clinical trials but did not have statistically significant clinical effectiveness in either mild or severe illness Comments
Epstein-Barr virus: Immunocompetent
Infectious mononucleosis Aseptic meningitis
Maintenance or maintenance with valganciclovir No antiviral treatment Acyclovir
800 mg PO 5 times/day for 7-10 days 10 mg/kg IV q8h for 10 days 0.4 gm/kg/day for 5 days 5 mg/kg IV q 12 hr for 4 wk then 900 mg PO qd 1000 mg PO tid for 14 days 800 mg PO 5 times/ day for 14 days 5 mg/kg IV q 12 hr for 14 days 15 mg/kg IV q 8 hr for 14 days 1000 mg PO tid 800 mg PO 5 times/day
Encephalitis Neuropathy: GuillainBarr syndrome, small-fiber sensory or autonomic Transverse myelitis, meningoencephalitis Postexposure (monkey bite)
Acyclovir IV immune globulin Ganciclovir then Valganciclovir Valacyclovir or Acyclovir
Epstein-Barr virus: Immunocompromised B virus (Cercopithecine herpesvirus 1)
Symptomatic CNS disease
Ganciclovir or Acyclovir
Successful therapy reported but not established by controlled clinical trials Start therapy within 5 days of exposure Culture wound or exposure site for virus Repeat serologic testing at 3-6 wk and 3 mo postexposure Neurologic complications include necrotizing myelitis and hemorrhagic encephalitis Duration of suppressive therapy not established but should be at least 6 mo to 1 yr
Chronic suppression
Valacyclovir or Acyclovir
*Consult current, detailed prescribing information provided by the manufacturer before prescribing and administering any drug. The drug names are generic. The trade names are listed in parentheses as follows: acyclovir (Zovirax); valacyclovir (Valtrex); famciclovir (Famvir); cidofovir (Vistide); foscarnet (Foscavir) ganciclovir (Cytovene); valganciclovir (Valcyte). HSV, Herpes simplex virus; HHV, human herpesvirus; EBV, Epstein-Barr virus; CSF, cerebrospinal fluid; PCR, polymerase chain reaction; HSE, herpes simplex encephalitis; TTP, thrombotic thrombocytopenic purpura; HUS, hemolytic-uremic syndrome; VZV, varicella zoster virus; CMV, cytomegalovirus; HIV, human immunodeficiency virus; HAART, highly active anti-retroviral therapy; CNS, central nervous system.
CHRONIC SUPPRESSION OF HSV REACTIVATION Chronic oral antiviral therapy with acyclovir, valacyclovir, or famciclovir may be used to suppress HSV reactivation in immunocompromised patients, particularly those with human immunodeficiency virus (HIV)-1 infection. The doses used in this setting are higher than those used to suppress recurrent oral or genital ulcers (see Table 1). There is no established advantage of either valacyclovir or famciclovir in this setting, and acyclovir is less costly. Long-term therapy does raise concern for the selection of acyclovir-resistant HSV strains.
Varicella Zoster Virus (Herpes Zoster Virus)

VZV is familiar to the neurologist as the cause of shingles and postherpetic neuralgia. VZV primary infection (varicella or chickenpox) typically occurs in childhood, and the virus then becomes latent in cranial nerve and dorsal root ganglia. In the immunocompetent, otherwise healthy child, varicella is generally not treated. Since varicella can be more complicated in adults and adolescents, oral antiviral therapy (see Table 1) may be more beneficial for these patients. Oral antiviral therapy has also been used to treat varicella with cerebellar
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Viral Infections
ataxia (varicella cerebellitis). However, the usual course of this neurologic presentation is benign, and antiviral therapy has not been proved to alter the course. Reactivation of latent viral infection (herpes zoster) results in a cutaneous vesicular rash, itching, dysesthesias, and pain localized along affected dermatomes (shingles). Shingles is more frequent or more extensive as virus-specific immune responses decline, such as occurs with aging or in immunocompromised states. In the severely immunocompromised patient, disseminated zoster may occur, with lesions covering the body surface. Varicella or herpes zoster occasionally leads to CNS complications, and these are much more common in immunocompromised patients. HERPES ZOSTER Herpes zoster includes shingles, cranial neuropathies such as Ramsay Hunt syndrome (zoster oticus and ipsilateral peripheral facial weakness), radiculoneuropathy, or ganglionitis. Herpes zoster ophthalmicus involves the first division of the trigeminal nerve and can result in ocular complications (e.g., iritis, keratopathy) leading to loss of sight. Zoster of cranial nerves may also cause ophthalmoplegia or optic neuritis. Radicular zoster may cause focal extremity weakness, bowel or bladder dysfunction, and, rarely, diaphragmatic paralysis. For the treatment of these neurologic presentations, oral valacyclovir provides higher plasma acyclovir concentrations than does oral acyclovir therapy, with a simpler daily dosing schedule (see Table 1). Valacyclovir may be more effective than acyclovir in resolving zosterassociated pain for patients older than 50 years of age. An alternative therapy for these older patients or for patients with peripheral facial weakness associated with Ramsay Hunt syndrome includes oral acyclovir combined with oral prednisone over a 10-day course (see Table 1). This combination may decrease acute zoster pain or enhance clinical improvement in facial movement. Rarely, zoster can manifest as dermatomal pain without rash (zoster sine herpete). This can be diagnosed by detecting rising titers of VZV-specific antibody and VZV DNA in the CSF. The efficacy of antiviral therapy has not been established, but successful treatment with IV acyclovir (see Table 1) has been reported. In immunocompromised patients, varicella or zoster can be more extensive, involving multiple dermatomes or disseminated throughout the body. IV acyclovir (see Table 1) should be used for these patients. Acyclovir-resistant zoster is treated with foscarnet (see Table 1). VZV MENINGITIS AND MYELITIS Aseptic meningitis associated with VZV DNA in CSF occurs in immunocompetent patients in approximately 1% of cases, of which approximately half may have associated rash. With benign, self-limited courses of aseptic meningitis due to VZV, antiviral therapy may be dictated by the presence of rash, since specific viral diagnosis may lag behind the resolution of symptoms when rash is not present. First-choice therapy is valacyclovir
(see Table 1). Myelitis may occur 1 to 2 weeks after rash in immunocompetent patients, but acute or, rarely, recurrent myelopathy may occur without rash. Direct viral infection of the brain or spinal cord parenchyma usually occurs with immunosuppression, which can be caused to varying degrees by cancer, steroid use, HIV infection, or immunosuppressive drug regimens. In immunocompromised patients, myelopathy may be slower and progressive, with severe inflammation and necrosis of the spinal cord. With these neurologic presentations, detection of VZV DNA and VZV-specific antibody in the CSF mandates aggressive treatment with IV acyclovir (see Table 1). VZV VASCULITIS IN THE CENTRAL NERVOUS SYSTEM VZV is unique among the human herpesviruses (HHVs) in the extent to which viral infection of large and small blood vessels causes variable clinical neurologic syndromes. Encephalitis related to VZV infection is frequently due to viral vasculopathy. Arteritis of the large vessels in the brain (granulomatous arteritis) occurs in immunocompetent patients, causing stroke due to bland or, infrequently, hemorrhagic infarction. Stroke often presents as motor weakness occurring weeks to months after prior, contralateral zoster ophthalmicus. Small-vessel disease occurs more frequently in immunocompromised patients, presenting clinically as chronic progressive encephalitis or, unusually, as ventriculitis or meningoencephalitis. CNS vasculopathies are treated with IV acyclovir for 7 to 10 days or longer in severely immunocompromised patients (see Table 1). With stroke, IV acyclovir may be combined with a 3- to 5-day course of oral prednisone. An encephalitis presentation associated with varicella or herpes zoster in immunocompetent patients may also result from postinfectious immune-mediated demyelination (encephalomyelitis). This would be treated with a course of IV methylprednisolone (see Table 1).
Cytomegalovirus
Human CMV is a ubiquitous herpesvirus that typically infects in utero, childhood, or young adult life. More than 50% of persons in urban American populations carry antibody to CMV. The virus establishes latency in hematogenous cells, primarily monocytes, and may reactivate to produce asymptomatic infection in immunocompetent hosts. Primary or reactivated infection may occur during pregnancy, posing a risk for intrauterine or perinatal mother-to-child viral transmission and congenital CMV infection. In immunocompetent patients, CMV primary infection after the neonatal interval is either subclinical or manifest as infectious mononucleosis, with less pharyngitis and lymphadenopathy than the similar illness associated with EBV infection. Infrequently (1% of cases) this illness is complicated by aseptic meningitis, or, even less frequently, by encephalitis, myelitis, or acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barr syndrome). Given the toxicity
128
of anti-CMV drugs, CMV illness in the otherwise healthy, immunocompetent patient is generally not treated with antiviral therapy. Clinical neurologic illness due to reactivated or occasionally primary CMV infection occurs predominantly in immunocompromised patients, particularly those with acquired immunodeficiency syndrome (AIDS) or those with organ transplants on immunosuppressive drug regimens. CMV antiviral therapy in these patients usually involves two stages: induction therapy to suppress viremia followed by maintenance therapy to suppress viral reactivation. In HIVinfected patients, the use of highly active antiretroviral therapy (HAART) to recover immune function may indirectly suppress CMV viremia and improve the response to anti-CMV therapy. CONGENITAL CMV INFECTION Asymptomatic congenital CMV infection can eventually lead to hearing loss or mental retardation in about 10% to 20% of cases. Approximately 5% of infected newborns have cytomegalic inclusion disease, with microcephaly, chorioretinitis, sensorineural deafness, and organomegaly with jaundice. This is more likely the result of primary rather than recurrent maternal infection. There is no safe and effective antiviral treatment for CMV maternal infection or for symptomatic congenital illness in the newborn. Though ganciclovir has been used and studied in symptomatic congenital CMV infection, the clinical efficacy (e.g., hearing improvement) may be countered by significant toxicity (e.g., neutropenia) in affected infants. Future therapy for congenital CMV infection will likely involve a combination of CMV hyperimmune globulin with antiviral drugs of lower toxicity than occurs with ganciclovir or foscarnet. CMV retinitis is the most common manifestation of CMV in HIV-infected patients, though its incidence has been declining since the introduction of HAART. CMV retinitis should be diagnosed and monitored by ophthalmologic specialists. Systemic anti-CMV therapy with ganciclovir or valganciclovir (see Table 1), used adjunctively with intraocular therapy, can prevent CMV disease in the contralateral eye or visceral organs. Cidofovir (see Table 1) is used as alternative systemic therapy if ganciclovir is not tolerated, although cidofovir may have the same antiviral resistance profile as ganciclovir. Ganciclovir-resistant CMV retinitis is treated with foscarnet or combination foscarnet plus ganciclovir (see Table 1). Immune recovery inflammatory vitreitis may occur in HIV-infected patients with inactive CMV retinitis whose CD4+ cell counts increase with HAART. Vitreitis may require steroid treatment. Current National Institutes of Health guidelines suggest discontinuing maintenance therapy for HIV-infected patients with CD4+ counts higher than 100 cells/mm3 after 6 months on HAART, if CMV retinitis is inactive. PERIPHERAL NERVE DISEASE CMV can infect the peripheral nervous system, causing mononeuritis multiplex associated with vasculitis of epineural arteries. A fairly common syndrome causing
back pain, ascending weakness, and sphincter dysfunction in AIDS patients is due to CMV infection in lumbosacral nerve roots (lumbosacral polyradiculitis), or the lumbosacral roots plus the conus medullaris (lumbosacral myelopathy). This is treated by induction therapy with IV ganciclovir, followed by maintenance therapy with oral valganciclovir, or, alternatively, IV ganciclovir (see Table 1). CNS complications of CMV infection in immunocompromised patients include encephalitis, ventriculoencephalitis, and myelitis. CMV encephalitis in AIDS may present as a rapidly progressive dementia, often with fluctuating sensorium and focal neurologic signs. CMV encephalitis is also a major cause of CMV-related morbidity in organ transplant patients, particularly after bone marrow transplantation. In both settings, encephalitis with prior or concurrent evidence of CMV disease, such as retinitis and CMV viremia, raises a high index of suspicion for CMV encephalitis. Ventriculoencephalitis, distinguished by ventriculomegaly with subependymal enhancement on magnetic resonance brain imaging, may result from CSF rather than hematogenous spread of CMV. No specific treatment for encephalitis has been established. In immunocompromised patients with established CMV infection, IV ganciclovir should be used, with induction at 5 mg/kg IV every 12 hours for 14 to 21 days followed by maintenance therapy at 5 mg/kg IV daily or 6 mg/kg IV daily 5 days per week. Combined anti-CMV therapy with ganciclovir and foscarnet (see Table 1) has been studied and reported to improve or stabilize the neurologic course in approximately 75% of HIV-infected patients with low CD4+ counts (<100 cells/mm3) and no use of HAART. In treating CMV-associated CNS disease, serial CSF PCR for CMV DNA may be useful to determine when to switch from induction to maintenance therapy. Long-term maintenance therapy may be necessary for patients who remain profoundly immunocompromised. Oral valganciclovir may replace IV ganciclovir for this purpose as more clinical experience accumulates.
Other Herpesviruses
HHV-6 is another ubiquitous human herpesvirus (HHV) that typically infects in childhood and establishes latency in peripheral blood mononuclear cells. HHV-6 is the viral cause of childhood roseola (exanthem subitum), which is associated with febrile convulsions in about one third of primary HHV-6 infections. In the immunocompetent patient population, the virus is generally silent throughout life. However, HHV-6 is increasingly recognized as an agent of opportunistic infection causing clinical neurologic illness in immunocompromised patients. Most reports in the past decade have documented HHV-6 as a cause of viral encephalitis after organ transplantation, particularly bone marrow, kidney, or liver transplantation. HHV-6 encephalitis may show focal features and/or demyelination and should be suspected in encephalitis patients with febrile exanthema. HHV-6 has antiviral susceptibility similar to that of CMV. Both foscarnet and ganciclovir (see Table 1) have been reported to
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Viral Infections
successfully treat HHV-6 encephalitis in immunocompromised patients. EBV is a lymphotro phic HHV that typically causes asymptomatic primary infection in childhood or infectious mononucleosis in adolescence or young adult life. Virus replicates in the pharyngeal lymphoid tissue and may be persistently or recurrently shed into oral secretions. In immunocompetent patients with infectious mononucleosis, neurologic complications occur rarely (<1% frequency). These complications include aseptic meningitis, encephalitis, or neuropathy, including small-fiber sensory or autonomic neuropathy or Guillain-Barr syndrome. EBV replication is sensitive to acyclovir, and both oral and IV regimens have been used to treat neurologic illness (see Table 1). However, a meta-analysis of several clinical trials that used acyclovir to treat EBV illness showed that acyclovir therapy does not have statistically significant clinical efficacy. Acyclovir therapy does reduce oropharyngeal EBV shedding, which may reduce the duration and severity of illness by limiting viral reinfection. The neuropathic complications of EBV infection may respond to IV immunoglobulin (see Table 1). In immunocompromised patients, more severe CNS illness has been reported, including transverse myelitis and meningoencephalitis. Ganciclovir induction therapy has been reported to successfully treat meningoencephalitis, but the incidence of these EBV neurologic presentations is low, so no clinical trials have established efficacy. For ganciclovir-treated patients who improve neurologically but remain severely immunocompromised, maintenance therapy with oral valganciclovir should be considered. Herpes B virus (Cercopithecine herpesvirus 1 or Herpes simiae) produces infection in macaque monkeys that is similar to human HSV infection. The B virus may be transmitted to humans via monkey bites, scratches, or percutaneous inoculation of infected materials. The bloodborne transmission of B virus can cause severe, often necrotizing myelitis or encephalitis, which may progress rapidly to death. Prophylaxis with antiviral therapy is recommended after skin or mucosal exposure to a high-risk source, such as an infected macaque monkey, and wound or exposure sites should be cultured for B virus. The first choice for postexposure prophylaxis is oral valacyclovir; alternatively, oral acyclovir (see Table 1). This should be instituted within 5 days of exposure and continued for 2 weeks, then discontinued if the patient is clinically asymptomatic. Postexposure serologic testing should be repeated 3 to 6 weeks and again 3 months after initial exposure for patients receiving antiviral prophylaxis. If wound cultures are initially positive for B virus, then repeat cultures should be obtained 1 to 2 weeks after antiviral prophylaxis is stopped. IV ganciclovir is recommended for patients with symptoms and signs of CNS involvement (see Table 1). This should be continued for at least 14 days and until the symptoms resolve and two or more sets of cultures are negative for B virus growth. Postexposure prophylaxis with oral therapy, preferably oral valacyclovir, should continue for 6 months to 1 year. Some authorities hold that lifelong suppressive therapy is needed since the B virus could reactivate months to years after primary infection.
SUGGESTED READING
Brady RC, Bernstein DI: Treatment of herpes simplex virus infections, Antivir Res 61:73-81, 2004. Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, et al: Neurologic complications of the reactivation of varicella-zoster virus, N Engl J Med 342:635-645, 2000. Naesens L, DeClercq E: Recent developments in herpesvirus therapy, Herpes 8:12-16, 2001. Redington JJ, Tyler KL: Viral infections of the nervous system, 2002: update on diagnosis and treatment, Arch Neurol 59:712-718, 2002. Singh N, Paterson DL: Encephalitis caused by human herpesvirus-6 in transplant recipients, Transplantation 69:2474-2479, 2000. Sissons JGP, Carmichael AJ: Clinical aspects and management of cytomegalovirus infection, J Infect 44:78-83, 2002.
PATIENT RESOURCES
http://www.webmd.com/This well-known site has a broad appeal and is relatively easy to navigate. It is widely referenced by patients. The site includes educational materials and links to patient support organizations. http://www.virology.net/Comprehensive site claiming all the virology on the World-Wide Web. Information and links to research, education, clinical, and patient support sites as well as comprehensive educational material on the human herpesviruses. http://www.gsu.edu/~wwwvir/National Herpes B Virus Resource Center

James J. Sejvar, M.D., and Grant L. Campbell, M.D., Ph.D.
Arboviruses (arthropod-borne viruses) include several families of viruses that share the feature of transmission by arthropod vectors and are the most common etiologic agents of epidemic encephalitis worldwide. Nearly 100 such viruses are recognized to cause clinical illness in humans. The most common arboviruses causing neurologic illness in North America include the following families and their members: FlaviviridaeWest Nile virus (WNV), St. Louis encephalitis virus (SLEV), Powassan viruses (POWV) BunyaviridaeCalifornia encephalitis virus (CEV); LaCrosse virus (LACV); Jamestown Canyon, snowshoe hare, and Cache Valley viruses Togaviridaeeastern equine encephalitis virus (EEEV) and western equine encephalitis virus (WEEV) ReoviridaeColorado tick fever virus (CTFV) Severe neuroinvasive disease from North American arboviruses generally occurs sporadically at low incidence, with occasional mosquito-borne epidemics occurring predominantly during the late summer and fall. Following its initial arrival in North America in 1999, WNV, a flavivirus in the Japanese encephalitis antigenic complex, quickly became the most important etiologic
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Viral Infections
successfully treat HHV-6 encephalitis in immunocompromised patients. EBV is a lymphotro phic HHV that typically causes asymptomatic primary infection in childhood or infectious mononucleosis in adolescence or young adult life. Virus replicates in the pharyngeal lymphoid tissue and may be persistently or recurrently shed into oral secretions. In immunocompetent patients with infectious mononucleosis, neurologic complications occur rarely (<1% frequency). These complications include aseptic meningitis, encephalitis, or neuropathy, including small-fiber sensory or autonomic neuropathy or Guillain-Barr syndrome. EBV replication is sensitive to acyclovir, and both oral and IV regimens have been used to treat neurologic illness (see Table 1). However, a meta-analysis of several clinical trials that used acyclovir to treat EBV illness showed that acyclovir therapy does not have statistically significant clinical efficacy. Acyclovir therapy does reduce oropharyngeal EBV shedding, which may reduce the duration and severity of illness by limiting viral reinfection. The neuropathic complications of EBV infection may respond to IV immunoglobulin (see Table 1). In immunocompromised patients, more severe CNS illness has been reported, including transverse myelitis and meningoencephalitis. Ganciclovir induction therapy has been reported to successfully treat meningoencephalitis, but the incidence of these EBV neurologic presentations is low, so no clinical trials have established efficacy. For ganciclovir-treated patients who improve neurologically but remain severely immunocompromised, maintenance therapy with oral valganciclovir should be considered. Herpes B virus (Cercopithecine herpesvirus 1 or Herpes simiae) produces infection in macaque monkeys that is similar to human HSV infection. The B virus may be transmitted to humans via monkey bites, scratches, or percutaneous inoculation of infected materials. The bloodborne transmission of B virus can cause severe, often necrotizing myelitis or encephalitis, which may progress rapidly to death. Prophylaxis with antiviral therapy is recommended after skin or mucosal exposure to a high-risk source, such as an infected macaque monkey, and wound or exposure sites should be cultured for B virus. The first choice for postexposure prophylaxis is oral valacyclovir; alternatively, oral acyclovir (see Table 1). This should be instituted within 5 days of exposure and continued for 2 weeks, then discontinued if the patient is clinically asymptomatic. Postexposure serologic testing should be repeated 3 to 6 weeks and again 3 months after initial exposure for patients receiving antiviral prophylaxis. If wound cultures are initially positive for B virus, then repeat cultures should be obtained 1 to 2 weeks after antiviral prophylaxis is stopped. IV ganciclovir is recommended for patients with symptoms and signs of CNS involvement (see Table 1). This should be continued for at least 14 days and until the symptoms resolve and two or more sets of cultures are negative for B virus growth. Postexposure prophylaxis with oral therapy, preferably oral valacyclovir, should continue for 6 months to 1 year. Some authorities hold that lifelong suppressive therapy is needed since the B virus could reactivate months to years after primary infection.
SUGGESTED READING
Brady RC, Bernstein DI: Treatment of herpes simplex virus infections, Antivir Res 61:73-81, 2004. Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, et al: Neurologic complications of the reactivation of varicella-zoster virus, N Engl J Med 342:635-645, 2000. Naesens L, DeClercq E: Recent developments in herpesvirus therapy, Herpes 8:12-16, 2001. Redington JJ, Tyler KL: Viral infections of the nervous system, 2002: update on diagnosis and treatment, Arch Neurol 59:712-718, 2002. Singh N, Paterson DL: Encephalitis caused by human herpesvirus-6 in transplant recipients, Transplantation 69:2474-2479, 2000. Sissons JGP, Carmichael AJ: Clinical aspects and management of cytomegalovirus infection, J Infect 44:78-83, 2002.
PATIENT RESOURCES
http://www.webmd.com/This well-known site has a broad appeal and is relatively easy to navigate. It is widely referenced by patients. The site includes educational materials and links to patient support organizations. http://www.virology.net/Comprehensive site claiming all the virology on the World-Wide Web. Information and links to research, education, clinical, and patient support sites as well as comprehensive educational material on the human herpesviruses. http://www.gsu.edu/~wwwvir/National Herpes B Virus Resource Center

James J. Sejvar, M.D., and Grant L. Campbell, M.D., Ph.D.
Arboviruses (arthropod-borne viruses) include several families of viruses that share the feature of transmission by arthropod vectors and are the most common etiologic agents of epidemic encephalitis worldwide. Nearly 100 such viruses are recognized to cause clinical illness in humans. The most common arboviruses causing neurologic illness in North America include the following families and their members: FlaviviridaeWest Nile virus (WNV), St. Louis encephalitis virus (SLEV), Powassan viruses (POWV) BunyaviridaeCalifornia encephalitis virus (CEV); LaCrosse virus (LACV); Jamestown Canyon, snowshoe hare, and Cache Valley viruses Togaviridaeeastern equine encephalitis virus (EEEV) and western equine encephalitis virus (WEEV) ReoviridaeColorado tick fever virus (CTFV) Severe neuroinvasive disease from North American arboviruses generally occurs sporadically at low incidence, with occasional mosquito-borne epidemics occurring predominantly during the late summer and fall. Following its initial arrival in North America in 1999, WNV, a flavivirus in the Japanese encephalitis antigenic complex, quickly became the most important etiologic
130
agent of epidemic viral encephalitis in the Western hemisphere and, in the span of 6 years, has become endemic in most of the continental United States and large areas of Canada and Mexico. Since 1999, WNV has caused thousands of cases of severe human neuroinvasive disease and has had tremendous public health impact. Large WNV epidemics are likely to recur annually for the foreseeable future; therefore, much of this chapter focuses on WNV. Although the spectrum of clinical illness associated with WNV and other arboviral infections in humans is still emerging, infection has been associated with a number of clinical syndromes, including aseptic meningitis, encephalitis, and an acute poliomyelitis-like syndrome. Treatment remains supportive; however, a number of investigational therapeutics are currently under assessment, and a human vaccine for WNV is undergoing early clinical trials.
is variable, but persistence of weakness and functional deficits is the rule; development of respiratory muscle weakness often necessitates prolonged endotracheal intubation and ventilatory support and is associated with high mortality. Clinical illness due to other North American arboviral infections varies with respect to the population and age groups at highest risk for infection, neurotropism and illness severity, and primary clinical manifestations (Table 1). In particular, EEE results in high mortality and high rates of neurologic sequelae among survivors.
Diagnosis
Infection with WNV or another arbovirus should be suspected in patients developing acute meningitis, encephalitis, or asymmetrical flaccid paralysis during the summer and fall months or other periods of mosquito activity. The gold standard for diagnosis of arboviral infections is virus isolation from clinical specimens (e.g., blood, serum, cerebrospinal fluid [CSF], or tissue) followed by demonstration of seroconversion of virusspecific neutralizing antibodies in serum. However, because virus isolation of WNV and many other arboviruses is technically difficult and lacks sensitivity, serology remains of central importance. A presumptive diagnosis of recent infection may be made by detection of virus-specific IgM antibodies in serum or CSF; however, with some arboviruses, including WNV, diagnosis of a recent infection is complicated by prolonged persistence of IgM antibodies in some previously infected persons. The observation of at least a fourfold rise in virus-specific neutralizing antibody titers in serial serum samples is considered confirmatory. Serologic crossreactivity between closely related arboviruses (e.g., WNV and SLEV) complicates the issue of what is virus specific, and this usually requires the demonstration of specific neutralizing antibody using a battery of geographically and epidemiologically appropriate arboviruses or arboviral antigens. Plaque reduction neutralization, the most widely used test method for detecting arboviral neutralizing antibody, requires the use of live virus and is not commercially available at present but can be performed at the Centers for Disease Control and Prevention and some state health department and other reference laboratories. Nucleic acid amplification tests (e.g., polymerase chain reaction) are also available for detecting WNV and several other arboviruses in clinical samples, but these tests have limited sensitivity and generally cannot substitute for serology. Head computed tomography is generally normal in arboviral encephalitis and is useful only in excluding other causes of acute encephalopathy. Magnetic resonance (MR) imaging in patients with WNE, although frequently normal, sometimes displays signal abnormalities in the basal ganglia, posterior thalami, and brainstem, best visualized on T2-weighted, diffusion-weighted images (DWI), or fluid-attenuated inversion recovery (FLAIR) sequences; the sensitivity and specificity of these findings are unknown, and similar findings have occasionally been noted with SLE. In WNP cases,
Clinical Arboviral Illness in Humans

Human infections with most arboviruses, including WNV, are usually asymptomatic. Symptomatic infections may range from mild systemic febrile illness to more severe neuroinvasive disease, manifesting as aseptic meningitis, encephalitis, or myelitis. WNV infection provides a good example of the spectrum of neurologic illness associated with arboviral infection. Self-limited febrile illness (West Nile fever) is characterized by an incubation period of 2 to 14 days, followed by the abrupt onset of fever, chills, myalgias, and fatigue; nausea and vomiting are common. West Nile meningitis (WNM) is similar to other aseptic meningitides and is characterized by fever, headache, and meningismus. Early in the course of infection, pleocytosis may be neutrophilic, with the lymphocytic pleocytosis more commonly seen in viral infections predominating later, sometimes obscuring the diagnosis. Outcome is generally favorable, though patients occasionally experience persistent headache and fatigue. West Nile encephalitis (WNE) occurs more commonly in elderly persons. Recent evidence suggests that immunosuppressed persons are also at greater risk for WNE. Severity of WNE may range from a mild confusional state to coma and death; mortality occurs in approximately 10% to 15% of those with severe illness and increases with age. Various neurologic signs, including pronounced postural and intentional tremor, focal myoclonus, and parkinsonism, are seen frequently and may persist. Poliomyelitis (West Nile poliomyelitis) is a particularly severe manifestation of WNV infection and, less frequently, infection with other arboviruses. Weakness may occur in the absence of meningitis, encephalitis, or even fever, headache, or other symptoms suggestive of WNV infection. Diaphragmatic and intercostal muscle weakness can result in acute respiratory failure; patients developing early lower bulbar findings, particularly dysarthria and dysphagia, are at high risk for impending respiratory failure and should be closely monitored. Outcome in patients with paralysis
TABLE 1 Geographic Distribution, Primary Arthropod Vectors, and Main Clinical and Epidemiologic Features of the Main Arboviral Agents of Neurologic Disease in North America
Family/ Virus Mosquitoes (Culex spp.) Birds Urban/ suburban/ rural Epidemic Currently, the most important cause of epidemic encephalitis in North America: during 1999-2003, >14,000 total human cases reported in the United States, including 6000 neuroinvasive disease cases and 600 deaths
Geographic Distribution
Primary Vectors
Primary Vertebrate Hosts Main Human Risk Areas
Main Epidemiologic Pattern
Incidence (All Clinical Categories)
Main Clinical/ Demographic Features
Known NonarthropodBorne Modes of Transmission to Humans
Viral Infections
Flaviviridae West Nile
Continental United States, southern Canada, Central America, Caribbean (also widely distributed in the eastern hemisphere)
St. Louis encephalitis
Continental United States, southern Canada, Central and South American, Caribbean
Mosquitoes (Culex spp.)
Birds
Urban/ suburban/ rural
Epidemic
Most (80%) Blood infections subclinical; transfusion, mild, self-limited organ febrile illness (West transplantation, Nile fever) in ~20% intrauterine, of infections (mainly laboratory young adults); accidents neuroinvasive disease in <1% of infections: meningitis (mainly young adults), encephalitis (mainly elderly, immunocompromised), poliomyelitis-like syndrome (mainly young adults, elderly), neuritis; case fatality in encephalitis 10-15% increases with age During 1964Most infections Laboratory 2002, 4589 subclinical; frequency accidents cases were of mild, self-limited reported to febrile illness unknown; the CDC, for neuroinvasive disease a national in <1% of infections: average of meningitis (mainly 118 cases/yr children, young adults), (median, 26; encephalitis (mainly range, 2-1967). elderly); case fatality In the 1975 10-15% in epidemic encephalitis cases, involving much increases with age of the eastern United States, 2000 cases and 200 deaths were reported
continued
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TABLE 1 Geographic Distribution, Primary Arthropod Vectors, and Main Clinical and Epidemiologic Features of the Main Arboviral Agents of Neurologic Disease in North Americacontd
Family/ Virus Ticks (Ixodes spp.) Small to mediumsized mammals (e.g., woodchucks) Rural; most cases from northeastern United States and Canada Endemic/ sporadic Rare (<35 cases documented)
Primary Vectors
Main Clinical/ Demographic Features Frequency of Laboratory subclinical or mild accidents illness unknown; neuroinvasive disease (<35 cases ever recognized): meningitis, encephalitis, poliomyelitis-like illness (symptomatic illness more frequently recognized in adults, elderly); case fatality in encephalitis ~20%; encephalitis may be associated with focal lesions on neuroimaging
Powassan
United States (especially northern), southern Canada
Bunyaviridae La Crosse
Eastern United States Small mammals (e.g., squirrels, chipmunks) Suburban, especially near oak woodlands Endemic/ sporadic and small case clusters
Aedes triseriatus (eastern treehole mosquito)
Most Most infections important subclinical; frequency cause of of mild illness endemic unknown; arboviral neuroinvasive encephalitis in disease: meningitis United States. and encephalitis During the (mainly children); 39-year encephalitis may be period of associated with 1964-2002, seizures; fatalities 3077 rare California serogroup viral CNS disease cases (nearly all presumed to be due to La Crosse virus
Viral Infections
Jamestown Canyon
United States (including Alaska), Canada
Mosquitoes (Aedes spp.?, Culiseta spp.?)
Large mammals (e.g., deer, elk)
Rural/ suburban
Endemic/ sporadic
Snowshoe hare
Northern United States, southern Canada
Mosquitoes (Aedes spp.?, Culiseta spp.?)
Small Rural/ mammals suburban (e.g., hares, rabbits)
Endemic/ sporadic
California encephalitis
Western United States
Mosquitoes (Aedes spp.)
Small mammals (e.g., ground squirrels, hares) Large mammals (e.g., deer, elk) Endemic/ sporadic
Endemic/ sporadic
Cache Valley
North America
Mosquitoes (spp. undetermined)
Rural/ suburban, especially in the California Central Valley Rural/ suburban
infection) were reported to the CDC, for a national average of 79 cases/yr (median, 67; range, 29-167) Rare Most infections (<40 cases subclinical; documented) frequency of mild illness unknown; neuroinvasive disease: meningitis more common than encephalitis (mainly adults) Rare Most infections (<15 cases subclinical; documented) frequency of mild illness unknown; neuroinvasive disease: meningitis, encephalitis (mainly adults) Rare Subclinical infections (<10 cases common in some documented) areas; neuroinvasive disease: meningitis, encephalitis (children and younger adults) Rare (only Most infections 1 case ever subclinical; recognized: frequency of mild fatal illness unknown; encephalitis neuroinvasive in an adult) disease: encephalitis (adult) Endemic/ sporadic During 19642002, 200 human cases were reported to the CDC, for a national Most infections subclinical; frequency of mild illness unknown; neuroinvasive disease: meningitis and encephalitis Laboratory accidents
Togaviridae Eastern equine encephalitis Mosquitoes (Culex spp., Aedes spp.) Birds
Eastern United States and Canada (especially in coastal states)
Rural/ suburban, mainly near freshwater hardwood swamps
continued
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TABLE 1 Geographic Distribution, Primary Arthropod Vectors, and Main Clinical and Epidemiologic Features of the Main Arboviral Agents of Neurologic Disease in North Americacontd
Family/ Virus average of 5 cases/yr (median, 4; range, 0-14) Mosquitoes (Culex tarsalis) Birds Rural/ suburban, especially in irrigated agricultural areas During 19642002, 640 human cases were reported to the CDC, for a national average of 16 cases/yr (median, 2; range, 0-172). For unknown reasons, the number of reported cases has declined dramatically since the late 1980s During 19872001, a total of 777 Colorado tick fever case reports were received by nine western state health departments, with Colorado (32), Utah (8), and Montana (7) Most infections subclinical; frequency of mild illness unknown; neuroinvasive disease: meningitis and encephalitis (children and elderly; extremes of age); case fatality <5% (higher in infants than adults) (children and elderly; extremes of age); case fatality ~30%; survivors often have severe sequelae
Primary Vectors
Main Clinical/ Demographic Features
Western equine encephalitis
Midwestern and western United States and Canada
Reoviridae Colorado tick fever
Western United States and Canada Small mammals (e.g., squirrels, chipmunks)
Dermacentor andersoni (Rocky Mountain wood tick)
Rural, Endemic/ mountainsporadic ous areas, at elevations >3000 ft
Rates of subclinical and mild illness unknown. Most clinical infections are nonspecific, self-limited febrile illnesses. Neuroinvasive disease is rare: meningitis, encephalitis (mainly children). Virus is sequestered in red blood cells
Blood transfusion, laboratory accidents
Viral Infections
reporting the greatest annual averages. For unknown reasons, the number of reported cases has declined steadily during the past 2 decades. Nevertheless, the disease is almost certainly greatly underrecognized and underreported
throughout their normal lifespan, protected from immune response; patients should not donate blood for at least 6 mo following clinical recovery
CDC, Centers for Disease Control and Prevention; CNS, central nervous system.
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spinal MR imaging may display anterior cord signal hyperintensity, and patients with respiratory weakness sometimes show signal abnormality in the lower medulla and high cervical cord. Electromyography/ nerve conduction studies generally display decreased or absent compound muscle action potentials with relative preservation of sensory nerve action potentials, widespread denervation changes, and reduced recruitment, consistent with a motor axonal or anterior horn cell process.
Options for Management

There is currently no definitive treatment for arboviral infections; therefore, prevention is critical and is possible only through protection from arthropod bites. Patients should be educated about WNV and other arboviral diseases in their home areas and about the importance of vector avoidance and personal protection measures. In the absence of definitive antiviral treatment, management remains supportive. Patients with severe arboviral meningitis may require hospital admission for headache pain control and for rehydration secondary to severe nausea and vomiting. Severe headache in the acute phase of WNM often responds to a brief course of analgesic, such as nonsteroidal anti-inflammatory agents (ketorolac, 10-30 mg intramuscularly [IM] or intravenously [IV] every 6 hours), codeine (15 to 60 mg orally [PO] every 4 to 6 hours when necessary), or morphine (10-30 mg PO/2-10 mg/70 kg body weight IM or IV, or the lowest dosage achieving pain relief, every 4 to 6 hours. These drugs should be discontinued as soon as possible to avoid rebound headache or dependence. Nausea and vomiting frequently respond to antiemetics such as promethazine (12.5 to 25 mg IM or IV every 4 hours) or prochlorperazine (2.5 to 10 mg IM or IV every 3 to 4 hours) without exacerbation of the parkinsonian features of WNE. In patients with arboviral encephalitis, attention to level of alertness and ability to protect the airway is obviously important. Seizures have been infrequently reported with WNE but are seen more commonly in LACV encephalitis and should be managed appropriately with anticonvulsants. Elevated intracranial pressure and cerebral edema has likewise been infrequently reported but should be suspected if suggested by neuroimaging, CSF opening pressures, or neurologic features (e.g., papilledema, Cheyne-Stokes/apneustic/ataxic respiratory patterns, posturing) and managed appropriately with hyperventilation or mannitol. Patients developing flaccid paralysis may not have concurrent meningitis or encephalitis; thus, WNV infection may not initially be suspected, and inappropriate diagnostic procedures or treatment modalities, such as anticoagulation for suspected acute stroke or muscle biopsy for suspected myopathy, may be rendered. It is important to suspect WNV infection in persons developing acute asymmetrical paralysis. As mentioned previously, patients developing early dysarthria and dysphagia are at higher risk for subsequent acute respiratory failure; for this reason, hospitalization and observation of patients with flaccid paralysis are advised, and development of dysarthria and dysphagia should be viewed
with concern. Experience in the management of paralysis is limited; management of poliomyelitis due to poliovirus infection suggests that initiation of aggressive physical activity during the acute febrile period of illness is associated with more profound and persistent weakness. In the absence of additional data, avoidance of aggressive physical therapy during the acute febrile illness or during the initial 48 to 72 hours of weakness seems a reasonable approach. Physical and occupational therapy should probably be initiated soon thereafter; the most effective rehabilitation strategies for improvement of limb strength are currently unknown. Definitive treatment of infection with WNV or other arboviruses is complicated by the fact that viremia is generally short-lived, and clinical illness may not develop until viremia has essentially ended; thus, to be efficacious, administration of a therapeutic agent may need to occur prior to the development of clinical neurologic disease. Recently, several therapeutic modalities, including use of antiviral agents, nucleic acid analogs, and immunomodulating agents, have been explored as potential treatments for WNV disease; unfortunately, data from animal studies are sparse, and the large number of human cases combined with the clinical desire to intervene medically has led to the empirical use of a number of agents. Anecdotal information suggesting the benefit of these agents in the treatment of severe WNV neuroinvasive disease has perpetuated such usage among many clinicians; however, the efficacy of these drugs is difficult to substantiate in the absence of randomized, blinded, placebo-controlled trials. It is clear, however, that no single therapy appears to have a dramatic impact on outcome. The antiviral agent ribavirin has been used empirically in the United States to treat WNE, but no clinical trials have been conducted. Ribavirin was used in an uncontrolled, nonblinded fashion in a group of patients with neuroinvasive WNV disease in Israel and was found to be ineffective and potentially harmful; for this reason, its use is discouraged. The immunoregulatory protein interferon- has shown in vitro inhibition of cytotoxicity due to WNV, SLEV, and EEEV infections but has not been fully evaluated in animal models. Results of an open-label trial in humans have not been encouraging; data from a blinded, placebo-controlled trial in the treatment of Japanese encephalitis failed to demonstrate efficacy, suggesting that interferon is likely to be ineffective in WNE and other flaviviral encephalitides. Based on mouse model data suggesting the benefit of early administration of high-titer WNV-specific IV immune globulin (IVIG) from Israel (Omr-IgG-am), as well as anecdotal reports of therapeutic efficacy in immunocompromised patients, a phase I/II randomized, double-blinded, placebo-controlled trial to evaluate the safety and efficacy of this product was initiated in 2003 by the Collaborative Antiviral Study Group and the National Institutes of Health. Experimental human WEEV, EEEV, and VEEV vaccines currently exist, but the low associated rates of human illness and the lack of licensure by the U.S. Food and Drug Administration make them impractical and
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unavailable for general public use. Human WNV vaccines are under development, but licensure is likely many years away. SUGGESTED READING
Agrawal AG, Peteresen LR: Human immunoglobulin as a treatment for West Nile virus infection, J Infect Dis 188:5-12, 2003. Calisher CH: Medically important arboviruses of the United States and Canada, Clin Microbiol Rev 7:89-116, 1994. Petersen LR, Marfin AA, Gubler DJ: West Nile virus, JAMA 290: 524-528, 2003.
Systemic Diagnostic Syndromes

The most common (>50%) systemic manifestation of an EV infection is a nonspecific febrile illness, with a fever of 38.5 to 40C, and lasting 2 to 4 days. Less frequent EV-specific systemic syndromes may be seen and can provide additional clues for diagnosis (Table 3).
Viral (Aseptic) Meningitis

CLINICAL MANIFESTATION Viral meningitis manifests with headache (may be intense), photophobia, nausea, fever, stiff neck, and general irritability. Onset can be abrupt. The presentation of viral meningitis is strongly influenced by age, and in younger children signs are much less specific (Table 4). Generally children younger than 3 years of age are most susceptible to viral meningitis. DIAGNOSTIC STRATEGIES The neurologic manifestations of viral meningitis are not diagnostically useful for differentiating among the causes. Therefore, systemic manifestations (see Table 3) combined with other clues (see Table 2) are useful in making the diagnosis. The differential diagnosis includes other viral infections (arbovirus, herpes simplex 2, mumps, varicella, LCM), Rocky Mountain spotted fever (RMSF), Lyme disease, bacterial meningitis, tuberculous meningitis, and fungal meningitis. DIAGNOSTIC TESTS Once viral meningitis is suspected, a number of tests can be performed to confirm the diagnosis, basically by ruling out other causes of meningitis. Computed tomography (CT), magnetic resonance (MR) imaging, and electroencephalography (EEG) are usually normal (Figure 1).
PATIENT RESOURCE
http://www.casg.uab.edu/: Collaborative Antiviral Study Group clinical trial of West Nile virus-specific high-titer intravenous immune globulin.
Burk Jubelt, M.D., and Stacie L. Ropka, Ph.D.
The human enterovirus (EV) genus, so called because the primary site of entry and replication is the gastrointestinal tract, includes the polioviruses (PVses), coxsackieviruses, echoviruses, and the unclassified EV-68 through EV-71. EVs are the etiologic agents of about a dozen neurologic syndromes, but from a practical standpoint, the important ones are meningitis, encephalitis, flaccid paralysis, and chronic infection. Although each of these syndromes can be caused by most of the different EVs, there are predominant species responsible for each syndrome (Table 1).
Epidemiologic Diagnostic Considerations

In tropical climates EVs are endemic. In temperate climates, however, most infections occur as epidemics from May through October. Because of this epidemic behavior, EVs are often referred to as summer viruses. People with EV infections shed virus for about a week in oral secretions and about a month in feces. Infection is spread primarily by the fecal-hand-oral route. EVs are spread horizontally in the community and are usually introduced into the household by young children. Therefore, transmission within a community depends on a number of factors, which are useful in diagnosing an enteroviral infection, especially host age, hygiene, crowded conditions, and overall sanitation (Table 2).
TABLE 1 Common Enteroviral (EV) Neurologic Syndromes*

Syndrome Meningitis Encephalitis Predominant Etiology Echoviruses Coxsackieviruses EV-71 Echoviruses Coxsackieviruses EV-71 Polioviruses Polioviruses EV-70 EV-71 Echoviruses Polioviruses, vaccine like
Flaccid paralysis Chronic infection
*Syndromes that are rarely caused by or have been related to EV include cranial nerve palsies, opsoclonus-myoclonus, febrile convulsions, cerebellar ataxia, transverse myelitis, Guillain-Barr syndrome, and rhabdomyolysis.
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Viral Infections
unavailable for general public use. Human WNV vaccines are under development, but licensure is likely many years away. SUGGESTED READING
Agrawal AG, Peteresen LR: Human immunoglobulin as a treatment for West Nile virus infection, J Infect Dis 188:5-12, 2003. Calisher CH: Medically important arboviruses of the United States and Canada, Clin Microbiol Rev 7:89-116, 1994. Petersen LR, Marfin AA, Gubler DJ: West Nile virus, JAMA 290: 524-528, 2003.
Systemic Diagnostic Syndromes

The most common (>50%) systemic manifestation of an EV infection is a nonspecific febrile illness, with a fever of 38.5 to 40C, and lasting 2 to 4 days. Less frequent EV-specific systemic syndromes may be seen and can provide additional clues for diagnosis (Table 3).
Viral (Aseptic) Meningitis

CLINICAL MANIFESTATION Viral meningitis manifests with headache (may be intense), photophobia, nausea, fever, stiff neck, and general irritability. Onset can be abrupt. The presentation of viral meningitis is strongly influenced by age, and in younger children signs are much less specific (Table 4). Generally children younger than 3 years of age are most susceptible to viral meningitis. DIAGNOSTIC STRATEGIES The neurologic manifestations of viral meningitis are not diagnostically useful for differentiating among the causes. Therefore, systemic manifestations (see Table 3) combined with other clues (see Table 2) are useful in making the diagnosis. The differential diagnosis includes other viral infections (arbovirus, herpes simplex 2, mumps, varicella, LCM), Rocky Mountain spotted fever (RMSF), Lyme disease, bacterial meningitis, tuberculous meningitis, and fungal meningitis. DIAGNOSTIC TESTS Once viral meningitis is suspected, a number of tests can be performed to confirm the diagnosis, basically by ruling out other causes of meningitis. Computed tomography (CT), magnetic resonance (MR) imaging, and electroencephalography (EEG) are usually normal (Figure 1).
PATIENT RESOURCE
http://www.casg.uab.edu/: Collaborative Antiviral Study Group clinical trial of West Nile virus-specific high-titer intravenous immune globulin.
Burk Jubelt, M.D., and Stacie L. Ropka, Ph.D.
The human enterovirus (EV) genus, so called because the primary site of entry and replication is the gastrointestinal tract, includes the polioviruses (PVses), coxsackieviruses, echoviruses, and the unclassified EV-68 through EV-71. EVs are the etiologic agents of about a dozen neurologic syndromes, but from a practical standpoint, the important ones are meningitis, encephalitis, flaccid paralysis, and chronic infection. Although each of these syndromes can be caused by most of the different EVs, there are predominant species responsible for each syndrome (Table 1).
Epidemiologic Diagnostic Considerations

In tropical climates EVs are endemic. In temperate climates, however, most infections occur as epidemics from May through October. Because of this epidemic behavior, EVs are often referred to as summer viruses. People with EV infections shed virus for about a week in oral secretions and about a month in feces. Infection is spread primarily by the fecal-hand-oral route. EVs are spread horizontally in the community and are usually introduced into the household by young children. Therefore, transmission within a community depends on a number of factors, which are useful in diagnosing an enteroviral infection, especially host age, hygiene, crowded conditions, and overall sanitation (Table 2).
TABLE 1 Common Enteroviral (EV) Neurologic Syndromes*

Syndrome Meningitis Encephalitis Predominant Etiology Echoviruses Coxsackieviruses EV-71 Echoviruses Coxsackieviruses EV-71 Polioviruses Polioviruses EV-70 EV-71 Echoviruses Polioviruses, vaccine like
Flaccid paralysis Chronic infection
*Syndromes that are rarely caused by or have been related to EV include cranial nerve palsies, opsoclonus-myoclonus, febrile convulsions, cerebellar ataxia, transverse myelitis, Guillain-Barr syndrome, and rhabdomyolysis.
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TABLE 2 Enteroviral Epidemiology

Variable Season Host characteristics Environment conducive to spread Factor(s) Epidemics, in the summer months in temperate climates Ageespecially young children Personal hygiene Overcrowding Poor sanitation Presence of young children Daycare centers Newborn nurseries
severe, fluid and electrolyte support may be needed. Infants in particular require fluid, electrolyte, and nutritional support. Although current treatment of viral meningitis is mostly supportive, specific agents are under study. Pleconaril, an antiviral agent specific for EVs, was developed by ViroPharma, Inc. Studies indicate that pleconaril is effective in treating enteroviral meningitis (38% to 50% improvement in drug group vs. placebo). It would appear to be particularly useful for stopping outbreaks of enteroviral meningitis in newborn nurseries. Pleconaril is still an investigational drug that was previously supplied on a compassionate use basis but currently is unavailable.
Occasionally the EEG may reveal diffuse slowing without clinical encephalitis. The cerebrospinal fluid (CSF) profile in viral meningitis usually consists of a mononuclear cell (lymphocytic) pleocytosis with a normal glucose level. However, virus has been recovered from the CSF with normal leukocyte counts. Occasionally during the first 24 to 48 hours of the infection, polymorphonuclear cells may be seen, mimicking bacterial meningitis. Rarely the CSF glucose level may be low, as in fungal and tuberculous meningitis. Echoviruses, coxsackieviruses, and EV-71, the predominant causes of viral meningitis (see Table 1), may be cultured from the CSF, usually from the stool, and occasionally from the throat. Polymerase chain reaction (PCR) analysis should also be ordered. Once virus is detected by culture or PCR, the specific species type can be determined by serology. TREATMENT Viral meningitis is usually a benign, self-limited illness. Many patients with viral meningitis are hospitalized to exclude bacterial meningitis and other treatable diseases. The headache may be intense, especially at onset, and may require narcotics for pain relief. If nausea is
Encephalitis and Rhombencephalitis

CLINICAL MANIFESTATIONS Encephalitis caused by echoviruses and coxsackieviruses resembles viral meningitis on initial presentation. Within 24 to 48 hours, however, signs of brain (parenchymal) involvement ensue, thus differentiating viral encephalitis from viral meningitis. The encephalitis is generally mild; however, neonates can develop a severe systemic group B coxsackievirus infection, including encephalitis, which can be fatal. Rhombencephalitis (brainstem encephalitis) has occurred with EV-71 epidemics of hand-foot-and-mouth disease (HFMD) in Taiwan and Malaysia over the last 6 to 7 years. This is a severe encephalitis, with a mortality rate of about 15%. Most cases occur in children younger than 5 years of age. The initial symptoms are tremor, myoclonic jerks, and ataxia. With progression, cranial nerve palsies (ocular and bulbar), respiratory failure, and coma occur. During these epidemics a few cases of aseptic meningitis and flaccid paralysis were also seen. Although PV-induced disease is now rare, when PV encephalitis did occur, it also frequently resulted in cranial nerve palsies and respiratory failure.
TABLE 3 Systemic Syndromes Caused by Enteroviruses (EVs)

Syndrome Rashes Hand-foot-and-mouth disease Herpangina Pleurodynia (epidemic myalgia, Bornholms disease) Myocarditis/pericarditis Conjunctivitis Associated Enterovirus Coxsackievirus Echovirus Coxsackievirus EV-71 Coxsackievirus Coxsackievirus groups A and B group A group A group B
TABLE 4 Typical Clinical Manifestations of Aseptic Meningitis

Age Group Older children and adults Presentation Severe headache Fever Photophobia Nausea Nuchal rigidity General irritability Kernig and/or Brudzinski signs (in 33%) Increased irritability Nonspecific rash Nuchal rigidity rare in infants Poor feeding Lethargy
Coxsackievirus group B EV-70 (acute hemorrhagic conjunctivitis) Coxsackievirus group A24
Infants and young children
Adapted from Ropka SL, Jubelt B: Enteroviruses. In Nata A, Berger JR, editors: Clinical neurovirology, New York, 2003, Marcel Dekker, 359-377.
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Symptoms and signs of acute meningitis Headache, fever, photophobia, nausea, nuchal rigidity, normal mental status
Normal
CT scan
Abnormal Focal lesion
LP
Collect serum and CSF samples for cultures, PCR, antibody testing, and cytology
Normal No CSF pleocytosis Normal glucose
Abnormal CSF pleocytosis Normal glucose
Abnormal CSF pleocytosis Low glucose
Not meningitis, evaluate for: Encephalitis Abscess Tumor Other
Not meningitis
Differential: Viral meningitis1 Lyme disease1 RMSF2 Mycoplasma2 Sarcoid1,4 Vasculitic meningitis1 Carcinomatous meningitis1
Non-viral meningitis: Bacterial3 Fungal1 TB1 Sarcoid1,4 Carcinomatous meningitis1
Culture or PCR positive for EV
Cultures and PCR negative for EV, Not EV meningitis: Other viral meningitis Other differential entity
Treat with pleconaril if in newborn nursery or immunocompromised
FIGURE 1. Algorithm for the diagnosis and treatment of enteroviral (EV) meningitis. CT, computed tomography; LP, Lumbar puncture; CSF, cerebrospinal fluid; PCR, polymerase chain reaction; RMSF, Rocky Mountain spotted fever; TB, tuberculous meningitis. 1Mononuclear cells (lymphocytes) predominate, although it is not unusual to find polymorphonuclear cells within the first 24 hours of clinical symptoms. 2A variable combination of lymphocytes and polymorphonuclear (PMN) cells is seen. 3In bacterial meningitis, PMN cells usually predominate. 4In sarcoid meningitis, the glucose level is low about 20% of the time.
DIAGNOSTIC STRATEGIES The neurologic manifestations of coxsackievirus and echovirus encephalitis are nonspecific. As with meningitis, systemic manifestations, epidemic activity, and household disease may give clues to the diagnosis. The differential would include other causes of viral encephalitis including herpes simplex and the arboviruses. Nonviral infections to consider are Lyme disease, mycoplasmal infection, endocarditis, toxoplasmosis, and Rocky Mountain spotted fever. Noninfectious diseases in the differential include vasculitis, sarcoidosis, and gliomatosis cerebri. During the EV-71 HFMD-rhombencephalitis epidemics in Asia, several other EVs were circulating at the same time, some of which also caused HFMD. The differential would include other causes of brainstem or severe encephalitis, herpes simplex, herpes zoster,
Japanese encephalitis virus, West Nile virus, and paraneoplastic syndrome. DIAGNOSTIC TESTS In coxsackievirus and echovirus encephalitis the CT scan and MR imaging are usually normal because focal parenchymal lesions are infrequently seen (Figure 2). In EV-71 rhombencephalitis, T2-weighted MR scans have revealed hyperintensities in the brainstem, most frequently in the pontine tegmentum. Occasionally, lesions extend to the thalamus and cervical cord (see Figure 2). In coxsackievirus and echovirus encephalitis the EEG usually reveals generalized slowing, but focal slowing or sharp waves may occur. In EV-71 rhombencephalitis there usually is severe, diffuse slowing.
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Symptoms and signs of acute encephalitis (or meningoencephalitis) Altered levels of consciousness, abnormal behavior, focal signs, seizure, fever, nuchal rigidity (plus headache, photophobia, nausea)
Normal Encephalitis Encephalopathy
CT scan
Abnormal Focal lesion(s) MRI for: Abscess Toxoplasmosis Endocarditis Vasculitis Tumor Other (mycoplasma3, sarcoid)
LP
Collect serum and CSF samples for culture, PCR and antibody testing
Normal No pleocytosis Normal glucose
Abnormal CSF pleocytosis Normal glucose
Abnormal CSF pleocytosis Low glucose
Encephalopathy
Viral encephalitis1 RMSF2 Mycoplasma2,3 Sarcoid1,4
Sarcoid1,4 Brucellosis Viral encephalitis5
MRI
MRI abnormal
MRI normal
Brainstem
Temporal lobe
Basal ganglia, thalamus > brainstem
Other: Mycoplasma Sarcoid
Culture or PCR
Culture or PCR positive for EV
EV-71 rhombencephalitis
Culture or PCR negative for EV: Other viral encephalitis Other differential entity
Probably HSV Probably arbovirus Start acyclovir
Positive for EV EV encephalitis Start pleconaril
Negative for EV Other encephalitides
Start pleconaril
FIGURE 2. Algorithm for the diagnosis and treatment of enteroviral (EV) encephalitis. CT, computed tomography; LP, Lumbar puncture; CSF, cerebrospinal fluid; PCR, polymerase chain reaction; RMSF, Rocky Mountain spotted fever; HSV, herpes simplex virus; MRI, magnetic resonance imaging. 1 Mononuclear cells (lymphocytes) predominate, although it is not unusual to find polymorphonuclear (PMN) cells within the first 24 hours of clinical symptoms. 2 A variable combination of lymphocytes and PMNs is seen. 3 In mycoplasma encephalitis, the CT is abnormal about 50% of the time. 4 In sarcoid parenchymal disease, the CT reveals parenchymal lesions about 50% of the time and the glucose level is low about 20% of the time. 5Rarely, the glucose may be mild to moderately low in viral encephalitis.
In these infections the CSF profile resembles that of aseptic meningitis. Coxsackievirus, echovirus, and EV71 may be isolated from the CSF, stool, or throat. PV is not found in the CSF but in the stool and throat. TREATMENT Treatment of enteroviral encephalitis is primarily supportive. Pleconaril has been used in a small number
of cases of severe neonatal enteroviral systemic infections. The results have been promising in these uncontrolled compassionate use studies. Supportive care includes respiratory support, which may require tracheostomy during a prolonged period of recovery during severe encephalitis. Fluid and electrolyte balance is important to maintain. This can be followed by intravenous nutrition and eventually a feeding tube. Physical therapy is initially important for passive range
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of motion to maintain joints and muscle tissue. Eventually with recovery, gait training and muscle strengthening will be required. Occupational therapy for activities of daily living (ADL) probably will be needed.
TREATMENT Treatment of paralytic disease, once it occurs, is supportive. Pleconaril has not been used for acute paralytic disease. It has decreased efficacy against PV as compared with other EVs. Supportive care includes physical therapy for paralysis and respiratory therapy for respiratory failure. Initially, treatment will include passive range of motion for paralysis, followed by strengthening exercises for mildly weak muscles. Respiratory therapy and artificial ventilation may be needed if respiratory failure occurs. Occupational therapy is also important during recovery for assistance with ADL. Eventually, braces and other assistive devices may be needed. Poliomyelitis (PV-induced paralysis) can be treated prophylactically with PV vaccine. In 2000 the recommended vaccine regimen for poliomyelitis was changed from live oral polio vaccine (OPV) to the inactivated poliomyelitis vaccine (IPV). This change was made because of the occurrence of about six cases yearly of vaccine-associated paralysis. IPV is given at 2, 4, and 6 to 18 months, and a booster is given at 4 to 6 years of age.
Paralytic Disease
CLINICAL MANIFESTATIONS Acute flaccid paralysis usually begins with fever, flulike symptoms, and sometimes muscle cramps followed by muscle weakness in one or more limbs. Paralysis is usually asymmetrical, flaccid, more proximal than distal, and often patchy. The reflexes are lost as paralysis progresses. Over the next several days, paralysis may develop in other extremities, and bulbar involvement with impaired respiration may occur. Extension of paralysis is unlikely to occur after the 5th or 6th day. Paralysis caused by coxsackievirus and echoviruses is usually mild compared with that seen with PV, EV-70, and EV-71. Generally the weakened muscles regain some strength. DIAGNOSTIC STRATEGIES Again, systemic manifestations may provide a clue to the causative agent (see Table 3). EV-70 has caused flaccid paralysis during epidemics of acute hemorrhagic conjunctivitis in Africa and Asia. During the EV-71 epidemics of HFMD with rhombencephalitis, about 10% of cases developed acute flaccid paralysis. There are no characteristic systemic manifestations of PV infections. Several other viruses, such as rabies virus, flaviviruses, (especially West Nile virus) and herpes zoster virus, can occasionally cause acute lower motor neuron paralysis. Other entities in the differential include acute inflammatory polyradiculitis (Guillain-Barr syndrome), botulism, acute toxic neuropathies, acute intermittent porphyria, acute transverse myelitis, and acute spinal cord compression. DIAGNOSTIC TESTS Radiographic studies are usually normal, but there have been a few reports of MR T2-weighted hyperintensities in the anterior horns of the spinal cord. Ventral root and anterior horn cell involvement may be seen with contrast T1-weighted scans. Neurophysiologic studies during the first week of paralysis may reveal reduced to absent compound muscle action potential amplitudes, unobtainable F waves, and decreased to absent motor unit potentials. Fibrillation potentials may be seen toward the end of the first week. The CSF findings are similar to those in aseptic meningitis and encephalitis. PV, coxsackievirus, echovirus, and EV-71 can be isolated from the stool and throat but rarely from the CSF when the presentation is paralytic. EV-70 is not found in the stool or throat and is usually not isolated from the CSF. These viruses may be detected in the CSF by PCR amplification.
Persistent Infections
CLINICAL MANIFESTATIONS Persistent central nervous system infections caused by EVs primarily occur in children with agammaglobulinemia. The viruses that cause these infections are of low virulence. Most are caused by echovirus. Vaccine-like PVs have caused several dozen cases, and coxsackieviruses have caused several cases. Persistent echovirus infections primarily involve the brain, with alterations in behavioral and mental status, headaches, seizures, pyramidal tract signs, ataxia, and tremors. About one half of the patients with chronic echovirus infections develop a dermatomyositis-like syndrome, presumably from viral invasion of the muscle, although virus has been isolated from muscle in only two instances. In the PV cases, there is a prolonged incubation period of several months from the time of vaccination until the onset of neurologic disease. Some cases begin with lower motor neuron paralysis, but the persistent central nervous system infection continues, causing progressive intellectual and cerebral dysfunction. Other cases begin with these later manifestations, but ultimately paralysis occurs. DIAGNOSTIC STRATEGIES Other infections that occur in agammaglobulinemic children include bacterial infections that may result in meningitis. Other chronic infections to consider might include toxoplasmosis and infections from other viruses, especially nonenveloped viruses such as adenovirus, although increases in these have not been reported in these patients. DIAGNOSTIC TESTS The EEG and MR scan are usually normal. Examination of the CSF reveals a mononuclear pleocytosis, 6
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usually with an elevated protein and normal glucose. Echovirus but not PV is frequently isolated from the CSF. Both can be detected with PCR techniques. Occasionally virus can be isolated from the stool. TREATMENT Live OPV should not be given to these immunodeficient patients. Currently, this is not a problem in the United States, but it may be in other countries where OPV is still used. Intravenous immunoglobulin (IVIG) for the treatment of the agammaglobulinemia has decreased the occurrence of these infections. However, once infection is established, it is difficult to eradicate it with IVIG. Pleconaril has been used experimentally to treat some of these cases. In one report of 16 patients, 12 improved and 3 stabilized. SUGGESTED READING
Abzug MJ, Clous G, Bradley J, et al, and the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group: Double-blind, placebo-controlled trial of pleconaril in infants with enterovirus meningitis, Pediatr Infect Dis J 22:335-341, 2003. Johnson RT: Viral infections of the nervous system, ed 2, New York, 1998, Lippincott-Raven. Romero JR: Pleconaril: a novel antipicornaviral drug, Exp Opin Invest Drugs 10:369-379, 2001. Ropka SL, Jubelt B: Enteroviruses. In Nata A, Berger JR, editors: Clinical neurovirology, New York, 2003, Marcel Dekker, 359-377.
and by corneal transplantation. After inoculation of rabies virus into muscles or subcutaneous tissues, there may be amplification of the virus in muscle at the site of exposure, accounting for the long incubation period. Rabies virus binds to the muscarinic acetylcholine receptor and spreads within axons of peripheral nerves by retrograde fast axonal transport at a rate of about 50 to 100 mm per day and reaches the spinal cord and brain and disseminates throughout the CNS along neuroanatomic pathways. Rabies virus replicates in neurons and causes neuronal dysfunction by uncertain mechanisms, which is likely responsible for the clinical features and fatal outcome of the disease. Behavioral changes occur in rabies, which leads to transmission by biting in infected animals. There is centrifugal spread of the virus from the brain to the salivary glands, which is important for transmission of virus in rabies vectors. Rabies virus may be present in an animals saliva before the onset of symptoms or signs of rabies.
Clinical Manifestations
There is usually an incubation period after an exposure lasting between a few days to a year or more (usually 20 to 90 days). Early symptoms of rabies are nonspecific and include headache, malaise, anorexia, and nausea. The earliest neurologic symptoms are paresthesias, pain, or pruritus at the site of the wound, which may have healed. There are two clinical forms of rabies: a classic or encephalitic form in 80% and a paralytic form in 20% of patients. In classic rabies there are periods of hyperexcitability lasting minutes separated by lucid periods. Autonomic dysfunction, including hypersalivation, gooseflesh, cardiac arrhythmias, and priapism in males, is common. Fever is usually present. Up to half of patients have hydrophobia, with spasms of pharyngeal and inspiratory muscles, including the diaphragm, on attempts to drink. This becomes a conditioned reflex and even the sight of water may precipitate the spasms. The neurologic illness is progressive, and patients may become comatose and develop failure of multiple organ systems. In paralytic rabies patients develop flaccid weakness that often initially involves the bitten extremity and progresses to weakness of all limbs (quadriparesis) with impairment of bladder function. Paralytic rabies may be misdiagnosed as Guillain-Barr syndrome.

Alan C. Jackson, M.D.
Rabies virus causes an acute infection of the central nervous system (CNS) in humans and animals. Worldwide, more than 50,000 people die of rabies every year, and most cases occur in developing countries with endemic dog rabies. Rabies is prevalent in wildlife in the United States, and the common vectors include bats, raccoons, skunks, and foxes. During the 1990s there was an increase in the number of human cases in the United States, and most cases were due to bat rabies virus variants, especially the silver-haired bat rabies virus. Many of these patients did not present with a history of a bat bite or even contact with bats. Silver-haired bats are small bats, and a bite may not be noticed or may be attributed to an insect.
Diagnosis
Rabies should be strongly suspected if there is a history of an animal bite that is followed by a typical neurologic illness, but patients may develop rabies without a history of an exposure, and in the United States these cases are usually due to transmission from bats. Electroencephalograms and imaging techniques (computed tomography, magnetic resonance) do not show specific findings in rabies. Cerebrospinal fluid may show a mononuclear pleocytosis. Diagnostic tests to confirm rabies include the demonstration of rabies virus antigen in small nerves around hair follicles in skin biopsies
Pathogenesis
Rabies virus is usually transmitted in the saliva of a biting animal, although transmission has rarely been documented from aerosolized virus in caves and laboratories
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usually with an elevated protein and normal glucose. Echovirus but not PV is frequently isolated from the CSF. Both can be detected with PCR techniques. Occasionally virus can be isolated from the stool. TREATMENT Live OPV should not be given to these immunodeficient patients. Currently, this is not a problem in the United States, but it may be in other countries where OPV is still used. Intravenous immunoglobulin (IVIG) for the treatment of the agammaglobulinemia has decreased the occurrence of these infections. However, once infection is established, it is difficult to eradicate it with IVIG. Pleconaril has been used experimentally to treat some of these cases. In one report of 16 patients, 12 improved and 3 stabilized. SUGGESTED READING
Abzug MJ, Clous G, Bradley J, et al, and the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group: Double-blind, placebo-controlled trial of pleconaril in infants with enterovirus meningitis, Pediatr Infect Dis J 22:335-341, 2003. Johnson RT: Viral infections of the nervous system, ed 2, New York, 1998, Lippincott-Raven. Romero JR: Pleconaril: a novel antipicornaviral drug, Exp Opin Invest Drugs 10:369-379, 2001. Ropka SL, Jubelt B: Enteroviruses. In Nata A, Berger JR, editors: Clinical neurovirology, New York, 2003, Marcel Dekker, 359-377.
and by corneal transplantation. After inoculation of rabies virus into muscles or subcutaneous tissues, there may be amplification of the virus in muscle at the site of exposure, accounting for the long incubation period. Rabies virus binds to the muscarinic acetylcholine receptor and spreads within axons of peripheral nerves by retrograde fast axonal transport at a rate of about 50 to 100 mm per day and reaches the spinal cord and brain and disseminates throughout the CNS along neuroanatomic pathways. Rabies virus replicates in neurons and causes neuronal dysfunction by uncertain mechanisms, which is likely responsible for the clinical features and fatal outcome of the disease. Behavioral changes occur in rabies, which leads to transmission by biting in infected animals. There is centrifugal spread of the virus from the brain to the salivary glands, which is important for transmission of virus in rabies vectors. Rabies virus may be present in an animals saliva before the onset of symptoms or signs of rabies.
There is usually an incubation period after an exposure lasting between a few days to a year or more (usually 20 to 90 days). Early symptoms of rabies are nonspecific and include headache, malaise, anorexia, and nausea. The earliest neurologic symptoms are paresthesias, pain, or pruritus at the site of the wound, which may have healed. There are two clinical forms of rabies: a classic or encephalitic form in 80% and a paralytic form in 20% of patients. In classic rabies there are periods of hyperexcitability lasting minutes separated by lucid periods. Autonomic dysfunction, including hypersalivation, gooseflesh, cardiac arrhythmias, and priapism in males, is common. Fever is usually present. Up to half of patients have hydrophobia, with spasms of pharyngeal and inspiratory muscles, including the diaphragm, on attempts to drink. This becomes a conditioned reflex and even the sight of water may precipitate the spasms. The neurologic illness is progressive, and patients may become comatose and develop failure of multiple organ systems. In paralytic rabies patients develop flaccid weakness that often initially involves the bitten extremity and progresses to weakness of all limbs (quadriparesis) with impairment of bladder function. Paralytic rabies may be misdiagnosed as Guillain-Barr syndrome.

Alan C. Jackson, M.D.
Rabies virus causes an acute infection of the central nervous system (CNS) in humans and animals. Worldwide, more than 50,000 people die of rabies every year, and most cases occur in developing countries with endemic dog rabies. Rabies is prevalent in wildlife in the United States, and the common vectors include bats, raccoons, skunks, and foxes. During the 1990s there was an increase in the number of human cases in the United States, and most cases were due to bat rabies virus variants, especially the silver-haired bat rabies virus. Many of these patients did not present with a history of a bat bite or even contact with bats. Silver-haired bats are small bats, and a bite may not be noticed or may be attributed to an insect.
Diagnosis
Rabies should be strongly suspected if there is a history of an animal bite that is followed by a typical neurologic illness, but patients may develop rabies without a history of an exposure, and in the United States these cases are usually due to transmission from bats. Electroencephalograms and imaging techniques (computed tomography, magnetic resonance) do not show specific findings in rabies. Cerebrospinal fluid may show a mononuclear pleocytosis. Diagnostic tests to confirm rabies include the demonstration of rabies virus antigen in small nerves around hair follicles in skin biopsies
Pathogenesis
Rabies virus is usually transmitted in the saliva of a biting animal, although transmission has rarely been documented from aerosolized virus in caves and laboratories
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Viral Infections
taken from the nape of the neck (rich in hair follicles) and in corneal impression smears. Rabies virus RNA may be detected in saliva, cerebrospinal fluid, brain tissue, or skin biopsies using polymerase chain reaction amplification. Brain biopsies are performed only infrequently, and brain tissue may show characteristic pathologic changes with cytoplasmic inclusions called Negri bodies, rabies virus antigen in neurons, and infectious rabies virus that can be cultured. Serum neutralizing antibodies do not usually appear until after the first week of clinical illness and are not useful in patients who have been immunized.
Did the animal bite the patient or did saliva contaminate a scratch, abrasion, open wound or mucous membrane? Yes Is rabies known or suspected to be present in the species and the geographic area? Yes
No
Rabies prophylaxis None
No None
No
Treatment
Treatment of rabies is supportive since no antiviral or immunotherapy therapy is effective. Survival has been reported in only six patients, and five received rabies vaccine prior to the onset of their neurologic disease. Intensive care has prolonged survival in patients with rabies. Barrier techniques, including the use of gowns, gloves, and masks, should be practiced when caring for patients with suspected rabies because of a theoretical risk of transmission. Health care workers may require postexposure prophylaxis (PEP) after high-risk contact with a patient with rabies.
Was the animal captured? Yes Was the animal a normally behaving dog, cat, or ferret? No Does laboratory examination of the brain by fluorescent antibody staining confirm rabies? Yes Yes
RIG and vaccine
Does the animal become ill under observation over the next 10 days? Yes
No None
None No RIG and vaccine
Prevention
Rabies can be prevented following an exposure if current guidelines, which are published in Morbidity and Mortality Weekly Report and available on the Internet at http://www.cdc.gov/mmwr, are carefully followed. A decision to initiate rabies PEP is based on details of the exposure, the species of animal, the animals availability for observation or laboratory testing, and the local epidemiological situation. Algorithms can be helpful in making management decisions concerning rabies PEP (Figure 1). Physicians may need to seek advice from local, state, or federal public health officials for assistance in making decisions about postexposure prophylaxis. Healthy dogs, cats, or ferrets may be closely observed, and if they remain healthy for 10 days, then rabies PEP is not necessary. If the dog, cat, or ferret is unwanted or if signs of rabies are present or develop during observation, the animal should be sacrificed immediately and the head transported under refrigeration for a laboratory examination. The brain should be examined for the presence of rabies virus antigen, which is usually performed with the fluorescent-antibody technique. Since the incubation period is uncertain in animals other than dogs, cats, and ferrets, they should be sacrificed immediately after an exposure, and the head should be submitted for a brain examination. In high-risk exposures, rabies prophylaxis should be initiated prior to obtaining results from a laboratory examination. If the brain examination is negative, then it can be safely concluded that the saliva of an animal did not contain rabies virus. If immunization has been initiated, it can be discontinued after a negative examination. If an
FIGURE 1. Algorithm for rabies postexposure prophylaxis. RIG, Rabies immune globulin. (Adapted from Corey L: Rabies virus and other rhabdoviruses. In Braunwald E, Fauci AS, Kasper DL, et al, editors: Harrisons principles of internal medicine, ed 15, New York, 2001, McGraw-Hill, 1149-1152.)
animal escapes after an exposure, it should be considered rabid unless information from public health officials indicates this is unlikely, and rabies prophylaxis should be initiated. Rodents (squirrels, chipmunks, hamsters, rats, and mice), rabbits, and hares rarely transmit rabies, and their bites do not normally require rabies prophylaxis. Abnormal behavior of animals suggests the possibility of rabies, and the risk is greater with an unprovoked attack than with a provoked attack. A provoked exposure may occur when a person attempts to feed or handle a healthy animal. Local wound cleansing is important to inactivate infectious rabies virus at the site of entry. Cleaning with soap and water is very useful, and the use of virucidal agents is important for deeper wounds. A combination of active and passive immunization should be used in previously unimmunized individuals with a rabies exposure. Five 1-mL doses of rabies vaccine (purified chick embryo cell vaccine, human diploid cell vaccine, or rabies vaccine adsorbed) should be given intramuscularly (IM) in the deltoid muscle (in infants in the anterolateral upper thigh) on days 0, 3, 7, 14, and 28. Pregnancy is not a contraindication for immunization. Live vaccines should not be given for 1 month after immunization. Local reactions (pain, swelling, and
144
itching) and mild systemic reactions (fever, myalgias, headache, and nausea) are quite common. Antiinflammatory and antipyretics can be used, but immunization should not be discontinued. Systemic allergic reactions are uncommon (11 per 10,000 vaccinees). Anaphylactic reactions should be treated with epinephrine and antihistamines. Corticosteroids can interfere with the development of active immunity. The risk of developing rabies should be carefully considered before discontinuing immunization because of an adverse reaction. A serum neutralizing antibody determination is necessary after immunization only if a patient is immunocompromised. In developing countries, alternative rabies vaccines are commonly used that are less expensive. These vaccines, particularly ones derived from neural tissues, are associated with frequent systemic and neurologic reactions. Passive immunization includes administration of 20 IU/kg of human rabies immune globulin (HRIG) on day 0. As much HRIG as anatomically feasible should be infiltrated into and around the wounds, and any remaining volume should be given IM (in the gluteal area or lateral thigh muscles). In the case of an exposure involving a mucous membrane, the entire dose should be administered IM. HRIG should be administered at the same time as rabies vaccine and should not be given more than 8 days after vaccine. They should never be given at the same site or in the same syringe. Side effects of HRIG include local pain and low-grade fever. Persons at risk of acquiring rabies, such as veterinarians, animal handlers, rabies laboratory workers, and certain international travelers, can be protected by immunization with three 1-mL doses of rabies vaccine (preexposure prophylaxis) given on days 0, 7, and 21 or 28. An adequate serum-neutralizing titer should be demonstrated and repeated at intervals of 6 to 24 months, depending on the risk of exposure. Boosters should be given if the titer is inadequate. If a rabies exposure occurs in these individuals, local wound care and two doses of rabies vaccine should be given. The first should be given immediately, and the second should be given 3 days later. Passive immunization (HRIG) should not be given to these patients. SUGGESTED READING
Centers for Disease Control and Prevention: Human rabies preventionUnited States, 1999: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR 48 (No. RR-1):1-21, 1999. Jackson AC: Human disease. In Jackson AC, Wunner WH, editors: Rabies, San Diego, 2002, Academic Press, 219-244. Jackson AC, Warrell MJ, Rupprecht CE, et al: Management of rabies in humans, Clin Infect Dis 36:60-63, 2003. Jackson AC, Wunner WH, editors: Rabies, San Diego, 2002, Academic Press.

Avindra Nath, M.D.
Human immunodeficiency virus (HIV) infection is the most common viral infection of the nervous system. It can affect the entire neuraxis. The nervous system is vulnerable to effects caused directly by invasion by the virus that may occur at any time during the course of the illness, though most commonly seen during the later stages of the disease. Several opportunistic infections can also invade the nervous system. In susceptible individuals early in the course of the illness, several autoimmune illnesses may also occur. Occasionally, patients may have more than one opportunistic infection simultaneously, which may be difficult to diagnose, and the clinician should also be alert to the occurrence of other common diseases that may occur independent of those seen in the setting of HIV infection.
HIV Meningitis
An acute viral meningitis may occur 3 to 6 weeks following primary HIV infection and thus prior to seroconversion. Cerebrospinal fluid (CSF) reveals an increased protein (>100 mg/dL), mononuclear pleocytosis (>200 cells/mm3), increased IgG, oligoclonal bands, and normal or mildly depressed glucose levels. HIV meningitis is typically a self-limited disease. However, when identified, early, aggressive antiretroviral therapy (ART) with central nervous system (CNS)-penetrant antiretrovirals may be warranted, as a window may exist for the substantial reduction of the virus from this compartment. At the least, early treatment may help limit trafficking of virus into the CNS.
HIV Dementia
Early recognition and treatment are key to the prevention of more severe forms of dementia, which may not respond well to treatment. The initial approach to a patient with HIV infection who has cognitive impairment should be to exclude other treatable causes of dementia (Figure 1). Hence investigations should include a careful history for depression, a neuroimaging study, preferably magnetic resonance (MR) imaging, to exclude opportunistic infections, thyroid function test, vitamin B12 levels, and a chemistry and hematology profile. CSF should be evaluated for opportunistic infections and for HIV viral load. A neuropsychological assessment is necessary to get a qualitative and quantitative baseline assessment. The Memorial Sloan-Kettering (MSK) Scale and HIV Dementia Scale (HDS) can be administered in the clinic. Assessment may be necessary for the patients ability to conduct his or her occupation and for
144
itching) and mild systemic reactions (fever, myalgias, headache, and nausea) are quite common. Antiinflammatory and antipyretics can be used, but immunization should not be discontinued. Systemic allergic reactions are uncommon (11 per 10,000 vaccinees). Anaphylactic reactions should be treated with epinephrine and antihistamines. Corticosteroids can interfere with the development of active immunity. The risk of developing rabies should be carefully considered before discontinuing immunization because of an adverse reaction. A serum neutralizing antibody determination is necessary after immunization only if a patient is immunocompromised. In developing countries, alternative rabies vaccines are commonly used that are less expensive. These vaccines, particularly ones derived from neural tissues, are associated with frequent systemic and neurologic reactions. Passive immunization includes administration of 20 IU/kg of human rabies immune globulin (HRIG) on day 0. As much HRIG as anatomically feasible should be infiltrated into and around the wounds, and any remaining volume should be given IM (in the gluteal area or lateral thigh muscles). In the case of an exposure involving a mucous membrane, the entire dose should be administered IM. HRIG should be administered at the same time as rabies vaccine and should not be given more than 8 days after vaccine. They should never be given at the same site or in the same syringe. Side effects of HRIG include local pain and low-grade fever. Persons at risk of acquiring rabies, such as veterinarians, animal handlers, rabies laboratory workers, and certain international travelers, can be protected by immunization with three 1-mL doses of rabies vaccine (preexposure prophylaxis) given on days 0, 7, and 21 or 28. An adequate serum-neutralizing titer should be demonstrated and repeated at intervals of 6 to 24 months, depending on the risk of exposure. Boosters should be given if the titer is inadequate. If a rabies exposure occurs in these individuals, local wound care and two doses of rabies vaccine should be given. The first should be given immediately, and the second should be given 3 days later. Passive immunization (HRIG) should not be given to these patients. SUGGESTED READING
Centers for Disease Control and Prevention: Human rabies preventionUnited States, 1999: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR 48 (No. RR-1):1-21, 1999. Jackson AC: Human disease. In Jackson AC, Wunner WH, editors: Rabies, San Diego, 2002, Academic Press, 219-244. Jackson AC, Warrell MJ, Rupprecht CE, et al: Management of rabies in humans, Clin Infect Dis 36:60-63, 2003. Jackson AC, Wunner WH, editors: Rabies, San Diego, 2002, Academic Press.

Avindra Nath, M.D.
Human immunodeficiency virus (HIV) infection is the most common viral infection of the nervous system. It can affect the entire neuraxis. The nervous system is vulnerable to effects caused directly by invasion by the virus that may occur at any time during the course of the illness, though most commonly seen during the later stages of the disease. Several opportunistic infections can also invade the nervous system. In susceptible individuals early in the course of the illness, several autoimmune illnesses may also occur. Occasionally, patients may have more than one opportunistic infection simultaneously, which may be difficult to diagnose, and the clinician should also be alert to the occurrence of other common diseases that may occur independent of those seen in the setting of HIV infection.
HIV Meningitis
An acute viral meningitis may occur 3 to 6 weeks following primary HIV infection and thus prior to seroconversion. Cerebrospinal fluid (CSF) reveals an increased protein (>100 mg/dL), mononuclear pleocytosis (>200 cells/mm3), increased IgG, oligoclonal bands, and normal or mildly depressed glucose levels. HIV meningitis is typically a self-limited disease. However, when identified, early, aggressive antiretroviral therapy (ART) with central nervous system (CNS)-penetrant antiretrovirals may be warranted, as a window may exist for the substantial reduction of the virus from this compartment. At the least, early treatment may help limit trafficking of virus into the CNS.
HIV Dementia
Early recognition and treatment are key to the prevention of more severe forms of dementia, which may not respond well to treatment. The initial approach to a patient with HIV infection who has cognitive impairment should be to exclude other treatable causes of dementia (Figure 1). Hence investigations should include a careful history for depression, a neuroimaging study, preferably magnetic resonance (MR) imaging, to exclude opportunistic infections, thyroid function test, vitamin B12 levels, and a chemistry and hematology profile. CSF should be evaluated for opportunistic infections and for HIV viral load. A neuropsychological assessment is necessary to get a qualitative and quantitative baseline assessment. The Memorial Sloan-Kettering (MSK) Scale and HIV Dementia Scale (HDS) can be administered in the clinic. Assessment may be necessary for the patients ability to conduct his or her occupation and for
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Viral Infections
Subacute cognitive impairment
MRI
Focal lesions
Diffuse white matter lesions/atrophy
Periventricular enhancement
Meningeal enhancement
Normal
See Figure 3
Likely HIV dementia
Likely CMV encephalitis
Likely cryptococcal or tubercular meningitis
CSF
CSF to rule out opportunistic infections
CSF PCR for CMV
CSF evaluation
Meningitis
Normal
Optimize ART with drugs that penetrate CNS
I.V. ganciclovir or foscarnet
Treat as shown in Table 4
Reinvestigate for other causes of dementia
Monitor plasma viral load and CD4+ cell count
Cognitive improvement
Continued cognitive impairment
Continue current therapy
Repeat MRI and CSF viral load
Normal viral load
Elevated viral load
Reinvestigate for other causes of dementia
Change ART regimen after HIV genotyping
FIGURE 1. Subacute cognitive impairment. CMV, Cytomegalovirus; HIV, human immunodeficiency virus; CSF, cerebrospinal fluid; PCR, polymerase chain reaction; ART, antiretroviral therapy; CNS, central nervous system.
the ability to drive and other psychosocial issues. Occupational therapists and social workers may assist with these assessments. In patients with progressive dementia, medicolegal issues such as establishing a power of attorney, completing a living will, and arranging for the dispersal of assets should be discussed at any early stage before the dementia becomes too severe. Pharmacologic intervention is challenging in patients with HIV infection. Tight control of viral load is necessary to prevent drug resistance and for treatment of dementia. However, patients with cognitive abnormalities may not remember to take their medications or realize the importance of drug adherence. Hence a system needs to be in place for maintaining drug adherence and
for assisting patients to keep regular clinic appointments. Techniques for improving adherence include directly observed therapy, pill counts, intensive education, and electronic monitors. Periodic viral loads and neuropsychological assessments may be needed to determine the effect of treatment. Other factors that may affect compliance with medications include pill burden, side effects, frequency of administration, and cost of therapy. Usage of combination pills and once-daily therapy if and when possible would greatly improve compliance. Drug side effects may also affect compliance. Although aggressive ART is the current approach to treating HIV dementia, it is also realized that some additional neuroprotective
146
therapy may be needed as well. Unfortunately, despite several clinical trials over the years, currently there is no single agent that has shown a clear benefit. In two small studies selegiline has showed some promise, and a larger phase II trial is currently under way using a transdermal form of the drug. The current approach is to hit early, hit hard. The wider availability of multiple, potent antiretroviral regimens can be combined in a variety of ways to provide effective suppression of HIV replication. Periodic follow-up should include monitoring the response to therapy through measurement of plasma HIV RNA levels and CD4+ cell counts. In addition, resistance to antiretrovirals can now be relatively easily measured with genotypic or phenotypic assays. In patients who fail to achieve HIV suppression with ART, it is often uncertain whether this reflects development of resistance, incomplete adherence, or inadequate delivery of antiretroviral agents to the target site. This is potentially of even greater importance for the treatment of CNS infection given the relatively limited penetrance of most of the available antiretroviral agents. Thus patients who progress neurologically despite good control of the virus peripherally should have repeat CSF evaluation with viral load in the CSF. Achieving control of the virus in CNS compartments is essential because patients who do not show CSF HIV RNA decreases may not have neuropsychological improvement. A typical antiretroviral regimen consists of at least three agents: one or two protease inhibitors or a nonnucleoside reverse transcriptase inhibitor (non-NRTI) combined with two nucleoside analogs. The goal of therapy is to reduce measurable plasma viral burden to below the level of detection. Viral load testing has made it possible to individualize therapy and to more accurately determine the best time to initiate or change therapy, long before declining CD4+ counts would have given evidence of active viral replication. The published pharmacokinetic data for CSF penetration for available agents are shown in Table 1. As a class, NRTIs can cause mitochondrial toxicity leading to lactic acidosis. Symptoms include fatigue, nausea, vomiting, abdominal pain, dyspnea, and weight loss. The NRTI should be discontinued if lactic acidosis is present with clinical symptoms. Peripheral neuropathies may occur. This is also likely due to mitochondrial toxicity, but the pathogenesis remains uncertain. Protease inhibitors can cause lipodystrophy that manifests as hyperlipidemia with risk of atherosclerosis; insulin resistance; fat redistribution with accumulation in abdomen, dorsal neck, and breasts; and fat atrophy in the face, extremities, and buttocks. Although fat redistribution is cosmetic, hyperlipidemia and diabetes should be managed as for that in non-HIV infected patients. Drug interactions involving antiretroviral agents have become increasingly important with the introduction of combination therapy involving protease inhibitors and non-NRTIs (http://aidsinfo.nih.gov/drugs) (Table 2). One of the most widely used protease inhibitor combinations uses this interaction to boost levels of lopinavir in combination with low-dose ritonavir. All protease
inhibitors are substrates and inhibitors of the hepatic cytochrome P-450 enzyme system. Ritonavir is the most powerful inhibitor, saquinavir the weakest, and indinavir and nelfinavir are intermediate. Examples of drug interactions arising from inhibition of cytochrome P-450 include the increases in rifampin and rifabutin levels with ritonavir and, to a lesser degree, with the other protease inhibitors. Some protease inhibitors are also inducers of cytochrome P-450. An example of this type of interaction is the lowering of ethinyl estradiol, triptans, (sildenafil), and zidovudine levels by nelfinavir and ritonavir. Dual protease inhibitor regimens make use of drug interactions to increase drug levels and/or prolong half-lives. Ritonavir increases saquinavir levels by more than 10-fold, allowing saquinavir to be given at a reduced dose twice daily. Nelfinavir also increases saquinavir levels, but the effect is less dramatic and does not allow dose reduction. Ritonavir also increases drug levels of nelfinavir and indinavir. The non-NRTIs are also metabolized through the CYP3A pathway, leading to significant drug interactions with protease inhibitors. Nevirapine induces cytochrome P-450 enzymes, leading to reductions in protease inhibitor levels. In contrast, delavirdine inhibits cytochrome P-450 and increases protease inhibitor levels. With both drugs, the effect is greatest with saquinavir, intermediate with indinavir, and negligible with ritonavir. There are conflicting data on drug interactions between nevirapine and nelfinavir. Efavirenz is both a modest inhibitor and a modest inducer of the cytochrome P-450 system. Although it decreases indinavir levels and reduces saquinavir levels by 61%, it increases the area under the plasma concentration-time curve (AUC) of nelfinavir by 20%. Of importance to neurologists are the anticonvulsants. Drugs such as phenytoin, carbamazepine, and phenobarbital should be used with caution and, if used, drug levels and viral loads should be closely monitored. Alternative anticonvulsants such as topiramate and gabapentin may be considered. Protease inhibitors may also induce withdrawal symptoms in patients on methadone. At this point, it is impossible to make definitive recommendations about the optimum ART for HIV dementia. Stavudine and abacavir appear to be useful alternatives to include in a combination regimen for patients with dementia, based on their pharmacokinetic properties, tolerability, and twice-daily dosing. Stavudine may have a role in treating neurologic disease based on favorable pharmacokinetic studies in CSF. The NRTI nevirapine and protease inhibitor indinavir achieve good CSF levels and may also be useful to include in ART regimens for patients with HIV dementia, based on accumulating clinical experience. Difficulties with ART of HIV dementia include the following: Drug resistance The role of resistance testing may become important in selection of ART combinations for demented patients, most of whom are heavily pretreated and are likely to have multiple resistance mutations (as in the abacavir trial where 90% of subjects had resistance mutations at baseline). There is no additional benefit of examining resistance patterns in
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Viral Infections
TABLE 1 Antiretroviral Drugs: Generic and Trade Names, Characteristics

Generic Name Zidovudine Didanosine Trade Name Retrovir Videx Usual Dosage 300 mg bid 200 mg bid (125 mg bid if <60 kg) or 300-400 mg qd 0.75 mg tid 40 mg bid (30 mg bid if <60 kg) 150 mg bid 300 mg bid 60-120 mg qd 200 mg qd for 14 days, then 200 mg bid 400 mg tid 600 mg qd 1000 mg bid with ritonavir 100 mg bid 1200 mg tid 800 mg q 8 hr 600 mg bid 750 mg tid or 1250 mg bid 1200 mg bid 400 mg qd 1400 mg bid 90 mg SQ q12 hr Common Side Effects (Comments) Bone marrow suppression, GI upset, headache, myopathy Peripheral neuropathy, pancreatitis, diarrhea (take on empty stomach) Peripheral neuropathy, pancreatitis, oral ulcers Peripheral neuropathy Anemia, GI upset GI upset, hypersensitivity reaction GI upset, elevated transaminases, nephrotoxicity (must take with L-carnitine 500 mg/day Rash Rash Dizziness, nightmares, disconnectedness, rash (take with a fatty meal, or up to 2 hours after meal) CSF-toPlasma Ratio 0.3-1.3 0.2
Drug Class Nucleoside RT inhibitor Nucleoside RT inhibitor
Abbreviation AZT, ZDV ddI
Zalcitabine Stavudine Lamivudine Abacavir Adefovir Nevirapine Delavirdine Efavirenz Saquinavir
Nucleoside RT inhibitor Nucleoside RT inhibitor Nucleoside RT inhibitor Nucleoside RT inhibitor Nucleotide RT inhibitor Non-nucleoside RT inhibitor Non-nucleoside RT inhibitor Non-nucleoside RT inhibitor Protease inhibitor
ddC d4T 3TC ABC ADV NVP DLV EFV SQV
HIVID Zerit Epivir Ziagen Preveon Viramune Rescriptor Sustiva Invirase Fortovase Crixivan Norvir Viracept Agen erase Reyataz Lexiva Fuzeon
0.1-0.4 0.2 0.1 0.3
0.5 <0.05 <0.05 <0.05
Indinavir Ritonavir Nelfinavir Amprenavir Atazanovir Fosamprenavir Enfuvirtide
Protease inhibitor Protease inhibitor Protease inhibitor Protease inhibitor Protease inhibitor Protease inhibitor Fusion inhibitor
IDV RTV NFV APV ATV FPV ENF
Kidney stones, hyperbilirubinemia (take on an empty stomach) GI upset, circumoral paresthesias, diarrhea, fatigue Diarrhea (take with food) Rash, headache, GI upset GI upset, prolongation of QTc, no hyperlipidemia Rash, GI upset, headache, hepatitis Site reactions, bacterial pneumonia
0.14 <0.05 Undetectable <0.05 Unknown Unknown Unknown
RT, Reverse transcriptase; GI, gastrointestinal; CSF, cerebrospinal fluid.
CSF because there is generally concordance between the CSF and plasma with respect to major genotypic resistance mutations. Drug adherence Adherence is important in maintaining virologic suppression, particularly in patients with cognitive impairment. New techniques for improving adherence, including directly observed therapy, pill counts, intensive education, and electronic monitors, are being applied to this problem. Patients with HIV dementia are extremely susceptible to the adverse effects of psychoactive drugs, so
hypnotics and anxiolytics should be avoided. Due to its selective action on D3 and D4 receptors, clozapine is the preferred neuroleptic. Small doses of neuroleptics such as haloperidol (Haldol), 0.5 mg, may be needed in the agitated or combative patient. In patients with HIV dementia and depression, tricyclic antidepressants or fluoxetine (Prozac) can be tried in doses 25% to 50% of the usual dose. Full doses of tricyclic antidepressants may precipitate delirium, and serum levels should be monitored frequently. If seizures are present, gabapentin and topiramate are the preferred anticonvulsants due to lack of drug-drug interactions.
148
TABLE 2 Drugs That Should Be Avoided with Protease Inhibitors*

Drug Category Analgesics Antimycobacterial Indinavir None Rifampin Ritonavir Meperidine, piroxicam, propoxyphene Rifabutin Saquinavir None Rifampin, rifabutin Nelfinavir None rifampin Alternative(s) Acetylsalicylic acid, oxycodone, acetaminophen For rifabutin (as alternative for Mycobacterium aviumintercellulare treatment): clarithromycin, ethambutol (treatment, not prophylaxis), or azithromycin Loratadine Limited experience Fluoxetine, desipramine Limited experience Temazepam, lorazepam
Antihistamine Gastrointestinal agent Antidepressant Neuroleptic Psychotropic
Astemizole, terfenadine Cisapride None None Midazolam, triazolam
Astemizole, terfenadine Cisapride Bupropion Clozapine, pimozide Clorazepate, diazepam, estazolam, flurazepam, midazolam, triazolam, zolpidem Dihydroergotamine ergotamine (various forms) Desipramine increased 145%: reduce dose Theophylline levels decreased: dose increase
Astemizole, terfenadine Cisapride None None None
Astemizole, terfenadine Cisapride None None Midazolam, triazolam
Ergot alkaloid Miscellaneous
Dihydroergotamine ergotamine (various forms) Grapefruit juice reduces indinavir levels by 26%
Dihydroergotamine ergotamine (various forms) Grapefruit juice increases saquinavir levels
Dihydroergotamine, ergotamine (various forms)
Limited experience
*The contraindicated drugs listed are based on theoretical considerations based on major metabolic contribution from cytochrome P450 3A, CYP2D6, or unknown pathways. Actual interactions may or may not occur in patients. Reduce rifabutin dose to one quarter of the standard dose (150 mg qod). This is likely a class effect.
Valproate should be particularly avoided because in vitro studies suggest that it can induce viral replication. Intractable vascular headaches may develop in some HIV-infected patients. Initial treatment should include migraine prophylaxis. Nonresponders may require treatment with opiates. Parkinsonism may be part of the symptom complex of HIV dementia. Dopamine agonists may be used for patients that manifest parkinsonism. However, the response is usually poor.
HIV Myelopathy
HIV myelopathy is also termed vacuolar myelopathy, and it an uncommon manifestation of HIV infection seen in terminal stages of the illness when it may be
accompanied by HIV dementia or neuropathy, which may make it difficult to diagnose. The presence of brisk reflexes, increased muscle tone of lower extremities, and symptoms of a spastic bladder may prompt the diagnosis, which may be confirmed by abnormal somatosensory evoked potentials. CSF is not diagnostic, and MR scanning is necessary to exclude other causes of a myelopathy. There is no definitive treatment for this condition. Supplementation with vitamin B12 is ineffective in improving the symptoms or delaying its progression. Nevertheless, it is commonly administered to patients with clinical evidence of HIV myelopathy. Corticosteroids and intravenous (IV) gamma globulin have also been ineffective in uncontrolled clinical experience. To date, there has been no controlled study describing the effect of highly active antiretroviral therapies (HAART) on the clinical manifestations or electrophysiologic
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Viral Infections
measures of vacuolar myelopathy. The effect of combination antiretroviral drugs, HAART, in improving the symptoms or slowing the progression of HIV myelopathy is therefore not known. Recently there have been attempts to treat the possible underlying metabolic disorder. A pilot study using high doses of oral L-methionine led to improvement in clinical and electrophysiologic features of the disease in an open-label clinical trial. Symptomatic treatment is obviously indicated for patients with spasticity and urinary dysfunction.
several days to weeks before an adequate response is achieved. Desipramine and amitriptyline at doses of up to 150 mg/day can be used. In general, the dosages of the anticonvulsants used for pain control may be lower than those used for seizure control. Gabapentin is an attractive therapy for painful neuropathy due to its favorable pharmacokinetic profile and sparse drug-drug interactions, although it has not been studied in controlled trials in HIV neuropathy. Topical agents such as lidocaine patches are also effective adjuncts; adequate relief requires continuous use for several days.
Distal Sensory Polyneuropathy

Distal sensory polyneuropathy (DSP) can occur due to HIV infection alone or may be caused by the use of some NRTI drugs. The clinical features of DSP caused by HIV or the NRTIs are indistinguishable. Hence the need for NRTIs in a patient with DSP needs to be carefully evaluated. Often dose reduction can be achieved without compromising virologic control. The mainstay in the management of DSP is symptomatic treatment, with adequate pain control (Figure 2). Patients may initially be treated with nonopioid analgesics such as acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID); however, generally the response to these drugs is poor in this patient population. Although the use of opiates is appropriate in view of the severity of the pain, the use of these drugs poses unique challenges, since often HIV-infected patients have a history of drug abuse. Neuromodulatory drugs such tricyclic antidepressants (e.g., amitriptyline, nortriptyline) and anticonvulsants (e.g., lamotrigine, gabapentin, topiramate, diphenylhydantoin, carbamazepine) may be effective in controlling neuropathic pain (Table 3); however, dosage needs to titrated gradually to avoid side effects, and it may take
FIGURE 2. Management of distal symmetrical peripheral neuropathies with human immunodeficiency virus infection. NRTI, Nucleoside reverse transcriptase inhibitor; ART, antiretroviral therapy. (Modified from Bartlett JG, Gallant JE, editors: Medical management of HIV infection, 2003 edition, Baltimore, 2003, Johns Hopkins University Press.)
Mononeuritis Multiplex
Early mononeuritis multiplex may resolve spontaneously within several months. In cases of delayed or incomplete recovery, corticosteroids, plasmapheresis, or IV immunoglobulins may be indicated. Mononeuritis multiplex can also occur with hepatitis B and C due to associated cryoglobulinemia. Deposition of immune complexes or cryoglobulins in the vasa nervosa leads to focal infarcts of the nerves often manifesting as wristdrop or footdrop or cranial nerve involvement. In lateonset mononeuritis multiplex occurring in advanced HIV infection, empirical therapy for cytomegalovirus (CMV) should be considered.
Inflammatory Demyelinating Neuropathy

Two major forms of inflammatory demyelinating polyneuropathy (IDP) may occur. The acute type, with rapidly progressive ascending weakness, minor sensory
Pain, paresthesia or numbness in feet, hyperesthesia, decreased pain or vibration and diminished ankle jerk
Diagnosis established
Nerve conduction velocities and electromyography to detect axonal neuropathy
NRTI therapy (ddC, ddI, d4T)
Skin biopsy for quantification of nerve endings
Evaluate for; Other neurotoxic drugs (INH, B6, metronidazole, dapsone) Alcoholism Diabetes B12 deficiency
Alter ART regimen
Symptoms resolve
Symptoms persist
Diagnosis established: treat accordingly Johnson: Current Therapy in Neurologic Disease (7/E)
No diagnosis and CD4+ count <300/mm3
Avoid tight footware, soak feet in ice water + symptomatic pharmacological therapy (Table 4)
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TABLE 3 Common Drugs Used in the Treatment of Distal Sensory Polyneuropathy

Class/Drug Nonprescription analgesics Nonsteroidal anti-inflammatory drugs Acetaminophen Tricyclic antidepressants Amitriptyline Nortriptyline Anticonvulsants Gabapentin Lamotrigine Topical analgesics Lidocaine patch Capsaicin 0.075% Narcotic analgesics Oxycodone Morphine Fentanyl patch Dosage Variable, depending on the agent 500-1000 mg q 4-6 hr 25-150 mg qhs 10-100 mg qhs 300-1200 mg tid 200-250 mg bid (after slow escalation) 1-3 patches to affected areas bid Apply on affected areas bid 1 or 2 tablets q 4-6 hr Variable depending on the pain intensity Variable, usually start at 25 g/hr q 72 hr
symptoms, and generalized areflexia, is referred to as acute IDP (also called Guillain-Barr syndrome). The chronic, more slowly progressive, monophasic, or relapsing form is chronic IDP. A lymphocytic pleocytosis (10 to 50 cells/mm3) in the CSF in HIV-infected patients with IDP helps distinguish HIV-infected from seronegative individuals. In fact, the presence of CSF lymphocytes greater than 5/mm3 in this setting should raise suspicion of undiagnosed HIV infection. Electrophysiologic findings in HIV-related IDP are similar to those in HIV-uninfected patients. Case series have shown a positive response of HIV-related IDP to immunomodulating therapy, such as corticosteroids, high-dose IV immunoglobulins (0.5 to 1 gm/kg for 2 days), and plasmapheresis (four or five exchanges). In advanced HIV infection, therapy against CMV may be indicated.
light-headedness, syncope, diarrhea, impotence, or urinary disturbance. Management of autonomic neuropathy is mainly supportive. It includes recognition and discontinuation of offending medications, correction of fluid and electrolyte imbalance, use of compressive stockings and abdominal binders, liberal salt intake, and reconditioning exercises, as well as maneuvers such as squatting and standing with crossed legs. In severe cases, pharmacologic agents such as fludrocortisone, midodrine, and antiarrhythmic agents may be needed. Treatment of impotence may require pharmacologic intervention with sildenafil or tadalafil. In some cases, surgical intervention may be needed. In these patients, safe sex practices should be advocated.
Progressive Polyradiculopathy
Progressive polyradiculopathy (PP) occurs most commonly in advanced HIV infection, with CD4+ cell counts less than 50 cells/mm3 but is rarely seen in the HAART era. PP is characterized clinically by the rapid onset of radicular pain and paresthesias in a cauda equina distribution, followed by signs of progressive involvement of multiple nerve roots, usually lumbar and sacral. Clinical signs include flaccid paraparesis, sphincter dysfunction, and lower extremity areflexia. CMV is the major cause of PP in patients with acquired immunodeficiency syndrome (AIDS), although less common causes include neurosyphilis and lymphomatous meningitis. Case series have reported improvement of CMV-associated PP with antiviral therapy, including ganciclovir, valganciclovir, foscarnet, and cidofovir.
Diffuse Infiltrative Lymphocytosis Syndrome

Infiltration of CD8+ lymphocytes in nerves may occur as part of a more systemic involvement involving multiple organs. Often there is associated involvement of the parotid glands resulting in sicca syndrome. Involvement of the nerves can clinically resemble mononeuritis multiplex, distal sensory neuropathy, or an inflammatory demyelinating neuropathy.
HIV Myopathy
A proximal myopathy may occur in some patients with HIV infection owing to polymyositis or toxicity of zidovudine. Muscle biopsy may be needed to differentiate the two. Recently another severe, rapidly progressive neuromuscular weakness syndrome has been described likely secondary to stavudine. Withdrawal of the offending agent may be useful in some. In patients with polymyositis, corticosteroids may provide benefit, but they should be used with caution because of the immunosuppressant effects. Although IV immunoglobulins may be an alternative option without risk of
Autonomic Neuropathy
Although frequently found by formal testing, autonomic neuropathy is an uncommon symptomatic manifestation of HIV infection. Patients may complain of
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Viral Infections
immunosuppression, there is only limited reported experience in HIV myopathy.
Other Autoimmune Diseases

Several autoimmune diseases such myasthenia gravis, polymyositis, multiple sclerosis, and acute inflammatory demyelinating neuropathy may occur in susceptible individuals that get unmasked early in the course of the illness, when a polyclonal gammopathy is present. As immunosuppression occurs, the diseases go into spontaneous remission. However, these manifestations may require disease-specific treatment, in which case the treatment strategy should be similar to that used in HIV-seronegative patients.
Toxoplasma Encephalitis
Toxoplasma encephalitis is the most common cause of cerebral brain abscess in patients with HIV infection, often occurring in patients with CD4+ cell counts of less than 100 cells/mm3; hence, patients who have multiple brain abscesses and are seropositive for Toxoplasma can be empirically treated for toxoplasmosis (Table 4). Patients with single brain lesions or who are seronegative for Toxoplasma gondii should undergo brain biopsy for confirmation of the diagnosis (Figure 3). Initial therapy includes sulfadiazine with pyrimethamine for 3 to 6 weeks with a repeat MR scan at 2 weeks post-therapy to monitor regression in size of abscesses, since a radiologic response may predate a change in clinical status. Sulfadiazine is the sulfonamide of choice. It is highly protein bound with good penetration into the CSF and other tissues. Unfortunately, hypersensitivity is a common side effect with prolonged treatment that is more frequently observed in HIV-infected patients than in other populations. Pyrimethamine is well absorbed and has a variable half-life from 1 to 4 days. The CSF levels of the drug are about one fifth of the serum levels. A small
starting dose for toxoplasmosis is recommended in patients with convulsive disorders to avoid the potential nervous system toxicity of pyrimethamine. This drug should always be used in conjunction with folinic acid to counterbalance the antifolate effects of the drug. In patients allergic to sulfonamides, clindamycin with pyrimethamine may be used. Clindamycin is less effective than sulfadiazine but better tolerated. Clindamycin is highly lipid soluble and highly protein bound. It has good penetration into the eye and dense tissues, such as bone. Its penetration into the CSF is poor; hence, it is used as a drug of second choice. Although less well studied, several other alternative regimens have been used that include either sulfadiazine or pyrimethamine in conjunction with one of the following: azithromycin, 900 to 1200 mg/day; atovaquone, 1500 mg twice daily; minocycline, 150 to 200 mg twice daily; or doxycycline, 300 to 400 mg/day. Clarithromycin 500 mg twice daily can be used as an add-on drug to these regimens if needed. A fundamental problem in the treatment of Toxoplasma infection is that chemotherapy targets the actively growing tachyzoite but has limited effects on the slow-growing bradyzoite. As a consequence, even prophylactic treatment in immunocompromised individuals is aimed at arresting tachyzoites should reactivation occur. Maintenance therapy should be continued indefinitely or until CD4+ counts are greater than 200 cells/mm3 for 6 months. In pregnant women, because of the low incidence of cerebral toxoplasmosis during pregnancy and the possible teratogenicity associated with pyrimethamine treatment, chemoprophylaxis with pyrimethamine-containing regimens can reasonably be deferred until after pregnancy.
Cryptococcus Meningitis
Cryptococcus is the most common cause of meningitis in HIV-infected populations in Western Europe and North America. Patients typically present with headache, fever, seizures, or altered sensorium. Symptoms may be
TABLE 4 Treatment of Cerebral Toxoplasmosis

Drug Sulfadiazine Mechanism of Action Inhibits de novo synthesis in microorganisms that are obliged to make their own folic acid Inhibits the microbial dihydrofolate reductase Inhibits protein synthesis in parasite ribosomes Dosage 1000-1500 mg q 6 hr Major Side Effect(s) Hypersensitivity, lupus, polyarteritis nodosa, myocarditis Bone marrow suppression Diarrhea due to suppression of normal flora Drug Interactions Increase levels of warfarin, barbiturates, hydantoins, sulfonylureas, tolbutamide, and uricosuric agents Increase in sulfadiazine levels with thiazides, indomethacin, probenecid, and salicylates Synergizes with sulfadiazine on Toxoplasma, with 10-fold greater activity than that expected with the drugs together Enhances the action of neuromuscular blocking agents
Pyrimethamine
Clindamycin
200 mg loading dose, 50-75 mg/ day + folinic acid 10-20 mg/day 600 mg q 6 hr
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Subacute onset of neurologic symptoms with focal lesion on MRI
Single lesion
Multiple lesions
FIGURE 3. Subacute onset of neurologic symptoms with focal lesion on MR imaging. SPECT, Single-photon emission computed tomography; PCNSL, primary central nervous system lymphoma; XRT, radiation therapy; CSF, cerebrospinal fluid; JCV, JC virus; PCR, polymerase chain reaction; ART, antiretroviral therapy.
SPECT scan
Enhancing
Non-enhancing
uptake
uptake
Toxoplasma titer in serum
Edema
No edema
Likely tumor
Abscess or necrotic lymphoma
Negative
Positive
Biopsy
CSF for JCV PCR
Biopsy center of lesion
Biopsy edge of lesion
Biopsy
Treat for toxoplasmosis
Negative
Positive
If PCNSL, treat with XRT
Repeat MRI in 10 days
Aggressive ART
No improvement
Improvement
Biopsy
Continue maintenance therapy
mild; hence a high level of suspicion is necessary. Since the infection occurs in the setting of advanced immunosuppression, meningeal signs may be absent and CSF may show only a mild mononuclear pleocytosis (5 to 100 cells/mL) with mild elevation in protein (50 to 150 mg/dL). However, the organism can be seen by India ink staining in 60% to 80% patients, and cryptococcal antigen and cultures are positive in nearly all patients. MR imaging of the brain may be normal or may show some meningeal enhancement. Management of intracranial pressure is critical in these patients and may require daily spinal punctures for drainage or the placement of a CSF drain or even a ventriculoperitoneal shunt. The aim is to maintain CSF pressures below 200 mm H2O. Pharmacologic therapy includes an induction phase of amphotericin B (0.7 mg/ kg/day IV; i.e., nearly twice the dosage used for non-HIV patients) in combination with flucytosine (Table 5). The duration of treatment may be for as little as 2 weeks if (1) a lumbar puncture is performed documenting negative CSF fungal cultures and (2) if followed by at least 10 weeks of high-dose fluconazole (400 to 800 mg daily orally) maintenance therapy. This is followed by a
prolonged maintenance course of fluconazole 200 mg daily orally for 6 months and then may be discontinued if CD4+ cell counts are greater than 200 cells/mm3. Patients with significant renal insufficiency or who are receiving other nephrotoxic agents should likely be treated with a liposomal preparation of amphotericin B (3 to 5 mg/kg daily IV). This formulation of amphotericin B is much more expensive than the conventional formulation. Premedication with acetaminophen or meperidine may decrease infusion-related untoward effect. Flucytosine should also be used with caution in patients with renal impairment. Dosage should be adjusted for renal insufficiency, and drug levels should be monitored to ensure appropriate dosing. Owing to the rapid development of resistance when used as monotherapy, this drug should not be used as the sole agent to treat cryptococcal disease. Hydrocephalus is a well-documented late sequela of cryptococcal meningitis, even after lasting sterilization of the CNS. New or progressive neurologic signs after successful treatment of cryptococcal meningitis should be evaluated with brain imaging to monitor for the development of hydrocephalus. If hydrocephalus is present, permanent shunt placement may be required.
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Viral Infections
TABLE 5 Drugs Used for Management of Neurologic Cryptococcus Meningitis in HIV-Infected Patients
Drug Amphotericin B Dosage 0.7 mg/kg/day IV for 2 wk Monitor electrolytes Major Side Effects Infusion-related erythema (red man syndrome), rigors, fever, decreased renal function, hypokalemia, hypomagnesemia Rarely, renal tubular acidosis, hypotension Bone marrow suppression, azotemia Rarely, causes severe hepatitis/ hepatic failure Hair loss with prolonged therapy Rarely, severe hepatic toxicity or severe exfoliative dermatitis Drug Interactions Use with caution with other nephrotoxic drugs
Flucytosine Fluconazole
100 mg/kg/day PO in four divided doses for 2 wk Initially 400-800 mg/day PO for 10 wk followed by 200 mg/day for at least 6 mo
Itraconazole
200-400 mg/day Oral absorption requires gastric acidity, so must be taken with meal or acidic beverages
Nausea, vomiting, rash, edema, headache Uncommonly, severe hepatic dysfunction, neuropathy, hypertriglyceridemia
Drugs that decrease glomerular filtration may increase serum concentration of flucytosine With warfarin, results in increased prothrombin time Increases half-life of phenytoin, cyclosporine, zidovudine, theophylline, and sulfonylureas Rifampin results in decreased fluconazole levels Contraindicated with terfenadine or astemizole Increases serum levels of cyclosporine and digoxin Level of itraconazole is decreased by phenytoin, rifampin, isoniazid, histamine H2 antagonists, proton pump inhibitors With oral hypoglycemics, may result in severe hypoglycemia
HIV, Human immunodeficiency virus.
Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy usually manifests as focal neurologic deficits over days or weeks in the setting of advanced immunosuppression. MR imaging typically shows multifocal white matter changes without surrounding edema and only rarely does contrast enhancement occur. Pathologic studies show infection by JC virus of oligodendrocytes causing demyelination, and the infected astrocytes assume a characteristic large shape. The prognosis of the illness remains poor and the treatment remains frustrating. To date there are no unequivocally successful therapeutic modalities. Restoration of immune function is likely critical to recovery. ART may be associated with prolonged survival and recovery; hence aggressive HAART therapy is advocated even though the benefit of HAART is not seen universally. Despite anecdotal reports of success, clinical trials with cytarabine (ara-C), vidarabine (araA), camptothecin, cidofovir, and interferons have been disappointing.
Primary CNS Lymphoma

Primary CNS lymphoma occurs in patients with advanced immunodeficiency with CD4+ counts less than 100 cells/mm3. It usually presents as a focal mass but can be multicentric. It is a B cell lymphoma, and the cells are nearly always positive for Epstein-Barr virus. Prominent cerebral edema is seen on MR imaging; hence, the mass effects can be controlled temporarily with dexamethasone 4 mg every 6 hours. The prognosis for survival is poor, but aggressive treatment with whole-brain radiation and optimization of HAART therapy can improve outcome. Use of chemotherapy remains controversial, but if malignant cells are found in the CSF, intrathecal cytosine arabinoside is recommended.
Cytomegalovirus Encephalitis and Radiculitis

Neurologic complications with CMV are uncommon, but due to the rapidity of progression and the poor prognosis untreated, early recognition and intervention are critical. CMV encephalitis presents in the setting of CD4+ counts <50 cells/mm3 with progressive severe dementia and can be confused with HIV dementia. MR imaging may be normal or may show evidence of ventriculitis. CMV radiculopathy presents initially with pain and paresthesias in the saddle distribution because of involvement of the sacral nerves. This may then spread
Cerebellar Atrophy
Cerebellar atrophy is a rare manifestation of HIV infection. Recently, it was demonstrated that there is infection of cerebellar granule cells with JC virus. No specific treatment is available for this entity.
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to involve both lower limbs and be accompanied by flaccid weakness and loss of sphincter tone. MR imaging shows swollen nerve roots with clumping and contrast enhancement in the lumbosacral region. CMV retinitis often accompanies or predates these syndromes; hence a careful ophthalmoscopic evaluation is needed. The clinical picture of a cauda equina syndrome can also be caused by syphilis or metastatic lymphoma. Demonstration of CMV by polymerase chain reaction (PCR) in CSF is diagnostic. However, this is the only viral infection that results in elevated neutrophils in the CSF (>100 cells/mm3). Owing to the poor prognosis for survival of CMV encephalitis and rapid progression of CMV radiculitis, treatment should be initiated while awaiting the CSF results. Combination therapy with ganciclovir (5 mg/kg IV twice a day) and foscarnet (90 mg/kg IV twice a day) for 3 to 6 weeks is recommended. In severe cases, induction therapy may need to be continued for several months, but tolerability is poor. This should be followed by lifelong maintenance therapy with valganciclovir (900 mg/day orally) plus foscarnet. Oral ganciclovir (1000 mg orally three times a day) can also be used, but serum levels are better with valganciclovir. Cidofovir maybe used as an alternate therapy, but there is minimal experience with the use of this drug for neurologic complications of CMV infection. The most important factor is the immune reconstitution with HAART. Electromyography and nerve conduction velocities may be useful in monitoring the response to treatment. They show widespread demyelination and denervation in the lower limbs. Decreased distal latencies suggest axonal involvement. Repeated CSF and MR imaging evaluations may also be needed for monitoring response to therapy. In CMV radiculopathy, clinical improvement is noticed within 2 to 3 weeks of treatment. If relapse occurs after 6 months, the possibility of ganciclovir resistance should be considered.
Neurosyphilis
Neurosyphilis may be a more common and more aggressive complication of syphilis in those infected with HIV. However, the diagnosis and treatment of neurosyphilis in persons infected with HIV are challenging. It may be more difficult to diagnose because, as with neurosyphilis, HIV infection itself may cause CSF pleocytosis or an elevated CSF protein concentration. In addition, retrospective studies suggest that for 23% to 60% of HIV-infected patients, currently recommended neurosyphilis therapy with penicillin G fails. PCR for Treponema pallidum in CSF is inconsistent and may be negative even when CSF VDRL is positive; hence, it is of
limited value as a diagnostic tool. Curiously, despite the associated immunosuppression, serum non-treponemal (VIDRL) titers in HIV-infected individuals with neurosyphilis are typically high, averaging 1:128. In the absence of visible blood contamination in the CSF, a positive CSF VDRL result is specific and establishes the diagnosis of neurosyphilis; however, the sensitivity of CSF VDRL against clinical diagnosis is only 30% to 70%. In contrast, treponemal tests are sensitive, but nonspecific; a negative CSF FTA-abs result virtually excludes the diagnosis of neurosyphilis. It has been suggested that asymptomatic HIV-infected patients be treated for neurosyphilis if they have a positive CSF FTA-abs result and a CSF pleocytosis (>5 white blood cells per cubic millimeter). Whether secondary prophylaxis in the AIDS patient with syphilis needs to be administered, as with Toxoplasma encephalitis and cryptococcal meningitis, remains uncertain. The Centers for Disease Control and Prevention has recommended that the initial therapy of IV aqueous penicillin be followed in HIV-infected individuals by weekly intramuscular injections of 2.4 million units of benzathine penicillin for 3 weeks. The latter component of this regimen fails to achieve treponemicidal levels of penicillin in the CSF. Furthermore, highdose penicillin regimens are not consistently effective in patients infected with HIV. A more logical course may be the administration of a 30-day course of doxycycline 200 mg twice daily, following the completion of IV therapy. Although secondary prophylaxis has been extensively employed, further studies are required before secondary prophylaxis can be widely recommended. It is prudent to carefully monitor HIV-seropositive patients for relapse of neurosyphilis for 2 or more years following initial treatment. Ceftriaxone (2 gm IV once daily for 10 days) may be an alternative to penicillin for treatment of HIV-infected patients with neurosyphilis. Reversion of a reactive CSF VDRL, the decline in a CSF pleocytosis, is probably of greatest diagnostic value in monitoring the success of therapy. The potential for relapse of neurosyphilis following a course of recommended therapy in HIV infection has been largely supported by anecdote but relapse occurs more than 12 months after initial therapy. Lumbar punctures may be repeated at weeks 14 and 26 and at 6-month intervals thereafter for 2 years. As with other opportunistic infections, immune reconstitution should be achieved if possible. SUGGESTED READING
Bartlett JG, Gallant JE, editors: Medical management of HIV infection, 2003 edition, Baltimore, 2003, Johns Hopkins University Press. NeuroAIDS clinical trials http://www.neuro.wistl.edu/narc
SECTION 7
Nonviral Infectious Disease

Allen J. Aksamit, Jr., M.D.
Haemophilus influenzae was the most frequent cause in children who are 3 months to 6 years of age. However, since the advent of the H. influenzae vaccine, incidence has declined. It can also occur in adults, especially if debilitated or with upper respiratory infection. Staphylococcus is especially associated with surgery or trauma. Its presence without that history should suggest a break in the blood-brain barrier or bacteremia. Gram-negative bacteria usually are associated with systemic bacteremia causing the meningitis. Group B Streptococcus is the most common cause of meningitis in newborn infants. Anthrax (Bacillus anthracis) causes hemorrhagic meningitis.
Bacterial meningitis is an acute to subacute purulent infection of the subarachnoid space and spinal fluid pathways, incited by bacterial seeding and growth. Inflammation of the leptomeninges produces the clinical syndrome of headache, fever, and nuchal irritation.
Clinical Aspects
Bacterial meningitis incidence approximates 5 to 10 per 100,000 population per year. Untreated, it is universally fatal. Headache is the usual heralding symptom. Seizures and altered consciousness are also common. Malaise, fever, and chills as a prodrome are followed in 12 to 24 hours by Brudzinskis and Kernigs signs of neck stiffness. Meningeal signs can be absent in elderly, comatose, and immunosuppressed patients. Focal signs are secondary to cerebritis, venous or arterial infarction, subdural empyema, or subdural effusion. Meningitis can manifest with cranial neuropathies, the syndrome of inappropriate antidiuretic hormone or hydrocephalus, as part of the primary inflammatory process.
Diagnosis
Blood cultures (positive in 70%) should be done, as well as cerebrospinal fluid (CSF) cultures. Early treatment determines outcome, so antibiotics should be started after blood cultures are performed, while other diagnostic studies are being undertaken. Computed tomographic or magnetic resonance head scanning is advisable in any patient suspected of having meningitis with focal neurologic signs, to look for brain abscess, subdural empyema, or subdural effusion, which could make lumbar puncture hazardous. The diagnosis of bacterial meningitis rests on spinal fluid bacterial culture or identification of bacterial antigen by latex agglutination. Rapid antigen detection assays for pneumococcus, Haemophilus, meningococcus, and Streptococcus group B are routinely available for spinal fluid. Grams stain should be done in all cases to help guide initial therapy. Spinal fluid abnormalities in bacterial meningitis usually include a protein value greater than 100 mg/dL, spinal fluid glucose level less than 40% of the serum glucose, and nucleated cell count greater than 500/L with a predominance of polymorphonuclear cells. When collecting CSF from the ventricles, some principles need be kept in mind. CSF glucose is always higher in the ventricles than in the lumbar sac (even when infection is present). CSF protein is normally lower in the ventricles than in the lumbar sac. Imaging helps identify patients with acute hydrocephalus, increased intracranial pressure, cerebritis, venous or arterial infarction, subdural empyema, or subdural effusion. 155
Infectious Agents
Pneumococcus (Streptococcus pneumoniae) is the most common cause in adults. Splenectomy and humoral defects are predisposing factors. Penicillin-resistant strains are becoming more common, which influences empirical treatment choices. With meningococcus (Neisseria meningitidis), 50% to 75% of the patients have skin petechiae or purpura, though rarely this sign can be seen with pneumococcus as well. This agent is responsible for 20% to 30% of all cases of meningitis. Peak age of incidence is in the teenage years and young adulthood. It is acquired by respiratory transmission.
156
Pathophysiology
Bacteria may enter the subarachnoid space by a number of different routes. In most cases the bacteria enter the body from the respiratory tract, sometimes infecting only the nasopharynx. The bacteria spread to the meninges by bacteremia. Once in the bloodstream the bacteria probably settle along the walls of the venous sinuses as the result of slow flow. The organisms then penetrate the dura or arachnoid granulations and enter the subarachnoid space. Bacteria may spread to the subarachnoid space from parameningeal infections of the sinuses, mastoids, middle ear, or nasopharynx. Spread from these foci is probably along connecting veins. Bacteria may also be directly implanted into the subarachnoid space in cases of broken barriers. Examples are craniospinal surgery, penetrating injuries, and skull fractures, especially with CSF rhinorrhea or otorrhea. Other predispositions include persistent sinus tracts in the sacrococcygeal or occipital area and foreign bodies such as CSF shunts, Ommaya reservoirs, or ventricular pressure monitors or drains. Once bacteria enter the subarachnoid space, they undergo unrestricted logarithmic growth because of an absence of complement and opsonization in CSF. The presence of bacteria in the subarachnoid space causes surrounding neural tissue damage by endotoxins from the bacteria as well as cytokines released from inflammatory cells. The blood-brain barrier and the blood-CSF barrier are disrupted as cells are recruited from the bloodstream to ingest the bacteria. The inflammatory response may partially block CSF flow and resorption. Cerebral edema occurs as a result of these processes. The limited natural defense against invading bacterial organisms of the leptomeninges and the damage produced by the organisms has led to two rules of treatment. Antibiotics used to treat bacterial meningitis must be bactericidal (capable of destroying bacteria) rather than bacteriostatic (limiting the proliferation of bacteria). The most effective antibiotics penetrate the blood-brain barrier. The levels of antibiotics in the CSF should be 10 times greater than the minimal inhibitory concentration.
the brain, they must pass through the endothelial cell, and such passage is limited by the lipid bilayer of the cell membrane, effects of cytoplasmic enzymes of the endothelial cell, and limited pinocytosis of endothelial cells. Astrocytic foot processes surround the capillaries. Brain endothelial formation of tight junctions is dependent on contact with the astrocyte foot processes. As implied earlier, there is also a barrier between the blood and CSF, the so-called blood-CSF barrier. The choroid plexus and the capillaries of the brain form the CSF. The capillaries of the choroid plexus do not have tight junctions, but the epithelial cells of the surface of the choroid plexus do have tight junctions constituting the blood-CSF barrier. The choroid plexus also actively removes some material from the CSF including the penicillins and aminoglycosides. Fortunately, in meningitis the removal of antibiotics from the CSF is slowed, resulting in higher levels of antibiotics for longer periods. The blood-brain CSF barrier restricts the entry of antibiotics into the brain and CSF. Some drugs pass the barrier better than others do. Most antibiotics permeate the barrier partially broken by meningitis much better than the normal barrier. However, as the meningitis remits and the bloodbrain barrier is repaired, the amount of antibiotic in the CSF will decrease. Also, steroids may partially repair the broken barrier and thus limit the concentration of antibiotics in the CSF (Table 1).
Treatment
To compensate for the limited defenses of the leptomeninges and CSF against bacterial infections, it is preferable to use a bactericidal antibiotic whenever possible. Bactericidal antibiotics include penicillins, cephalosporins, aminoglycosides, and metronidazole. Bacteriostatic antibiotics include chloramphenicol, tetracyclines, erythromycin, and sulfonamides. In selecting an antibiotic to use for the treatment of bacterial meningitis, several factors should be considered, including the concentration of the antibiotic that can be achieved in the CSF in the presence of inflamed meninges. The minimal concentration in micrograms per milliliter necessary to inhibit 90% of bacterial isolates is the minimal inhibitory concentration (MIC). The MIC is used by most experts despite the fact that the minimal bactericidal concentration would theoretically be a better measurement. Most important is the relationship between the obtainable CSF concentration and the MIC, referred to as the inhibitory quotient. The inhibitory quotient should probably exceed 10 to 30 for the treatment of meningitis. In summary, Inhibitory quotient = CSF concentration MIC where CSF concentration and MIC are measured in micrograms per milliliters. The interactions between various drugs must also be kept in mind. Examples of synergism of antibiotics include penicillins and aminoglycosides against enterococci, and carbenicillin or ticarcillin and aminoglycosides against Pseudomonas. Examples of antagonism of
Blood-Brain Barrier
To understand the changes in the CSF and brain in meningitis as well as the complexities of the treatment, one has to understand the blood-brain barrier. This term developed when it was noted that the injection of dyes into the bloodstream would result in the staining of all the organs of the body except the brain. It was reasoned that there had to be some special barrier between the brain and the blood that was not present in other organs. The blood-brain barrier consists of several components. Gap junctions that allow the passage of molecules separate the endothelial cells of the capillaries of other organs besides the brain. The endothelial cells of the capillaries in the brain are joined together by tight junctions. For materials to pass from the blood into
157
TABLE 1 Antibiotic Concentrations in the CSF

Good Concentrations in CSF with and without Meningitis Chloramphenicol Sulfonamides Cephalosporins Cefotaxime Ceftriaxone Ceftazidime Moxalactam Metronidazole Trimethoprim-sulfamethoxazole Isoniazid Adequate Concentrations in CSF in Meningitis Penicillin Ampicillin Methicillin Oxacillin Nafcillin Carbenicillin Ticarcillin Tetracycline Erythromycin Ethambutol Rifampin Vancomycin Meropenem Fair to Poor Concentrations in Meningitis First-generation cephalosporins Cephalothin Cefoxitin Aminoglycosides Gentamicin Tobramycin Amikacin Clindamycin Benzathine penicillin
antibiotics are coincident use of ampicillin and tetracyclines, and of penicillin and chloramphenicol. Other drug interactions need to be kept in mind. Phenobarbital reduces the peak serum concentration of chloramphenicol by 35%. Phenytoin causes a 60% increase in peak serum concentrations of chloramphenicol. Treatment needs to be a minimum of 14 days of intravenous (IV) therapy. The need for repeat CSF examination at 2 to 7 days of treatment to prove sterilization of CSF in every case is controversial. Corticosteroids in children have been shown to reduce the incidence of late complications, hearing loss in particular. They are used routinely as dexamethasone, 0.6 mg/kg/day in four divided doses for 4 days. The duration remains controversial. Use of steroids routinely in adults is more controversial. A recent prospective study in adults suggested a reduction in mortality, fever, and unfavorable outcomes. Dexamethasone can be used, and should probably be used for all patients with CSF obstruction, coma, significant cerebral edema, or parenchyma invasion (cerebritis). Caution needs to be observed because of the previously mentioned reduction of CSF penetration by some antibiotics potentiated by steroids. The dose of dexamethasone is 10 mg four times a day in adults for 4 days. Empirical therapy should usually consist of a third-generation cephalosporin (e.g., ceftriaxone) and vancomycin (because of penicillin-resistant streptococci and staphylococci). Additionally, metronidazole can be added if dirty or anaerobic contamination is suspected. Once identification and sensitivity of the organism are known, antibiotics can be simplified. Vancomycin resistance has been reported, but staphylococci or penicillinresistant streptococci justify its use in the circumstance of bacterial meningitis (Table 2). Pneumococcus (S. pneumoniae) meningitis is still in some circumstances sensitive to penicillin, but penicillin-resistant strains are becoming more common, which influences empirical treatment choices. Usually the initial ceftriaxone (2 gm every 12 hours IV) or cefotaxime (3 gm every 6 hours IV) treatment will be completed if the organism is sensitive, rather than
switching to penicillin. If penicillin is used, the dose is 20 to 24 million units per day IV, in a divided every4-hour infusion schedule. If the organism is cephalosporin resistant, vancomycin, 1 gm every 12 hours IV, should be continued for a minimum of 14 days, with dose adjustment based on monitoring of levels in the blood. Meningococcus (N. meningitidis) meningitis is treated with penicillin, although ampicillin, ceftriaxone, or cefotaxime can be used. If penicillin is used, the dose is 20 to 24 million units per day, in a divided every-4-hour infusion schedule for 14 days. The organism is acquired by
TABLE 2 Empirical Antibiotic Therapy of Bacterial Meningitis
Age, Disability Children Drug, Dosage Ceftriaxone 50 mg/kg q 12 hr IV or Cefotaxime 150 mg/kg q 8 hr IV and Vancomycin 15 mg/kg q 6 hr IV plus Dexamethasone 0.15 mg/kg q 6 hr for 4 days Vancomycin 1 gm q 12 hr IV (until sensitivities of organism are known) and Ceftriaxone 2 gm q 12 hr IV or Cefotaxime 3 gm q 6 hr IV and Dexamethasone 10 mg q 6 hr for 4 days above, plus Ampicillin 2 gm q 4 hr IV (for Listeria) Cefepime 2 mg q 8 hr
Adults Community acquired
Alcoholism Neurosurgical procedure or head trauma
plus Vancomycin (above doses) plus Metronidazole 500 mg q 6 hr IV (if contaminated wound is suspected)
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respiratory transmission, so contacts need prophylaxis of rifampin 10 mg/kg every 12 hours for four doses. H. influenzae meningitis is treated with ceftriaxone, 2 gm every 12 hours IV, or cefotaxime, 3 gm every 6 hours IV. Alternatively, ampicillin plus chloramphenicol, 12.5 mg/kg every 8 hours IV) can be considered, depending on sensitivities of the organism. Staphylococcus meningitis is treated with vancomycin, 1 gm every 12 hours IV, until sensitivities are known. Dose adjustment is based on monitoring of levels in the blood. If methicillin susceptible, nafcillin, 2 gm every 4 hours IV, can be used. Gram-negative bacteria (Klebsiella, Escherichia coli, Proteus sp.) usually are associated with systemic bacteremia causing the meningitis. Treatment is guided by sensitivities and is somewhat organism dependent. Usual initial treatment is cefepime 2 gm every 8 hours. Meropenem, 2 gm every 8 hours IV; or aminoglycosides, 6 mg/kg every 8 hours IV, can be considered. For Pseudomonas sp., cefepime, 2 gm every 8 hours IV, should be the initial therapy. Ceftazidime, 2 gm every 8 hours IV, with an aminoglycoside (gentamicin, 6 mg/kg every 8 hours IV) can be considered as an alternative. For anaerobic bacteria (e.g., Bacteroides fragilis), metronidazole, 500 mg every 6 hours IV, should be used. Clindamycin has poor spinal fluid penetration with an intact blood-brain barrier. Listeria monocytogenes meningitis is treated with ampicillin, 2 gm every 4 hours IV, with or without an aminoglycoside for 14 to 21 days. IV sulfamethoxazoletrimethoprim is used for those who are penicillin allergic. L. monocytogenes meningitis often occurs in the elderly, in transplant patients, and in those with liver disease or alcoholism. Brainstem encephalitis has also been described associated with Listeria meningitis.
Diagnosis
Identification of cases is the first challenge because early-stage TM is protean in its manifestations and lacks pathognomonic physical examination and laboratory findings (Figure 1). Depending on the stage of disease, the most common signs and symptoms include fever, headache, changes in mentation, and meningismus in most patients. Other signs include focal neurologic deficits such as cranial nerve palsies, paresis, seizures, and diminished cognition. Symptoms indistinguishable from acute pyogenic meningitis have also been described, although most patients with TM have a prolonged prodromal period (>7 days). The diagnosis of TM should be considered in any patient with subacute meningitis. Even when antituberculous medications are administered, morbidity and mortality are very high, especially with late-stage disease, so after reasonable efforts to make a diagnosis are made, empirical treatment may be warranted. Epidemiologic links to a case of active TB may be helpful but are absent in most cases. High-risk groups include the human immunodeficiency virus (HIV)-infected, injection drug users, alcoholics, and some racial groups (African American and Native American). Patients are divided into three stages based on the examination at presentation. Stage I disease is characterized by lucid patients with fever, malaise, headache, and possibly meningismus. Stage II patients often have single cranial nerve impairment due to basilar disease, paresis, and focal seizures. Hyperactive deep tendon reflexes, worsening headache, and impaired cognitive capacity are often seen. Stage III patients are comatose or stuporous and have marked neurologic impairment, including multiple cranial nerve palsies, hemiparesis, or paraplegia. Hydrocephalus is common. This stage of disease has a high rate of neurologic sequelae (30%) or death (30%) despite antibiotic therapy. Tuberculin skin testing (PPD) is positive in only 31% to 64% of patients with known TM. Chest radiography and chest computed tomographic (CT) scan may provide adjunctive clues, with 30% to 74% of patients having an abnormal study with evidence of miliary or focal tuberculous disease. Nonspecific laboratory tests, such as elevated sedimentation rate, peripheral leukocytosis, anemia, and thrombocytosis, occur as a result of subacute or chronic inflammation and are common in all granulomatous diseases. Mild to moderate hyponatremia may be seen in some patients as a result of the syndrome of inappropriate antidiuretic hormone secretion. Examination of the cerebrospinal fluid (CSF) is the most helpful diagnostic procedure, with larger volumes of CSF (>5 mL) often leading to higher microbiologic yields for smear and culture. The possibility of high opening pressures and noncommunicating hydrocephalus should be highlighted because herniation is a distinct danger in these settings. The CSF may be turbid with more chronic infections and is more likely to be smear positive with acid-fast bacilli. A lymphocyte-predominant pleocytosis in the CSF occurs in most patients except early in disease when polymorphonuclear cells may be predominant. Elevated protein in the range of 100 to
Yukari Manabe, M.D.
Tuberculosis (TB) is a global infectious disease problem with an estimated 8 million new cases yearly and 2 million deaths. Coinfection with human immunodeficiency virus (HIV) has compounded the problem, causing increasing incidence rates in areas where rates were previously decreasing due to better treatment control strategies. Tuberculous meningitis (TM) remains a dreaded manifestation of TB infection because it is often difficult to diagnose, requires a long course of therapy, and is associated with significant morbidity and mortality despite antituberculous chemotherapy.
158
respiratory transmission, so contacts need prophylaxis of rifampin 10 mg/kg every 12 hours for four doses. H. influenzae meningitis is treated with ceftriaxone, 2 gm every 12 hours IV, or cefotaxime, 3 gm every 6 hours IV. Alternatively, ampicillin plus chloramphenicol, 12.5 mg/kg every 8 hours IV) can be considered, depending on sensitivities of the organism. Staphylococcus meningitis is treated with vancomycin, 1 gm every 12 hours IV, until sensitivities are known. Dose adjustment is based on monitoring of levels in the blood. If methicillin susceptible, nafcillin, 2 gm every 4 hours IV, can be used. Gram-negative bacteria (Klebsiella, Escherichia coli, Proteus sp.) usually are associated with systemic bacteremia causing the meningitis. Treatment is guided by sensitivities and is somewhat organism dependent. Usual initial treatment is cefepime 2 gm every 8 hours. Meropenem, 2 gm every 8 hours IV; or aminoglycosides, 6 mg/kg every 8 hours IV, can be considered. For Pseudomonas sp., cefepime, 2 gm every 8 hours IV, should be the initial therapy. Ceftazidime, 2 gm every 8 hours IV, with an aminoglycoside (gentamicin, 6 mg/kg every 8 hours IV) can be considered as an alternative. For anaerobic bacteria (e.g., Bacteroides fragilis), metronidazole, 500 mg every 6 hours IV, should be used. Clindamycin has poor spinal fluid penetration with an intact blood-brain barrier. Listeria monocytogenes meningitis is treated with ampicillin, 2 gm every 4 hours IV, with or without an aminoglycoside for 14 to 21 days. IV sulfamethoxazoletrimethoprim is used for those who are penicillin allergic. L. monocytogenes meningitis often occurs in the elderly, in transplant patients, and in those with liver disease or alcoholism. Brainstem encephalitis has also been described associated with Listeria meningitis.
Diagnosis
Identification of cases is the first challenge because early-stage TM is protean in its manifestations and lacks pathognomonic physical examination and laboratory findings (Figure 1). Depending on the stage of disease, the most common signs and symptoms include fever, headache, changes in mentation, and meningismus in most patients. Other signs include focal neurologic deficits such as cranial nerve palsies, paresis, seizures, and diminished cognition. Symptoms indistinguishable from acute pyogenic meningitis have also been described, although most patients with TM have a prolonged prodromal period (>7 days). The diagnosis of TM should be considered in any patient with subacute meningitis. Even when antituberculous medications are administered, morbidity and mortality are very high, especially with late-stage disease, so after reasonable efforts to make a diagnosis are made, empirical treatment may be warranted. Epidemiologic links to a case of active TB may be helpful but are absent in most cases. High-risk groups include the human immunodeficiency virus (HIV)-infected, injection drug users, alcoholics, and some racial groups (African American and Native American). Patients are divided into three stages based on the examination at presentation. Stage I disease is characterized by lucid patients with fever, malaise, headache, and possibly meningismus. Stage II patients often have single cranial nerve impairment due to basilar disease, paresis, and focal seizures. Hyperactive deep tendon reflexes, worsening headache, and impaired cognitive capacity are often seen. Stage III patients are comatose or stuporous and have marked neurologic impairment, including multiple cranial nerve palsies, hemiparesis, or paraplegia. Hydrocephalus is common. This stage of disease has a high rate of neurologic sequelae (30%) or death (30%) despite antibiotic therapy. Tuberculin skin testing (PPD) is positive in only 31% to 64% of patients with known TM. Chest radiography and chest computed tomographic (CT) scan may provide adjunctive clues, with 30% to 74% of patients having an abnormal study with evidence of miliary or focal tuberculous disease. Nonspecific laboratory tests, such as elevated sedimentation rate, peripheral leukocytosis, anemia, and thrombocytosis, occur as a result of subacute or chronic inflammation and are common in all granulomatous diseases. Mild to moderate hyponatremia may be seen in some patients as a result of the syndrome of inappropriate antidiuretic hormone secretion. Examination of the cerebrospinal fluid (CSF) is the most helpful diagnostic procedure, with larger volumes of CSF (>5 mL) often leading to higher microbiologic yields for smear and culture. The possibility of high opening pressures and noncommunicating hydrocephalus should be highlighted because herniation is a distinct danger in these settings. The CSF may be turbid with more chronic infections and is more likely to be smear positive with acid-fast bacilli. A lymphocyte-predominant pleocytosis in the CSF occurs in most patients except early in disease when polymorphonuclear cells may be predominant. Elevated protein in the range of 100 to
Yukari Manabe, M.D.
Tuberculosis (TB) is a global infectious disease problem with an estimated 8 million new cases yearly and 2 million deaths. Coinfection with human immunodeficiency virus (HIV) has compounded the problem, causing increasing incidence rates in areas where rates were previously decreasing due to better treatment control strategies. Tuberculous meningitis (TM) remains a dreaded manifestation of TB infection because it is often difficult to diagnose, requires a long course of therapy, and is associated with significant morbidity and mortality despite antituberculous chemotherapy.
159
FIGURE 1. Diagnostic work-up for tuberculous meningitis. PE, Physical examination; HA, headache; CN, cranial nerve; ESR, erythrocyte sedimentation rate; SIADH, syndrome of inappropriate antidiuretic hormone; CXR, chest radiograph; PPD, purified protein derivative; CSF, cerebrospinal fluid; Cx, culture; PCR, polymerase chain reaction; M. tb., Mycobacterium tuberculosis; AFB, acid-fast bacillus.
Suspect tuberculous meningitis
Diagnostic work-up: 1) History prodrome > 7 days, fever, HA, meningismus 2) PE focal neurologic deficits (CN palsies, paresis, seizures, diminished cognition) 3) Labs leukocytosis, anemia, ESR, hyponatremia 2 SIADH, albumin, plts 4) CXR/chest CT abnormal 3074% of time 5) Sputum smear and Cx (or gastric aspirate) 6) PPD skin test
Consider screening head CT to rule out hydrocephalus prior to lumbar puncture
Lumbar puncture: CSF acid-fast bacilli smear and Cx protein (100500 mg/dL), glucose, lymphocyte-predominant pleocytosis (>50% lymphs)
Negative/ low suspicion
Positive/ high suspicion
7
Consider brain MRIsuperior to brain CT for examining basilar area for meningeal enhancement, tuberculoma CSF PCR for M. tb suffers from poor sensitivity, but has high specificity; result is likely to be positive Multiple high-volume (5 mL) CSF samples may increase yield for organism Treat (see Figure 2)
Await cultures
Adjust treatment based on sensitivities
In enigmatic patients consider meningeal biopsy in inflamed areas for culture and histology, AFB stain.
500 mg/dL is most common, although up to one fourth of patients may have a CSF protein concentration of less than 100 mg/dL. Rare cases of protein levels higher than 1000 mg/dL have been reported, especially in those with a noncommunicating hydrocephalus or longstanding inflammatory disease. Low CSF glucose level is seen in 43% to 88% of patients. The gold standard for diagnosing TM remains CSF acid-fast bacilli smear and subsequent culture. Multiple high-volume samples may increase the yield, but treatment should not be withheld if large volumes cannot be obtained. CT and magnetic resonance imaging of the brain may provide important adjunctive information about hydrocephalus, tuberculomas, and basilar meningeal enhancement and can help rule out other differential diagnostic possibilities. CSF polymerase chain reaction (PCR) may be helpful especially in smear-positive disease. In general, however, CSF PCR assay is specific, and positive results are likely to be real cases. False-negative results occur even in true cases of TM secondary to low bacillary numbers and PCR inhibitors in the CSF. Therefore, sensitivity varies widely and PCR assay cannot be used as a screening tool.
For particularly enigmatic patients, meningeal biopsy may be helpful in diagnosing TM. Specimens should be sent for culture and histopathology to look for caseating granulomas and acid-fast bacilli.
Treatment
Treatment for TM should be initiated with four antituberculous drugs because the drug levels achieved in CSF may be marginally adequate (Figure 2). Unlike the treatment of pulmonary TB, daily dosing for the duration of the course is recommended. The only drug with documented CSF penetration and clinical efficacy is isoniazid; it should be the cornerstone of any regimen for TM. A dose of 5 mg/kg daily with a 300 mg maximum daily dose is recommended, although rapid acetylators may benefit from increased doses of 10 to 15 mg/ kg/day with TM. The risk for liver toxicity increases with increasing dose and therefore high-dose therapy is not recommended for patients with underlying liver disease. Rifampin has poor CSF penetration but is an
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Tuberculous meningitis
FIGURE 2. Treatment of tuberculous meningitis (TM). ICP, Intracranial pressure; CSF, cerebrospinal fluid; LFT, liver function test; TB, tuberculosis; MDR-TB, multidrug-resistant tuberculosis; h/o, history of. Stage III: comatose, multiple cranial nerve palsies, hemiplegia, hydrocephalus, ICP
Stage I: fever, headache, meningismus, malaise, prodrome > 3 weeks, conscious, rational
Stage II: single cranial nerve impairment, paresis, focal seizures, impaired cognition, fever
Culture and susceptibilitiesCSF and sputum (if possible)
If PANSENSITIVE: 4 drug therapy INH mainstay of Rx 510 mg/kg/day 300 mg/day Rifampin poor penetration, 10 mg/kg/day 600 mg/day Pyrazinamide 25 mg/kg/day for 2 months (max 2 gm), 15 mg/kg/day (max 1.5 gm) + Ethambutol 1525 mg/kg/day (standard) OR Streptomycin IM 2535 mg/kg 3x/wk max 1.5 gm (alternative) OR Ethionamide 1015 mg/kg/day (alternative in pediatric patients) If DRUG-RESISTANT: INH 10 mg/kg/day + 3 other drugs Tailor treatment based on sensitivities; if limited choices, consider increasing dose of INH to 20 mg/kg/day; monitor LFTs closely; consider addition of a fluoroquinolone such as moxifloxacin Daily directly observed therapy is standard for 12 month minimum goal (can decrease to 9 months if toxicity is an issue and patient improved). May need to extend for as long as 1824 months.
Stage II and Stage III disease: Add corticosteroids to decrease IC pressure and as adjunctive therapy. Dexamethasone 812 mg/day OR prednisone 1 mg/kg/day for 48 weeks, then taper over 34 weeks. If clinical worsening, go back up to lowest asymptomatic dose. If h/o treatment for TB (inadequate), at high risk for MDR-TB, or documented MDR-TB with no clinical improvement on oral medications, considering broadening coverage. Anecdotal reports of intrathecal amikacin/ levofloxacin in MDR-TB case with progression of TM, despite improvement in other areas.
important sterilizing drug in pulmonary TB and is recommended as part of the regimen. A dose of 10 mg/kg with a maximum daily dose of 600 mg is recommended although up to 750 mg daily may be used for TM. Liver function tests should be monitored closely because the risk for jaundice increases at the higher doses. Pyrazinamide is recommended in TM because it has good CSF penetration even in the absence of inflammation and is also an important sterilizing drug in pulmonary TB. Doses of 25 mg/kg/day are recommended for the first 2 months of therapy to a maximum dose of 2 gm, then 15 mg/kg/day for the duration of therapy. Ethambutol 25 mg/kg/day has some CSF penetration and is the least toxic fourth drug to add to the regimen but is static and has no proven efficacy with TM. Optic neuritis is its most worrisome side effect, and ethionamide 10 to 15 mg/kg/day may be a better choice in children, in whom it is difficult to monitor for the presence of color discrimination. Streptomycin is also a reasonable alternative for a fourth drug because it has
been used successfully in the past as monotherapy. Intramuscular streptomycin given three times per week at 22 mg/kg appears to be associated with less frequent cranial nerve VIII nerve toxicity. If a patient has a history of inadequate treatment for TB, epidemiologic links to a multidrug-resistant (MDR) TB case, or hails from an area with high rates of MDR-TB, consider broadening coverage to include a fluoroquinolone. If microbiologic failure is evident or progression of TM occurs in the face of treatment, intrathecal amikacin and levofloxacin have been used. For patients with MDR-TB, therapy must be tailored to the susceptibilities of the organism. The addition of other active drugs to an isoniazid-based regimen may not be unreasonable because the population may not be clonal, and isoniazid has the most documented clinical efficacy. Treatment should be continued for at least 12 months. For patients who are unable to take medications orally or by nasogastric tube, isoniazid, rifampin, and streptomycin are available parenterally, as is moxifloxacin.
Fungal Infections
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In patients with stage II or III disease, dexamethasone 8 to 12 mg/day or prednisone 1 mg/kg/day should be given for 4 to 8 weeks followed by a slow taper over 3 to 4 weeks. If symptomatic worsening occurs, the steroid dose should be increased to the lowest dose used before worsening, with treatment for an additional 3 to 4 weeks before attempting to taper the steroid dose again. SUGGESTED READING
Dooley DP, Carpenter JL, Rademacher S: Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature, Clin Infect Dis 25:872-887, 1997. Iseman M: A clinicians guide to tuberculosis, Philadelphia, 2000, Lippincott Williams & Wilkins. Manabe YC, Chaisson RE: Tuberculosis. In Asbury AK, McDonald WI, McArthur JC, et al, editors: Diseases of the nervous system, New York, 2001, Cambridge University Press.
Fungal Infections
Larry E. Davis, M.D., and Beth S. Porter, M.D., Ph.D.
Aspergillus sp., and Candida sp., can invade cerebral blood vessels, causing an arteritis that can thrombose or rarely, rupture. Most pathogenic fungi are dimorphic. Depending on growth conditions, they may be in the yeast phase (unicellular and round with reproduction by budding or fission) or in a filamentous or mold phase (hyphae that grow by extension and produce spores). In general, fungi found in the meninges and CSF are in the yeast phase, whereas those found in the brain parenchyma are in the filamentous phase. Fungi that cause CNS infections can be classified as primary or secondary pathogens. Primary pathogens are fungi that occasionally cause disease in healthy individuals. The most common primary pathogen, Cryptococcus neoformans, accounts for more than half of all CNS fungal infections. Other important primary pathogens include Coccidioides immitis, Histoplasma capsulatum, and Blastomyces dermatitidis. In the setting of immunosuppression, the incidence of primary CNS fungal pathogens is markedly increased. Secondary fungal pathogens are opportunistic fungi that cause CNS infection in the setting of obvious immune dysfunction or anatomic abnormalities. Major secondary pathogens include Aspergillus sp., Zygomycetes sp. (mucormycosis), and Candida sp., but numerous other species rarely cause CNS infections, such as Fusarium and Scedosporium.
Although fungal infections of the central nervous system (CNS) remain uncommon, their incidence has increased primarily due to increased prevalence of immunosuppression (from acquired immunodeficiency syndrome [AIDS], transplants, corticosteroids, and chemotherapy). Accordingly, a fungal infection should be in the differential diagnosis for all patients with subacute or chronic meningitis, particularly the immunocompromised patient (Table 1). Of the more than 100,000 species of fungi, most are nonpathogenic for healthy humans or cause only a short-lived infection. Only a handful regularly cause CNS infections. Fungal spores enter the body mainly from inhalation and are small enough in particle size to reach the lungs to create a localized infection. The infection usually is asymptomatic or causes vague, brief pulmonary symptoms. Less common routes of initial fungal infection are from a skin puncture wound, chronic sinusitis, wounds, indwelling catheters, and fungal overgrowth from prolonged administration of systemic antibiotics. CNS fungal infections usually result from a systemic fungal infection elsewhere in the body leading to a fungemia that successfully invades the meninges or brain parenchyma. Most pathogenic fungi cause meningitis, but some fungi cause meningoencephalitis (meningitis with microabscesses) or localized brain abscesses. Fungi that invade the brain can produce an abscess with a necrotic center surrounded by a fibrous capsule or an intense inflammatory reaction that forms a granuloma. The organisms of Zygomycetes sp.,
SUBACUTE MENINGITIS Meningitis is the most common presentation of CNS fungal disease but lacks specific characteristics that distinguish it from other types of subacute meningitis, such as tuberculous meningitis. Individuals typically present with a 1- to 3-week history of meningeal signs (low-grade fever and progressive lethargy, malaise, nausea, headache, stiff neck, and mental status changes). If the patient has AIDS or another form of immunosuppression, presenting signs may be only confusion and fever without headache or nuchal rigidity. As the fungal meningitis progresses, meningoencephalitis often develops with additional signs and symptoms that may include (1) stupor, nausea and vomiting, dizziness, diplopia, and papilledema from increased intracranial pressure; (2) diplopia, facial numbness or weakness, dysarthria, dysphagia, and hearing loss from trapping of cranial nerves by the basilar meningitis; and (3) hemiparesis, aphasia, visual loss, and cerebellar ataxia from cerebral infarctions due to meningeal vessel thrombosis or from localized brain damage from a fungal abscess/granuloma. BRAIN PARENCHYMAL INFECTION Patients with brain parenchymal infection develop an invasive fungal infection of the brain that manifests as an abscess, granuloma, or angioinvasion leading to vessel thrombosis or rarely rupture. CNS symptoms are based on the location of the involved brain. Common presenting
Fungal Infections
161
In patients with stage II or III disease, dexamethasone 8 to 12 mg/day or prednisone 1 mg/kg/day should be given for 4 to 8 weeks followed by a slow taper over 3 to 4 weeks. If symptomatic worsening occurs, the steroid dose should be increased to the lowest dose used before worsening, with treatment for an additional 3 to 4 weeks before attempting to taper the steroid dose again. SUGGESTED READING
Dooley DP, Carpenter JL, Rademacher S: Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature, Clin Infect Dis 25:872-887, 1997. Iseman M: A clinicians guide to tuberculosis, Philadelphia, 2000, Lippincott Williams & Wilkins. Manabe YC, Chaisson RE: Tuberculosis. In Asbury AK, McDonald WI, McArthur JC, et al, editors: Diseases of the nervous system, New York, 2001, Cambridge University Press.
Fungal Infections
Larry E. Davis, M.D., and Beth S. Porter, M.D., Ph.D.
Aspergillus sp., and Candida sp., can invade cerebral blood vessels, causing an arteritis that can thrombose or rarely, rupture. Most pathogenic fungi are dimorphic. Depending on growth conditions, they may be in the yeast phase (unicellular and round with reproduction by budding or fission) or in a filamentous or mold phase (hyphae that grow by extension and produce spores). In general, fungi found in the meninges and CSF are in the yeast phase, whereas those found in the brain parenchyma are in the filamentous phase. Fungi that cause CNS infections can be classified as primary or secondary pathogens. Primary pathogens are fungi that occasionally cause disease in healthy individuals. The most common primary pathogen, Cryptococcus neoformans, accounts for more than half of all CNS fungal infections. Other important primary pathogens include Coccidioides immitis, Histoplasma capsulatum, and Blastomyces dermatitidis. In the setting of immunosuppression, the incidence of primary CNS fungal pathogens is markedly increased. Secondary fungal pathogens are opportunistic fungi that cause CNS infection in the setting of obvious immune dysfunction or anatomic abnormalities. Major secondary pathogens include Aspergillus sp., Zygomycetes sp. (mucormycosis), and Candida sp., but numerous other species rarely cause CNS infections, such as Fusarium and Scedosporium.
Although fungal infections of the central nervous system (CNS) remain uncommon, their incidence has increased primarily due to increased prevalence of immunosuppression (from acquired immunodeficiency syndrome [AIDS], transplants, corticosteroids, and chemotherapy). Accordingly, a fungal infection should be in the differential diagnosis for all patients with subacute or chronic meningitis, particularly the immunocompromised patient (Table 1). Of the more than 100,000 species of fungi, most are nonpathogenic for healthy humans or cause only a short-lived infection. Only a handful regularly cause CNS infections. Fungal spores enter the body mainly from inhalation and are small enough in particle size to reach the lungs to create a localized infection. The infection usually is asymptomatic or causes vague, brief pulmonary symptoms. Less common routes of initial fungal infection are from a skin puncture wound, chronic sinusitis, wounds, indwelling catheters, and fungal overgrowth from prolonged administration of systemic antibiotics. CNS fungal infections usually result from a systemic fungal infection elsewhere in the body leading to a fungemia that successfully invades the meninges or brain parenchyma. Most pathogenic fungi cause meningitis, but some fungi cause meningoencephalitis (meningitis with microabscesses) or localized brain abscesses. Fungi that invade the brain can produce an abscess with a necrotic center surrounded by a fibrous capsule or an intense inflammatory reaction that forms a granuloma. The organisms of Zygomycetes sp.,
SUBACUTE MENINGITIS Meningitis is the most common presentation of CNS fungal disease but lacks specific characteristics that distinguish it from other types of subacute meningitis, such as tuberculous meningitis. Individuals typically present with a 1- to 3-week history of meningeal signs (low-grade fever and progressive lethargy, malaise, nausea, headache, stiff neck, and mental status changes). If the patient has AIDS or another form of immunosuppression, presenting signs may be only confusion and fever without headache or nuchal rigidity. As the fungal meningitis progresses, meningoencephalitis often develops with additional signs and symptoms that may include (1) stupor, nausea and vomiting, dizziness, diplopia, and papilledema from increased intracranial pressure; (2) diplopia, facial numbness or weakness, dysarthria, dysphagia, and hearing loss from trapping of cranial nerves by the basilar meningitis; and (3) hemiparesis, aphasia, visual loss, and cerebellar ataxia from cerebral infarctions due to meningeal vessel thrombosis or from localized brain damage from a fungal abscess/granuloma. BRAIN PARENCHYMAL INFECTION Patients with brain parenchymal infection develop an invasive fungal infection of the brain that manifests as an abscess, granuloma, or angioinvasion leading to vessel thrombosis or rarely rupture. CNS symptoms are based on the location of the involved brain. Common presenting
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Fungal Infections
TABLE 1 CNS Fungal Manifestations

CNS Predilection Common Common Frequency of Meningitis Common Common Frequency of Abscess/ Granuloma/Cerebral Infarction Uncommon Uncommon
Genus
Incidence Common Common
High-Risk Settings HIV, steroid usage, normal host HIV, pregnancy, immunosuppression, diabetes mellitus, prednisone > 20 mg/day, normal host HIV, steroid use Immunosuppression, corticosteroids, HIV, excessive antibiotics, CNS indwelling catheters, neonatal period Normal host Neutropenia, transplants, sinusitis, HIV Diabetes mellitus, neutropenia
Cryptococcus Coccidioides
Histoplasma Candida
Uncommon Uncommon
Uncommon Uncommon
Common Common
Common Less common
Blastomyces Aspergillus Zygomycetes (mucormycosis)
Uncommon Uncommon Uncommon
Uncommon Uncommon Common
Common Uncommon Uncommon
Common as epidural or cranial abscess Common Common
HIV, Human immunodeficiency virus; CNS, central nervous system. Modified from Perfect JR: Fungal meningitis. In Scheld WM, Whitley RJ, Marra CM, editors: Infections of the central nervous system, ed 3, Philadelphia, 2004, Lippincott Williams & Wilkins, 691-712.
symptoms and signs include those of increased intracranial pressure, seizures, and focal neurologic signs that can be either acute from a cerebral infarction or progressive from an expanding abscess. Zygomycetes infection (mucormycosis) often extends from an initial sinus or nasal infection, producing a localized mass with adjacent cerebral infarctions due to thrombosis from hyphal invasion of arteriole vessel walls. A common location involves the cavernous sinus with the presentation of facial nerve pain, cranial nerve palsies (cranial nerves V and III) and orbital and facial edema. Some patients with fungal meningitis also develop microabscesses from brain invasion via Virchow-Robin spaces adjacent to the meninges, or occasionally large intraparenchymal abscesses, especially in the basal ganglia and cerebellum. Common fungi causing both include C. neoformans, C. immitis, H. capsulatum, and B. dermatitidis.
Diagnosis
Fungal meningitis represents a small percentage of cases of subacute meningitis. Thus, before starting empirical antifungal drugs, one should have reasonable evidence for a CNS fungal infection since administration of amphotericin B, the most commonly used CNS antifungal drug, is associated with a number of disagreeable, often serious, adverse effects. Establishing the diagnosis of a CNS fungal infection is often challenging. The clinical course, CSF values,
and neuroimaging for fungal meningitis do not differ markedly from those for many other causes of subacute meningitis. The opening pressure can be normal or elevated. The CSF white blood cell count ranges from 20 to 1000 cells/mm3 with lymphocytes normally predominating. If neutrophils predominate, the risk of infection with B. dermatitidis, Aspergillus sp., or Zygomycetes sp. increases. If CSF eosinophils are present, the possibility of coccidioidal meningitis increases. CSF glucose level is usually depressed, ranging from 10 to 39 mg/dL, and the CSF protein level is elevated, ranging from 50 to 700 mg/dL. Protein levels above 1 gm/dL suggest a subarachnoid block. Magnetic resonance imaging with gadolinium often demonstrates meningeal enhancement, especially in the basal cisterns consistent with subacute meningitis. Other radiographic findings can include hydrocephalus, brain abscesses, and infarctions. Fungi are difficult to isolate or identify from CSF. Culturing the fungus from CSF occurs in only 50% of cases for C. immitis and H. capsulatum, 10% for Candida sp., and less than 5% for Aspergillus and Zygomycetes sp. Cryptococcal meningitis is the exception with C. neoformans isolated from CSF in more than 75%. Sensitive and specific serologic tests are available for only a few fungi (Table 2). Polymerase chain reaction assays for fungal nucleic acid are not particularly sensitive and not widely available. As a consequence of these problems, the clinician must use multiple strategies to establish the diagnosis (see Table 2). One important approach is to search for evidence of a fungal infection elsewhere in the body.
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TABLE 2 Recommended Work-up of Patient with Possible CNS Fungal Infection

Part of Work-Up History Physical examination Radiologic tests Needed Focus Geographic locationendemic and travel history Risk factorsmay include immunosuppression, AIDS, transplants, chemotherapy, corticosteroids, pregnancy, diabetes mellitus Signs of systemic fungal infection, especially in lungs, skin, joints, bones, liver, spleen Chest radiograph or chest CT Cranial MRI with gadolinium or CT with contrastmay demonstrate enhancement of basal cisterns, brain abscesses, infarctions, and hydrocephalus Joint radiographs of swollen joints with or without bone lesions Bone scan Lumbar puncture 3 with 30 mL CSF removal Opening pressure, glucose, protein Differential cell count looking for eosinophils or predominance of neutrophils Centrifugation and fungal culture of pellet Hemogram and urinalysis Liver and renal function studies Antibody tests Coccidioides immitisCF and EIA of CSF and serum Histoplasma capsulatumCF and immunodiffusion of serum and ? CSF Blastomyces dermatitidisCF and immunodiffusion of serum and ? CSF Aspergillus sp.CF and immunodiffusion of serum Antigen tests of CSF Cryptococcus neoformanslatex agglutination and EIA of CSF H. capsulatumEIA of CSF, urine, serum B. dermatitidisCSF, serum Aspergillus sp. (Platelia aspergillus or galactomannan antigen)EIA of serum, CSF Candida sp. (mannan antigen)EIA of latex agglutination of CSF CSF Sputum or tracheal aspirate Urine culture Bone marrow aspirate or aspirate of lytic lesion Skin biopsy of suspicious lesions Joint aspirate of swollen joints Sinus biopsy or aspirate Brain or meningeal biopsy if necessary
Laboratory tests
Antibody and antigen tests that are commercially available
Fungal cultures*
Bold tests are the most important to consider. *If Coccidioides immitis is suspected, notify the microbiology laboratory so the personnel can protect themselves. CF, Complement fixation; EIA, enzyme immune assay (also known as ELISA); CNS, central nervous system; AIDS, acquired immunodeficiency syndrome; CSF, cerebrospinal fluid.
Common extrapulmonary sites include skin, bone, bone marrow, joints, sinuses, liver, and genitourinary system. Identification of the organism from one of these other sites greatly improves the probability that the CNS infection is from the same organism. Thus, workup of the patient with a suspected CNS fungal infection often involves a search for other infected organs (see Table 2). One important exception to this rule is that Candida organisms rarely indicate a CNS infection when isolated from blood. The diagnosis of CNS Candida infection usually requires direct evidence of the fungus in CSF, meninges, or brain.
Antifungal Drugs
At present only three classes of antifungal drugs (polyenes, pyrimidines, and azoles) achieve high enough CSF and brain concentrations to be used in CNS fungal infections. Caspofungin, currently the only available
echinocindin class drug, does not adequately penetrate CSF or brain to be clinically useful. Treatment of systemic fungal infections typically consists of three different phases: induction, consolidation, and maintenance (Table 3). The induction phase is the initial treatment of the CNS fungal infection and may be a different drug or at a higher dose than used in the consolidation phase. The consolidation phase is the duration of active therapy and varies depending on the fungus, degree of host immune competence, and host response to treatment. The maintenance phase is the long-term therapy aimed to prevent recurrence, and the length of time given varies again with the fungus and host immune competence. Not infrequently the maintenance phase is lifelong due to the high risk of relapses. Although it is tempting to combine amphotericin B with fluconazole, animal studies have found an antagonism when both are given. In general, the recommended antifungal drugs and doses in the subsequent sections follows the practice guidelines from the Infectious Diseases Society of America
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TABLE 3 Recommended Antifungal Treatment

Fungus Induction Phase* Amphotericin B 0.7-1 mg/kg/day IV or liposomal amphotericin B 3-5 mg/kg/day IV for 6-10 wk with or without flucytosine 100 mg/kg/day PO in 4 divided doses for 2 wk plus CSF removal if intracranial pressure is elevated Liposomal amphotericin B 3-5 mg/kg/day IV for 6-10 wk or fluconazole 400-600 mg/day or intrathecal amphotericin B 0.2-0.5 mg/day (see text) Liposomal amphotericin B 3-5 mg/kg/day IV or amphotericin B 0.7-1 mg/kg/day IV Amphotericin B 0.7-1 mg/kg/day or liposomal amphotericin B 3-5 mg/kg/day IV plus flucytosine 100 mg/kg/day PO (in 4 divided doses) for 2 wk Consolidation Phase* Fluconazole 400 mg/day PO for at least 8-10 wk Maintenance Phase*
Cryptococcus neoformans
Coccidioides immitis
Fluconazole 400-600 mg/day PO for 9-18 mo PO
Healthy : fluconazole 200-400 mg/day PO for up to 1-2 yr and when CSF and clinical symptoms have resolved High risk : lifelong fluconazole 200400 mg/day PO (see text) Healthy and high risk : lifelong fluconazole 200-400 mg/day PO Healthy : fluconazole 800 mg/day for 12 mo High risk : lifelong fluconazole 800 mg/day Healthy and high risk : fluconazole 400 mg/day for prolonged period if strain is nonresistant
Histoplasma capsulatum
Candida sp.
Blastomyces dermatitidis
Amphotericin B 0.7-1 mg/kg/day or liposomal amphotericin B 3-5 mg/kg/day IV Amphotericin B 0.7-1 mg/kg/day or liposomal amphotericin B 5 mg/kg/day IV Surgically dbride abscess plus voriconazole 200 mg bid IV Surgically dbride infected brain plus liposomal amphotericin B 5 mg/kg/day IV
Sporothrix schenckii Aspergillus sp. Zygomycetes sp. (mucormycosis)
Liposomal amphotericin B 3-5 mg/kg/day IV qd or qod over 3-4 mo (total of 100150 mg/kg) or amphotericin B 0.7-1 mg/kg/day for 3-4 mo (total of 35 mg/kg) IV Amphotericin B 0.7-1 mg/kg/day up to total of 2 gm) IV after neurologic signs and symptoms and neuroimaging have resolved for 4 wk or liposomal amphotericin B* 3-5 mg/kg/day IV for at least 4 wk (total of 100-150 mg/kg) Amphotericin B 0.7-1 mg/kg/day IV for a total dose of 2 gm or liposomal amphotericin B 3-5 mg/kg/day IV over 3-4 mo (total of 100-150 mg/kg) Amphotericin B 0.7 to 1 mg/kg/day IV up to 2 gm or liposomal amphotericin B 5 mg/kg/day IV for 100-120 mg Voriconazole 200 mg bid PO for indeterminate time Liposomal amphotericin B 5 mg/kg/day IV for 6-8 wk
High risk : fluconazole 400-800 mg/day PO for prolonged period High risk : fluconazole 400-800 mg/day PO for prolonged period High risk: voriconazole 200 mg bid PO for prolonged period Unclear
*Maximum daily dose, total dosage, and duration of induction and consolidation phases vary considerably depending on the ability of the patient to tolerate the drug and the clinical, neuroimaging, and cerebrospinal fluid responses to therapy. Duration of the maintenance phase depends on assessment of the risk of recurrence.
but have been modified to accommodate the results of recent clinical studies. Since optimal dosages of antifungal regimens frequently change and new antifungal drugs (ravuconazole, posaconazole, micafungin, and anidulafungin) are in active development, the reader is advised to consult the latest literature and infectious disease experts whenever possible. AMPHOTERICIN B DEOXYCHOLATE Amphotericin B deoxycholate, first approved in 1958, is a polyene class drug that is fungicidal and currently is
the drug of choice for most CNS fungal infections. Polyenes bind to ergosterol in the fungal cell wall, disrupting the cell, altering its permeability, and killing the fungus. Since mammals lack cell walls, the fungus is specifically targeted. Amphotericin B is strongly bound to plasma proteins (>90%) with peak levels of 6 to 8 hours and a plasma half-life of 1 to 2 days. The drug is mainly excreted in urine. Unfortunately, amphotericin B is far from an ideal drug for CNS infections since it must be given intravenously (IV) or intrathecally and possesses numerous adverse effects. The drugs toxicity is divided into
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infusion-related events and cumulative dose-related renal toxicity. Infusion-related events include chills, fever, headache, nausea, and vomiting. These acute adverse events usually diminish with repeated amphotericin B administration. If an adverse event persists or is severe, pretreatment with diphenhydramine, acetaminophen, prochlorperazine, narcotics, and/or corticosteroids is helpful. Hypokalemia and normochromic anemia can also develop with treatment, so serum electrolytes and complete blood counts should be monitored frequently. Amphotericin B is usually begun at a daily dose of 0.25 mg/kg/day prepared as a 0.1 mg/mL infusion and slowly administered via a central venous catheter for 3 to 6 hours eliminating the need for pretreatment with heparin to prevent phlebitis commonly seen when the drug is administered in peripheral veins. The daily dosage is slowly increased to 0.5 to 1 mg/kg/day or higher for Aspergillus and Zygomycetes infections. Amphotericin B is frequently nephrotoxic, with accumulating dosage limiting the total amount that can be administered. Patients should be well hydrated before drug administration and followed with frequent serum creatinine and urinalyses in which red blood cell or white blood cell casts can be seen. Potentially nephrotoxic agents such as aminoglycoside antibiotics, cisplatin, cyclosporine, tacrolimus, and radiocontrast agents should be avoided if possible. If these drugs are necessary, use of the liposomal amphotericin B should be considered since it is the least nephrotoxic. Rare life-threatening idiosyncratic reactions of anaphylaxis, seizures, ventricular fibrillation, and cardiac arrest have been reported and require the drug to be discontinued. An intrathecal formulation of amphotericin B is available and has been used to achieve higher CSF levels of the drug than are possible by IV infusion. This is necessary since IV amphotericin B does not cure some fungal meningitides such as coccidioidal meningitis. At first, amphotericin B (0.2 to 0.5 mg/day) can be administered into the lumbar subarachnoid space from a lumbar puncture. The amphotericin B is usually mixed with 2 mL of a hyperbaric (hypertonic) solution of 10% dextrose in water, which has a greater specific gravity than CSF. After slow administration, the patient is placed in the Trendelenburg position for 45 minutes to allow the injected bolus to flow via gravity to the basal cisterns (see Stevens and Shatsky article in Suggested Reading list for more details of intrathecal administration). Complications of lumbar antifungal therapy following lumbar puncture or lumbar reservoir include severe headaches, nausea, vomiting, back pain, cranial nerve palsies, paresthesias, radiculopathy, and myelopathy from drug toxicity, and spinal arachnoiditis is triggered by the drug. Over time, the spinal arachnoiditis may prevent the drug from reaching cerebral subarachnoid spaces. At this point amphotericin B must be administered into the cisternal subarachnoid space via cisternal puncture or catheter reservoir system. Infusionrelated inflammation augments the existing cerebral subarachnoiditis, hastening the development of communicating hydrocephalus and creating isolated pockets of infected meninges that cannot be reached by the cisternally injected amphotericin B.
To lessen the adverse effects of amphotericin B, the U. S. Food and Drug Administration has approved three lipid formulations of amphotericin B called liposomal amphotericin B (AmBisome), amphotericin B cholesteryl sulfate (Amphotec), and amphotericin B lipid complex (ABLC) (Abelcet). These three expensive lipid formulations possess markedly less renal toxicity and produce fewer infusion-related events. The liposomal formulation has the smallest particle size (45 to 80 nm in diameter) and fewest infusion-related events. Currently, no studies clearly demonstrate better efficacy among the formulations or between any lipid formulation and amphotericin B. However, CNS infections have not been adequately studied to determine whether lipid formulations are superior. In favor of this possibility, liposomal amphotericin B can be given in higher concentrations (3 to 5 mg/kg) than amphotericin B (0.5 to 1.5 mg/kg), with increased brain amphotericin B (but not CSF) concentrations achieved in experimental animals. Current indications for using the lipid amphotericin B formulations include (1) development of renal dysfunction (serum creatinine >2.5 mg/dL); (2) severe or persistent infusion-related events despite pretreatment with medications; (3) disease progression after more than 500 mg total dose of amphotericin B; and (4) necessary concomitant administration of nephrotoxic drugs such as cyclosporine or tacrolimus. Although sufficient human studies have not been completed to be certain of benefit, we believe that for CNS fungal infections, liposomal amphotericin B is excellent as the initial amphotericin treatment. At present all lipid formulations are considerably more expensive. Thus, for non-CNS fungal infections and some CNS fungal infections, conventional amphotericin B is often started and converted to a lipid formulation if the above indications develop. FLUCYTOSINE 5-Flurocytosine, a fungicidal nucleoside analog, is converted within cells to 5-fluorouracil, which inhibits DNA synthesis. Flucytosine is well absorbed from the gastrointestinal tract, minimally binds to serum proteins, and is excreted unchanged in urine. CSF concentrations approach 85% of serum levels. The drug is particularly active against Candida sp., C. neoformans, and some molds. Unfortunately, the drug cannot be used as a single agent because of the rapid development of drug resistance. Flucytosine is usually combined with amphotericin B and is administered for only 2 weeks during the induction phase of treatment. Adverse effects of flucytosine include rash, nausea and vomiting, diarrhea, hepatic dysfunction, and bone marrow suppression. To minimize the risk of toxicity, twice-weekly hemograms and liver function studies should be obtained and serum flucytosine levels can be obtained. Therapeutic levels measured in serum 2 hours after a dose range between 30 and 80 mg/mL. Serum levels greater than 100 mg/mL are considered toxic. If renal failure is present, flucytosine dosage reduction is essential and blood levels should be monitored.
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AZOLES Azoles act by inhibiting fungal cytochrome P-450 (CYP) and sterol C-14--demethylation leading to a loss of fungal membrane sterols. At present, four azoles (fluconazole, ketoconazole, itraconazole, and voriconazole) are available for systemic fungal infections. Azoles are effective against many common fungal pathogens, including C. neoformans, H. capsulatum, C. immitis, Candida sp., B. dermatitidis, Paracoccidioides brasiliensis, and Sporothrix schenckii. Voriconazole and itraconazole are also active against Aspergillus sp., but no azoles are effective against Zygomycetes sp. The CSF penetration is best for fluconazole (>75% of serum levels) and voriconazole (>50% of serum levels). Itraconazole and ketoconazole achieve CSF levels less than 10% of serum and are seldom used as primary drugs for CNS infections. Fluconazole can be administered orally and IV. The oral form has good bioavailability, long half-life, low protein binding, and wide tissue distribution, including brain and CSF. The drug has few adverse effects that include rash, nausea, abdominal pain, reversible alopecia, elevated liver enzymes, and, rarely, Stevens-Johnson syndrome. Fluconazole should be used with caution in pregnant or nursing mothers since congenital defects have been reported and breast milk contains similar azole concentrations to those in serum. One potential problem with azole drugs is their interactions with coadministered drugs (Table 4). One type of interaction leads to decreased azole plasma concentrations by either decreasing azole absorption or increasing its metabolism. The second type of interaction leads to increased plasma concentrations of other coadministered drugs by altering hepatic metabolism via the cytochrome P-450 system. This could lead to toxicity of the coadministered drug. The emergence of fluconazole-resistant fungi appears rare but has been reported to occur with Candida sp. Voriconazole is well absorbed after oral administration, is moderately protein bound, enters the CSF reasonably well (50% to 60% of serum levels), and is extensively metabolized by the liver, with only 1% excreted in urine. An IV form of the drug is also available. The drug is usually begun with a loading dose of twice the daily dose. Voriconazole has many adverse effects and drug interactions similar to those of fluconazole (see Table 4), and visual disturbances occur in 20% to 45%. The transient visual effects generally occur 30 minutes after dosing and last for 15 to 30 minutes and include altered visual perception, color vision change, blurred vision, and photophobia. Voriconazole, but not fluconazole, has better efficacy than amphotericin B for systemic infections, including the brain, with Aspergillus sp. and is becoming the drug of choice for CNS Aspergillus, Fusarium, and Scedosporium infections. However, its efficacy compared with that of fluconazole for other CNS fungal infections is unclear. All azoles are fungistatic, leading to suppression, but not necessarily cure, of the fungal infection. As such, relapses are common when the azole is discontinued.
TABLE 4 Drug Interactions with Oral Fluconazole and Voriconazole

Drug Potential Sequelae
Increased plasma concentration of coadministered drug leading to potential toxicity of coadministered drug and altered fluconazole or voriconazole blood levels Sirolimus Bone marrow toxicity, diarrhea Ribufutin Uveitis, eye pain, visual loss Ergot alkaloids Nausea, vasospastic ischemia Cyclosporine Nephrotoxicity Tacrolimus Nephrotoxicity Phenytoin and Nystagmus, ataxia, sedation fosphenytoin Carbamazepine Ataxia, nystagmus, headache, vomiting Sulfonylureas Hypoglycemia Warfarin Increased INR and bleeding diathesis Benzodiazepines Sedation Tricyclic antidepressants Sedation, cardiac arrhythmias Statins Rhabdomyolysis Calcium channel blockers Dizziness, peripheral edema HIV protease inhibitors Variable toxicity, especially ritonavir HIV non-nucleoside Variable toxicity, especially reverse transcriptase efavirenz inhibitors Coadministration of the following drugs can result in cardiac toxicity with QT prolongation and, rarely, torsade de pointes Terfenadine Astemizole Cisapride Pimozide Quinidine Sulfamethoxazole Tricyclic antidepressants Chloroquine and mefloquine Antiarrhythmic agents (classes IA and III) Foscarnet Antipsychotics Pentamidine Probucol Vasopressin Venlafaxine Increased metabolism of fluconazole and voriconazole leading to lower azole blood levels Rifampin and rifabutin Carbamazepine Phenobarbital Phenytoin Cimetidine Herbal preparations may cause hepatitis and jaundice if coadministered Chaparral (Larrea tridentata) Valerian (Valeriana officinalis) Skullcap (Scutellaria baicalensis) Pennyroyal (Mentha pulegium) Kava (Piper methysticum) Germander (Teucrium chamaedrys) Coltsfoot (Tussilago farfara) Petasites (Petasites japonicus)
Bold drugs are not recommended for coadministration with fluconazole and/or voriconazole per the manufacturer. HIV, Human immunodeficiency virus; INR, international normalized ratio.
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Specific CNS Infections

CRYPTOCOCCAL MENINGITIS C. neoformans is the most common fungus to invade the CNS and infects healthy (20% of total cases with incidence of 1/100,000 population) and immunocompromised (80% of cases with incidence of 20 to 50/1000 in human immunodeficiency virus [HIV] patients not receiving effective HIV therapy) persons alike. C. neoformans is a ubiquitous fungus found worldwide in association with bird excrement and decaying plant material. C. neoformans differs from most fungal pathogens in that it is neurotrophic and has a predilection to disseminate from the localized lung infection via blood to the CNS. Thus, patients with cryptococcal meningitis may lack fungus present in other organs. Most patients develop subacute meningitis, but a few may also have cryptococcomas in the basal ganglia or cortex. When considered, the diagnosis is straightforward because organisms usually are isolated from CSF within a few days and the CSF cryptococcal antigen test is highly sensitive and specific. Recent studies demonstrate a faster time to CSF sterilization with amphotericin B and flucytosine (60% to 90% CSF sterilization at 2 weeks) than with fluconazole (see Table 3). If a repeat lumbar puncture at 2 weeks shows the CSF is still positive for growth of C. neoformans, a longer period of induction should be considered. Relapse after primary treatment is a concern if the patient is immunosuppressed or has AIDS. Relapse rates as high as 50% have been reported. Accordingly, these patients should be continued on lifelong maintenance therapy. However, for HIV patients on modern antiretroviral therapy with normal CD4+ counts and nondetectable serum HIV viral titers, lifelong maintenance therapy may not always be needed. More than 50% of patients with cryptococcal meningitis, especially patients with AIDS, have demonstrated increased intracranial pressure with a lumbar CSF opening pressure of greater than 250 mm CSF. Elevated CSF pressure is associated with papilledema, hearing loss, visual acuity problems, marked confusion, and severe headaches and has a poorer prognosis. Although the pathogenesis is unclear, inflammatory cell debris and capsule material from C. neoformans likely interfere with CSF absorption into the superior sagittal vein resulting in a communicating hydrocephalus and secondary cryptococcomas. Large-volume removal of lumbar CSF to reduce CSF pressure by 50%, done daily until the opening pressure returns to normal for several consecutive days, improves outcome. If the opening pressure is extremely high (>400 mm CSF), a temporary ventricular drain should be considered. If there is obstructive hydrocephalus or the ventricular drain is unsuccessful, a ventriculoperitoneal shunt may be necessary. Corticosteroids, mannitol, and acetazolamide have demonstrated little benefit for reduction of elevated CSF pressures. COCCIDIOIDAL MENINGITIS C. immitis infections occur in the California San Joaquin valley, Arizona, New Mexico, southwestern Texas, and
northern Mexico. The risk of dissemination from the initial lung infection is about 0.5%. Nearly one third of the time dissemination affects the CNS and occurs within several months of the primary infection. Occasional patients also develop C. immitis granulomas in brain. Coccidioidal meningitis may be the only extrapulmonary infection, but other organs commonly involved are skin, joints, and bones. CSF complement fixation test for C. immitis antibody is an excellent test to diagnose coccidioidal meningitis and may be helpful in following treatment response. Successful antifungal treatment is difficult, and patients are at risk for development of communicating or obstructive hydrocephalus during therapy. Successful treatments have employed lifelong fluconazole and intrathecal amphotericin B (see Table 3). Because liposomal amphotericin B achieves higher brain levels and effects more cures in experimental animals than amphotericin B, its use should be considered for the induction phase of treatment. There are insufficient data to recommend exact duration and total dose of therapy.
HISTOPLASMA MENINGITIS
H. capsulatum infections are associated with the moist, temperate Mississippi and Ohio river valleys but have been reported in South America, Europe, and Asia. The risk of dissemination from the initial lung infection is rare but is highest in those who are immunosuppressed, very young, or elderly. When dissemination occurs, the CNS is infected in 5% to 20% of the cases, producing a meningitis and/or brain abscesses. The mortality rate from a CNS infection is high (20% to 40%) even when treated with amphotericin B, and up to 50% of patients relapse when treatment is discontinued. As a consequence, liposomal amphotericin B should be considered since higher CNS amphotericin B concentrations can be achieved (see Table 3). Prolonged maintenance therapy with an azole should also be considered. 7
CANDIDA MENINGITIS
Candida sp. is now the most common etiologic agent of fungal infections but uncommonly causes CNS infections. Candida sp. may cause meningitis, brain microabscesses, and cerebral infarction following thrombosis or hemorrhage from angioinvasion. Healthy individuals rarely develop CNS Candida infections. The diagnosis may be difficult because isolation from blood does not establish a CNS infection and isolation from CSF is uncommon. A recent enzyme immune assay (EIA) or latex agglutination Candida antigen test looking for mannan, a Candida antigen, may prove helpful if positive in CSF. Definite diagnosis may require meningeal or cerebral abscess biopsy. Current induction treatment is with amphotericin B often with flucytosine, except for Candida lusitaniae, which is amphotericin resistant (see Table 3). However, liposomal amphotericin B has successfully cured five of six cases of newborn Candida meningitis. Fluconazole and voriconazole are alternatives. However, if an azole is to be given in the setting of prior azole therapy or
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isolation of a non-albicans species, laboratory testing of the isolate for fluconazole or voriconazole resistance should be considered. The CSF often becomes sterilized before brain and meningeal tissues, so neuroimaging and CSF findings should be followed for resolution. If CSF shunts are present before the development of Candida meningitis, they should be removed because Candida biofilms may be present, leading to a relapse. The shunt ideally should be replaced after CSF sterilization. However, if the patient is on full antifungal therapy, new shunts seldom become infected. The duration of therapy has not been established, but maintenance therapy should continue a minimum of 4 weeks after resolution of all clinical signs and associated neuroimaging lesions. CNS ASPERGILLOSIS Aspergillus fumigatus, Aspergillus terreus, and Aspergillus flavus are the main species that cause human disease. CNS infections typically develop either by direct extension from infected paranasal sinuses or following head trauma or cranial surgery or by hematogenous spread from infected lung (occurs in 15% of patients with pulmonary aspergillosis and 50% of patients with disseminated aspergillosis). Hematogenous spread producing multiple cerebral abscesses typically develops in severely immunocompromised patients such as neutropenic patients who have an underlying hematologic malignancy, or patients receiving solid organ, bone marrow, or stem cell transplants. Extension from infected sinuses usually produces lesions in the frontal or temporal lobes, which are pathologically characterized by granulomas and cerebral infarctions following hyphal angioinvasion and vessel thrombosis. Diagnosis is often difficult since CSF is usually sterile. Cerebral or sinus biopsy with fungal culture and histologic examination of tissue for hyphae is diagnostic. The presence of galactomannan in CSF by EIA looks promising. Definitive therapy usually requires surgical resection of infected brain tissue plus antifungal therapy (see Table 3). A recent study finds that treatment of systemic infections including the brain with voriconazole is superior to amphotericin B. However, lipid formulations of amphotericin B were not studied.
Likewise, phenobarbital and carbamazepine interact with azoles (see Table 4). The duration of anticonvulsant therapy depends on the cause of the seizures. NAUSEA AND VOMITING Repeated vomiting can lead to dehydration and electrolyte imbalance. Causes include meningeal inflammation, increased intracranial pressure, and treatment with amphotericin B. Phenergan often lessens the nausea. Other antinausea medications may interact with azoles (see Table 4). STUPOR AND COMA The development of stupor or coma is serious, and its cause should be sought. Neuroimaging may suggest hydrocephalus, bilateral thalamic damage, or brainstem damage from an abscess, hemorrhage, or infarction. Patients may require mechanical ventilation or surgical intervention with ventricular shunting or removal of the localized infection. SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION SYNDROME AND CEREBRAL SALT WASTING (CSW) Chronic basilar meningitis may result in either syndrome of inappropriate antidiuretic hormone (SIADH) or cerebral salt wasting (CSW) leading to hyponatremia. The hyponatremia predisposes to seizures. Serum sodium levels and serum and urine osmolality can be followed. For symptomatic patients with SIADH, therapy is usually fluid restriction. Therapy for symptomatic CSW is replacement of sodium and extracellular volume deficits, avoiding rapid correction. INCREASED INTRACRANIAL PRESSURE Papilledema and depressed mental status may be due to obstructive or communicating hydrocephalus, expanding intracranial mass (abscess, infarction, or hemorrhage), or interference with CSF resorption in the superior sagittal sinus. Neuroimaging is helpful in establishing the diagnosis and should determine the best plan to lower CSF pressure. (See section on cryptococcal meningitis for methods to remove CSF to lower the pressure.) SUGGESTED READING
Cortez KJ, Walsh TJ: Space-occupying fungal lesions. In Scheld WM, Whitley RJ, Marra CM, editors: Infections of the central nervous system, ed 3, Philadelphia, 2004, Lippincott Williams & Wilkins, 713-733. Galgiani JN, Ampel NM, Cantanzaro A, et al: Practice guidelines for treatment of coccidioidomycosis, Clin Infect Dis 30:658-661, 2000. Pappas PG, Rex JH, Sobel JD, et al: Guidelines for treatment of candidiasis, Clin Infect Dis 38:161-189, 2004. Perfect JR: Fungal meningitis. In Scheld WM, Whitley RJ, Marra CM, editors: Infections of the central nervous system, ed 3, Philadelphia, 2004, Lippincott Williams & Wilkins, 691-712. Saag MS, Graybill RJ, Larsen RA, et al: Practice guidelines for the management of cryptococcal disease, Clin Infect Dis 30:710-718, 2000. Johnson: Current Therapy in Neurologic Disease (7/E)
Management of CNS Complications

SEIZURES Focal or generalized seizures occur in up to 33% of patients with CNS fungal infections. Evaluation includes neuroimaging, looking for a fungal abscess, infarction, or hemorrhage, and serum sodium levels for hyponatremia. Anticonvulsive therapy is usually with phenytoin. However, if the patient is receiving fluconazole or voriconazole, reduction of phenytoin dosage and monitoring of phenytoin blood levels should be done because azoles interfere with phenytoin metabolism.
Brain Abscess and Parameningeal Infection Stevens DA, Kan VL, Judson MA, et al: Practice guidelines for diseases caused by Aspergillus, Clin Infect Dis 30:696-709, 2000. Stevens DA, Shatsky SA: Intrathecal amphotericin in the management of coccidioidal meningitis, Semin Resp Infect 16:263-269, 2001. Wheat J, Sarosi G, McKinsey D, et al: Practice guidelines for management of patients with histoplasmosis, Clin Infect Dis 30:688-695, 2000.
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When a patient presents with fever and focal neurologic deficits, a central nervous system (CNS) abscess or parameningeal focus of infection must be suspected so treatment can begin without delay. Treatment of brain abscesses and parameningeal infections usually combines antibiotic therapy with surgical treatment. The urgency of treatment depends somewhat on the anatomic location because brainstem, cerebellum, and spinal cord foci are less well tolerated than infections affecting the cerebral hemispheres. The clinical status of the patient, the function of the patients immune system, and the nature of the infection are other factors that can influence treatment options (Figure 1).
Brain Abscess
Brain abscesses most commonly arise from hematogenous spread, direct extension from local infections, neurosurgical procedures or penetrating head injury. The organisms responsible for brain abscesses are often streptococcal, staphylococcal, or anaerobic. Risk factors include acquired immunodeficiency syndrome, organ transplantation, intravenous (IV) drug use, chemotherapy, cardiac anomaly or prosthetic cardiac valves, and diabetes. Clinically, patients present with fever, headache (which may be unilateral), and signs and symptoms of increased intracranial pressure (nausea, vomiting, lethargy, papilledema); they may also have meningismus, focal neurologic deficits, and seizures. Diagnosis is most commonly made with contrast-enhanced computed tomographic (CT) scanning of the brain, which will show a space-occupying lesion with stages that correlate with histologic findings. The cerebritis stages (early cerebritis, days 1 to 3; late cerebritis, days 4 to 9) show a poorly demarcated, hypodense lesion with associated localized edema. Histologically, this correlates with acute inflammation but no tissue necrosis. The encapsulation stages (early encapsulation, days 10 to 13; late encapsulation, days 14 and up) show ring enhancement with surrounding edema on CT, and histologically this correlates
with necrosis and liquefaction, and the lesion becomes surrounded by a fibrotic capsule. Magnetic resonance (MR) imaging with gadolinium enhancement is more sensitive for detecting satellite lesions and early cerebritis and can more adequately characterize the extent of capsule formation, central necrosis, and cerebral edema. Lumbar puncture is relatively contraindicated in brain abscesses that are causing mass effect, because of the herniation risk, but is sometimes done before brain abscess is suspected. The cerebrospinal fluid (CSF) may show a moderate pleocytosis. Glucose is usually normal, and protein may be normal or elevated. Cultures are usually negative. If the CSF is more consistent with bacterial meningitis (very elevated white blood cell count (WBC), positive cultures, or low glucose), rupture of the abscess into the ventricular system should be suspected. Serologic studies useful in the diagnosis may include complete blood count, which will usually show an elevated WBC, and blood cultures, which are usually negative (but if positive can provide useful information about the organism responsible for the abscess). Treatment of brain abscesses depends on the severity on presentation; the number, size, and location of lesions; and the organisms implicated. Medical treatment consisting of antibiotic therapy (Table 1) should be initiated in all patients once the diagnosis is suspected, without delay for pending diagnostic studies. Until specific culture and sensitivity data are available, empirical antibiotics are chosen based on common organisms and patient risk factors. Initial antibiotic therapy should include a third-generation cephalosporin, such as ceftriaxone or cefotaxime, plus vancomycin and metronidazole. If cultures show methicillinsensitive Staphylococcus aureus, the vancomycin can be changed to nafcillin or oxacillin. If methicillin-resistant S. aureus is present, consider adding rifampin for synergy with vancomycin. Metronidazole should be continued until the presence of anaerobes is excluded. If the cultures are consistent with Streptococcus, penicillin G therapy is usually sufficient. Immunocompromised patients are at risk for CNS toxoplasmosis and Nocardia infection, which are treated with trimethoprim-sulfamethoxazole. Listeria should be suspected in patients on chronic steroid therapy and is best covered by ampicillin. Some fungal species known to cause brain abscesses include Aspergillus, Cryptococcus, Coccidioides, Candida albicans, and the group Mucorales which cause mucormycosis (Zygomycetes). These fungal infections are treated with amphotericin. Certain patient populations can be susceptible to parasitic infections due to travel or immigration, most commonly cysticercosis, which is treated with praziquantel. Antibiotics should be adjusted based on culture and sensitivity results and on the known pathogenic flora in the area of treatment. Total duration of therapy should be 6 to 8 weeks, 4 weeks of which should be IV. Medical treatment alone is not generally advocated, although it may be considered if a patient is too sick to undergo surgical therapy. This is rare; almost any patient can undergo stereotactic needle aspiration, unless an underlying coagulopathy or thrombocytopenia exists. Medical treatment alone may be considered if the lesions are multiple (especially if small); if the location
Brain Abscess and Parameningeal Infection Stevens DA, Kan VL, Judson MA, et al: Practice guidelines for diseases caused by Aspergillus, Clin Infect Dis 30:696-709, 2000. Stevens DA, Shatsky SA: Intrathecal amphotericin in the management of coccidioidal meningitis, Semin Resp Infect 16:263-269, 2001. Wheat J, Sarosi G, McKinsey D, et al: Practice guidelines for management of patients with histoplasmosis, Clin Infect Dis 30:688-695, 2000.
169

When a patient presents with fever and focal neurologic deficits, a central nervous system (CNS) abscess or parameningeal focus of infection must be suspected so treatment can begin without delay. Treatment of brain abscesses and parameningeal infections usually combines antibiotic therapy with surgical treatment. The urgency of treatment depends somewhat on the anatomic location because brainstem, cerebellum, and spinal cord foci are less well tolerated than infections affecting the cerebral hemispheres. The clinical status of the patient, the function of the patients immune system, and the nature of the infection are other factors that can influence treatment options (Figure 1).
Brain Abscess
Brain abscesses most commonly arise from hematogenous spread, direct extension from local infections, neurosurgical procedures or penetrating head injury. The organisms responsible for brain abscesses are often streptococcal, staphylococcal, or anaerobic. Risk factors include acquired immunodeficiency syndrome, organ transplantation, intravenous (IV) drug use, chemotherapy, cardiac anomaly or prosthetic cardiac valves, and diabetes. Clinically, patients present with fever, headache (which may be unilateral), and signs and symptoms of increased intracranial pressure (nausea, vomiting, lethargy, papilledema); they may also have meningismus, focal neurologic deficits, and seizures. Diagnosis is most commonly made with contrast-enhanced computed tomographic (CT) scanning of the brain, which will show a space-occupying lesion with stages that correlate with histologic findings. The cerebritis stages (early cerebritis, days 1 to 3; late cerebritis, days 4 to 9) show a poorly demarcated, hypodense lesion with associated localized edema. Histologically, this correlates with acute inflammation but no tissue necrosis. The encapsulation stages (early encapsulation, days 10 to 13; late encapsulation, days 14 and up) show ring enhancement with surrounding edema on CT, and histologically this correlates
with necrosis and liquefaction, and the lesion becomes surrounded by a fibrotic capsule. Magnetic resonance (MR) imaging with gadolinium enhancement is more sensitive for detecting satellite lesions and early cerebritis and can more adequately characterize the extent of capsule formation, central necrosis, and cerebral edema. Lumbar puncture is relatively contraindicated in brain abscesses that are causing mass effect, because of the herniation risk, but is sometimes done before brain abscess is suspected. The cerebrospinal fluid (CSF) may show a moderate pleocytosis. Glucose is usually normal, and protein may be normal or elevated. Cultures are usually negative. If the CSF is more consistent with bacterial meningitis (very elevated white blood cell count (WBC), positive cultures, or low glucose), rupture of the abscess into the ventricular system should be suspected. Serologic studies useful in the diagnosis may include complete blood count, which will usually show an elevated WBC, and blood cultures, which are usually negative (but if positive can provide useful information about the organism responsible for the abscess). Treatment of brain abscesses depends on the severity on presentation; the number, size, and location of lesions; and the organisms implicated. Medical treatment consisting of antibiotic therapy (Table 1) should be initiated in all patients once the diagnosis is suspected, without delay for pending diagnostic studies. Until specific culture and sensitivity data are available, empirical antibiotics are chosen based on common organisms and patient risk factors. Initial antibiotic therapy should include a third-generation cephalosporin, such as ceftriaxone or cefotaxime, plus vancomycin and metronidazole. If cultures show methicillinsensitive Staphylococcus aureus, the vancomycin can be changed to nafcillin or oxacillin. If methicillin-resistant S. aureus is present, consider adding rifampin for synergy with vancomycin. Metronidazole should be continued until the presence of anaerobes is excluded. If the cultures are consistent with Streptococcus, penicillin G therapy is usually sufficient. Immunocompromised patients are at risk for CNS toxoplasmosis and Nocardia infection, which are treated with trimethoprim-sulfamethoxazole. Listeria should be suspected in patients on chronic steroid therapy and is best covered by ampicillin. Some fungal species known to cause brain abscesses include Aspergillus, Cryptococcus, Coccidioides, Candida albicans, and the group Mucorales which cause mucormycosis (Zygomycetes). These fungal infections are treated with amphotericin. Certain patient populations can be susceptible to parasitic infections due to travel or immigration, most commonly cysticercosis, which is treated with praziquantel. Antibiotics should be adjusted based on culture and sensitivity results and on the known pathogenic flora in the area of treatment. Total duration of therapy should be 6 to 8 weeks, 4 weeks of which should be IV. Medical treatment alone is not generally advocated, although it may be considered if a patient is too sick to undergo surgical therapy. This is rare; almost any patient can undergo stereotactic needle aspiration, unless an underlying coagulopathy or thrombocytopenia exists. Medical treatment alone may be considered if the lesions are multiple (especially if small); if the location
170
Fever, mental status change, headache/back pain, seizure, or other factors that suggest central nervous system infection
Focal neurologic deficits
None
Neurologic deficits localize to brain
Neurologic deficits localize to spinal cord
Work-up based on clinical and radiographic suspicion CT of brain with and without IV contrast
Emergent MRI of spine with and without gadolinium
Negative or other lesion Brain abscess Subdural empyema
Negative or other lesion
Epidural abscess
Antibiotic therapy, strongly consider surgery (unless multiple small lesions or high risk of bleeding complications), supportive care prn Follow up with serial CTs and reassess surgical options and antibiotics based on clinical and radiographic response Emergent surgical drainage and antibiotics
Work-up based on clinical and radiographic suspicion
Emergent surgical drainage (unless complete spinal cord dysfunction >3 days, prohibitive operative risk factors, or involvement of extensive length of spinal cord) and antibiotics
Surgery (especially if abscess is larger than 3 cm, close to a ventricle, in the cerebellum; or if definitive culture data are needed) Supportive care
Empiric antibiotics: third generation cephalosporin plus vancomycin plus metronidazole
Aspiration Can be done under local anesthesia if patient is unstable
Excision Especially if abscess is encapsulated or debridement is indicated
Anticonvulsants if patient seizes; consider steroids if significant vasogenic edema is contributing to clinical deterioration
Adjust antibiotics based on culture and sensitivity data, and patients clinical response and information about patients immune status
FIGURE 1. Approach to the patient with possible brain abscess or parameningeal infection.
171
TABLE 1 Antibiotics Used in the Treatment of Brain Abscess and Parameningeal Infections
Antibiotic Vancomycin Cefotaxime Ceftriaxone Metronidazole Nafcillin Oxacillin Penicillin G Ampicillin Rifampin Trimethoprimsulfamethoxazole Praziquantel Amphotericin Dosage 1 gm IV q 12 hr 2 gm IV q 6-8 hr 2 gm IV q 12 hr 500 mg IV q 6 hr 2 gm IV q 4 hr 2 gm IV q 4 hr 3-4 million units IV q 4 hr 2 gm IV q 4 hr 600 mg IV/PO qd 5-6 mg/kg IV q 6 hr 15 mg/kg PO tid 1 mg/kg/day IV Coverage MRSA Broad spectrum Broad spectrum Anaerobes MSSA MSSA Streptococcus
Listeria Synergy with vancomycin for MRSA Toxoplasmosis, Nocardia Cysticercosis Fungus
respiratory status of the patient may need to be supported. Steroids can be considered in patients who have clinical deterioration due to vasogenic edema surrounding the abscess. The use of steroids is not advocated in all patients because it may reduce the penetration of antibiotics into the abscess, and they may increase the risk of rupture into the ventricle. The use of steroids can slow the reduction of capsule formation and may reduce the amount of contrast enhancement on CT, so when these patients are followed up with CT, it is important to not consider the lessening degree of contrast enhancement as a sign of improvement. Serial CTs (once every week or two) should show decrease in the size of the abscess. If the patient develops seizures, an antiepileptic medication should be started. The role of prophylactic anticonvulsant therapy is controversial, but such therapy is likely not to be of benefit in cerebellar or deep cerebral abscesses.
Subdural Empyema
Subdural empyemas are mostly intracranial and rarely spinal. They are often formed after the direct extension of a local infection (usually sinusitis or middle ear infection), neurosurgical procedure, or compound skull fracture. The organisms implicated most commonly are Staphylococcus, Streptococcus, gram-negative bacilli, and anaerobes. Patients often present with headache, fever, and focal neurologic deficits, such as hemiparesis. They can also have meningismus, seizures, and signs of increased intracranial pressure, such as nausea, vomiting, and lethargy. Symptoms may be related to thrombophlebitis of cerebral veins traversing the subdural space that has become occupied with pus. The diagnosis can be made by head CT with IV contrast or MR imaging with gadolinium enhancement. Lumbar puncture is contraindicated due to risk of herniation and is often low yield, since organisms are present only if the empyema arises from meningitis. If CSF is obtained, it often shows a moderate pleocytosis, normal glucose, and elevated protein. Opening pressure is usually high. Complete blood count often shows an elevated WBC count, and blood cultures are not often helpful in recovering organisms because septicemia is not a common cause of subdural empyema. The treatment of subdural empyema should combine emergent surgical treatment with antibiotics. The preferred surgical approach is wide craniotomy. Antibiotics should focus on staphylococcal species, so vancomycin should be started, along with a third-generation cephalosporin plus metronidazole. Modification can be based on the results of the culture of specimens obtained surgically.
MRSA, Methicillin-resistant Staphylococcus aureus; MSSA, methicillinsensitive Staphylococcus aureus.
is surgically inaccessible or if the surgical approach would traverse eloquent tissue or the ventricular system; if there is concomitant meningitis or ependymitis; or if the patient has hydrocephalus requiring a shunt that could become infected during the operative procedure. Medical therapy alone is more likely to be successful if treatment is begun in the cerebritis stage before a capsule forms (generally within 10 days of symptom onset), if the lesions are small (<3 mm), and if patients show definite clinical improvement in the first week. If an abscess is larger than 3 cm or if a patient is deteriorating clinically, surgical therapy should be initiated. Because of the limited space in the posterior fossa and the mild clinical deficits associated with removal of cerebellar tissue, cerebellar abscesses should be managed surgically unless the patient cannot tolerate surgery due to excessive bleeding risk. The indications for surgical management of brain abscesses include significant mass effect, the need for culture and sensitivity information, proximity to a ventricle with risk for intraventricular rupture, clinical deterioration of the patient, no improvement with medical therapy, or if the abscess is due to traumatic brain injury (since surgery will likely be required to remove bone chips or other foreign bodies). The two surgical options currently in use are aspiration and excision. Stereotactic aspiration can be done under local anesthesia if necessary. The location of the burr hole is chosen to minimize the length of the tract; to avoid vital neural structures, blood vessels, and the ventricles; and to avoid an infected surface wound or infected bone. Surgical excision of an abscess can be done only if the abscess is encapsulated (usually after 10 days of symptom onset) but can dramatically reduce the length of antibiotic therapy, down to as short as 2 weeks. For supportive therapy, patients need to be hospitalized to initiate IV antibiotics, and a neurosurgeon should be involved in the patients care. The hemodynamic and
Epidural Abscess
Epidural abscesses are mostly spinal and rarely intracranial. The intracranial epidural abscesses often manifest less acutely, usually are caused by less virulent organisms, and are most commonly a result of direct extension from a contiguous focus of infection or by inoculation during
172
Neurosyphilis
neurosurgery or penetrating head injury. Spinal epidural abscesses (SEAs) can arise from hematogenous spread (especially in IV drug users), direct spread of infection (including local skin infections, vertebral osteomyelitis, and intervertebral discitis), or spinal procedures (both open, as with lumbar discectomy, and closed, such as epidural catheter insertion or lumbar puncture). In many cases, the source of infection cannot be identified. A history of back trauma is common. Common organisms causing SEA are Staphylococcus, Streptococcus, Escherichia coli, those responsible for chronic infections (e.g., tuberculosis, fungal and parasitic infections), multiple organisms, and anaerobes. Risk factors include diabetes, IV drug abuse, alcoholism, and chronic renal failure. The clinical presentation of SEA is classically fever with back pain and spine tenderness to percussion. Patients may also have sweats and rigors, meningismus with Kernigs sign, and encephalopathy; a furuncle may be present on the skin of the back. Neurologic deficits localizing to the spinal cord may be present. Progressive myelopathy or radicular symptoms may progress precipitously to distal cord dysfunction. The signs may be from mechanical compression, but this is not always found pathologically, so a vascular mechanism of cord dysfunction has been postulated. Any patient in whom SEA is suspected should undergo emergent MR imaging of the spine with gadolinium enhancement. Lumbar puncture should be performed with caution, if at all. If it is performed, the level of the puncture should be distant to the clinically suspected level of the abscess. If pus is found while performing a lumbar puncture, do not advance the needle. Aspirate the pus and send it for culture. When spinal fluid is obtained, it will often show an elevated WBC and protein with normal glucose. CSF cultures are usually negative unless the abscess is violated. Peripheral WBC count is also usually elevated. Blood cultures can be helpful in identifying the offending organism. Erythrocyte sedimentation rate (ESR) is often elevated above 30 mm/hr. Treatment of SEA is emergent surgical drainage and antibiotic therapy. Surgery can decompress neural tissue, provide satisfactory culture of the infecting organism, and stabilize the spine if necessary. There are some reasons patient are not operated on emergently, however, including spinal cord dysfunction for more than 3 days (it is thought that there is no chance of regaining function by this time), prohibitive operative risk factors, and involvement of extensive length of the spinal cord. Some patients are not operated on emergently due to absence of significant neurologic deficits; this is highly controversial because a patient with SEA can have precipitous clinical deterioration. S. aureus is the most common organism, and empirical therapy should include the agents mentioned previously (vancomycin plus a third-generation cephalosporin plus metronidazole). Antibiotics can be modified if other organisms are suspected, or based on culture results as described for brain abscesses earlier. The course of therapy is 3 to 4 weeks of IV antibiotics plus 4 weeks of oral antibiotics. The IV course should be extended to 6 to 8 weeks if osteomyelitis is documented. Decline in serial ESRs may be a helpful marker of response to therapy.
SUGGESTED READING
Greenberg MS: Cerebral abscess, subdural empyema, and spinal epidural abscess. In Handbook of neurosurgery, ed 4, Lakeland, FL, 1997, Greenberg Graphics. Jansson AK, Enblad P, Sjolin J: Efficacy and safety of cefotaxime in combination with metronidazole for empirical treatment of brain abscess in clinical practice: a retrospective study of 66 consecutive cases, Eur J Clin Microbiol Infect Dis 23:7-14, 2004. Johns Hopkins Division of Infectious Disease Antibiotic Guide: http://www.hopkins-abxguide.org/ Nussbaum ES, Rigamonti D, Standiford H, et al: Spinal epidural abscess: a report of 40 cases and review, Surg Neurol 38:225, 1992.
Neurosyphilis
Neurosyphilis continues to be one of the most daunting neurologic diseases to understand because of uncertainty regarding diagnostic criteria, optimal therapy, and expected response to therapy. These uncertainties are particularly troublesome because neurosyphilis is most commonly seen in patients also infected with human immunodeficiency virus (HIV)-1. Both HIV infection and neurosyphilis can cause neurologic and cerebrospinal fluid (CSF) abnormalities, and distinguishing the contribution of each may be difficult. Moreover, compared with HIV-uninfected persons, HIV-infected persons with neurosyphilis respond differently to neurosyphilis therapy and may be more likely to fail therapy. The goal of this chapter is to provide guidelines for diagnosis, treatment, and management of neurosyphilis, based on our current state of knowledge. Although progress has been made in the last few years, additional study will allow these recommendations to be further refined and improved in the future.
Early Central Nervous System Invasion

Syphilis and neurosyphilis are caused by Treponema pallidum subspecies pallidum, a noncultivable bacterium that is not visualized by light microscopy. The organism invades the central nervous system (CNS) early in the course of disease, as demonstrated by its identification in CSF in about 25% of patients with early syphilis (primary, secondary, and early latent syphilis) by inoculation of samples into rabbits or by polymerase chain reaction (PCR) or reverse transcriptase (RT)-PCR. In addition, 10% to 70% of patients with early syphilis have CSF pleocytosis; elevated CSF protein concentration, albumin ratio, or IgG index; or reactive CSF VDRL test. Based on observations in humans and experimentally infected animals, detection of T. pallidum in CSF is the first identifiable abnormality. This is followed by
172
Neurosyphilis
neurosurgery or penetrating head injury. Spinal epidural abscesses (SEAs) can arise from hematogenous spread (especially in IV drug users), direct spread of infection (including local skin infections, vertebral osteomyelitis, and intervertebral discitis), or spinal procedures (both open, as with lumbar discectomy, and closed, such as epidural catheter insertion or lumbar puncture). In many cases, the source of infection cannot be identified. A history of back trauma is common. Common organisms causing SEA are Staphylococcus, Streptococcus, Escherichia coli, those responsible for chronic infections (e.g., tuberculosis, fungal and parasitic infections), multiple organisms, and anaerobes. Risk factors include diabetes, IV drug abuse, alcoholism, and chronic renal failure. The clinical presentation of SEA is classically fever with back pain and spine tenderness to percussion. Patients may also have sweats and rigors, meningismus with Kernigs sign, and encephalopathy; a furuncle may be present on the skin of the back. Neurologic deficits localizing to the spinal cord may be present. Progressive myelopathy or radicular symptoms may progress precipitously to distal cord dysfunction. The signs may be from mechanical compression, but this is not always found pathologically, so a vascular mechanism of cord dysfunction has been postulated. Any patient in whom SEA is suspected should undergo emergent MR imaging of the spine with gadolinium enhancement. Lumbar puncture should be performed with caution, if at all. If it is performed, the level of the puncture should be distant to the clinically suspected level of the abscess. If pus is found while performing a lumbar puncture, do not advance the needle. Aspirate the pus and send it for culture. When spinal fluid is obtained, it will often show an elevated WBC and protein with normal glucose. CSF cultures are usually negative unless the abscess is violated. Peripheral WBC count is also usually elevated. Blood cultures can be helpful in identifying the offending organism. Erythrocyte sedimentation rate (ESR) is often elevated above 30 mm/hr. Treatment of SEA is emergent surgical drainage and antibiotic therapy. Surgery can decompress neural tissue, provide satisfactory culture of the infecting organism, and stabilize the spine if necessary. There are some reasons patient are not operated on emergently, however, including spinal cord dysfunction for more than 3 days (it is thought that there is no chance of regaining function by this time), prohibitive operative risk factors, and involvement of extensive length of the spinal cord. Some patients are not operated on emergently due to absence of significant neurologic deficits; this is highly controversial because a patient with SEA can have precipitous clinical deterioration. S. aureus is the most common organism, and empirical therapy should include the agents mentioned previously (vancomycin plus a third-generation cephalosporin plus metronidazole). Antibiotics can be modified if other organisms are suspected, or based on culture results as described for brain abscesses earlier. The course of therapy is 3 to 4 weeks of IV antibiotics plus 4 weeks of oral antibiotics. The IV course should be extended to 6 to 8 weeks if osteomyelitis is documented. Decline in serial ESRs may be a helpful marker of response to therapy.
SUGGESTED READING
Greenberg MS: Cerebral abscess, subdural empyema, and spinal epidural abscess. In Handbook of neurosurgery, ed 4, Lakeland, FL, 1997, Greenberg Graphics. Jansson AK, Enblad P, Sjolin J: Efficacy and safety of cefotaxime in combination with metronidazole for empirical treatment of brain abscess in clinical practice: a retrospective study of 66 consecutive cases, Eur J Clin Microbiol Infect Dis 23:7-14, 2004. Johns Hopkins Division of Infectious Disease Antibiotic Guide: http://www.hopkins-abxguide.org/ Nussbaum ES, Rigamonti D, Standiford H, et al: Spinal epidural abscess: a report of 40 cases and review, Surg Neurol 38:225, 1992.
Neurosyphilis
Neurosyphilis continues to be one of the most daunting neurologic diseases to understand because of uncertainty regarding diagnostic criteria, optimal therapy, and expected response to therapy. These uncertainties are particularly troublesome because neurosyphilis is most commonly seen in patients also infected with human immunodeficiency virus (HIV)-1. Both HIV infection and neurosyphilis can cause neurologic and cerebrospinal fluid (CSF) abnormalities, and distinguishing the contribution of each may be difficult. Moreover, compared with HIV-uninfected persons, HIV-infected persons with neurosyphilis respond differently to neurosyphilis therapy and may be more likely to fail therapy. The goal of this chapter is to provide guidelines for diagnosis, treatment, and management of neurosyphilis, based on our current state of knowledge. Although progress has been made in the last few years, additional study will allow these recommendations to be further refined and improved in the future.
Early Central Nervous System Invasion

Syphilis and neurosyphilis are caused by Treponema pallidum subspecies pallidum, a noncultivable bacterium that is not visualized by light microscopy. The organism invades the central nervous system (CNS) early in the course of disease, as demonstrated by its identification in CSF in about 25% of patients with early syphilis (primary, secondary, and early latent syphilis) by inoculation of samples into rabbits or by polymerase chain reaction (PCR) or reverse transcriptase (RT)-PCR. In addition, 10% to 70% of patients with early syphilis have CSF pleocytosis; elevated CSF protein concentration, albumin ratio, or IgG index; or reactive CSF VDRL test. Based on observations in humans and experimentally infected animals, detection of T. pallidum in CSF is the first identifiable abnormality. This is followed by
Neurosyphilis
173
pleocytosis and then reactivity of CSF VDRL. Unlike in other bacterial CNS infections, T. pallidum is cleared from the CNS in about 70% of patients, and CSF pleocytosis may resolve; CSF VDRL reactivity, on the other hand, is less likely to spontaneously normalize. Normalization of CSF carries a good prognosis, predicting a low likelihood of developing symptomatic neurosyphilis, whereas persistence of CSF abnormalities carries a poor prognosis. Unfortunately, it is not possible to predict which syphilis patients who have abnormal CSF will spontaneously clear these abnormalities and which ones will not. To deal with this uncertainty, the Centers for Disease Control and Prevention (CDC) does not recommend that patients with early syphilis undergo lumbar puncture unless they have neurologic symptoms and signs and, in fact, recommends lumbar puncture routinely in asymptomatic syphilis patients only if they have late latent syphilis and are HIV infected. We have shown that the likelihood of CSF abnormalities is less dependent on syphilis stage and more dependent on serum rapid plasma reagin (RPR) titer (6- to 11-fold increased risk of abnormal CSF when the titer is 1:32), and in HIV-infected individuals, on peripheral blood CD4+ T cell count (see later). Thus, we recommend that these factors be used to determine which syphilis patients should be evaluated for neurosyphilis. Moreover, we recommend that all syphilis patients with CSF abnormalities consistent with neurosyphilis (see later), regardless of stage of disease or lack of neurologic symptoms or signs, be treated for neurosyphilis to prevent progression to symptomatic disease.
TABLE 1 Clinical Findings in the Forms of Neurosyphilis

Type of Neurosyphilis Early Neurosyphilis Asymptomatic Clinical Findings CSF abnormalities, no neurologic findings Occurs any time after infection, most common in the first few years Treatment prevents progression to symptomatic neurosyphilis Headache, stiff neck, nausea and vomiting; cranial nerve abnormalities; hydrocephalus Most common in the first year of infection Treatment results in clinical improvement Stroke involving brain or spinal cord Peak incidence 7 years after primary infection Treatment results in clinical improvement, but residual deficits common Forgetfulness, personality changes; psychiatric symptoms including mania, depression, or psychosis; dementia eventually develops in all Examination may show pupillary abnormalities, hypotonia, intention tremor Onset usually 10-20 yr after primary infection Treatment may halt progression but does not usually result in clinical improvement Sensory loss, ataxia, lancinating pains, bowel and bladder dysfunction Longest latency between primary infection and onset of symptoms, average 20 yr Treatment may halt progression but does not usually result in clinical improvement
Meningeal
Meningovascular
Late Neurosyphilis General paresis
Clinical Features
Neurosyphilis has been traditionally categorized into specific syndromes, each occurring at an estimated time after primary infection. I think that it is easier to envision neurosyphilis as the early forms (asymptomatic neurosyphilis, symptomatic meningitis, and meningovasculitis), characterized by meningeal involvement, and the late forms (general paresis and tabes dorsalis), characterized by parenchymal involvement. Early neurosyphilis occurs weeks to a few years after infection, and late neurosyphilis occurs decades after infection. The key features of the classic descriptions of early and late neurosyphilis are outlined in Table 1. Of note, many recent case reports describe patients with neurosyphilis who do not fit neatly into one of these descriptors. They presented with acute or chronic changes in memory and behavior accompanied by seizures and had unilateral or bilateral medial temporal lobe increased signal on T2weighted and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging sequences. This constellation of findings led to treatment for herpes encephalitis. The patients were subsequently diagnosed with neurosyphilis based on serum and CSF tests. The imaging abnormalities resolved after neurosyphilis treatment. In the preantibiotic (and pre-HIV) era, most patients with syphilis did not develop neurosyphilis. In 1946, Merritt and coworkers reported the frequency of
Tabes dorsalis
neurosyphilis in syphilis patients at Boston City Hospital. Symptomatic neurosyphilis was found in about 17.5% of these patients: symptomatic meningitis in less than 0.5%, meningovasculitis in 3%, general paresis in 5%, and tabes dorsalis in 9%; asymptomatic neurosyphilis was identified in 25% of patients. In another series, only 62 (6.5%) of 953 patients with untreated early syphilis developed symptomatic neurosyphilis. Today, although incidence data are not available, neurosyphilis is seen most commonly in patients also infected with
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Neurosyphilis
HIV. This observation is primarily due to two factors: Syphilis and HIV share common risk factors, and currently up to 75% of individuals newly diagnosed with syphilis in the developed world are already HIV infected. In addition, failure of early syphilis treatment with subsequent development of early neurosyphilis (neurorelapse) is more commonly reported in HIVinfected individuals. The latter observation suggests that HIV-induced immunodeficiency may impair CNS clearance. Our observation that neurosyphilis is three times more likely in HIV-infected individuals with peripheral blood CD4+ T cells lower than 350/L, compared with those with higher cell counts, supports this contention.
HIV-UNINFECTED PATIENT WITH SUSPECTED NEUROSYPHILIS Serum TPPA or FTA-ABS
Nonreactive
Reactive
No neurosyphilis
CSF VDRL
Nonreactive
Reactive
CSF WBC
Diagnosis
In addition to identification of any neurologic or ophthalmologic symptoms and signs, laboratory tests including serologic tests for syphilis on serum and CSF, assessment of CSF white blood cell count (WBC), and CSF protein concentration are integral elements in the diagnosis of neurosyphilis. Although identification of T. pallidum in CSF is possible by PCR or RT-PCR, these tests lack diagnostic sensitivity, particularly in later stages of disease. Nontreponemal serologic tests such as the VDRL or the RPR may be nonreactive in blood in individuals with late neurosyphilis. However, specific treponemal serologic tests such as the serum T. pallidum particle agglutination (TPPA) or fluorescent treponemal antibody-absorption (FTA-ABS) test are reactive in blood in all patients with neurosyphilis and can be used as the first screen to determine whether neurosyphilis should be considered as a diagnostic possibility in a given patient (Figures 1 and 2). Mononuclear CSF pleocytosis and a modestly elevated protein concentration are characteristic of neurosyphilis. Higher cell counts and protein concentrations are more common in the early forms of disease. Although the specificity of the CSF VDRL is high, the sensitivity has been estimated to be 22% to 69%, and a nonreactive result does not exclude the diagnosis of neurosyphilis. The low sensitivity of the CSF VDRL in the diagnosis of neurosyphilis is particularly problematic in HIVinfected patients, because mild CSF pleocytosis and elevated CSF protein concentration are common in these individuals even when they do not have syphilis. Lack of CSF treponemal test reactivity, particularly the FTA-ABS test, may be useful in these cases because nonreactivity excludes a diagnosis of neurosyphilis with a high degree of certainty. In contrast, reactivity of CSF treponemal tests does not confirm the diagnosis of neurosyphilis.
5/L > 5/L
CSF protein
45 mg/dL
> 45 mg/dL
CSF FTA-ABS
Nonreactive
Reactive
No neurosyphilis
Treat for neurosyphilis
FIGURE 1. Algorithm for the laboratory diagnosis of neurosyphilis in an HIV-uninfected patient. TPPA, Treponema pallidum particle agglutination; FTA-ABS, fluorescent treponemal antibody absorption test; CSF, cerebrospinal fluid; VDRL, Venereal Disease Research Laboratory test; WBC, white blood cell count; HIV, human immunodeficiency virus.
Treatment
The CDC recommends either high-dose intravenous (IV) penicillin or a combination of intramuscular procaine penicillin and oral probenecid for the treatment of neurosyphilis (Table 2). Over the years, several alternative
antibiotic regimens have been proposed, based not on efficacy in clinical trials but on their ability to produce sufficient antibiotic concentrations in CSF to kill T. pallidum. The Adult AIDS Clinical Trials Group conducted a study that compared 10 days of neurosyphilis therapy with ceftriaxone, 2 gm IV once daily, and aqueous crystalline penicillin G, 4 million units IV every 4 hours, in 30 HIV-infected subjects. There were clinical differences between the two groups, and more of the ceftriaxone-treated subjects than the penicillin-treated subjects had early syphilis. Nonetheless, there was no difference in the proportion of subjects in each group with improved CSF measures after therapy. However, even after controlling for differences in the two groups at baseline, decline in serum RPR titers was significantly greater in the ceftriaxone-treated subjects. These data suggest that ceftriaxone may be an alternative to penicillin in HIV-infected individuals with neurosyphilis
Neurosyphilis HIV-INFECTED PATIENT WITH SUSPECTED NEUROSYPHILIS Serum TPPA or FTA-ABS
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TABLE 2 Treatment for Neurosyphilis*

Type of Neurosyphilis Drug, Dosage Aqueous crystalline penicillin G, 3-4 million units IV q 4 hr or 24 million units IV as a continuous infusion, for 10-14 days or Procaine penicillin, 2.4 million units IM qd plus probenecid 500 mg PO qid, both for 10-14 days (probenecid contraindicated if severe sulfa allergy) Ceftriaxone, 2 gm IV qd for 10-14 days Penicillin desensitization then Aqueous crystalline penicillin G, 3-4 million units IV q 4 hr or 24 million units IV as a continuous infusion for 10-14 days or Procaine penicillin, 2.4 million units IM qd plus probenecid 500 mg PO qid, both for 10-14 days (probenecid contraindicated with severe sulfa allergy)
Nonreactive
Reactive
All forms
No neurosyphilis
CSF VDRL
Nonreactive
Reactive
CSF WBC
5/L
620/L
> 20/L
CSF protein
Penicillin-allergic patients with early neurosyphilis Penicillin-allergic patients with late neurosyphilis
45 mg/dL
> 45 mg/dL
CSF FTA-ABS
Nonreactive
Reactive
No neurosyphilis
Treat for neurosyphilis
*Many experts recommend following high-dose IV or IM penicillin therapy for neurosyphilis with IM benzathine penicillin G 2.4 million units weekly for 3 wk.
FIGURE 2. Algorithm for the laboratory diagnosis of neurosyphilis in an HIV-infected patient. TPPA, Treponema pallidum particle agglutination; FTA-ABS, fluorescent treponemal antibody absorption test; CSF, cerebrospinal fluid; VDRL, Venereal Disease Research Laboratory test; WBC, white blood cell count; HIV, human immunodeficiency virus.
and concomitant early syphilis. There are no data on whether ceftriaxone would be effective for late parenchymal neurosyphilis. Thus, I recommend that ceftriaxone may be considered as an alternative treatment for early neurosyphilis in individuals who are allergic to penicillin. Patients who have late neurosyphilis and are allergic to penicillin should be desensitized and treated with one of the two recommended penicillin regimens (see Table 2).
Response to Therapy
The best outcome after treatment of neurosyphilis in terms of resolution of symptoms or signs is seen in patients with CSF pleocytosis before treatment. Although treatment does not reverse parenchymal damage seen in patients with meningovascular neurosyphilis, general
paresis, or tabes dorsalis, it prevents further disease progression. Traditionally, the criteria for assessing response to treatment of neurosyphilis have relied on improvement, or lack of progression, of neurologic findings and resolution of serum and CSF abnormalities. The CDC guidelines recommend that CSF should be examined every 6 months after neurosyphilis treatment until the cell count is normal. Retreatment is advised if the cell count has not declined at 6 months or if the CSF is not entirely normal by 2 years after therapy. No recommendations are provided regarding rate of decline of CSF protein concentration or of decline in CSF VDRL or serum VDRL or RPR titers. We recently examined the time to normalization and likelihood of normalization of CSF WBC, CSF protein, CSF VDRL reactivity, and serum RPR reactivity in 59 individuals treated with one of the regimens in Table 2. We found that the median time for normalization of all measures except CSF protein was about 4 months and that by 12 to 14 months after treatment, virtually all subjects had normalized CSF WBC and CSF VDRL reactivity. In contrast, CSF protein concentration remained abnormal despite resolution of the other CSF abnormalities. These results suggest that
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TABLE 3 Suggested Criteria for Retreatment of Neurosyphilis

Increase in serum VDRL or RPR titer by two dilutions (fourfold increase) at any time after therapy (repeat the test to confirm) Increase in CSF WBCs 3 mo after therapy Increase in CSF VDRL titer by two dilutions (fourfold increase) 3 mo after therapy CSF WBC > 5/L 6 mo after therapy in an HIV-uninfected patient CSF WBC > 5/L and no change in CSF VDRL or serum VDRL or RPR titer 6 mo after therapy in an HIV-infected patient Persistence of any CSF abnormality 2 yr after therapy in an HIV-uninfected patient Persistent CSF VDRL reactivity 2 yr after therapy in an HIV-infected patient Worsening neurologic symptoms or signs Development of new neurologic symptoms or signs
VDRL, Venereal Disease Research Laboratory; RPR, rapid plasma reagin; CSF, cerebrospinal fluid; WBC, white blood cell count; HIV, human immunodeficiency virus.
SELECTED READING
Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002, MMWR Morb Mortal Wkly Rep 51:18-30, 2002. Golden MR, Marra CM, Holmes KK: Update on syphilis: resurgence of an old problem, JAMA 290:1510-1514, 2003. Katz DA, Berger JR, Duncan RC: Neurosyphilis: a comparative study of the effects of infection with human immunodeficiency virus, Arch Neurol 50:243-249, 1993. Lukehart SA, Hook EW III, Baker-Zander SA, et al: Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and therapy, Ann Intern Med 109:855-862, 1988. Marra CM, Boutin P, McArthur JC, et al: A pilot study evaluating ceftriaxone and penicillin G as treatment agents for neurosyphilis in human immunodeficiency virus-infected individuals, Clin Infect Dis 30:540-544, 2000. Marra CM, Maxwell CL, Smith SL, et al: Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features, J Infect Dis 189:369-376, 2004. Marra CM, Maxwell CL, Tantalo L, et al: Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter? Clin Infect Dis 38:1001-1006, 2004. Marra CM, Tantalo LC, Maxwell CL, et al: Alternative cerebrospinal fluid tests to diagnose neurosyphilis in HIV-infected individuals, Neurology 63:85-88, 2004. Merritt HH, Adams RD, Solomon HC: Neurosyphilis, New York, 1946, Oxford University Press.
persistently abnormal CSF protein concentration may not necessarily be an indication of treatment failure. Of note, we found that among the HIV-infected subjects, those with peripheral blood CD4+ T cell counts less than 200/L were approximately four times less likely to normalize CSF VDRL than those with CD4+ cell counts higher than 200/L. These results suggest that HIV-infected individuals, particularly those with low peripheral blood CD4+ T cell counts, might require more intensive therapy for neurosyphilis than those who are HIV uninfected. Previous case reports of neurosyphilis treatment failure in HIV-infected individuals underscore the need to carefully follow HIV-infected patients after neurosyphilis treatment. With these findings in mind, I suggest that serum VDRL or RPR titers be determined every 3 months and CSF be examined at 3 and 6 months, and then every 6 months thereafter, following treatment for neurosyphilis in both HIV-uninfected and HIV-infected individuals. Earlier follow-up than is recommended by the CDC will decrease the likelihood of loss to follow-up and will allow for earlier identification of treatment failure. Serial CSF examinations should continue until CSF pleocytosis and CSF VDRL reactivity normalize by this I mean that the CSF WBC should be less than or equal to 5/L and the CSF VDRL should revert to nonreactive, or the titer should drop by two dilutions (fourfold decline, such as a drop from 1:64 to 1:16). Serial serum examinations can be terminated when the serum VDRL or RPR becomes nonreactive or the titer drops by two dilutions. Although it is easy to devise such criteria for cure, we do not know if failure to meet these criteria is equivalent to treatment failure. Despite these limitations, suggested criteria for retreatment are listed in Table 3.
Lyme Disease
Lyme borreliosis (LB) is a multisystemic illness caused by the tick-transmitted spirochete Borrelia burgdorferi. The neurologic manifestations of LB, often called Lyme neuroborreliosis (LNB), can be difficult to diagnose and treat. Many excellent reviews of LB and LNB are available, and this chapter focuses on practical aspects of management for the neurologist. Although ideally the diagnosis would be straightforward and management would be primarily focused on issues of therapy, the major efforts of the neurologist, and the most perplexing problems, lie in diagnosis. If diagnosis is approached in a rational manner, therapy and management are generally straightforward. Thus, this chapter addresses the diagnosis in depth first and then discusses therapy.
Diagnosis
The diagnosis of LNB can occasionally be made purely from the history and neurologic examination. Usually, the diagnosis is considered as possible or probable on the initial evaluation and then confirmed by laboratory testing.
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TABLE 3 Suggested Criteria for Retreatment of Neurosyphilis

Increase in serum VDRL or RPR titer by two dilutions (fourfold increase) at any time after therapy (repeat the test to confirm) Increase in CSF WBCs 3 mo after therapy Increase in CSF VDRL titer by two dilutions (fourfold increase) 3 mo after therapy CSF WBC > 5/L 6 mo after therapy in an HIV-uninfected patient CSF WBC > 5/L and no change in CSF VDRL or serum VDRL or RPR titer 6 mo after therapy in an HIV-infected patient Persistence of any CSF abnormality 2 yr after therapy in an HIV-uninfected patient Persistent CSF VDRL reactivity 2 yr after therapy in an HIV-infected patient Worsening neurologic symptoms or signs Development of new neurologic symptoms or signs
VDRL, Venereal Disease Research Laboratory; RPR, rapid plasma reagin; CSF, cerebrospinal fluid; WBC, white blood cell count; HIV, human immunodeficiency virus.
SELECTED READING
Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002, MMWR Morb Mortal Wkly Rep 51:18-30, 2002. Golden MR, Marra CM, Holmes KK: Update on syphilis: resurgence of an old problem, JAMA 290:1510-1514, 2003. Katz DA, Berger JR, Duncan RC: Neurosyphilis: a comparative study of the effects of infection with human immunodeficiency virus, Arch Neurol 50:243-249, 1993. Lukehart SA, Hook EW III, Baker-Zander SA, et al: Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and therapy, Ann Intern Med 109:855-862, 1988. Marra CM, Boutin P, McArthur JC, et al: A pilot study evaluating ceftriaxone and penicillin G as treatment agents for neurosyphilis in human immunodeficiency virus-infected individuals, Clin Infect Dis 30:540-544, 2000. Marra CM, Maxwell CL, Smith SL, et al: Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features, J Infect Dis 189:369-376, 2004. Marra CM, Maxwell CL, Tantalo L, et al: Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter? Clin Infect Dis 38:1001-1006, 2004. Marra CM, Tantalo LC, Maxwell CL, et al: Alternative cerebrospinal fluid tests to diagnose neurosyphilis in HIV-infected individuals, Neurology 63:85-88, 2004. Merritt HH, Adams RD, Solomon HC: Neurosyphilis, New York, 1946, Oxford University Press.
persistently abnormal CSF protein concentration may not necessarily be an indication of treatment failure. Of note, we found that among the HIV-infected subjects, those with peripheral blood CD4+ T cell counts less than 200/L were approximately four times less likely to normalize CSF VDRL than those with CD4+ cell counts higher than 200/L. These results suggest that HIV-infected individuals, particularly those with low peripheral blood CD4+ T cell counts, might require more intensive therapy for neurosyphilis than those who are HIV uninfected. Previous case reports of neurosyphilis treatment failure in HIV-infected individuals underscore the need to carefully follow HIV-infected patients after neurosyphilis treatment. With these findings in mind, I suggest that serum VDRL or RPR titers be determined every 3 months and CSF be examined at 3 and 6 months, and then every 6 months thereafter, following treatment for neurosyphilis in both HIV-uninfected and HIV-infected individuals. Earlier follow-up than is recommended by the CDC will decrease the likelihood of loss to follow-up and will allow for earlier identification of treatment failure. Serial CSF examinations should continue until CSF pleocytosis and CSF VDRL reactivity normalize by this I mean that the CSF WBC should be less than or equal to 5/L and the CSF VDRL should revert to nonreactive, or the titer should drop by two dilutions (fourfold decline, such as a drop from 1:64 to 1:16). Serial serum examinations can be terminated when the serum VDRL or RPR becomes nonreactive or the titer drops by two dilutions. Although it is easy to devise such criteria for cure, we do not know if failure to meet these criteria is equivalent to treatment failure. Despite these limitations, suggested criteria for retreatment are listed in Table 3.
Lyme Disease
Lyme borreliosis (LB) is a multisystemic illness caused by the tick-transmitted spirochete Borrelia burgdorferi. The neurologic manifestations of LB, often called Lyme neuroborreliosis (LNB), can be difficult to diagnose and treat. Many excellent reviews of LB and LNB are available, and this chapter focuses on practical aspects of management for the neurologist. Although ideally the diagnosis would be straightforward and management would be primarily focused on issues of therapy, the major efforts of the neurologist, and the most perplexing problems, lie in diagnosis. If diagnosis is approached in a rational manner, therapy and management are generally straightforward. Thus, this chapter addresses the diagnosis in depth first and then discusses therapy.
Diagnosis
The diagnosis of LNB can occasionally be made purely from the history and neurologic examination. Usually, the diagnosis is considered as possible or probable on the initial evaluation and then confirmed by laboratory testing.
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177
HISTORY Travel to Endemic Areas It is important to get a travel history for three reasons. First, patients without exposure to field mice, generally in forested areas, are unlikely to have been infected. Secondly, European and American LNB may differ somewhat in clinical presentation in that a painful radiculitis is more common in the former, and thus a history of travel to Europe and outdoor activity there may be helpful. Third, there is a range of endemicity of the infection in the United States: from hyperendemic states in New England and the upper Midwest to states where LB is extremely rare such as Florida or Arizona. Travel to the former areas is more likely to be associated with infection. Erythema Migrans The only uniquely diagnostic clinical finding in LNB is a history of erythema migrans (EM), the skin rash of early infection. A careful attempt to document the type of skin rash involved will pay off for the neurologist, since many times what a patient considers as a likely skin rash will turn out to have been an insect bite reaction or an allergic reaction of some sort. Thus, with respect to the history, the neurologist considering LNB must function briefly as a dermatologist. EM is rarely present at the time the patient is initially seen by the neurologist, and thus accurate questions help identify a history of this extremely helpful diagnostic sign. EM is the dermatologic sign indicating an inflammatory reaction to the spread of the spirochete through the skin shortly after initial infection. Therefore, EM in the highly endemic areas of the United States appears in the late spring, summer, or early fall. A rash in February in Connecticut is unlikely to be EM, no matter what its other characteristics. EM is a red, often raised lesion, usually near the site of the tick bite, which increases in diameter over days. Because the spirochete disseminates from the skin, systemic symptoms (malaise, lethargy, fatigue) are often present at some point during the rash and can persist for many days to weeks. The maximal size of the lesion is usually well over 5 cm. Characteristics that differentiate EM from insect bite reaction, the lesion most frequently confused with it, are summarized in Table 1. Arthritis Many patients with LNB have arthralgias, but intermittent joint pain is nonspecific. However, the occurrence of actual arthritis ( joint swelling, pain, erythema, heat, limitation of movement), especially in a characteristic pattern, can be a helpful diagnostic clue. The joints most commonly involved in LB are the knees. Other joints less commonly affected are large joints such as hips, elbows, or ankles. Hands are rarely involved.
TABLE 1 Erythema Migrans (EM) Versus Insect Bite Reaction

Characteristic General appearance Itchiness Diameter (cm) Time course Systemic symptoms Occurring in low endemic areas EM Raised erythema +/ >5 Increasing in size over 1 wk Frequent Unusual Insect Bite Reaction Raised erythema ++ <5 Decreasing in size over 1 wk Unusual Frequent
Neurologic Symptoms The most common presentation for LNB in the United States is that of a chronic basilar meningitis, often with seventh cranial nerve palsy. Headache, stiff neck, malaise, mild encephalopathy, and fatigue are common symptoms. Sometimes, patients have an associated radiculoneuropathy, especially in Europe, so that radiculitic or neuropathic symptoms can occur. The radiculitis is usually unilateral and cervical, whereas the neuropathy generally is that consistent with mononeuritis multiplex rather than diffuse stocking-glove. Thus, LNB can manifest as either a primarily central nervous system (CNS) or a peripheral nervous system process or a combination. Fatigue is a common symptom in LNB but almost never occurs alone. Thus, chronic fatigue, especially lasting for more than a few weeks, as the predominant symptom without other findings, should not prompt a vigorous search for LNB. Another symptom complex that requires considerable clinical skill is encephalopathy. Many patients ill with a variety of inflammatory problems note problems with attention and concentration and complain of difficulties with short-term memory. Thus, these symptoms are highly nonspecific. On the other hand, spirochetal invasion of the brain in LNB is well documented, and true encephalopathies can be seen, albeit uncommonly. Therefore, I generally attempt to differentiate between attention/concentration problems and symptoms more compatible with significant encephalopathy. If I have any question about the severity of the symptoms, I usually obtain formal neuropsychological testing, since encephalopathic symptoms can be extremely disabling. EXAMINATION Erythema Migrans The evaluation for LNB should include a search for skin lesions compatible with LNB, especially if the symptoms suggest a basilar meningitis and have been present for less than 6 weeks. The finding of one or more EM-like lesions, even if faded, is helpful.
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Facial Palsy Facial palsy is common in LNB and cannot be distinguished clinically from routine idiopathic Bells palsy. In fact, it is my opinion that all Bells palsies are due to infections with one of a wide variety of organisms, many not yet discovered or easily diagnosed. The same rules for the finding of any facial weakness applies in LNB; that is, the finding of facial asymmetry should prompt questions of whether it has been noted by the patient and whether it is present in pictures of the patient, as in picture IDs carried in the wallet or purse. Radiculoneuropathic Findings Patients with LNB frequently have symptoms of tingling, numbness, and dysesthesias. In Europe, Bannwarths syndrome is common, in which patients complain of severe, radiculitic pain; this is not common in the United States. Examination in LNB patients can display loss of deep tendon reflexes, especially in symptomatic limbs, and areas of dysthesia or hypesthesia. Paresis is uncommon. Encephalopathy Routine mental status testing is rarely abnormal in LNB, and most patients with encephalopathic symptoms require formal neuropsychological testing for adequate evaluation. Laboratory Testing The major clinically useful tests for specific diagnosis are those measuring the antibody to B. burgdorferi present in the blood or cerebrospinal fluid (CSF). The two antibody assays used most commonly and with the greatest effectiveness are the enzyme-linked immunosorbent assay (ELISA) and immunoblot. The usefulness of these diagnostic tests varies depending on how long the patient has been infected. The assays of antibody activity increase in usefulness with time after infection. Thus, a negative serum ELISA in a patient who has had symptoms for 3 months almost rules out the diagnosis of LNB. The ELISA measures antibody-binding activity in serum or CSF. Different laboratories use different techniques in performing the assay, and they use different ways of reporting the results. Most laboratories use an index to report results, in which normal sera are used to generate a cutoff value, and then the patients serum has a value relative to the cutoff. Positive values near the cutoff often represent artifactually positive or falsepositive results, whereas values considerably above the cutoff have a higher likelihood of representing true seropositivity. The most serious problem in the ELISA is the high incidence of false-positive results, a situation ameliorated by the availability of the immunoblot. A potent tool for determining whether a positive ELISA is a true versus false positive is the immunoblot. This technique gives a qualitative picture of antibody binding (what proteins of the organism are targeted by
antibody) in distinction to the ELISA, which simply gives quantitative information (antibody-binding activity). The immunoblot has proved to be an indispensable tool in the diagnosis of other infections. A similar situation is ideal for Lyme disease; what currently prevents application of this tool is the lack of standardization of the B. burgdorferi immunoblot and the lack of a single diagnostic band that is always positive in infected patients and negative in uninfected patients. The CDC has recently recommended criteria for positive immunoblots that are an important step for standardization, but at this time (2005), different laboratories do their immunoblots in different ways. Therefore, in an ELISA-positive patient in whom the clinical picture does not match the results of the immunoblot at one laboratory, testing at another laboratory may be indicated for confirmation. The neurologist is fortunate in having availability of the CSF for diagnosis. The diagnosis of LNB cannot be made confidently without the presence of an abnormal CSF, generally a lymphomonocytic pleocytosis and presence of anti-B. burgdorferi antibody in the CSF. There are some patients who do not have both a pleocytosis and an antibody, but absence of both is distinctly unusual. Given the vagaries of other diagnostic tools in this infection, I obtain CSF on all patients in whom I am strongly considering the diagnosis, even those in whom the clinical diagnosis appears straightforward. To proceed in therapy of LNB without obtaining a lumbar puncture (LP) is a dangerous practice and has led many physicians into trouble. The LP is the only laboratory test useful for the positive diagnosis of LNB; magnetic resonance scanning, electroencephalogram, evoked responses, and other tests are useful usually only in ruling out other processes. Anti-B. burgdorferi antibody in the CSF is almost always positive in LNB. In Europe, the intrathecal production of antibodies in LNB is so strong that the antibody index above 1 or 1.5 is used as a diagnostic test. However, in the United States, LNB does not always induce levels of CSF antibodies higher than serum antibodies, so simply the presence or absence of antibodies suffices. Using simply the presence of CSF antibody, rather than a raised index, makes it possible that a patient with viral meningitis and an exposure positivity to the spirochete can be misdiagnosed (i.e., false-positive Lyme diagnosis), but that is a rare scenario. Polymerase chain reaction (PCR) testing for B. burgdorferi DNA in the CSF has not been helpful. The main reason is the low diagnostic sensitivity, since the spirochete is tropic to tissue and does not remain in body fluids for long. In addition, this test does not have widespread availability, and for many neurology practices the turnaround time for the assay is not optimal.
Therapy
All patients with probable or definite LNB should be treated with antibiotics. The routine practice for antibiotic therapy of disseminated Lyme disease in the United States and Europe is different. Thus, patients in Europe tend to receive oral antibiotics for LNB,
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whereas American patients tend to be treated with IV antibiotics. The discussion of the therapy of LNB is divided into three parts: management of patients (1) with probable LNB, (2) without LNB, and (3) with possible LNB. The discussion also includes therapy of the inflammation associated with Lyme disease. PATIENTS WITH PROBABLE LNB In this group of patients are those with a convincing history of EM, and/or a clinical picture consistent with LNB and diagnostic laboratory findings. (The diagnosis of definite LNB can now be made only by culture of the spirochete from the CSF; culture is such a low-yield procedure that it is generally done only in a research setting.) Patients with active infection of their nervous systems with B. burgdorferi have two almost independent processes occurring: infection and inflammation. Therapy should be focused on both of these processes. Infection B. burgdorferi in vitro is extraordinarily sensitive to antibiotics. Studies of infection in vivo have demonstrated less dramatic responses, frequently because measures of response have sometimes confused infection with inflammation; that is, many of the patients symptoms are secondary to inflammation, which may linger despite adequate therapy of the infection. Thus, relatively little is known about the actual response of B. burgdorferi to antibiotics in vivo, since measures of infection in vivo are imprecise. My experience has been that therapy for 2 to 3 weeks with intravenous penicillin or ceftriaxone is curative of infection in LNB. This therapy results in reversal of rising serum antibody titers, stabilization and subsequent decline of CSF antibody levels, resolution of CSF pleocytosis, decrease in symptoms, and eradication of organisms in the CNS as demonstrated by resolution of PCR positivity. Doses of penicillin to use are identical to those in neurosyphilis (20 million units per day in six divided doses). Ceftriaxone is effective at 1 gm IV twice daily. I use 2 gm rather than 4 gm of ceftriaxone since the latter has resulted in an unacceptable incidence of pseudomembranous colitis. I tend to use ceftriaxone in most of my patients since I can give it to them on an outpatient basis. In cephalosporin- and penicillin-allergic patients (most penicillin-allergic patients can still receive ceftriaxone with the first dose under supervision), administration of oral doxycycline 200 mg twice daily for 21 days would be a reasonable alternative. In some centers, intravenous chloramphenicol 1 gm per day divided into four doses for 14 days has been used; data on this option are not adequate to evaluate its efficacy. Patients should be counseled that sometimes their symptoms resolve quickly, whereas at other times their symptoms take many weeks to months to go away. Often the sickest patients resolve the quickest and less symptomatic patients may take longer to become asymptomatic. In those individuals with slow resolution,
I tell them that they should expect the sum total of their symptoms over a month to improve month by month. They should definitely not get worse. If patients do not improve or get worse, they fall into that unusual category of refractory. Inflammation In some patients infection with B. burgdorferi triggers a marked inflammatory syndrome, with extensive symptoms consistent with other highly inflammatory diseases. These patients are identified by their symptoms of arthralgias, myalgias, and severe intermittent fatigue, not by sedimentation rates or other laboratory parameters since these are not always elevated. This subgroup of patients may require considerable longterm follow-up and therapy with anti-inflammatory agents. The situation is reminiscent of eosinophiliamyalgia syndrome, in which marked inflammation can persist for long periods despite withdrawal of the inciting agent. The disorder in these patients can be differentiated from fibromyalgia by the absence of trigger spots and sleep disorder. However, some patients can have an overlap syndrome and may respond to antifibromyalgia therapy, such as antidepressants for sleep and increase in aerobic exercise. I begin treating inflammation with over-the-counter anti-inflammatory agents such as aspirin, ibuprofen, or naproxen, sometimes going to high doses. I then move to prescription nonsteroidal anti-inflammatory drugs
TABLE 2 Features Casting Doubt on the Diagnosis of Lyme Neuroborreliosis (LNB)

Feature Clinical Finding Guillain-Barr syndrome Stroke Psychiatric disease Motor neuron disease Trigeminal neuralgia Acute, overt encephalitis Fibromyalgia alone Fatigue alone Neurologic condition believed to be LNB but without effect of antibiotics Transverse myelopathy with a sharp sensory level Significant cognitive impairment without other signs or laboratory findings of encephalomyelitis Clinical syndrome of CNS mass lesion Lack of CSF pleocytosis Predominant PMN differential in CSF Lack of detectable anti-Borrelia burgdorferi antibodies in serum > 2 mo after onset Lack of detectable anti-B. bugdorferi antibodies in CSF > 2 mo after onset
Laboratory
CNS, Central nervous system; CSF, cerebrospinal fluid; PMN, polymorphonuclear leukocyte. Adapted from Hansen K: Lyme neuroborreliosis: improvements in the laboratory diagnosis and a survey of epidemiological and clinical features in Denmark 1985-1990, Acta Neurol Scand Suppl 151:5-44,1994.
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(NSAIDs) if over-the-counter agents do not work. I have needed to use corticosteroids in the rare patient, but this therapy was begun only after adequate antibiotic therapy and after failure of NSAIDs. Daily steroids are initiated, switched within a few weeks to every-other-day steroids, and then tapered over a few months. PATIENTS WITHOUT LNB Frequently in my practice patients are referred to me for therapy of LNB when there is little or nothing to suggest this diagnosis. The patient history outlined here is a particularly striking and tragic example. S.W. was a talented young artist who in June 1990 began to note some mild left arm tingling while summering with her other artist friends on Marthas Vineyard, a highly
endemic area for Lyme disease. She had had a small round skin lesion on her calf 3 weeks earlier, consistent with an insect bite reaction, which had cleared within a few days. Her friends were convinced that she had Lyme disease and vociferously convinced both S.W. and the local physician. She was begun initially on doxycycline for 1 month, but when that had no lasting effect, she was given 3 weeks of intravenous ceftriaxone (Rocephin). A persistent trend of an initial few days of improvement coupled with long-term failure of response led to a multitude of oral and intravenous antibiotics by her physicians. By the time I first saw her in November, when she carried the diagnosis of CNS Lyme disease refractory to multiple courses of antibiotics, she had an unmistakable left hemiparesis. CT scan revealed a right temporoparietal mass, which on surgery was a glioblastoma.
History and examination suggestive of LNB and absence of other diagnoses
Lumbar puncture
FIGURE 1. Diagnosis and therapy of Lyme neuroborreliosis (LNB). CSF, Cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; PCN, penicillin; CEF, ceftriaxone; NSAID, nonsteroidal anti-inflammatory drug.
CSF lymphomonocytic pleocytosis Negative CSF anti-B. burgdorferi antibody Negative Not LNB Negative Positive sAb* Positive Negative Recheck CSF Ab Pleocytosis from other cause Positive Repeat sAb in 2 wks Negative sAb* Negative Positive CSF anti-B. burgdorferi antibody Positive sAb* Positive
Probable LNB
Therapy with PCN/CEF and NSAIDs 26 months later Treatment failure Treatment success
Revisit diagnosis
Consider increasing anti-inflammatories
No further evaluation or Rx
*sAb = serum ELISA and immunoblot
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Surgery and irradiation were partially successful, but she died in the summer of 1991. The surgeons felt that surgery at an earlier date may have been curative. This patient, who had a number of features casting doubt on the diagnosis of Lyme neuroborreliosis (Table 2), should never have been given the diagnosis of CNS Lyme disease, since an evaluation for other causes would have yielded the correct diagnosis. Alternatively, there are patients who do not have clear diagnoses even after evaluation and have symptoms that might be attributable to LNB but are highly nonspecific, such as intermittent headache, numbness and tingling, and low-grade encephalopathy. Patients with protracted symptoms deserve thorough analysis, but if after serum and CSF analysis, there is nothing to implicate LNB, it is questionable medical judgment to treat these patients to see what will happen. Antibiotic therapy in patients without LNB has a low chance of success, a significant chance of side effects, and distracts diagnostic focus; it should thus not be done. PATIENTS WITH POSSIBLE LNB The group of patients with possible LNB has some features that may be consistent with LNB but do not meet diagnostic criteria. This is perhaps the most difficult variety of situations to manage. For instance, patients with viral (aseptic) meningitis have symptoms and CSF pleocytosis indistinguishable from those of LNB. The second series of tests outlined in Figure 1, antibody tests of CSF and serum, often are not available immediately after the LP. Thus, depending on the clinical suspicion of LNB and the degree of illness of the patient, I sometimes initiate doxycycline or ceftriaxone therapy. I do not do this in a patient with mild symptoms and nothing to implicate LNB other than lymphocytic pleocytosis. If positive serologies return after a few days on the latter type of patient, antibiotics can be initiated at that time. The delay of a few days does not adversely affect the outcome and saves the patient from potential adverse effects of the antibiotics. A similarly difficult presentation to treat is that of the patient with sudden onset of facial palsy without other indicators of LB. Most of these patients have idiopathic Bells palsies, and LP or antibiotics are not justified. In such patients I obtain an initial serum Lyme antibody. If that is negative, I treat the patients palsy as a routine Bells palsy but I repeat the serology in 3 weeks. If the patient seroconverts, or if the initial serology is positive, I obtain an LP and use the CSF results to guide therapy. Thus, patients with pleocytosis or a positive CSF antibody are treated with ceftriaxone, while those with a negative CSF profile but a positive serum antibody are treated with doxycycline. Given the complexity of the disease, and the complexity of the nervous system, there are many more potential scenarios that raise important management questions. In general, LNB is not a medical emergency, and there is time to evaluate data and obtain more information before making major management decisions. There has been a recent increase in the overdiagnosis of
LNB and in its overtreatment, two mistakes that can be prevented by obtaining adequate studies and carefully considering treatment options. SUGGESTED READING
Halperin JJ, Luft B, Anand AK, et al: Lyme neuroborreliosis: central nervous system manifestations, Neurology 39:753-759, 1989. Hansen K: Lyme neuroborreliosis: improvements in the laboratory diagnosis and a survey of epidemiological and clinical features in Denmark 1985-1990, Acta Neurol Scand Suppl 151:5-44, 1994. Pachner AR: Early disseminated Lyme disease: Lyme meningitis, Am J Med 98:4A30S-4A43S, 1995. Pachner AR, Dail D, Bai Y, et al: Genotype of infecting strain determines phenotype of infection in experimental Lyme borreliosis, Ann Neurol 56:361-370, 2004. Shadick NA, Phillips CB, Logigian EL, et al: The long-term clinical outcomes of Lyme disease: a population-based retrospective cohort study, Ann Intern Med 121:560-567, 1994.
PATIENT RESOURCES
American Lyme Disease Foundation Phone: 914-934-9155 Phone hotline: 800-876-5963 Centers for Disease Control and Prevention (CDC) Phone: 404-332-4555 New York State Health Department Phone: 518-474-4568
Cerebral Malaria
Tom Solomon, M.D., Ph.D., and Tom Blanchard, M.D.
Cerebral malaria is an acute cerebral dysfunction (an encephalopathy) caused by infection with the parasite Plasmodium falciparum. The three other malaria parasitesPlasmodium vivax, Plasmodium malariae, and Plasmodium ovaledo not cause cerebral malaria, though they may cause febrile seizures in children. P. falciparum can cause a range of severe complications affecting many organs of the body. Thus there are many potential causes of reduced consciousness in someone infected with P. falciparum, including hypoglycemia, acid-base disturbance, severe anemia, and seizures. For research purposes the World Health Organization has defined cerebral malaria as unrousable coma (i.e., a nonpurposeful response to a painful stimulus) in patients in whom these metabolic deficits and seizures have been corrected. However, for practical purposes, all patients with P. falciparum infection and altered consciousness, including those who are drowsy or irritable, should be treated as if they have severe disease. How P. falciparum infection causes cerebral malaria is not known, but sludging of parasitized red blood cells as they pass through the blood vessels of the brain (known as sequestration) is thought to be critically important.
Cerebral Malaria
181
Surgery and irradiation were partially successful, but she died in the summer of 1991. The surgeons felt that surgery at an earlier date may have been curative. This patient, who had a number of features casting doubt on the diagnosis of Lyme neuroborreliosis (Table 2), should never have been given the diagnosis of CNS Lyme disease, since an evaluation for other causes would have yielded the correct diagnosis. Alternatively, there are patients who do not have clear diagnoses even after evaluation and have symptoms that might be attributable to LNB but are highly nonspecific, such as intermittent headache, numbness and tingling, and low-grade encephalopathy. Patients with protracted symptoms deserve thorough analysis, but if after serum and CSF analysis, there is nothing to implicate LNB, it is questionable medical judgment to treat these patients to see what will happen. Antibiotic therapy in patients without LNB has a low chance of success, a significant chance of side effects, and distracts diagnostic focus; it should thus not be done. PATIENTS WITH POSSIBLE LNB The group of patients with possible LNB has some features that may be consistent with LNB but do not meet diagnostic criteria. This is perhaps the most difficult variety of situations to manage. For instance, patients with viral (aseptic) meningitis have symptoms and CSF pleocytosis indistinguishable from those of LNB. The second series of tests outlined in Figure 1, antibody tests of CSF and serum, often are not available immediately after the LP. Thus, depending on the clinical suspicion of LNB and the degree of illness of the patient, I sometimes initiate doxycycline or ceftriaxone therapy. I do not do this in a patient with mild symptoms and nothing to implicate LNB other than lymphocytic pleocytosis. If positive serologies return after a few days on the latter type of patient, antibiotics can be initiated at that time. The delay of a few days does not adversely affect the outcome and saves the patient from potential adverse effects of the antibiotics. A similarly difficult presentation to treat is that of the patient with sudden onset of facial palsy without other indicators of LB. Most of these patients have idiopathic Bells palsies, and LP or antibiotics are not justified. In such patients I obtain an initial serum Lyme antibody. If that is negative, I treat the patients palsy as a routine Bells palsy but I repeat the serology in 3 weeks. If the patient seroconverts, or if the initial serology is positive, I obtain an LP and use the CSF results to guide therapy. Thus, patients with pleocytosis or a positive CSF antibody are treated with ceftriaxone, while those with a negative CSF profile but a positive serum antibody are treated with doxycycline. Given the complexity of the disease, and the complexity of the nervous system, there are many more potential scenarios that raise important management questions. In general, LNB is not a medical emergency, and there is time to evaluate data and obtain more information before making major management decisions. There has been a recent increase in the overdiagnosis of
LNB and in its overtreatment, two mistakes that can be prevented by obtaining adequate studies and carefully considering treatment options. SUGGESTED READING
Halperin JJ, Luft B, Anand AK, et al: Lyme neuroborreliosis: central nervous system manifestations, Neurology 39:753-759, 1989. Hansen K: Lyme neuroborreliosis: improvements in the laboratory diagnosis and a survey of epidemiological and clinical features in Denmark 1985-1990, Acta Neurol Scand Suppl 151:5-44, 1994. Pachner AR: Early disseminated Lyme disease: Lyme meningitis, Am J Med 98:4A30S-4A43S, 1995. Pachner AR, Dail D, Bai Y, et al: Genotype of infecting strain determines phenotype of infection in experimental Lyme borreliosis, Ann Neurol 56:361-370, 2004. Shadick NA, Phillips CB, Logigian EL, et al: The long-term clinical outcomes of Lyme disease: a population-based retrospective cohort study, Ann Intern Med 121:560-567, 1994.
PATIENT RESOURCES
American Lyme Disease Foundation Phone: 914-934-9155 Phone hotline: 800-876-5963 Centers for Disease Control and Prevention (CDC) Phone: 404-332-4555 New York State Health Department Phone: 518-474-4568
Cerebral Malaria
Tom Solomon, M.D., Ph.D., and Tom Blanchard, M.D.
Cerebral malaria is an acute cerebral dysfunction (an encephalopathy) caused by infection with the parasite Plasmodium falciparum. The three other malaria parasitesPlasmodium vivax, Plasmodium malariae, and Plasmodium ovaledo not cause cerebral malaria, though they may cause febrile seizures in children. P. falciparum can cause a range of severe complications affecting many organs of the body. Thus there are many potential causes of reduced consciousness in someone infected with P. falciparum, including hypoglycemia, acid-base disturbance, severe anemia, and seizures. For research purposes the World Health Organization has defined cerebral malaria as unrousable coma (i.e., a nonpurposeful response to a painful stimulus) in patients in whom these metabolic deficits and seizures have been corrected. However, for practical purposes, all patients with P. falciparum infection and altered consciousness, including those who are drowsy or irritable, should be treated as if they have severe disease. How P. falciparum infection causes cerebral malaria is not known, but sludging of parasitized red blood cells as they pass through the blood vessels of the brain (known as sequestration) is thought to be critically important.
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The most common clinical picture in cerebral malaria is of a diffuse symmetrical encephalopathy, which may manifest as gradually increasing drowsiness, confusion, or agitation or may follow a seizure. Seizures are common in cerebral malaria, especially in children. Often there are no focal neurologic signs, but bruxism (teeth grinding), increased tone, decreased tone, flexor or extensor posturing, and opisthotonus may occur. In children coma may occur without any preceding fever or other symptoms. A characteristic retinopathy, which consists of patchy whitening of the fundus and small vessels, with retinal hemorrhages, may be seen on funduscopy.
Diagnosis
The diagnosis of cerebral malaria should not be difficult, but there are some common pitfalls (Table 1). One of the biggest mistakes is in not thinking of the diagnosis in the first place; unless you ask about travel for every patient with an acute encephalopathy, you will miss some cases. Be wary of diagnosing flu in a returning traveleran urgent examination of blood films is required to exclude malaria. Make sure that the laboratory does thick films, which have the maximum chance of seeing parasites, and thin films, which allow the Plasmodium species to be identified. Another common mistake is to assume that because a traveler took antimalarial chemoprophylaxis, malaria is not possible. Antimalarials do not provide complete protection, but unwary travelers may allow mosquitoes to bite them in the mistaken belief that they are protected. Furthermore antimalarial chemoprophylactic drugs can make the diagnosis harder; they lengthen the incubation period beyond the 1 to 2 weeks that is quoted in many textbooks, and they make it less likely that parasites will be
seen on a blood film. In a similar way, do not be misled by patients who cannot have malaria because they were brought up in Africa and have natural immunity. Such natural immunity wanes in those who have been living in nonendemic areas for awhile; the native African who has lived in the West for many years and then returns home for a holiday may well get malaria. However, because they have some immunity, the incubation period may again be prolonged, and diagnosis by blood film examination may again be difficult. Sometimes, in partially treated patients, malaria pigment within neutrophils or monocytes may be easier to see than parasites. Mild thrombocytopenia (<100,000 platelets/L) is common in malaria and may be a clue that a patient has malaria, even if the parasites cannot be seen; a normochromic normocytic anemia is also common, and a leukopenia is also sometimes seen. At least three blood films should be examined before declaring a patient to be negative for malaria. However, for most patients with severe malaria, the parasites are easily identified on a thick film in an experienced laboratory. Newer rapid diagnostic methods include stick tests for malaria antigens and polymerase chain reaction, but they should not replace blood film examination. In patients in whom there is no contraindication, a lumbar puncture should be considered to exclude other pathologies. This is especially important in patients living in malaria-endemic areas, where many people have asymptomatic parasitemia, and coma may be due to a coexistent bacterial meningitis. In the West it may be preferable to perform a computed tomography scan before lumbar puncture, especially in patients with deep coma or focal neurologic signs. But do not allow performing the lumbar puncture to delay treatment with antimalarial drugs. Although raised intracranial pressure, as determined by cerebrospinal fluid opening pressure, is common in cerebral malaria, it is unclear whether this contributes to the pathophysiology.
TABLE 1 Suspicion of Cerebral Malaria

Category Caveats Assessment Always take a travel history Beware of patients who cannot have malaria because they took prophylaxis or are immune Coma Score Seizures?obvious or subtle Hyperventilation?acidosis, pulmonary edema, or pneumonia Fluid balancedehydration? Thick and thin blood film for parasites and pigment (repeated if necessary) Clues if blood film negative: thrombocytopenia? malaria pigment in neutrophils and monocytes? Blood glucose Complete blood count; urea and electrolytes; blood gases or venous lactate for acidosis; blood culture Lumbar puncture if no contraindication
Management
General supportive measures include giving oxygen by mask, nursing the patient at an angle of 30 degrees, and using antipyretics to control high fevers (Table 2). In an unconscious patient the airway should be secured, and a nasogastric tube should be passed to prevent aspiration pneumonia. If cerebral malaria seems likely, and there will be a delay in obtaining the malaria film result, antimalarial treatment should be started.
Evaluations
Initial investigations
Antimalarial Drugs
Since the Jesuit missionaries brought Peruvian cinchona bark back to the West more than 400 years ago, quinine has been the mainstay of treatment for severe malaria. Although oral quinine can be useful in nonsevere malaria, intravenous quinine should be used in cerebral malaria. Give a loading dose of 20 mg/kg (up to a maximum of 1400 mg) of quinine dihydrochloride salt over 4 hours in 5% dextrose saline or a similar fluid.
Cerebral Malaria
183
TABLE 2 Treatment of Cerebral Malaria

Category General approach Quinine dihydrochloride salt: Adult Loading Maintenance Oral Quinine dihydrochloride salt: Children Loading Maintenance Oral Second drug Adult Children Unexpected deterioration Other treatable complications Measures Oxygen administration, nurse at 30 degrees, antipyretics; secure airway, insert nasogastric tube 20 mg/kg IV over 4 hr 10 mg/kg IV over 4 hr; starting 8 hr after start of loading dose and repeated q 8 hr, until patient can swallow then 10 mg/kg q 8 hr to complete 7-day course 20 mg/kg IV over 4 hr 10 mg/kg IV over 4 hr; starting 12 hr after start of loading dose and repeated q 12 hr, until patient can swallow then 10 mg/kg q 8 hr to complete 7-day course Doxycycline 100 mg q 12 hr for 7 days Fansidar (sulfadoxine 500 mg + pyrimethamine 25 mg): Aged 4 yr, 1/2 tablet; 5-6 yr, 1 tablet; 7-9 yr, 1 1/2 tablet; 10-14 yr, 2 tablets Check for hypoglycemia, subtle motor seizures, bacterial coinfection Resistance to quinine? consider using artemisinin derivatives Anemia, acidemia, acute renal failure, pulmonary edema, hyperparasitemia
*Consider using artesunate if the patient originated in Southeast Asia.
Note that, unlike with other antimalarial drugs, quinine doses are usually prescribed as doses of salt rather than base; mistakes here can lead to overtreatment. Eight hours after the first dose was started, give 10 mg/kg (up to a maximum of 700 mg) over 4 hours, and repeat this every 8 hours, until the patient is sufficiently recovered to take the drug orally. This should be given as quinine sulfate 10 mg/kg every 8 hours to complete treatment for 7 days. Quinine is followed by a second drug to prevent recrudescence of parasites. Until recently Fansidar (sulfadoxine 500 mg and pyrimethamine 25 mg; three tablets as a single dose) was usually given, but because of increasing resistance to Fansidar, many now give doxycycline (100 mg every 12 hours for 7 days), which can be started as soon the patient can swallow. Warn your patients that the quinine may cause an unpleasant buzzing in the ears, sometimes with nausea and vomiting; this cinchonism is temporary. Children should be treated with intravenous quinine, calculated on the same milligram per kilogram basis as for adults, but given less frequently (see Table 2), followed by oral quinine (10 mg/kg to complete 7 days). This should be followed by a single dose of Fansidar (ranging from 1/2 to 2 tablets, depending on age (see Table 2). Doxycycline should not be used in children younger than 8 years of age or pregnant women. Malarone (atovaquone-proguanil) is an alternative second-line drug, but mefloquine should not be used because of an increased risk of late neuropsychiatric sequelae (see later). In pregnancy the adult intravenous and oral doses of quinine can be used, though there is an increased risk of hypoglycemia (see later). In parts of the tropics with limited resources
quinine dihydrochloride can be given as a deep intramuscular injection. In China, the herb qinghaosu (artemisinin) has been used to treat fevers for at least 2000 years. Its derivatives, including artesunate and the oil-soluble artemether, are often used to treat cerebral malaria in Asia. They are as effective as quinine, clearing parasites more quickly; are less toxic; and are easier to give. In addition they are effective against chloroquine-resistant and multidrug-resistant P. falciparum. The artemisinin derivatives are not yet widely available in the West. However, in some centers they are used for patients who became infected in mainland Southeast Asia (Thailand, Burma, Cambodia, Vietnam), where there is quinine resistance, or because of a failure to respond to treatment. They are likely to be used increasingly in the future. Intravenous artesunate is given as a loading dose of 2.4 mg/kg, followed by 1.2 mg/kg at 12 and 24 hours, and then 1.2 mg/kg daily. Intramuscular artemether is given as a loading dose of 3.2 mg/kg followed by 1.6 mg/kg daily. Its absorption can be a little erratic, so artesunate is preferable. They should be given for at least 7 days and should be used in combination with oral doxycycline (100 mg every 12 hours) once the patient can swallow.
Treating Seizures
Seizures are common in cerebral malaria, occurring in 40% of adults and an even higher percentage of children. In addition to clinically obvious generalized tonic-clonic
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seizures, subtle motor seizures frequently occur, particularly in children. These may manifest as twitching of digit, lip, or eyebrow; tonic deviation of the eyes; excess salivation; or changes in the respiratory pattern. All patient should be examined carefully for such features; if there is any doubt, an electroencephalogram should be performed, which will show status epilepticus. However, prophylactic treatment of seizures with phenobarbitone in African children was found to be deleteriouspossibly because of an interaction with benzodiazepines leading to respiratory depression. Treatment of seizures in cerebral malaria is similar to that in other conditions. A single intravenous dose of lorazepam (4 mg in adults, 0.1 mg/kg in children) or diazepam (10 to 20 mg in adults, 0.25 to 0.5 mg/kg in children) is followed after 10 minutes by a second dose if needed. Lorazepam is preferred because it has a longer half-life and is thought to be less sedating; diazepam has the advantage that it can be given rectally if there is no intravenous access. For children still in status, paraldehyde 0.4 mL/kg (mixed with an equal volume of olive oil) is given rectally. If seizures persist, intravenous phenytoin, 15 mg/kg, at a rate not exceeding 50 mg/min, is given. Check phenytoin levels 2 hours after the infusion, and be prepared to reload (or half reload) if necessary. The loading dose is followed by maintenance phenytoin dose of 100 mg every 6 to 8 hours (in adults), with monitoring of plasma concentrations. In children give 5 mg/kg daily for maintenance. Fosphenytoin is a prodrug of phenytoin that can be given more rapidly and with fewer local reactions than phenytoin. If seizures persist despite phenytoin loading, most patients in the West would be electively paralyzed and ventilated in an intensive care unit. If that is not possible, giving phenobarbitone 15 to 20 mg/kg over 20 minutes, in addition to phenytoin, may help. Sodium valproate, 10 mg/kg over 5 minutes, is also sometimes used as an additional measure to try to control status, short of admitting a patient to the intensive care unit.
renal failure often occurs. Acute renal failure is usually treated with renal dialysis in the West, but peritoneal dialysis is also often used in the tropics. Blackwater fever is a severe hemolytic syndrome, associated with hemoglobinuria and acute renal failure, seen in adults with P. falciparum infection. It is more common in those with glucose-6-phosphatase deficiency, and may be precipitated by quinine treatment. Anemia, particularly in young children, follows red blood cell destruction by parasites and indirect effects on the bone marrow and is treated with blood transfusion. If more than 5% of a patients red blood cells contain parasites, this is defined as hyperparasitemia. Although the management of mild hyperparasitemia is not different from that of other severe manifestations of disease, exchange blood transfusion should be considered if there is more than 10% hyperparasitemia. Secondary bacterial infections including aspiration pneumonia and urinary tract infections are common. An unexpected drop in the blood pressure may herald the onset of septic shock, and appropriate antibiotic therapy should be started without delay. With effective antimalarial drugs, and appropriate supportive treatment of the other complications, most patients with cerebral malaria begin to improve within a few days, but approximately 20% of patients die. Neurologic sequelae were thought to be almost unknown in survivors, but recent studies have shown that 5% to 10% of patients are left with a deficit, such as a hemiparesis, cerebellar ataxia, amnesia, diffuse spasticity, or epilepsy.
Related Problems
A variety of late neurologic complications may occur following recovery from acute P. falciparum malaria. These postmalaria neurologic syndromes may include encephalopathy, psychosis, parkinsonian rigidity and tremor, and cerebellar dysfunction. Although they are most often described 1 to 2 days after recovery from cerebral malaria, they are also reported after uncomplicated malaria. The cause of these late manifestations is not known, but treatment with mefloquine is a risk factor. Symptoms usually resolve over days or weeks. Mefloquine is one of many drugs used as antimalarial prophylaxis in those visiting or living in tropical areas. A detailed discussion of prophylaxis is beyond the scope of this chapter. However, it is worth noting that mefloquine prophylaxis is associated with neuropsychiatric adverse events, ranging from vivid dreams to convulsions. The drug should be avoided in those with a history of neuropsychiatric diseases, including depression and seizures. Chloroquine should also be avoided in those with epilepsy. SUGGESTED READING
Anonymous: Management of severe malaria, ed 2, Geneva, 2000, World Health Organization. White NJ: Malaria. In Cook GC, Zumla A, editors: Mansons tropical diseases. London, 2003, WB Saunders, 1205-1295. Johnson: Current Therapy in Neurologic Disease (7/E)
Managing Other Complications of Severe Disease

P. falciparum infection can lead to a range of other severe complications, in addition to cerebral disease, which must be looked for and treated. Hypoglycemia is common in children with P. falciparum malaria, and in adults (especially pregnant women) treated with quinine; it is a common cause of sudden deterioration and should be corrected with a dextrose solution. Assessment of fluid balance is critical. Careful assessment of the jugular venous pressure, peripheral perfusion, skin turgor, and urine output should be made. Insertion of a central venous pressure line may be necessary. Dehydration is common in patients who have had recurrent vomiting, and deep respiration may indicate severe acidemia. Both of these should be corrected with rapid fluid volume replacement. However, fluid balance should be carefully monitored because of the risk of precipitating pulmonary edemaespecially in pregnant womenand because
SECTION 8
Other Inflammatory and Demyelinating Diseases

Optic Neuritis
Neha P. Amin, B.S., and Laura J. Balcer, M.D., M.S.C.E.
is usually subacute, progressing over hours to days. In fact, worsening or progression of visual loss beyond 2 weeks, or failure of visual recovery to begin within a 2- to 4-week period, should be considered atypical for acute demyelinating optic neuritis. Alternative etiologies for visual loss should be sought in such cases. Ocular or periorbital pain is also a common presenting symptom of acute demyelinating optic neuritis (92% in ONTT). The pain typically persists for no longer than a few days, may precede or occur simultaneously with visual loss, and usually worsens with eye movement (87% in ONTT). During and even beyond the recovery of vision, patients frequently experience temporary worsening of symptoms with exposure to heat (hot shower or exercise); this is referred to as Uhthoffs symptom. Eye movements may also precipitate photopsias (30% of ONTT patients). Visual function tests, performed at baseline within 8 days of symptom onset in the ONTT, revealed abnormalities of visual acuity, visual fields, contrast sensitivity, and color vision in both affected and fellow eyes. The degree of visual loss in the ONTT varied from mild field defects to marked loss of visual acuity (no light perception vision was noted in 3% of ONTT participants). Patients who retain some degree of vision in an affected eye tend to have reduced contrast sensitivity that parallels the severity of visual loss. Patients with optic neuritis also have decreased color vision that, unlike contrast sensitivity, is often more severe than the visual acuity would predict and is of a mixed red-green and blue-yellow type. Although a central visual field defect is common in patients with optic neuritis, the typical central scotoma occurs in only a few patients. In fact, a variety of patterns of visual field loss may occur, including altitudinal, arcuate, cecocentral, diffuse, and even unilateral hemianopic visual field defects. In almost all cases of acute demyelinating optic neuritis, an afferent pupillary defect is present (unless there is a related or unrelated organic visual disturbance in the contralateral eye). Such patients also have a reduced sensation of brightness in the affected eye that can be demonstrated by simply asking them to compare the brightness of a light between the two eyes. 185
The term optic neuritis refers to primary inflammation of the optic nerve. Although numerous inflammatory disorders, such as sarcoidosis, may be associated with acute or chronic optic neuritis, the treatment of optic neuritis in this setting is most often dictated by guidelines appropriate for the underlying disease. This chapter focuses on the treatment of acute demyelinating optic neuritis, the most common form of optic neuritis and the type most familiar to neurologists. Acute demyelinating optic neuritis may be the first sign of multiple sclerosis (MS) and is one of the most common clinical manifestations. When signs or symptoms of MS are not present at diagnosis, acute optic neuritis is referred to as monosymptomatic. Among populations at highest risk for MS, the incidence of acute demyelinating optic neuritis is approximately 3 to 5/100,000 per year (compared with 1/100,000 per year in lower risk populations). The prevalence is 115/100,000, affecting primarily women aged 20 to 50 years.
Clinical Features
Subacute visual loss and pain on eye movements are the two most characteristic symptoms of optic neuritis. The Optic Neuritis Treatment Trial (ONTT) has provided the most extensive information to date about the clinical features of acute demyelinating optic neuritis. ONTT was a multicenter, randomized trial of 457 patients that examined the effect of corticosteroid treatment on visual recovery in acute optic neuritis by comparing intravenous (IV) methylprednisolone with oral prednisone alone and with placebo (see Treatment section). In the ONTT, more than 90% of patients reported central visual acuity loss. Onset of visual loss
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Optic Neuritis
A normal optic disk appearance (termed retrobulbar optic neuritis) is present in approximately two thirds of patients. When optic disk swelling (papillitis) occurs, peripapillary hemorrhages are uncommon (6% in ONTT), and should suggest an alternative diagnosis such as anterior ischemic optic neuropathy. In fact, in patients with acute demyelinating optic neuritis and no white matter lesions on brain magnetic resonance (MR) imaging, certain ocular funduscopic features have been associated with an extremely low to zero risk of clinically definite MS. These findings, as determined by 10-year follow-up data from the ONTT cohort, include absence of pain, no light perception vision, severe disk swelling, hemorrhage of the optic disc or surrounding retina, or retinal exudates. Thus, although a macular star figure composed of lipid can also develop in some patients with anterior optic neuritis (neuroretinitis), this condition is not associated with the eventual development of MS. Although persistent symptoms may be reported months to years following acute demyelinating optic neuritis, visual recovery in the ONTT was generally favorable in all treatment groups. In a 10-year follow up of 319 patients from the ONTT, it was found that many retained good to excellent vision (20/20 or better in 74%). Patients who developed MS generally had worse visual function in both affected and fellow eyes and were twice as likely to experience recurrent optic neuritis (48% vs. 24%; p < 0.001).
and the Early Treatment of Multiple Sclerosis (ETOMS) study. OPTIC NEURITIS TREATMENT TRIAL ONTT and its subsequent follow-up study (Longitudinal Optic Neuritis Study [LONS]) have had a significant impact on the practice patterns of neurologists and ophthalmologists and have provided important data regarding long-term visual outcome and the role of MR imaging in determining prognosis for MS in monosymptomatic patients. The ONTT enrolled 457 patients, aged 18 to 46 years, with acute unilateral optic neuritis. In addition to information on the visual profile and recovery of optic neuritis (primary outcomes), follow-up data have provided important information regarding the role of brain MR imaging in determining risk for clinically definite MS (secondary outcome). Patients in the ONTT were randomized as follows: (1) oral prednisone (1 mg/kg/day) for 14 days, with 4-day taper (20 mg on day 1, 10 mg on days 2 and 4); (2) IV methylprednisolone sodium succinate (250 mg every 6 hours for 3 days) followed by oral prednisone (1 mg/kg/day) for 11 days, with 4-day taper; or (3) oral placebo for 14 days. Visual acuity and contrast sensitivity were primary visual outcome measures. MR imaging of the brain was performed for all participants. The major findings of the ONTT were the following: IV methylprednisolone hastened recovery of visual function but did not affect long-term visual outcome at 6 months to 10 years compared with placebo or oral prednisone; this benefit for IV methylprednisolone was greatest within the first 2 weeks (15 days). Oral prednisone alone (without preceding course of IV methylprednisolone) was unexpectedly associated with an increased risk of recurrent optic neuritis in both affected and fellow eyes (30% at 2 years vs. 16% and 13% for placebo and IV steroids) that has persisted throughout follow-up of the cohort (10 years). Monosymptomatic patients in the IV methylprednisolone group had a reduced rate of development of clinically definite MS during the first 2 years, but this benefit did not persist beyond 2 years and was seen only in patients with brain MR imaging scans that indicated a high risk for MS (defined as 2 white matter lesions). As an alternative to the regimen used in the ONTT (250 mg every 6 hours), the 3-day course of IV methylprednisolone may be given in single doses of 1 gm/day (Figure 2). Short-term corticosteroid therapy is relatively safe when administered to young, healthy adults as in the ONTT. One patient in the ONTT who received IV methylprednisolone developed acute depression, and another developed acute pancreatitis (both recovered without sequelae). Minor side effects in the ONTT included mild mood changes, sleep disturbances, facial flushing, stomach upset, and weight gain. IV methylprednisolone was initiated within 8 days after symptom onset in the ONTT; however, such timing is frequently not realistic in the clinical setting. Therefore, beyond
Diagnosis
The diagnosis of acute demyelinating optic neuritis is based on the clinical history (typical vs. atypical course) and clinical features. In patients with monosymptomatic optic neuritis, MR imaging of the brain (T2-weighted and T1-weighted gadolinium-enhanced images) should be performed. MR imaging is recommended, even in typical cases, to determine the presence of white matter lesions that would indicate that the patient is at high risk for development of MS. In fact, the presence of even one characteristic white matter lesion at the time of acute optic neuritis in the ONTT was associated with greater than twice the risk of MS within 10 years (risk, 22% for patients with 0 lesions vs. 56% for those with 1 lesion) (Figure 1). MR imaging of the orbits with gadolinium and fat saturation is also useful in patients whose clinical course is not typical for acute demyelinating optic neuritis. In patients for whom MR imaging findings are abnormal but not classic for demyelination, oligoclonal banding in the cerebrospinal fluid may be helpful. Serologic studies and evoked potentials are generally not necessary for diagnosis of typical acute demyelinating optic neuritis.
Treatment
Recommendations for short- and long-term treatment in patients with acute demyelinating optic neuritis originate from findings of the ONTT, the Controlled High-Risk Avonex MS Prevention Study (CHAMPS),
Optic Neuritis 70 60 Development of multiple sclerosis, % 50 40 30 20 10
187
>1 lesion 1 lesion
Overall No lesions
10
11
12
Follow-up study, year Overall Patients at risk 388* Multiple sclerosis 33 15 Censored Brain MRI: No lesion 191 Patients at risk 4 Multiple sclerosis 10 Censored Brain MRI: 1 lesion Patients at risk Multiple sclerosis Censored
340 17 6
317 23 4
290 18 1
271 13 5
253 12 9
232 8 6
218 4 4
210 3 0
207 6 2
199 2 35
162 2 79
FIGURE 1. The cumulative probability of multiple sclerosis was statistically significantly higher in patients with one or more lesions seen on the baseline MRI scan of the brain than in patients with no brain lesions (p < 0.001, log rank test) but was not significantly different comparing patients with a single brain lesion and patients with multiple lesions (p = 0.22, log rank test). The numbers of patients at risk are the numbers who had not developed multiple sclerosis at the beginning of each year. The multiple sclerosis rows indicate the number of patients classified as having multiple sclerosis during each yearly interval. The censored rows indicate the number of patients not developing multiple sclerosis whose last available follow-up data occurred during each yearly interval. Asterisk indicates 37 patients who had no baseline MRIs. (From Optic Neuritis Study Group: High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis, Arch Ophthalmol 121:944-949, 2003.)
177 5 4
168 6 3
159 6 1
152 7 3
142 3 6
133 0 4
129 2 1
126 0 0
126 4 1
121 0 24
97 1 54
44 3 2
39 2 0
37 5 0
32 2 0
30 2 1
27 3 1
23 1 0
22 1 0
21 1 0
20 1 0
19 1 2
16 0 8
Brain MRI: >1 lesion 116 Patients at risk Multiple sclerosis 24 2 Censored
90 8 2
80 8 1
71 7 0
64 1 1
62 6 1
55 7 2
46 0 2
44 2 0
42 1 1
40 0 8
32 0 9
this time period, treatment decisions should be based on the potential benefits versus risks of therapy. The ONTT also demonstrated that MR imaging findingsspecifically, the presence of two or more, or even one, white matter lesion(s) at baselineare a powerful predictor of risk for a development of MS in patients with acute monosymptomatic optic neuritis (see Figure 1). This demonstration of increased MS risk in the subgroup of patients with optic neuritis and two or more MR imaging white matter lesions provided a rationale for clinical trials examining the potential role for early disease-modifying therapy in patients with clinically isolated syndromes, such as those discussed in the following sections. CONTROLLED HIGH-RISK AVONEX MS PREVENTION STUDY CHAMPS was a randomized trial of 383 patients who presented with clinically isolated syndromes (acute optic neuritis, brainstem syndromes, or incomplete transverse myelopathy) and brain MR imaging scans showing high risk for MS as per ONTT criteria ( 2 white matter lesions, 3 mm in diameter, at least 1 lesion periventricular or ovoid). All patients in CHAMPS received IV methylprednisolone 1 gm/day for 3 days, initiated within 14 days of symptom onset; this was followed by
oral prednisone (1 mg/kg/day for 11 days, with a 4-day taper). Patients were then randomized (within 27 days of symptom onset) to receive interferon beta-1a (Avonex) 30 g intramuscularly weekly) or placebo. To minimize potential flulike side effects of interferon beta-1a, all patients were given 650 mg of acetaminophen prior to each injection and then every 6 hours for 24 hours. Results of CHAMPS demonstrated that interferon beta-1a significantly reduced the 3-year cumulative probability of MS versus placebo (probability of MS 35% for interferon beta-1a vs. 50% for placebo, rate ratio 0.56; p = 0.002, Kaplan-Meier analysis/Mantel log-rank test). Treated patients also had significantly reduced accumulation of new but clinically silent brain MR imaging white matter lesions (p < 0.001 for both T2-weighted and gadolinium-enhancing brain MR imaging lesions at 18 months). Results were similar in the CHAMPS subgroup that presented with optic neuritis as the first demyelinating event (192 patients), supporting the initiation of interferon beta-1a in optic neuritis patients at high risk for MS by MR imaging criteria. During the first 6 months in CHAMPS, an influenzalike syndrome (fever, chills, myalgias) was reported by 54% in the interferon beta-1a group, compared with 26% for placebo (p < 0.001). Depression was the only other adverse event whose incidence was at least 5 percentage
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1. Clinical features Typical for acute demyelinating optic neuritis? Yes No MRI brain/orbits with gadolinium Consider CSF analysis/serologic studies Treatment as appropriate
initiation of interferon beta-1a was associated with a 35% reduction in the risk of developing MS. A 42% reduction in the number of new T2-weighted or enlarging MR imaging lesions was also noted at 5 years in patients treated with interferon beta-1a from the time of study initiation. EARLY TREATMENT OF MULTIPLE SCLEROSIS STUDY Early interferon therapy following a first demyelinating event is also supported by results of the ETOMS, a randomized trial of interferon beta-1a (Rebif ) performed in Europe. Participants in ETOMS (n = 308) were randomized to interferon beta-1a (Rebif ) 22 g subcutaneously weekly or placebo. Treatments were initiated within 3 months; many participants (40%), however, had multifocal neurologic deficits at presentation. Seventy percent of ETOMS patients received corticosteroids (variable dose and route of administration) prior to initiation of study medication. During the 2-year follow-up, a significantly lower proportion of patients in the interferon beta-1a group developed MS compared with placebo (52/154 [34%] vs. 69/154 [45%]; p = 0.047). The time to occurrence of a second demyelinating event (MS) in 30% of ETOMS participants in each treatment group was also significantly shorter for interferon beta-1a (569 vs. 252 days for placebo; hazard ratio, 0.65; p = 0.023, Cox proportional hazards model). With respect to MR imaging parameters, patients on interferon beta-1a had significantly fewer new lesions on T2-weighted images throughout follow-up (p < 0.001, analysis of covariance). Similarly, the proportion of patients without MR imaging activity (new T2 lesions) was significantly higher in the interferon beta-1a group (23/146 [16%] vs. 8/133 [6%]; p = 0.005). Side effects reported more frequently among patients receiving active treatment in ETOMS included injection site inflammation (60% for interferon beta-1a vs. 12% for placebo), fever (28% vs. 12%), myalgias (17% vs. 9%), and chills (11% vs. 5%). As suggested by the ETOMS Study Group, differences between CHAMPS and ETOMS with respect to interferon beta-1a dosage (22 g vs. 30 g), timing of initiation of therapy (3 months vs. 14 days following first demyelinating event), and patient population/disease severity (multifocal vs. unifocal neurologic deficits at presentation) may account for the slightly greater effet on delay of clinically definite MS observed in CHAMPS. Data from ETOMS nonetheless support initiation of early interferon beta-1a therapy in patients with acute optic neuritis or other clinically isolated syndromes. Figure 2 represents a potential treatment paradigm for patients with acute demyelinating optic neuritis and is likely applicable to patients with other clinically isolated syndromes. In monosymptomatic patients with less than two white matter lesions by MR imaging, and in patients for whom a diagnosis of MS has been established, IV methylprednisolone followed by oral prednisone should be considered on an individual basis and may hasten visual recovery but has not been demonstrated to affect long-term visual outcome.
2. MRI brain w/gadolinium High risk for MS? ( 2 white matter lesions, 3 mm diameter, at least 1 lesion periventricular or ovoid) Yes No Consider IV methylprednisolone on individual basis to hasten visual recovery
3. Consider treatment 1. Intravenous methylprednisolone sodium succinate (1 gram IV/day for 3 days) followed by oral prednisone (1 mg/kg/day for 11 days) with 4-day taper (20 mg on day 1, 10 mg on days 2 and 4), followed by: 2. Interferon beta 1-a (Avonex 30 g intramuscularly [IM] weekly, or Rebif 22 g subcutaneously [SQ] weekly) demonstrated to significantly reduce the risk of MS and the development of clinically silent MRI lesions in high-risk patients within 25 years follow-up.
FIGURE 2. Management of acute monosymptomatic demyelinating optic neuritis. CSF, Cerebrospinal fluid; MS, multiple sclerosis; IV, intravenous. (From Balcer LJ, Galetta SL: Optic neuritis. In Conns current therapy, ed 56, Philadelphia, 2004, WB Saunders, 187-190.)
points higher in the interferon beta-1a group (20% vs. 13%; p = 0.05). Patients on interferon beta-1a should undergo laboratory testing prior to initiation and after 3 and 6 months (complete blood count with differential, platelet count, blood chemistries, liver function tests). Compliance rates in CHAMPS were high: more than 90% of patients receiving interferon beta-1a were compliant at least 80% of the time. Although the potential for long-term benefit of interferon beta-1a in high-risk patients with acute monosymptomatic demyelinating optic neuritis is not known, data from CHAMPS provide rationale for early therapy. An extension study of CHAMPS with all patients on active interferon beta-1a therapy, the Controlled High-Risk Avonex MS Prevention Surveillance (CHAMPIONS), has provided more data in support of early treatment. Five-year follow-up has shown that despite the fact that all patients in the extension study were placed on active treatment, those initially randomized to interferon beta-1a still had a lower cumulative probability of MS (21% for initially treated vs. 35% for former placebo patients; rate ratio, 0.65; 95% confidence interval, 0.43 to 0.97; p = 0.03). Thus, immediate
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Although evidence for treatment of patients with one white matter lesion with immunomodulatory agents has not been established by class I studies, initiation of early therapy and/or continued MR imaging surveillance at 3 to 6 months following a first demyelinating event are not unreasonable. In all cases of typical acute monosymptomatic demyelinating optic neuritis, oral prednisone alone at a dose of 1 mg/kg/day, without prior treatment with IV methylprednisolone (1 gm/day for 3 days), may increase the risk for recurrent optic neuritis and should be avoided. SUGGESTED READING
Balcer L J, Galetta SL: Optic neuritis. In Conns current therapy, ed 56, Philadelphia, 2004, WB Saunders, 187-190. Comi G, Fillippi M, Barkhof F, et al: Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomized study, Lancet 357:1576-1582, 2001. Jacobs LD, Beck RW, Simon JH, et al: Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis, N Engl J Med 343:898-904, 2000. Optic Neuritis Study Group: High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis, Arch Ophthalmol 121:944-949, 2003. Optic Neuritis Study Group: Visual function more than 10 years after optic neuritis: experience of the Optic Neuritis Treatment Trial, Am J Ophthalmol 137:77-83, 2004.
MS is diagnosed clinically through the demonstration of CNS lesions disseminated in time and space and with no better explanation for the disease process. There is no single diagnostic test, and several other diseases can mimic MS. Therefore, diagnostic criteria based on clinical features supplemented by laboratory tests have been used. The new McDonald criteria were developed by a panel of world MS experts and were based on review of extensive supportive scientific studies focusing on the sensitivity and specificity of magnetic resonance (MR) imaging diagnostic criteria. The major change associated with the latest criteria is that a diagnosis of MS can be made early after a clinically isolated demyelinating syndrome if a follow-up MR imaging performed 3 months later demonstrates the formation of a new lesion. Clinical disease subtypes have been recognized for years, but recently pathologic subtypes of disease have been demonstrated and provide confirmation that different pathologic mechanisms may be occurring in individual MS patients. Whether noninvasive studies such as MR imaging or serum antibody titers could be used to predict these subtypes and guide therapy remains to be determined.
Nonpharmacologic Therapy
The care of MS patients requires a health care team approach including experienced nurses, physical and occupational therapists, social workers, and mental health specialists, in addition to a neurologist. The importance of an appropriate support team should not be underestimated. Frequently, nonpharmacologic interventions are as effective as drugs in improving the quality of life for patients with MS. We have found that education and counseling at the time of diagnosis are critical and should be provided by the neurologist, nurse, and support staff from the National Multiple Sclerosis Society at MS specialty centers. There are several useful Web sites, which provide unbiased educational material (see Patient Resources). Counseling and discussion of psychological, social, work, and family-related issues are useful and should be continued throughout the changing stages of the disease. Physical and occupational therapy as well as education and formal assessment and training regarding the use of assistive devices and rehabilitative equipment should be a routine part of the care of patients with MS.
Multiple Sclerosis
Multiple sclerosis (MS) is the most common nontraumatic cause of neurologic disability in young adults and affects between 250,000 and 400,000 persons in the United States. MS usually presents in young adults and affects women two to three times more commonly than men. Most patients start with a period of unpredictable relapses and remissions, which in most is followed by accumulation of neurologic dysfunction and a chronic, progressive course. The life expectancy has been shown to be only 6 to 7 years less than that for a control population without MS, but the emotional and economic costs to society as a result of the disability are enormous. Although the etiology of MS is unknown, it is thought to be an immune-mediated disease of the central nervous system (CNS), in which mononuclear cells (lymphocytes and macrophages) cause demyelination, followed by varying degrees of secondary axonal degeneration. The partial success of immunomodulatory agent (IMA) therapies in the treatment of MS supports a primary role of the immune system but does not exclude the possibility that neurodegenerative mechanisms are also critical. It is recognized that oligodendrocyte and neuronal apoptosis may also play an important role in the pathogenesis of the disease.
Immunomodulatory Therapies
There are four U.S. Food and Drug Administration (FDA)-approved IMAs for relapsing-remitting MS (RRMS) (two interferon beta-1a drugs, interferon beta-1b, and glatiramer acetate [Copaxone]) and one chemotherapeutic agent approved for worsening forms of relapsing MS and secondary progressive MS (SPMS) (mitoxantrone) (Table 1). In addition, one of these drugs (Avonex) carries an indication for patients with a clinically isolated (demyelinating) syndrome and MR imaging suggestive of MS. In all situations the clinician
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Although evidence for treatment of patients with one white matter lesion with immunomodulatory agents has not been established by class I studies, initiation of early therapy and/or continued MR imaging surveillance at 3 to 6 months following a first demyelinating event are not unreasonable. In all cases of typical acute monosymptomatic demyelinating optic neuritis, oral prednisone alone at a dose of 1 mg/kg/day, without prior treatment with IV methylprednisolone (1 gm/day for 3 days), may increase the risk for recurrent optic neuritis and should be avoided. SUGGESTED READING
Balcer L J, Galetta SL: Optic neuritis. In Conns current therapy, ed 56, Philadelphia, 2004, WB Saunders, 187-190. Comi G, Fillippi M, Barkhof F, et al: Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomized study, Lancet 357:1576-1582, 2001. Jacobs LD, Beck RW, Simon JH, et al: Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis, N Engl J Med 343:898-904, 2000. Optic Neuritis Study Group: High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis, Arch Ophthalmol 121:944-949, 2003. Optic Neuritis Study Group: Visual function more than 10 years after optic neuritis: experience of the Optic Neuritis Treatment Trial, Am J Ophthalmol 137:77-83, 2004.
MS is diagnosed clinically through the demonstration of CNS lesions disseminated in time and space and with no better explanation for the disease process. There is no single diagnostic test, and several other diseases can mimic MS. Therefore, diagnostic criteria based on clinical features supplemented by laboratory tests have been used. The new McDonald criteria were developed by a panel of world MS experts and were based on review of extensive supportive scientific studies focusing on the sensitivity and specificity of magnetic resonance (MR) imaging diagnostic criteria. The major change associated with the latest criteria is that a diagnosis of MS can be made early after a clinically isolated demyelinating syndrome if a follow-up MR imaging performed 3 months later demonstrates the formation of a new lesion. Clinical disease subtypes have been recognized for years, but recently pathologic subtypes of disease have been demonstrated and provide confirmation that different pathologic mechanisms may be occurring in individual MS patients. Whether noninvasive studies such as MR imaging or serum antibody titers could be used to predict these subtypes and guide therapy remains to be determined.
Nonpharmacologic Therapy
The care of MS patients requires a health care team approach including experienced nurses, physical and occupational therapists, social workers, and mental health specialists, in addition to a neurologist. The importance of an appropriate support team should not be underestimated. Frequently, nonpharmacologic interventions are as effective as drugs in improving the quality of life for patients with MS. We have found that education and counseling at the time of diagnosis are critical and should be provided by the neurologist, nurse, and support staff from the National Multiple Sclerosis Society at MS specialty centers. There are several useful Web sites, which provide unbiased educational material (see Patient Resources). Counseling and discussion of psychological, social, work, and family-related issues are useful and should be continued throughout the changing stages of the disease. Physical and occupational therapy as well as education and formal assessment and training regarding the use of assistive devices and rehabilitative equipment should be a routine part of the care of patients with MS.
Multiple Sclerosis
Multiple sclerosis (MS) is the most common nontraumatic cause of neurologic disability in young adults and affects between 250,000 and 400,000 persons in the United States. MS usually presents in young adults and affects women two to three times more commonly than men. Most patients start with a period of unpredictable relapses and remissions, which in most is followed by accumulation of neurologic dysfunction and a chronic, progressive course. The life expectancy has been shown to be only 6 to 7 years less than that for a control population without MS, but the emotional and economic costs to society as a result of the disability are enormous. Although the etiology of MS is unknown, it is thought to be an immune-mediated disease of the central nervous system (CNS), in which mononuclear cells (lymphocytes and macrophages) cause demyelination, followed by varying degrees of secondary axonal degeneration. The partial success of immunomodulatory agent (IMA) therapies in the treatment of MS supports a primary role of the immune system but does not exclude the possibility that neurodegenerative mechanisms are also critical. It is recognized that oligodendrocyte and neuronal apoptosis may also play an important role in the pathogenesis of the disease.
Immunomodulatory Therapies
There are four U.S. Food and Drug Administration (FDA)-approved IMAs for relapsing-remitting MS (RRMS) (two interferon beta-1a drugs, interferon beta-1b, and glatiramer acetate [Copaxone]) and one chemotherapeutic agent approved for worsening forms of relapsing MS and secondary progressive MS (SPMS) (mitoxantrone) (Table 1). In addition, one of these drugs (Avonex) carries an indication for patients with a clinically isolated (demyelinating) syndrome and MR imaging suggestive of MS. In all situations the clinician
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TABLE 1 FDA-Approved Immunomodulatory Drugs: Indications and Side Effects

Drugs Interferon beta-1a (Avonex) Dosage 30 g IM weekly Comments Used in CIS, less aggressive presentations, patient preference/lifestyle, as platform agent in combination therapy Flulike side effects Monitor CBC and LFTs Low risk of NABs Used in aggressive presentations with two or more relapses, polysymptomatic onset, multiple enhancing lesions on MR imaging Flulike side effects Injection site reactions and local pain Monitor CBC and LFTs Moderate risk of NABs Used in aggressive presentations with two or more relapses, polysymptomatic onset, multiple enhancing lesions on MR imaging, or if Rebif shots too painful Flulike side effects Injection site reactions Monitor CBC and LFTs High risk of NABs Used in early RRMS with nonaggressive presentation, depressed patients, side effectintolerant patients, or patients on interferon beta who have high-titer NABs or are poorly controlled Injection site reactions Rare benign systemic reaction lasting 15-20 min No blood monitoring necessary Carries indication for worsening RRMS and SPMS Mild chemotherapy-related side effects Cardiotoxicity (may occur asymptomatically in 1st yr) Small increased risk of leukemia
Interferon beta-1a (Rebif)
22-44 g SC three times/wk
Interferon beta-1b (Betaseron)
8 million IU SC qod
Glatiramer acetate (Copaxone)
20 mg SC qd
Mitoxantrone (Novantrone)
5-12 mg/m2 IV q 3 mo
FDA, U.S. Food and Drug Administration; CIS, clinically isolated syndrome; CBC, complete blood count; LFT, liver function test; NAB, neutralizing antibody; RRMS, relaxing-remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis.
should be extremely careful about making a diagnosis of MS and ruling out appropriate mimics of the disease as discussed elsewhere. Recent clinical trial evidence and immunologic studies suggest that an early diagnosis and initiation of IMA may afford the patient the best chance for disease stability because the changes in the immune response over time may become more difficult to halt, lesion burden accumulates and is not reversed by presently available drugs. Pathologic and MR imaging studies have shown that axonal injury and progressive degeneration of demyelinated axons occur early and may become more prominent with time. Several trials have shown that patients on an IMA have less accumulated disability over time, but this is probably the result of the anti-inflammatory effects of the drugs and prevention of relapses rather than any effect on the progressive aspects of the disease. There are situations in which the clinician might recommend not initiating an IMA. There are clearly cases of benign MS in which after 20 to 40 years the patient has minimal to no physical or cognitive disability. Unfortunately, there is a tendency to overestimate the number of patients who fall into this category because we either do not follow the patient long enough or have not examined all aspects of the disease adequately
(cognitive impairment, fatigue, and depression are often underestimated). If one has the luxury of knowing a patients history for 20 years or longer and the clinical course has been benign (e.g., optic neuritis at 20 years of age and paresthesias in the 40s), it is reasonable to continue to monitor such a patient without an IMA. However, more often than not we are faced with a young patient presenting with a first episode of demyelination, a clinically isolated syndrome. In this situation, it is difficult to know what course the patient may follow, and initiation of an IMA is indicated immediately or when there is evidence for disease activity either clinically or radiologically (new enhancing lesion on an MR imaging scan after 3 months), at which time a definite diagnosis of MS can be made, presuming alternative explanations have been appropriately excluded. The choice of IMA is highly controversial and fraught with inconclusive data. In general the interferon beta drugs have the most dramatic effect on decreasing permeability of the blood-brain barrier, and hence their effect can be monitored on a contrast-enhanced MR imaging scan. The more frequently dosed interferon beta drugs, Rebif and Betaseron, have been shown in 1- to 2-year head-to-head trials against Avonex, to have more immediate efficacy in reducing relapses and
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MR imaging activity and therefore may be preferred in very active patients in whom a rapid effect is desirable. Unfortunately, these two drugs also seem to carry the highest risk for development of neutralizing antibodies (NABs) against interferon beta (Rebif ~20%, Betaseron ~33%), which, depending on the NAB titer and duration, may partially or completely negate the efficacy of the drug. Since NABs tend to develop at year 1, the detrimental effects of NAB may not be entirely evident at year 2, but after 3 years persistent NAB appears to reduce the benefit of the drug. There is no consensus on what is considered a high titer, but NABs greater than 100 are likely to persist for long enough to be detrimental. In this situation, there is no known strategy for clearing NABs, and because NABs cross-react between all interferon beta agents, it is recommended to switch to a noninterferon. Avonex has the lowest incidence of NAB (3% to 5%) and may therefore provide a more sustained benefit. Patients fail interferon beta therapy for reasons other than NABs; therefore, if a patient has had two relapses in a year or develops more than three new lesions on a yearly follow-up MR imaging, one should consider switching IMAs regardless of NABs. The interferon beta drugs also commonly cause a flulike reaction characterized by low-grade fever, chills, myalgias, and asthenia 6 to 24 hours after each injection. These symptoms improve after 3 to 6 months and, with the use of appropriate prophylactic medications, become tolerable in most patients. We start the more frequently dosed interferon beta drugs (Rebif and Betaseron) at quarter dose and titrate up by quarter doses each week as tolerated to the full dose if possible. For Avonex, we initiate treatment at one-half dose for 2 weeks and then increase to full dose if it is being tolerated. We recommend two acetaminophen 325 mg and 400 to 800 mg of ibuprofen or 500 mg naproxen prior to injection in the evening and again the next morning if needed. These agents can gradually be tapered off if the patient is tolerating the interferon beta well. We have also found that starting interferon beta immediately following a course of intravenous (IV) methylprednisolone, sometimes during the prednisone taper, helps mask some of the side effects. The propensity of interferon beta to aggravate underlying depression is an issue, in our experience, and careful attention to the patients mood is important. Interferon beta can also aggravate migraine headaches and contribute to fatigue or menstrual irregularity. Rarely, patients feel remarkably better after discontinuation of interferon beta therapy, presumably because of unrecognized side effects. Glatiramer acetate is also an effective drug in RRMS and has an entirely different side effect profile. Glatiramer seems to work differently than interferon beta drugs and does not have its predominant effect at the blood-brain barrier and therefore has a less dramatic effect on reducing contrast-enhancing lesions. Animal and in vitro data suggest that the drug may work inside the CNS and could have some neuroprotective properties through release of brain-derived neurotrophic factor by glatiramer-reactive T cells, but whether glatiramerreactive T cells access the CNS and are neuroprotective in MS patients remains uncertain.
We use glatiramer for RRMS in patients who are worried about or cannot tolerate interferon beta side effects and in patients with moderate or severe affective disease in whom interferon beta may aggravate their depression. The onset of action appears to be delayed in glatiramer such that in a monthly MR imaging trial there was no significant reduction in MR imaging activity until month 6. This suggests that the immunologic response and benefit of the drug may be delayed, and one should not consider switching patients off this drug in the first 6 to 12 months unless the patient is doing extremely poorly (two or more relapses or three or more active MR imaging lesions). The decision to pursue combination therapy or chemotherapy is even more challenging because the risk of side effects increases and less conclusive data exist. Nonetheless, the marked efficacy in MS of the FDA-approved immunosuppressive drug mitoxantrone in reducing relapses, disability, and MR imaging activity provides a strong rationale for considering more aggressive immunosuppression before the patient becomes permanently disabled. The simplest and most commonly employed strategy is to add on pulses of IV methylprednisolone at the time of relapse or at scheduled intervals (1 day a month or 3 days bimonthly). Some trials have provided support for this approach, but conclusive data are lacking. We have found that a subset of patients respond to this approach for a limited period. Several oral immunosuppressive drugs, such as azathioprine, methotrexate, and mycophenolate mofetil are being used in MS, based on preliminary efficacy in pilot studies, but double-blind, placebo-controlled trial data are not available. We use immunosuppressive drugs only in conjunction with interferon beta drugs because it may counteract the benefit of glatiramerreactive T cells. The ease of use and minimal toxicity of the oral drugs make them more acceptable than chemotherapy to the less disabled breakthrough patient. We frequently use oral immunosuppressive drugs in combination with interferon beta therapy before initiating high-dose chemotherapy or as part of a maintenance regimen following chemotherapy as has been done in lupus. Oral methotrexate starting at 10 mg once weekly and then 20 mg weekly, is well tolerated except for nausea and is the simplest combination therapy to use. Methotrexate can be given at 20 mg weekly intramuscularly to avoid the gastrointestinal side effects. Mycophenolate mofetil can be started at 500 mg twice daily and increased to 1000 mg twice daily as tolerated and is also a useful adjunct to interferon beta in our experience. Azathioprine is a less expensive alternative and should be started gradually at one half a 50-mg tablet daily and increased to either 2 or 3 mg/kg in split doses or until the white blood cell count (WBC) is 4000/L or lower, because of the known heterogeneity in genetic metabolism of this drug. Although mitoxantrone has proven efficacy in worsening and early SPMS, the risk of therapy-related leukemias and cardiotoxicity has limited its use. There are several reports suggesting that a significant subset of patients (10% to 25%) may have an asymptomatic reduction in
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left ventricular ejection fractions after only 1 year of therapy. We therefore prefer cyclophosphamide, an older chemotherapy drug, which has a rapid onset of action and is also highly effective in reducing relapses and MR imaging activity but causes more acute side effects such as nausea, mild alopecia, and neutropenia than does mitoxantrone. It does not have cardiotoxicity at conventional pulse doses (800 to 1200 mg/m2), and the risk of hematologic malignancy appears to be less than mitoxantrone. We initiate treatment at 800 mg/m2 and titrate upward each month based on the 10-day WBC nadir. After 6 to 12 months of monthly pulses, we reconsider alternative maintenance regimens or continue with bimonthly pulses. Bladder toxicity and malignancy have been reported at high doses acutely, but with the pulse regimen used earlier, malignancy rarely occurs and only after many years, presumably due to the oncogenic potential of human papilloma virus in a chronically immunosuppressed host. Yearly urine collections for cytology should be obtained. Intravenous immunoglobulin (IVIg) given monthly has been shown in some clinical trials to reduce relapses. We rarely use this approach because of its cost and unproven efficacy. Plasma exchange has been advocated in steroid-refractory fulminant cases of demyelination. We have seen dramatic improvement in isolated cases and reserve this approach for acute severe and refractory cases. Perhaps the presence of serum antibodies will allow us to prospectively identify responders to plasma exchange in the future. Two novel monoclonal antibody approaches have shown promise in phase II trials: (1) daclizumab (Zenapax) (FDA approved to avoid transplantation rejection), which targets the interleukin 2 receptor; and (2) natalizumab (Antegren), which blocks the leukocyte adhesion molecule VLA-4. Natalizumab was recently shown to be markedly effective in reducing relapses (66%), Gd-enhancing MRI lesions (92%), and in slowing disease progression in RRMs versus placebo. It was FDA approved in late 2004 and then suspended in February 2005 because of 2 cases of PML in patients treated with natalizumab and Avonex in combination. The future use of this drug will depend on the results of the risk of JC virus in treated patients.
TABLE 2 Treatment of Multiple Sclerosis Exacerbations

Rule out treatable infection (e.g., urinary tract infection, sinusitis, bronchitis) Five-day course of IV methylprednisolone, 1 gm, or equivalent corticosteroid if the patient is having acute disability from the episode; prednisone taper optional Supportive care, physical and occupational therapy, social work, temporary disability status MR imaging (prior to steroids, if possible) to assess extent of disease activity and exclude alternative process Consider additional 5 days of IV methylprednisolone or plasma exchange for refractory and severely disabling exacerbations
Careful attention to blood glucose levels and bone density is necessary especially after repeated usage.
Symptomatic Therapy (Table 3)

FATIGUE Fatigue is one of the most common and disabling symptoms of MS. Our algorithm for the management of fatigue includes first ruling out alternative etiologies including thyroid disease (thyroid-stimulating hormone), iron deficiency anemia (complete blood count, iron, ferritin, total iron-binding capacity), and infections (urinalysis, possibly chest radiograph, erythrocyte sedimentation rate, Epstein-Barr virus IgM, ELISA for Lyme disease). A detailed sleep history can also help discriminate fatigue from impaired sleep secondary to depression, spasticity, pain, or nocturia. Our first-line drug treatment for fatigue is a trial of amantadine (100 mg on awakening and again in the early afternoon) for 2 weeks. Sometimes amantadine stops working after 6 months and a drug holiday is indicated. We therefore target its use to winter months, when its anti-influenza A properties are most beneficial. Modafinil, 200 mg in the morning, is a nonaddictive stimulant with a good safety profile and can be useful for MS fatigue. Some patients feel jittery at this dose and can tolerate only 100 mg/day. Occasionally, activating selective serotonin receptor inhibitor (SSRI) antidepressants (see later) can have positive effects on fatigue in the absence of overt depression. DEPRESSION Depression is a major treatable complication of MS and interferon beta therapy. A combination of counseling and drug therapy is often required. We use many of the available antidepressants depending on the specific features of the individuals symptoms, but in general we often start with an activating SSRI in the morning (fluoxetine, citalopram, escitalopram). Paroxetine may be useful for anxious depression and sometimes is best given in the evening because it can be sedating. If sexual side effects are a problem even with escitalopram (least offensive of the SSRIs), then we switch to bupropion. Venlafaxine has noradrenergic properties and is a good alternative for some patients. Low doses
Treatment of Exacerbations (Table 2)

The first response to exacerbation of MS symptoms is to determine if there are any provoking factors, specifically infection and/or elevation of body temperature. Occasionally treating these is all that is required to ameliorate the symptoms. For disabling attacks characterized by visual loss greater than 20/60, impaired ambulation, pain, or extremely active MR imaging (two or more enhancing lesions or single lesion > 1 cm), we initiate IV methylprednisolone (or equivalent) 1 gm daily in the morning for 5 days. We usually do not use a prednisone taper unless the patient has a history of difficulty withdrawing from high-dose steroids.
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TABLE 3 Symptomatic Therapies in Multiple Sclerosis

Symptom Fatigue Depression Therapeutic Approach Amantadine (100 mg bid) can cause rash and edema; modafinil (100-200 mg q AM) can cause jittery sensation and palpitations SSRIs (e.g., fluoxetine 10-80 mg, sertraline 50-200 mg, citalopram 20-60 mg, escitalopram 10-20 mg) preferred once in the morning because of activating properties Discuss sexual side effects Alternative is bupropion 150-400 mg SR Oxybutynin 5-20 mg/day and tolterodine 2-4 mg bid for urgency cause dry mouth and can exacerbate glaucoma or worsen urinary retention Baclofen 10-40 mg tid-qid or tizanidine 2-8 mg tid; both can cause weakness and fatigue in excessive dosing Antiepileptic drugs such as gabapentin 300-1200 mg tid-qid cause fatigue at high doses; carbamazepine 100-600 mg tid requires CBC and LFT monitoring, causes rash and neurologic side effects at high doses; can load with IV phenytoin in severe cases in hospital setting
Bladder Spasticity Paroxysmal symptoms and pain
SSRI, Selective serotonin receptor inhibitor; CBC, complete blood count; LFT, liver function test.
of tricyclic antidepressants amitriptyline, nortriptyline (less anticholinergic side effects), or trazodone are useful in patients with concomitant insomnia or nocturnal pain. Combination antidepressants may be required, but such patients are usually referred to our neuropsychiatry team. One must pay careful attention to the possibility of unmasking bipolar disease, and valproic acid and other antiepileptic drugs can be useful mood stabilizers. NEUROGENIC BLADDER The first step in treating a neurogenic bladder is determining whether the problem is one of failure to empty, failure to store, or a combination of both, as in detrusor external sphincter dyssynergia. Urinary frequency, urgency, and incontinence are the most common symptoms. After a careful history in which there are no symptoms of retention or hesitancy, and exclusion of a urinary tract infection, we initiate a trial of oxybutynin at a 5-mg dose and warn the patient to discontinue if they have trouble voiding. Higher doses 10 to 20 mg/day, long-acting variations and alternatives (tolterodine), or dermal patches are often useful. Failure to empty is difficult to treat medically, but a trial of an alpha1-adrenergic receptor antagonist such as terazosin, doxazosin, or tamsulosin is worthwhile prior to initiating catheterization. Inhaled desmopressin acetate (DDAVP) may be useful for nocturnal incontinence, but it causes rebound symptoms in the morning and is contraindicated in patients with hypertension. Patients who require chronic catheterization or are refractory to these medical therapies are referred to a urologist. BOWEL SYMPTOMS Constipation is common in MS and should be managed aggressively to avoid long-term complications. Fortunately, fecal incontinence is rare, but when it occurs the addition of fiber in the form of Metamucil
twice a day can provide enough bulk to the stool to allow a partially incompetent sphincter to hold in the bowel movement long enough to allow the patient to reach a bathroom. The use of anticholinergics or antidiarrheal agents may be effective for short periods to combat incontinence associated with diarrhea. SEXUAL SYMPTOMS A careful sexual history, sometimes done by a health care provider of the same sex, may reveal several problematic sexual issues. These include feelings of sexual inadequacy, impaired libido, and direct sexual dysfunction from erectile dysfunction, impaired lubrication, spasticity, or heat-related sensory dysesthesias. Counseling, review of sexual side effects of medication, and medical therapy may be appropriate. Erectile dysfunction in MS can be effectively managed in some patients with sildenafil (50 to 100 mg). SPASTICITY Mild spasticity may be managed by stretching and exercise programs such as aqua therapy and yoga. Drug therapy is indicated when stiffness, spasms, or clonus interfere with function or sleep. We start treatment with baclofen 10 mg at bedtime, then add 5-mg doses in the morning and afternoon, and increase as tolerated, almost always with higher doses at night. Some patients, especially those requiring chronic therapy, may need up to 160 mg of baclofen a day. Limiting side effects include fatigue and weakness from loss of muscle tone. The addition of tizanidine using 2-mg tablets often provides a synergistic effect in those who cannot tolerate higher doses of baclofen. Alternative adjunct agents include gabapentin and benzodiazepines. Intrathecal baclofen has had a major impact on medically intractable spasticity, but we rarely use this approach because the implantable pump obviates further MR imaging scans and can be uncomfortable.
194
Transverse Myelitis
PAROXYSMAL DISORDERS AND PAIN Dystonic spasms respond well in most instances to gabapentin (100 to 300 mg) or carbamazepine (100 to 200 mg), sometimes at very low doses. Paroxysmal pain or electrical burning sensations can be effectively treated with these antiepileptics or amitriptyline. We use gabapentin starting at 300 mg at bedtime the first day, twice daily the second day, and three times a day on the third day. If after 1 week there is no benefit, we double the dose every week until benefit or intolerable side effects occur (usually fatigue). Some patients require extremely high doses (up to 5600 mg/day) for complete pain control. TREMOR We have found tremor to be extremely refractory to medical therapy. Clonazepam sometimes appears to provide benefit, but perhaps more through its sedating and muscle-relaxing properties. COGNITIVE PROBLEMS Difficulty with concentration, short-term memory loss, and mental fatigue are common in MS. Some patients may benefit from stimulant drugs used for fatigue or attention deficit disorder, including modafinil, methylphenidate, or protriptyline. We also try acetylcholinesterase inhibitors such as donepezil (5 to 10 mg at bedtime) despite mixed results in clinical trials. ALTERNATIVE AND COMPLEMENTARY THERAPIES We actively discuss alternative therapies so that we know what else our patients are taking. We discourage the use of expensive or potentially dangerous regimens with unproved efficacy (bee stings). Some herbal remedies (St. Johns wart) are mildly effective but should not be used to the exclusion of prescription drugs if necessary. Some of our patients report benefit from marijuana and acupuncture for pain and spasticity. Nonmedical approaches such as yoga, tai chi, and meditation can be quite useful and are encouraged. We do not advocate a specific diet but recommend a multivitamin and specific supplementation of calcium and vitamin D. PATIENT RESOURCES
National Multiple Sclerosis Society http://www.nmss.org/ The Consortium of Multiple Sclerosis Centers Website for organization of MS healthcare professionals. The Consortium publishes the International Journal of MS Care, available online http://www.mscare.org/ Hablemos de Esclerosis MltipleLets Talk about Multiple Sclerosis http://www.hablemosdeem.com/ MSWorld, the National MS Societys collaborative partner, provides the official chat and bulletin board site for the Society http://www.msworld.org/communications.htm/ The Brain Matters Neurology Patient Education, including MS http://www.thebrainmatters.org/
Transverse Myelitis
David Irani, M.D.
The clinical entity of transverse myelitis (TM) is broadly defined as any acute inflammatory process affecting the spinal cord having a clear rostral border of involvement. In many cases only a focal area of tissue is affected; however, other patients have more extensive cord pathology below this defined upper level. In addition to the salient clinical features that accompany spinal cord dysfunction, current diagnostic criteria define acute TM as having a duration from onset to nadir of between 4 hours and 21 days. Likewise, these criteria mandate that cord inflammation be presumptively identified by finding inflammatory changes in the cerebrospinal fluid (CSF) or by demonstrating gadolinium enhancement of the involved cord region using magnetic resonance (MR) imaging techniques. TM is distinguished to some degree from transverse myelopathy that encompasses other noncompressive syndromes such as vascular events involving the spinal cord that can reach clinical nadir in less than 4 hours or that fail to reveal any evidence of an underlying inflammatory pathology. TM is rare (1 to 4 cases per million population per year); affects individuals of all ages; and shows no predisposition to known ethnic, gender, or environmental factors. Multiple systemic conditions have been identified as causes underlying acute TM, but most patients have no predisposing disorder identified at presentation and remain categorized as idiopathic cases. Serial imaging data suggest that the acute cord inflammation in most TM patients resolves over a period of a few weeks, implying that long-term neurologic sequelae are dictated largely by the degree of collateral injury to adjacent neuronal cell bodies and their axonal extensions. Overall, about one third of patients make a good functional recovery after the initial episode, one third recover partially but are left with a moderate level of disability, and one third have no meaningful recovery and remain severely impaired. A poorer prognosis can be indicated by clinical features noted in the acute phase (rapid progression of symptoms, prominent back pain, and early spinal shock), by electrophysiologic measures (absent central conduction on somatosensory evoked potentials), and by detection of the 14-3-3 protein in CSF. In keeping with all these disease features, the therapeutic interventions I advocate in acute TM focus largely on terminating spinal cord inflammation as soon as possible to minimize collateral nerve injury. On the other hand, there is usually little role for such interventions beyond the acute stage of disease (cord inflammation has often resolved at this point), and my focus shifts to managing the numerous complications of chronic spinal cord dysfunction. Restoring function to the injured spinal cords of TM patients is an exciting prospect, but it also remains quite distant on the therapeutic horizon.
194
Transverse Myelitis
PAROXYSMAL DISORDERS AND PAIN Dystonic spasms respond well in most instances to gabapentin (100 to 300 mg) or carbamazepine (100 to 200 mg), sometimes at very low doses. Paroxysmal pain or electrical burning sensations can be effectively treated with these antiepileptics or amitriptyline. We use gabapentin starting at 300 mg at bedtime the first day, twice daily the second day, and three times a day on the third day. If after 1 week there is no benefit, we double the dose every week until benefit or intolerable side effects occur (usually fatigue). Some patients require extremely high doses (up to 5600 mg/day) for complete pain control. TREMOR We have found tremor to be extremely refractory to medical therapy. Clonazepam sometimes appears to provide benefit, but perhaps more through its sedating and muscle-relaxing properties. COGNITIVE PROBLEMS Difficulty with concentration, short-term memory loss, and mental fatigue are common in MS. Some patients may benefit from stimulant drugs used for fatigue or attention deficit disorder, including modafinil, methylphenidate, or protriptyline. We also try acetylcholinesterase inhibitors such as donepezil (5 to 10 mg at bedtime) despite mixed results in clinical trials. ALTERNATIVE AND COMPLEMENTARY THERAPIES We actively discuss alternative therapies so that we know what else our patients are taking. We discourage the use of expensive or potentially dangerous regimens with unproved efficacy (bee stings). Some herbal remedies (St. Johns wart) are mildly effective but should not be used to the exclusion of prescription drugs if necessary. Some of our patients report benefit from marijuana and acupuncture for pain and spasticity. Nonmedical approaches such as yoga, tai chi, and meditation can be quite useful and are encouraged. We do not advocate a specific diet but recommend a multivitamin and specific supplementation of calcium and vitamin D. PATIENT RESOURCES
National Multiple Sclerosis Society http://www.nmss.org/ The Consortium of Multiple Sclerosis Centers Website for organization of MS healthcare professionals. The Consortium publishes the International Journal of MS Care, available online http://www.mscare.org/ Hablemos de Esclerosis MltipleLets Talk about Multiple Sclerosis http://www.hablemosdeem.com/ MSWorld, the National MS Societys collaborative partner, provides the official chat and bulletin board site for the Society http://www.msworld.org/communications.htm/ The Brain Matters Neurology Patient Education, including MS http://www.thebrainmatters.org/
Transverse Myelitis
David Irani, M.D.
The clinical entity of transverse myelitis (TM) is broadly defined as any acute inflammatory process affecting the spinal cord having a clear rostral border of involvement. In many cases only a focal area of tissue is affected; however, other patients have more extensive cord pathology below this defined upper level. In addition to the salient clinical features that accompany spinal cord dysfunction, current diagnostic criteria define acute TM as having a duration from onset to nadir of between 4 hours and 21 days. Likewise, these criteria mandate that cord inflammation be presumptively identified by finding inflammatory changes in the cerebrospinal fluid (CSF) or by demonstrating gadolinium enhancement of the involved cord region using magnetic resonance (MR) imaging techniques. TM is distinguished to some degree from transverse myelopathy that encompasses other noncompressive syndromes such as vascular events involving the spinal cord that can reach clinical nadir in less than 4 hours or that fail to reveal any evidence of an underlying inflammatory pathology. TM is rare (1 to 4 cases per million population per year); affects individuals of all ages; and shows no predisposition to known ethnic, gender, or environmental factors. Multiple systemic conditions have been identified as causes underlying acute TM, but most patients have no predisposing disorder identified at presentation and remain categorized as idiopathic cases. Serial imaging data suggest that the acute cord inflammation in most TM patients resolves over a period of a few weeks, implying that long-term neurologic sequelae are dictated largely by the degree of collateral injury to adjacent neuronal cell bodies and their axonal extensions. Overall, about one third of patients make a good functional recovery after the initial episode, one third recover partially but are left with a moderate level of disability, and one third have no meaningful recovery and remain severely impaired. A poorer prognosis can be indicated by clinical features noted in the acute phase (rapid progression of symptoms, prominent back pain, and early spinal shock), by electrophysiologic measures (absent central conduction on somatosensory evoked potentials), and by detection of the 14-3-3 protein in CSF. In keeping with all these disease features, the therapeutic interventions I advocate in acute TM focus largely on terminating spinal cord inflammation as soon as possible to minimize collateral nerve injury. On the other hand, there is usually little role for such interventions beyond the acute stage of disease (cord inflammation has often resolved at this point), and my focus shifts to managing the numerous complications of chronic spinal cord dysfunction. Restoring function to the injured spinal cords of TM patients is an exciting prospect, but it also remains quite distant on the therapeutic horizon.
Transverse Myelitis
195
Acute Evaluation
All patients suspected of having acute spinal cord dysfunction require emergent evaluation. Furthermore, because few of these patients present with the full clinical constellation of motor, sensory, and autonomic disturbances at disease onset, clinicians must have a low threshold for pursuing disease processes affecting the spinal cord. Many patients with a rapidly progressive paraparesis are incorrectly diagnosed with GuillainBarr syndrome; unlike with TM, these patients often have cranial nerve involvement and usually do not manifest early bladder dysfunction or bandlike sensory complaints. When in doubt, a spinal MR scan is easily justified and should always take precedent over more elective imaging studies. Conversely, the consequences of failing to perform a timely scan and missing a spinal cord lesion can be catastrophic for the patient. The initial evaluation of a patient with a new myelopathy must include a search for evidence of a structural lesion causing spinal cord compression. The diagnostic procedure of choice, a gadolinium-enhanced spinal MR scan, should ideally be completed within a few hours of presentation. Computed tomography (CT) with myelography is another option if MR imaging is not immediately available, but this modality has a much more limited capacity to identify intramedullary spinal cord lesions. If no imaging study can immediately be performed, I suggest treating all patients with evolving neurologic deficits and short symptom durations as if they have acute traumatic spinal cord compression by administering high-dose intravenous (IV) methylprednisolone according to defined protocols. Here, a 30 mg/kg bolus over 1 hour followed by a 5.4 mg/kg/hr continuous infusion for the next 23 hours is given to patients within 3 hours of symptom onset, whereas a 30 mg/kg bolus over 1 hour followed by a 5.4 mg/kg/hr continuous infusion for the next 47 hours is given to patients between 3 and 8 hours of symptom onset. Any structural lesion identified by MR imaging (e.g., vertebral fracture, herniated disk, epidural hematoma or abscess, spondylolisthesis) mandates immediate neurosurgical consultation regarding the options for mechanical decompression of the cord. Following the exclusion of a compressive cord lesion, the next step in the proper evaluation of a patient with suspected TM is to perform a lumbar puncture and undertake a complete CSF analysis. This can help to confirm an inflammatory process, facilitate the search for a possible underlying cause, and may even generate information that can be of long-term prognostic significance. The CSF sample should be sent for routine studies (cell count and differential, total protein and glucose levels), as well as for oligoclonal bands, immunoglobulin G (IgG) index, polymerase chain reaction (PCR)-based assays for viral nucleic acids, syphilis serology, and Lyme and mycoplasma antibodies. Since the CSF cell count and differential should be available within a few hours of sample acquisition, one can begin the therapeutic decision-making process right away. Again, any gadolinium enhancement of the cord on MR imaging or the discovery of a CSF pleocytosis is considered
presumptive evidence of TM and should point strongly toward the initiation of acute therapy.
Acute Therapy
Planning therapeutic interventions for a patient with suspected acute TM should happen in parallel to the initial diagnostic evaluation being undertaken. If an inflammatory basis for the acute spinal cord dysfunction is identified, I urge the immediate initiation of IV methylprednisolone at a dose of 1000 mg in an adult (30 mg/kg for a child) as a single daily infusion over 60 to 90 minutes for a period of 5 to 7 days. Although a prospective, randomized, placebo-controlled trial documenting the benefit of such an intervention in acute TM has never been performed, there are enough published reports documenting the utility of highdose methylprednisolone in shortening the time to independent ambulation and in enhancing the degree of eventual motor recovery that this has become the de facto intervention of choice in this setting. Indeed, I believe that corticosteroids should be withheld only in those patients with some absolute contraindication to the drug. Prophylaxis against gastrointestinal ulceration should always accompany these treatments. Although some cases of acute TM occur as a result of direct infection of the spinal cord by an infectious pathogen (certain viruses and bacteria, in particular, are culprits), the prophylactic use of antimicrobial therapies in all cases is not advised. I do not, as a rule, start an empirical antibiotic or antiviral agent in patients with acute TM unless there is some clear evidence of recent viral or bacterial infection (e.g., shingles, genital herpes, mycoplasma pneumonia). Nevertheless, I do advocate a thorough search for such infectious agents, and if a serologic screen or a CSF PCR assay reveals evidence of such a process, then starting the appropriate antimicrobial agent is advised. Finding an infectious cause for acute TM should not, however, dissuade one from continuing the aggressive use of IV corticosteroids. Other cases of acute TM occur in patients with previously known or newly identified connective tissue disorders. The acute diagnostic investigation of new patients should always include serologic screening for such processes, in addition to a search for historical features that might suggest a systemic vasculitis or a prothrombotic state resulting from antiphospholipid antibodies. In these cases, starting IV corticosteroids is still highly appropriate, but the presence of antiphospholipid antibodies may also require consideration of both acute and chronic anticoagulation. Once again, the decision to anticoagulate a patient in the acute setting should not supersede the need for ongoing corticosteroid therapy.
Follow-Up to Acute Interventions

The management of patients with acute TM who fail to respond to high-dose corticosteroids is both difficult and controversial. In my opinion, however, other acute
196
Transverse Myelitis
interventions should be strongly considered within a week of completing corticosteroid infusions if there is no reasonable evidence of improvement. At this point, my preferred strategy is to give alternate-day cycles of plasmapheresis over a total of 14 days. Weinshenker and colleagues (see Selected Reading) were the first to show favorable results using this treatment modality in patients with acute inflammatory demyelinating events (including acute TM) that did not respond to steroids, and we have since found that nearly 50% of patients in our TM center who fail steroid therapy derive significant and sustained benefit from plasmapheresis. Indeed, one can often see noticeable clinical improvement in many patients after the second or third exchange. Another option worth considering in steroidnonresponsive TM patients who are still in the acute phase of disease is the use of IV cyclophosphamide at a dose of 750 to 1000 mg/m2. This approach may, in fact, be optimal for the patient with a previously known or a newly identified connective tissue disorder. Indeed, many patients with active systemic lupus erythematosus require monthly cyclophosphamide pulses for the next 4 to 6 months, aiming for a white blood cell count nadir of 3000 to 4000 cells/mm3 to achieve adequate control of the presumed disease flare. Although fraught with substantial risk, both plasmapheresis and cyclophosphamide have the advantage of working rapidly during a time when spinal cord inflammation is presumably still active. I do not advocate IV immune globulin in this situation, because my personal experience suggests that it is quite ineffective in these patients. I also suggest obtaining a second gadolinium-enhanced spinal MR scan within 4 to 6 weeks of clinical nadir to look for resolution of cord inflammation and to determine whether any loss of cord caliber has developed. Ongoing cord inflammation (persistent enhancement on MR imaging or a continued CSF pleocytosis) with sustained neurologic deficits should be aggressively treated with repeated plasmapheresis or monthly pulses of IV cyclophosphamide to make every effort that collateral injury to motor, sensory, and autonomic pathways in the spinal cord is minimized. On the other hand, there is no role for any of these aggressive immunotherapies in patients whose inflammatory component has largely resolved.
Long-Term Considerations
Although many patients with acute TM make good functional recoveries from their illnesses, most are left with moderate or severe disability due to irreversible injury of the spinal cord. As these patients transition out of the acute phase of disease with active cord inflammation, chronic management focuses on addressing the wide range of symptoms that accompany these lesions. Standard physical and occupational rehabilitation strategies can prevent complications and promote meaningful improvement over time. Some patients with less severe disability report motor and autonomic improvement with 4-aminopyridine (fampridine), a potassium channel blocker that can enhance conduction in damaged nerve fibers. This drug, which is not approved by the U.S. Food and Drug Administration and must be obtained from compounding pharmacies, can be started at a dose of 10 mg/day and slowly increased to a dose of 0.5 to 0.7 mg/kg/day. It may cause a host of adverse effects, most notably seizures when used at higher doses, limiting its long-term usefulness. Chronic symptoms following acute TM are extremely common, and it is mandatory to ask patients about such things as bowel, bladder, and sexual function; pain; disturbed mood; fatigue; and spasticity in muscles of their extremities. All of these complaints may respond to various medications that can significantly improve the quality of their lives. Although space limitations preclude me from being able to outline a detailed approach for every symptom, the medications I most commonly use are outlined in Table 1. We are fortunate to have physicians from many other disciplines available to help us manage patients in our TM Center, and I firmly believe that complex pain management and urological, psychiatric, or rehabilitative issues are best addressed by involving the appropriate specialist. Having said this, all patients benefit from maintaining a relationship with their primary care physician, who ideally can help to coordinate care between multiple specialists and who can maximize the vigilance for various complications of disability including pneumonia, venous thrombosis, decubitus ulcers, osteoporosis, and the like.
TABLE 1 Management of Chronic Symptoms in Patients Having Experienced Previous Acute Transverse Myelitis
Symptom Pain, dysesthesias Fatigue Spasticity Urinary urgency Constipation Suggested Therapy Gabapentin Amantadine Baclofen Oxybutynin Bisacodyl, senna Alternative Treatments Nortriptyline, carbamazepine, tramadol, TENS unit, intrathecal opioids Modafinil, methylphenidate Tizanidine, diazepam, intrathecal baclofen Hyoscyamine, tolterodine, propantheline Mineral oil enemas, manual disimpaction
TENS, Transcutaneous electrical nerve stimulation.
197
Disease Relapses
Most episodes of acute TM are isolated clinical events that result in varying degrees of injury to the cord with attendant disability but show no evidence of ongoing disease progression or future relapse. In the experience at our TM Center, that has seen well over 250 cases, however, a small proportion of patients (<5%) will experience repeated clinical episodes over the coming months or years without ever showing evidence of brain or optic nerve involvement. Serum anti-Ro (SSA) antibodies are present in a high proportion of these relapsing TM cases, although this test alone does not identify this patient subset with complete accuracy. Still, once an SSA-positive patient has experienced a second clinical event, I generally recommend long-term oral immunosuppressive therapy to prevent further clinical attacks once the most recent episode has run its course. Although methotrexate, 20 to 25 mg/week, or azathioprine, 2 to 3 mg/kg/day, are potential options, I usually start mycophenolate mofetil (CellCept) at a dose of 500 mg/day, aiming to titrate up to a dose of 2000 to 2500 mg/day over the next several weeks. Women being started on this drug should have a negative pregnancy test and be advised about its potential teratogenic effects (pregnancy category C), and all patients should be watched closely for neutropenia and gastrointestinal bleeding. SUGGESTED READING
The Transverse Myelitis Consortium Working Group: Proposed diagnostic criteria and nosology of acute transverse myelitis, Neurology 59:499-505, 2002. Weinshenker BG, OBrien PC, Petterson TM, et al: A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease, Ann Neurol 46:878-886, 1999.
individuals, sexual dysfunction despite also having physical and emotional significance has been mostly overlooked in this same group. Both areas deserve attention because of their significance in the routine bodily functioning and overall sense of wellness and normalcy of humans. Both areas undoubtedly require further evolution in pathophysiologic understanding and ideal clinical management; however, basic approaches to preserve and optimize functional levels in patients must be sought and applied today. This brief review describes current clinical strategies and available treatments for the management of urinary and sexual dysfunctions in this population.
Urinary Dysfunction
Urinary symptoms are common among patients with demyelinating diseases of the spinal cord, with as much as 75% of individuals experiencing such complaints. The symptoms are typically irritative in nature and usually are manifest as urgency, frequency, and urge incontinence. Detrusor hyperreflexia (involuntary detrusor contraction due to neuropathy), resulting from suprasacral neurologic impairment, is attributed to this symptomatic presentation. Dyssynergic external urethral sphincteric function may also occur concomitantly with the dysfunctional storage phase of urinary function in these patients, producing additional symptomatic features of incomplete emptying and hesitancy. The loss of coordinated lower urinary tract function also is explained by disrupted neuronal pathways between the brainstem and sacral spinal cord. It is perceived that urinary symptoms range in severity and can fluctuate even in a single individual, depending on their present neurologic status. Similarly, in the event of progression of the neurologic illness by other nonurologic manifestations, there is commonly greater severity of urinary complaints. Since urinary symptoms rather than clinical manifestations (upper urinary tract damage, urinary tract infection) typically dominate the clinical picture, management is primarily focused on providing symptomatic relief. This observation suggests the limited need for extensive urodynamic investigation for many initial presentations. However, an essential diagnostic step following recognition of presenting or deteriorating symptoms is the objective assessment of emptying ability by measuring postvoid residual (PVR) amount (Figure 1). The PVR determination can be made either by sonographic bladder scan or catheterization, whereas the former may be preferable in men to avoid urethral trauma. The basic scheme is that PVR amounts less than 100 mL can be treated with anticholinergic medication, whereas PVR amounts greater than 100 mL require initiation of clean intermittent catheterization (CIC) with or without anticholinergic medication. The goals of treatment are to stabilize involuntary bladder contractions and associated symptoms while reducing risks of urinary stasis, infection, urolithiasis, and upper urinary tract damage. If the endpoints are not met with these conservative measures, a urologic consultation should be sought.
PATIENT RESOURCES
Transverse Myelitis Association http://www.myelitis.org/ The Johns Hopkins Transverse Myelopathy Center http://www.med.jhu.edu/jhtmc/

Dysfunctions of the lower urinary tract (bladder and urethra) and genitalia are commonly experienced by individuals afflicted by demyelinating diseases of the spinal cord. Although urinary dysfunction has long been recognized as a major physical disability among these
197
Disease Relapses
Most episodes of acute TM are isolated clinical events that result in varying degrees of injury to the cord with attendant disability but show no evidence of ongoing disease progression or future relapse. In the experience at our TM Center, that has seen well over 250 cases, however, a small proportion of patients (<5%) will experience repeated clinical episodes over the coming months or years without ever showing evidence of brain or optic nerve involvement. Serum anti-Ro (SSA) antibodies are present in a high proportion of these relapsing TM cases, although this test alone does not identify this patient subset with complete accuracy. Still, once an SSA-positive patient has experienced a second clinical event, I generally recommend long-term oral immunosuppressive therapy to prevent further clinical attacks once the most recent episode has run its course. Although methotrexate, 20 to 25 mg/week, or azathioprine, 2 to 3 mg/kg/day, are potential options, I usually start mycophenolate mofetil (CellCept) at a dose of 500 mg/day, aiming to titrate up to a dose of 2000 to 2500 mg/day over the next several weeks. Women being started on this drug should have a negative pregnancy test and be advised about its potential teratogenic effects (pregnancy category C), and all patients should be watched closely for neutropenia and gastrointestinal bleeding. SUGGESTED READING
The Transverse Myelitis Consortium Working Group: Proposed diagnostic criteria and nosology of acute transverse myelitis, Neurology 59:499-505, 2002. Weinshenker BG, OBrien PC, Petterson TM, et al: A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease, Ann Neurol 46:878-886, 1999.
individuals, sexual dysfunction despite also having physical and emotional significance has been mostly overlooked in this same group. Both areas deserve attention because of their significance in the routine bodily functioning and overall sense of wellness and normalcy of humans. Both areas undoubtedly require further evolution in pathophysiologic understanding and ideal clinical management; however, basic approaches to preserve and optimize functional levels in patients must be sought and applied today. This brief review describes current clinical strategies and available treatments for the management of urinary and sexual dysfunctions in this population.
Urinary Dysfunction
Urinary symptoms are common among patients with demyelinating diseases of the spinal cord, with as much as 75% of individuals experiencing such complaints. The symptoms are typically irritative in nature and usually are manifest as urgency, frequency, and urge incontinence. Detrusor hyperreflexia (involuntary detrusor contraction due to neuropathy), resulting from suprasacral neurologic impairment, is attributed to this symptomatic presentation. Dyssynergic external urethral sphincteric function may also occur concomitantly with the dysfunctional storage phase of urinary function in these patients, producing additional symptomatic features of incomplete emptying and hesitancy. The loss of coordinated lower urinary tract function also is explained by disrupted neuronal pathways between the brainstem and sacral spinal cord. It is perceived that urinary symptoms range in severity and can fluctuate even in a single individual, depending on their present neurologic status. Similarly, in the event of progression of the neurologic illness by other nonurologic manifestations, there is commonly greater severity of urinary complaints. Since urinary symptoms rather than clinical manifestations (upper urinary tract damage, urinary tract infection) typically dominate the clinical picture, management is primarily focused on providing symptomatic relief. This observation suggests the limited need for extensive urodynamic investigation for many initial presentations. However, an essential diagnostic step following recognition of presenting or deteriorating symptoms is the objective assessment of emptying ability by measuring postvoid residual (PVR) amount (Figure 1). The PVR determination can be made either by sonographic bladder scan or catheterization, whereas the former may be preferable in men to avoid urethral trauma. The basic scheme is that PVR amounts less than 100 mL can be treated with anticholinergic medication, whereas PVR amounts greater than 100 mL require initiation of clean intermittent catheterization (CIC) with or without anticholinergic medication. The goals of treatment are to stabilize involuntary bladder contractions and associated symptoms while reducing risks of urinary stasis, infection, urolithiasis, and upper urinary tract damage. If the endpoints are not met with these conservative measures, a urologic consultation should be sought.
PATIENT RESOURCES
Transverse Myelitis Association http://www.myelitis.org/ The Johns Hopkins Transverse Myelopathy Center http://www.med.jhu.edu/jhtmc/

Dysfunctions of the lower urinary tract (bladder and urethra) and genitalia are commonly experienced by individuals afflicted by demyelinating diseases of the spinal cord. Although urinary dysfunction has long been recognized as a major physical disability among these
198
Urinary symptoms
Measure PVR
<100 ml Anticholinergic medication and monitor PVR <100 ml
>100 ml CIC Stable Urologic consultation Stable Urologic consultation >100 ml CIC Stable Urologic consultation
side effects. All anticholinergic medication has the potential to cause dry mouth, constipation, somnolence, and headache among anticholinergic side effects. Uncontrolled narrow-angle glaucoma represents a contraindication. Desmopressin (DDAVP), an analog of the posterior pituitary hormone antidiuretic hormone, has been employed in this population for persistent nocturia refractory to anticholinergics or frank enuresis. This therapy works to promote water reabsorption in the collecting ducts of the kidney, hence reducing nocturnal urine production. Oral forms (0.1, 0.2 mg) as well as nasal sprays (10 to 40 g) of the therapy used at bedtime are available. Potential adverse effects are headache, nausea, and nasal congestion. Since no class of pharmacologic agents has been shown to selectively relax the striated musculature of the pelvic floor, the specific management of detrusor-sphincter dyssynergia is usually not routinely sought and, if indicated, standardly requires the involvement of a urologic surgeon.
Sexual Dysfunction
In the past decade, the management of sexual dysfunction in general has undergone a major evolution resulting from the availability of effective and convenient pharmacotherapy for sexual problems combined with a renewed appreciation of the medical significance and quality-of-life impact associated with these particular problems. This climate has prompted all clinical practitioners to be familiar with and ready to manage sexual dysfunction of all etiologies. In both men and women, spinal cord demyelinating disorders are increasingly understood to affect various components of the human sexual response cycle from libidinal to arousal to orgasmic aspects. Approximately 75% of male patients with such disorders experience erectile dysfunction, and 50% experience ejaculatory abnormalities; more than 50% of female patients with these disorders experience sexual problems that comprise low libido, arousal dysfunction, and orgasmic dysfunction. In clinical surveys, it has been shown that erectile dysfunction in particular is not particularly associated with multiple sclerosis severity or type, although close associations exist with bladder and bowel dysfunctions. As for any presentation of sexual dysfunction today, the management of sexual dysfunction associated with demyelinating spinal cord neuropathies should consist of the fundamental elements of assessment and treatment. Since individuals with these disorders do represent an identifiable high risk population for sexual dysfunction, all individuals within this population warrant consideration for screening of sexual problems, which may then allow opportunities for proper diagnosis and treatment. The association underscores the neurologic regulatory basis for sexual functioning, with respect to the autonomic efferent and afferent circuits from spinal cord levels governing genital blood flow and pelvic floor muscular activity. Current reports suggest that simple questioning for sexual problems generally suffices to ascertain their presence, whereas elaborate diagnostic
FIGURE 1. Algorithm for the management of urinary symptoms in multiple sclerosis. PVR, Postvoid residual; CIC, clean intermittent catheterization.
Adjunctive basic tests include urine culture to exclude the presence of infected urine as well as renal sonography and serum creatinine to establish baseline upper urinary tract function. Creatinine measurement can be used annually for upper tract monitoring. Complications of CIC to be monitored for include false passages and bladder perforation. Bacteriuria is a common occurrence with CIC and does not warrant treatment, whereas rarely occurring symptomatic infection should be treated with short-term antibiotic therapy. The institution of pharmacotherapy is an important component of this plan of management. First-line agents consist of anticholinergic medications, perceived to offer benefit in controlling neurologic mechanisms of aberrant detrusor expulsive function. The oral anticholinergic drugs, oxybutynin (Ditropan bid or tid or Ditropan XL as an extended-release daily form) at 2.5, 5, 10, and 15 mg, or tolterodine (Detrol bid or tid or Detrol LA as an extended-release daily form) at 1, 2, and 4 mg, have been used quite successfully, starting at low dosages and then titrating for effect and toleration. Most recently, a topical formulation of oxybutynin (Oxytrol) at 3.9 mg/day every 3 to 4 days has been U.S. Food and Drug Administration (FDA) approved and is gaining in use because of its convenience, tolerability, and reduced
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questionnaires used in clinical trials are not required for practical management. On the recognition of a sexual problem, subsequent steps to systematically define the extent of the problem and grasp the patients perspective to initiate management are performed. The latter reflects the consideration that patients and/or partners vary in their acceptance of treatment of sexual problems in accordance with specific needs, expectations, and priorities. In practice, a comprehensive clinical history and physical examination is routinely performed that addresses sexual, medical, and psychosocial factors. Sexual history should be assessed for the complete range of sexual issues that include libido, erectile dysfunction, ejaculation and orgasm in men, and libido, arousal (clitoral swelling, vaginal lubrication), and orgasm in women. Additionally, sexual history encompasses circumstances enabling sexual function such as stimuli required for sexual encounters, circumstances associated with impairment such as performance anxiety, and issues of availability, interest, and health of a partner. Basic queries may also be made regarding prior attempts to manage the problem by the patient or another caregiver. It is noteworthy that other risk factors for sexual dysfunction than neurologic illness may be identified during this evaluation that would prompt additional consideration in supporting the diagnosis and facilitating treatment objectives. Laboratory testing such as serum chemistries and complete blood count is tailored to the clinical situation and may be done to screen for concomitant chronic disease associated with sexual dysfunction that would require specialized management. The requirement for extensive endocrinologic assessment remains controversial, although it may be appropriately performed under particular indications such as poor sexual libido. Complicated or atypical presentations of sexual dysfunction may be referred to a sexual dysfunction specialist for advanced diagnostic testing and subsequent corrective action. For instance, irrespective of the neurologic basis for sexual dysfunction, the additional presence of significant penile deformities, complicated endocrinopathies, and complicated psychiatric or psychosexual disorders may justify referrals to a urologist, endocrinologist, and psychiatrist, respectively. The initiation of therapy for sexual problems should ideally involve nondrug adjunctive therapies prior to and in conjunction with pharmacotherapeutic interventions. Most certainly, impediments to optimal sexual functioning among individuals with demyelinating neuropathies should be addressed. Consequently, interventions that reduce pain complaints, facilitate physical ability, and manage bowel and bladder dysfunction, among specific therapies for this population, should be invoked. At the same time, lifestyle modifications including dietary improvement, smoking cessation, and physical conditioning may be worthily initiated according to the premise that they favorably impact sexual functioning, particularly arousal functions. A notable adjunct is psychosexual therapy, often involving a psychologist or sexual therapist, since attention to nonphysical and emotional factors may contribute significantly to sexual
dysfunction management, irrespective of the etiology of the problem. Among sexual dysfunctions, arousal dysfunction (erectile dysfunction) in men has achieved at this time the most clearly defined basis for treatment recommendations. According to several consensus bodies, a stepwise approach can be applied for clinical decision making about erectile dysfunction treatment in patients who do not require treatment of an underlying specific disorder (Table 1). The approach is based on ease of administration, reversibility, level of invasiveness, and cost. It is importantly acknowledged that hormone replacement therapy uncommonly serves a primary therapeutic role in men for erectile dysfunction, whereas its use is best supported in the treatment of libidinal problems associated with a documented endocrine abnormality (hypogonadism). Similarly, penile revascularization therapy is offered only under the uncommon circumstance of focal, traumatic arterial insufficiency. Erectogenic pharmacologic therapies currently represent the centerpiece of therapeutics for erectile dysfunction. Oral agents, as first-line therapy, refer readily to recently developed, highly effective phosphodiesterase type 5 (PDE-5) inhibitors, which preserve cyclic guanosine monophosphate (cGMP)-induced corporal smooth muscle relaxation required for erection. By name and dosages, commercially available PDE-5 inhibitors are sildenafil (Viagra) at 25, 50, and 100 mg; tadalafil (Cialis) at 5, 10, and 20 mg; and vardenafil (Levitra) at 2.5, 5, 10, and 20 mg. In principle, these agents all work by augmenting the basic biochemical mechanism of the erectile response rather than inducing spontaneous erection. Hence, they require sexual stimulation causing release of endogenous effectors for efficacy. The medications are generally taken at recommended mid-range starting dosages an hour before intended sexual activity. Responses may occur as soon as an hour after administration, with effectiveness that lasts as much as several hours for sildenafil and vardenafil and 36 hours for tadalafil. Food effects appear to be least concerning for vardenafil and tadalafil. All agents are associated with potential adverse events, which occur in less than one in five individuals and are transient. These include headache, facial flushing, dyspepsia, and nasal congestion. Visual disturbances (color or brightness changes) have been associated with use of sildenafil. Back pain and myalgias have been associated with use
TABLE 1 Stepwise Treatment Approach for Erectile Dysfunction

Step First line Second line Third line Therapy Oral erectogenic agents Vacuum constriction devices Pyschosexual therapy Intraurethral suppositories Intracavernous injections Surgical prostheses
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of tadalafil. The main contraindication for use of this therapy is concomitant administration of nitrates, which in combination produces systemic hypotension that may be so severe as to cause fatality. Alpha-blocker considerations are also important in applying this therapy, also because of hypotension concerns. The therapy has been shown to be highly effective among individuals with spinal cord injury as much as for those with demyelinating spinal cord disorders, allowing sexual intercourse in as many as 90% of users. Intraurethral suppositories and intracavernous injections, representing second-line interventions, offer local forms of administration of vasoactive drug, most commonly prostaglandin E1 (alprostadil). The agent works by stimulating the production of cyclic adenosine monophosphate (cAMP) that induces corporal smooth muscle relaxant effects. An applicator system termed MUSE (medicated urethral system for erection) for dispensing a small pellet of the medication within the distal urethra at 125, 250, 500, and 1000 g dosages characterizes the intraurethral technique. Preformulated or immediately reconstituted medication from powder forms termed Prostin VR, Caverject, or Edex that is then injected with a small diabetic needle directly into a corporal body of the penis at 5- to 60-g dosages characterizes the intracavernous technique. The treatment is administered on demand with fairly immediate efficacy that does not rely on endogenously released biochemicals with sexual stimulation. Adverse effects are generally local, most likely urethral bleeding for intraurethral suppositories and penile scarring for intracavernous injections (both complications occurring in < 10% of users), whereas urogenital aching sensations (associated with the metabolism of the medication) may occur for both in as many as 30% of users. In-office instruction and titration are highly recommended for the safe initiation of these therapies. Intracavernous drug administrations may also contain off-label papaverine and phentolamine in varying combinations with alprostadil, concocted usually under the direction of a urologic surgeon. Therapeutic benefit defined as successful intercourse approximates 30% for intraurethral suppositories and 75% to 90% for intracavernous injections, mostly irrespective of the etiology of the erectile dysfunction. These therapies are contraindicated for patients with priapism histories and histories of severe coagulopathy. Vacuum constriction devices refer to a nonpharmacologic, mechanical means to produce an erection. A cylinder is temporarily placed externally around the penis and sealed at the penoscrotal junction that allows for the creation of negative pressure resulting in blood engorgement of the penis. The subsequent placement of a temporary constricting elastic ring at the base of the penis, after which the cylinder is removed, preserves the erection-like state. The effect allows sexual intercourse in at least 95% of applications, irrespective of the etiology of erectile dysfunction. Basic instruction usually suffices to initiate therapy. Significant complications are rare, with typical concerns related to cumbersomeness, unnaturalness, and local penile trauma such as petechiae and ecchymosis.
Penile prosthesis surgery represents third-line, nonspecific therapy requiring the expertise of a urologic surgeon. The devices are surgically implanted within the corporal bodies of the penis. The two main varieties are semirigid malleable devices and hydraulic inflatable devices. After receiving basic instruction, patients can expect to experience uniformly successful sexual intercourse. Potential complications (<5% at 5 years) include infection, erosion, and device malfunction, usually necessitating device removal and/or replacement. Ejaculatory abnormalities are generally managed in this population, as for men with spinal cord injury, primarily for infertility purposes. Seminal emission that produces sperm suitable for assisted reproductive techniques has required vibratory stimulation or electroejaculation sometimes with the patient under general anesthesia. Female sexual dysfunction associated with demyelinating spinal cord disorders, as is the case for any association, remains a significantly understudied area. Although limited, current progress in the field establishes the significance of sexual arousal problems in women. This disturbance may actually be the primary circumstance in many women presenting with sexual dysfunction and be the root of other sexual problems, including low sexual libido and orgasmic dysfunction. There is also the suggestion that coitus with insufficient arousal contributes to the etiology of vulvar pain syndromes and vaginismus. Arousal function in women combines genital changes and nongenital somatic changes such as increased heart rate and breast sensations as well as subjective states of arousal. Nonetheless, attention has increasingly been given to genital changes in the female sexual response cycle since this realm may afford opportunities at this time for effective pharmacotherapeutic intervention. Traditional focus has been given to estrogen hormone replacement in women to optimize the genital environment, such as facilitating vaginal lubrication and sensitivity. Increased understanding of the role of androgens in the female sexual response has also prompted investigation into the role of androgen administration to improve sexual libido as well as sexual arousal. Widespread use of testosterone therapy in women, however, remains controversial at this time. Although vasoactive medications have been quite effective for erectile problems in men, equivocal findings have been reported about its role in women with sexual dysfunction. Notably, PDE-5 inhibitor therapy has been investigated in women with sexual dysfunction due to multiple sclerosis, with recent reports describing improved lubrication and sensation but no change in orgasm compared with placebo. As an alternative, noninvasive treatment for arousal problems in women, a recently FDA-approved mechanical device known as Eros-CTD may be used. The device is a battery-operated suction device applied to the clitoris that promotes sensation, vaginal lubrication, and orgasmic capacity. Conventional treatments such as lubricants, sexual therapy, and sexual aids including dilators and vibrators remain options to facilitate sensory function and reduce dysesthesias during sexual activity.
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Conclusion
Given the recognition that urinary and sexual dysfunctions are commonplace among both men and women afflicted by demyelinating spinal cord disorders, the proper identification, diagnosis, and treatment of these problems should be pursued by all clinical practitioners involved in the care of these individuals. Appropriate initial management and subsequent referral to specialists when indicated constitute a reasonable plan for successful management of these problems and in turn can be expected to allow patients experiencing these problems to enjoy the best possible quality of life. SUGGESTED READING
Burnett AL: Erectile dysfunction module. In Goldman DR, editor: Physicians information and education resources (PIER), Philadelphia, 2004, American College of PhysiciansAmerican Society of Internal Medicine. Das Gupta R: Sexual and urological dysfunction in multiple sclerosis: better understanding and improved therapies, Curr Opin Neurol 15:271-278, 2002. Wein A J: Neuromuscular dysfunction of the lower urinary tract and its management. In Walsh PC, Retik AB, Vaughan ED Jr, Wein A J, editors: Campbells urology, ed 8, Philadelphia, 2002, WB Saunders, 931-1026.
sarcoidosis is variable among different populations worldwide but appears to be frequent in African Americans and whites of northern European heritage. In some developing countries such as those in Latin America, Africa, and Asia, the prevalence of sarcoidosis remains uncertain as the high incidence of infectious granulomatous disorders such as tuberculosis, an infectious disorder that closely resembles sarcoidosis, predominates as a clinical diagnosis.
Clinical Problems in Neurosarcoidosis

The clinical manifestations of neurosarcoidosis are heterogenous as noncaseating granulomata and associated inflammation may affect any structure and compartment of the CNS and PNS. An approach to classify the different forms of this disorder is presented in Table 1. The most frequent manifestations of neurosarcoidosis include meningeal, cranial neuropathy, encephalitic, and neuroendocrine forms; clinical presentations that may overlap and produce complex neurologic symptoms. Clinical investigation of patients with suspected sarcoidosis of the nervous system requires a careful assessment of the systemic manifestations of the disease along with the neurologic evaluation. In most patients with clinical manifestations of neurosarcoidosis, evidence of systemic disease is already established. However, in almost 50% of patients with suspected neurosarcoidosis, the neurologic symptomatology may represent the first defining manifestation of sarcoidosis. In these patients, a more extensive and careful assessment of the systemic involvement is required to establish a definite or possible diagnosis of neurosarcoidosis (Figure 1). A possible diagnosis of neurosarcoidosis can be established using clinical and imaging assessment in patients that have a high likelihood of association with sarcoidosis and pathologic diagnosis established in non-CNS or PNS tissues (e.g., lung or lymph node). In patients with symptoms consistent with any of the neurologic forms of sarcoidosis and pathologic documentation of granulomatous inflammation obtained from CNS or PNS tissue biopsies, a definite diagnosis of neurosarcoidosis can be established. In patients with unknown history of sarcoidosis and neurologic disease suspected to be associated with this disorder, diagnostic strategies should focus on the evaluation of systemic disease as well as the nature of neurologic involvement. Since pulmonary and lymphatic involvement is the most frequent systemic manifestation of sarcoidosis, a careful pulmonary assessment and the use of imaging techniques such as chest computed tomographic (CT) scan, gallium scan, or fluorodeoxyglucose-positron emission tomography are valuable diagnostic approaches to identify areas of disease involvement and potential sites for biopsy. The investigation of CNS and PNS involvement in neurosarcoidosis may involve the use of different diagnostic strategies including magnetic resonance (MR) imaging, cerebrospinal fluid (CSF) studies, and CNS or PNS tissue biopsy. MR imaging of the brain or
Neurosarcoidosis
Sarcoidosis is a multisystemic granulomatous inflammatory disorder with central or peripheral nervous system manifestations seen in 5% to 10% of patients. Neurosarcoidosis may be the first localized manifestation of the disease or may be part of multisystemic disease. The pathologic hallmark of sarcoidosis is the presence of granulomatous noncaseating focal tissue reactions and inflammation dominated by macrophage activation as well as mononuclear and lymphocytic infiltration. In the nervous system, noncaseating granulomatas and inflammation may occur in any structural component of the central (CNS) or peripheral nervous system (PNS) and may produce focal or multifocal tissue reactions that result in neurologic dysfunction. The etiologic factors involved in the pathogenesis of sarcoidosis remain elusive, but several hypotheses suggest potential roles for genetic susceptibility and exposure to environmental infectious and noninfectious factors. Mycobacterium tuberculosis, Propionibacterium acnes, and Propionibacterium granulosum infections have been suggested as potential etiologic factors in sarcoidosis; however, this has not been demonstrated so far. Pulmonary and lymph node involvement are the most frequent manifestations of sarcoidosis, typically in young adults between the ages of 20 and 40 years. The prevalence of
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Conclusion
Given the recognition that urinary and sexual dysfunctions are commonplace among both men and women afflicted by demyelinating spinal cord disorders, the proper identification, diagnosis, and treatment of these problems should be pursued by all clinical practitioners involved in the care of these individuals. Appropriate initial management and subsequent referral to specialists when indicated constitute a reasonable plan for successful management of these problems and in turn can be expected to allow patients experiencing these problems to enjoy the best possible quality of life. SUGGESTED READING
Burnett AL: Erectile dysfunction module. In Goldman DR, editor: Physicians information and education resources (PIER), Philadelphia, 2004, American College of PhysiciansAmerican Society of Internal Medicine. Das Gupta R: Sexual and urological dysfunction in multiple sclerosis: better understanding and improved therapies, Curr Opin Neurol 15:271-278, 2002. Wein A J: Neuromuscular dysfunction of the lower urinary tract and its management. In Walsh PC, Retik AB, Vaughan ED Jr, Wein A J, editors: Campbells urology, ed 8, Philadelphia, 2002, WB Saunders, 931-1026.
sarcoidosis is variable among different populations worldwide but appears to be frequent in African Americans and whites of northern European heritage. In some developing countries such as those in Latin America, Africa, and Asia, the prevalence of sarcoidosis remains uncertain as the high incidence of infectious granulomatous disorders such as tuberculosis, an infectious disorder that closely resembles sarcoidosis, predominates as a clinical diagnosis.
Clinical Problems in Neurosarcoidosis

The clinical manifestations of neurosarcoidosis are heterogenous as noncaseating granulomata and associated inflammation may affect any structure and compartment of the CNS and PNS. An approach to classify the different forms of this disorder is presented in Table 1. The most frequent manifestations of neurosarcoidosis include meningeal, cranial neuropathy, encephalitic, and neuroendocrine forms; clinical presentations that may overlap and produce complex neurologic symptoms. Clinical investigation of patients with suspected sarcoidosis of the nervous system requires a careful assessment of the systemic manifestations of the disease along with the neurologic evaluation. In most patients with clinical manifestations of neurosarcoidosis, evidence of systemic disease is already established. However, in almost 50% of patients with suspected neurosarcoidosis, the neurologic symptomatology may represent the first defining manifestation of sarcoidosis. In these patients, a more extensive and careful assessment of the systemic involvement is required to establish a definite or possible diagnosis of neurosarcoidosis (Figure 1). A possible diagnosis of neurosarcoidosis can be established using clinical and imaging assessment in patients that have a high likelihood of association with sarcoidosis and pathologic diagnosis established in non-CNS or PNS tissues (e.g., lung or lymph node). In patients with symptoms consistent with any of the neurologic forms of sarcoidosis and pathologic documentation of granulomatous inflammation obtained from CNS or PNS tissue biopsies, a definite diagnosis of neurosarcoidosis can be established. In patients with unknown history of sarcoidosis and neurologic disease suspected to be associated with this disorder, diagnostic strategies should focus on the evaluation of systemic disease as well as the nature of neurologic involvement. Since pulmonary and lymphatic involvement is the most frequent systemic manifestation of sarcoidosis, a careful pulmonary assessment and the use of imaging techniques such as chest computed tomographic (CT) scan, gallium scan, or fluorodeoxyglucose-positron emission tomography are valuable diagnostic approaches to identify areas of disease involvement and potential sites for biopsy. The investigation of CNS and PNS involvement in neurosarcoidosis may involve the use of different diagnostic strategies including magnetic resonance (MR) imaging, cerebrospinal fluid (CSF) studies, and CNS or PNS tissue biopsy. MR imaging of the brain or
Neurosarcoidosis
Sarcoidosis is a multisystemic granulomatous inflammatory disorder with central or peripheral nervous system manifestations seen in 5% to 10% of patients. Neurosarcoidosis may be the first localized manifestation of the disease or may be part of multisystemic disease. The pathologic hallmark of sarcoidosis is the presence of granulomatous noncaseating focal tissue reactions and inflammation dominated by macrophage activation as well as mononuclear and lymphocytic infiltration. In the nervous system, noncaseating granulomatas and inflammation may occur in any structural component of the central (CNS) or peripheral nervous system (PNS) and may produce focal or multifocal tissue reactions that result in neurologic dysfunction. The etiologic factors involved in the pathogenesis of sarcoidosis remain elusive, but several hypotheses suggest potential roles for genetic susceptibility and exposure to environmental infectious and noninfectious factors. Mycobacterium tuberculosis, Propionibacterium acnes, and Propionibacterium granulosum infections have been suggested as potential etiologic factors in sarcoidosis; however, this has not been demonstrated so far. Pulmonary and lymph node involvement are the most frequent manifestations of sarcoidosis, typically in young adults between the ages of 20 and 40 years. The prevalence of
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Neurosarcoidosis
TABLE 1 Neurologic Presentations of Neurosarcoidosis

Clinical Types of Neurosarcoidosis Meningeal forms Neurologic Presentation Aseptic meningitis Basal meningitis Chronic meningitis/pachymeningitis Dural tumor-like sarcoid lesions Facial paralysis Optic neuropathy Multiple cranial neuropathies Clinical Profile Headaches Increased intracranial pressure Hydrocephalus Papilledema Cranial nerve palsies, single or multiple Single or multiple cranial nerve palsies Bilateral Bells palsy Diplopia Visual blurriness Vestibular symptoms Headaches Psychosis Seizures Neuroendocrine manifestations Increased intracranial pressure Focal neurologic symptoms Gait disturbances Paraparesis/paraplegia Bladder dysfunction Paresthesias/dysesthesias Sensory level Multifocal or localized dysesthesias, paresthesias, weakness, monoradiculopathies or polyradiculopathies Weakness, muscle pain Clinical Course Subacute, relapsing-remitting, or chronic
Cranial neuropathies
Acute, subacute Monophasic or relapsing-remitting
Encephalitic forms
Focal encephalitis Focal or multifocal leukoencephalitis Tumor-like sarcoid lesions Subacute or progressive myelopathy
Subacute Relapsing-remitting or chronic
Myelopathic form
Subacute Monophasic, relapsing-remitting, or chronic Subacute Relapsing-remitting or chronic Acute, subacute or chronic Occasionally indolent
Neuropathic form
Multiple mononeuropathies Polyradiculoneuropathies Focal myositis Polymyositis
Myopathic forms
spinal cord is a necessary step to evaluate the magnitude and extension of the disease. Enhanced MR imaging studies help determine the magnitude of disease activity and inflammation, particularly in encephalitic and meningeal forms, and are necessary to identify potential sites for biopsy. CSF analysis is required to investigate and rule out other potential etiologies such as tuberculous, fungal, or neoplastic meningitis, or other neurologic disorders as well as to determine the magnitude of inflammatory activity. Mononuclear pleocytosis, increase in protein concentration, increased IgG index, and presence of oligoclonal bands are useful parameters in the evaluation of inflammatory activity. Unfortunately, the assessment of angiotensin-converting enzyme in CSF is rarely useful because this test lacks sensitivity and specificity in the evaluation of patients with neurosarcoidosis. CNS or PNS tissue biopsy establishes a definite diagnosis of neurosarcoidosis, but in many circumstances a diagnosis of probable neurosarcoidosis is enough to initiate treatment. In patients with existing or previous history of systemic sarcoidosis, the diagnostic approach may be relatively uncomplicated because the main focus of assessment would be the establishment of nervous system involvement. The clinical course of neurosarcoidosis is variable and may exhibit temporal profiles consistent with monophasic, relapsing-remitting, and chronic patterns.
The evolution and clinical course of the neurologic problems and the magnitude of CNS or PNS involvement in sarcoidosis frequently determine the treatment approach. Some of the acute manifestations of neurosarcoidosis such as cranial neuropathies have a monophasic pattern that resolves quickly with steroid treatment, whereas others such as the meningeal, encephalitic, and myelopathic forms frequently have a subacute course that may evolve to relapsing-remitting or chronic forms requiring aggressive treatment approaches. MENINGEAL FORMS Basal, chronic meningitis and pachymeningitis are frequent manifestations of the meningeal forms of neurosarcoidosis. A careful clinical assessment, imaging studies including a noncontrast and contrast-enhanced brain MR imaging as well as a complete examination of the CSF are required to rule out the presence of other disorders such as tuberculous, fungal, or neoplastic meningitis that frequently affect the basal meningeal compartment. Since the basal region of the brain is one of the most common areas affected by meningeal forms, cranial nerve palsies and hydrocephalus are the most frequent clinical manifestations. In patients with chronic meningitis, pachymeningitis, and basal meningitis, inflammatory reactions may impair the reabsorption of
Patient with suspected neurosarcoidosis
Known history of sarcoidosis
No history of sarcoidosis
Johnson: Current Therapy in Neurologic Disease (7/E) Evaluate neurological involvement Evaluate systemic involvement CNS, visual or endocrine symptoms Pulmonary assessment Brain MRI Spinal cord MRI Neuroendocrine assessment CSF analysis Negative findings CNS/meningeal biopsy High probability or identifiable lesion in CNS/meninges Identifiable lesion or high probability Other: ACE, calcium, LFT Lymph node, lung, liver, skin or other biopsy Negative findings Chest CT scan Gallium scan or FDG-PET Evaluate other diagnostic options Negative findings Ophthalmology assessment Evaluate other diagnostic options Granulomatous/ inflammatory lesion Granulomatous/ inflammatory lesion Definite diagnosis of neurosarcoidosis Probable diagnosis of neurosarcoidosis
PNS, neuromuscular symptoms
EMG/NCS
Low probability or negative findings
High probability
Muscle or nerve biopsy
Evaluate other diagnostic options
Granulomatous/ inflammatory lesion
Definite diagnosis of neurosarcoidosis
Neurosarcoidosis
FIGURE 1. Diagnostic algorithm for suspected neurosarcoidosis. PNS, Peripheral nervous system; CNS, central nervous system; EMG, electromyogram; NCS, nerve conduction study; CSF, cerebrospinal fluid; FDG-PET, fluorodeoxyglucose-positron emission tomography; ACE, angiotensin-converting enzyme; LFT, liver function test.
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the CSF in the arachnoid villi and/or produce obstruction of CSF flow thru the Luschka and Magendie foramina that lead to aggressive forms of hydrocephalus and elevated intracranial pressure. Special caution should be taken in patients with hydrocephalus associated with neurosarcoidosis because lumbar puncture procedures may increase the risk of decompensation and cerebellar tonsillar herniation. Some of these patients may require ventriculostomy or ventriculoperitoneal shunts to avoid further complications with increased intracranial pressure, but the decision for this approach must be evaluated carefully. Occasionally, some patients with neurosarcoidosis may present with dural tumor-like lesions that resemble meningiomas and produce focal symptoms or increased intracranial pressure. These tumor-like lesions are associated with extensive but localized noncaseating granulomatous and inflammatory reactions of the dura mater and respond well to medical treatment without need for surgical resection except in situations in which there is marked mass effect or increased intracranial pressure. Other forms of meningeal involvement such as chronic pachymeningitis frequently have refractory response to conventional treatment with steroids and may require aggressive immunosuppressive treatment. CRANIAL NEUROPATHY FORMS Cranial neuropathies are one of the most frequent clinical forms of neurosarcoidosis and may manifest acutely following a monophasic or relapsing-remitting course. Facial palsy frequently presenting as bilateral facial involvement is perhaps one of the classic manifestations of the disease. In most patients, the presence of facial palsy or other cranial neuropathies is frequently associated with basal meningitis and may be the result of perineural inflammation rather than intra-axial, axonal, or demyelinating nerve lesions. Other cranial nerves including optic, oculomotor, vestibular, and other lower cranial nerves may also be involved in neurosarcoidosis. In general, patients with cranial neuropathy forms usually respond well to treatment with steroids, but some patients with optic neuropathy or acousticvestibular involvement may evolve into relapsingremitting or chronic forms. ENCEPHALITIC FORMS Focal encephalitis, leukoencephalitis, or multifocal white matter involvement represents aggressive forms of neurosarcoidosis because these manifestations are frequently associated with subacute, relapsing-remitting, or chronic patterns. Symptoms associated with encephalitic forms include seizures, headache, symptoms of increased intracranial pressure, psychosis, motor dysfunction, cognitive decline, and other focal manifestations. Focal or multifocal leukencephalitic forms of neurosarcoidosis may mimic the clinical and MR imaging features of multiple sclerosis. Patients with suspected demyelinating diseases should be evaluated to rule out the presence of sarcoidosis before establishing the definite diagnosis of
such disorders. Some of the focal encephalitic forms represent aggressive forms of parenchymal CNS sarcoidosis that become refractory to the conventional treatment with steroids. A localized form of encephalitis that affects the hypothalamic region and may be associated with basal or peri-infundibular meningitis is responsible for a complex neuroendocrine manifestation of sarcoidosis such as diabetes insipidus and/or other endocrine symptomatology. In patients with this form of neuroendocrine involvement, the granulomatous inflammatory activity is frequently monophasic and subacute but produces important longstanding endocrine problems. MYELOPATHIC FORMS Though not as frequent as other forms of neurosarcoidosis, myelopathic forms may represent a diagnostic challenge if there is no previous history of the systemic sarcoidosis. Myelopathic forms manifest frequently as subacute or slowly progressive myelopathies associated with both motor and sensory symptomatology. A presumptive or possible diagnosis of sarcoid myelopathy may be established if a patient has a previous history of systemic sarcoidosis, clinical evidence of myelopathy documented by clinical findings, and MR imaging findings of focal or multifocal intra-axial spinal cord lesions. A definite diagnosis is established if there is histopathologic documentation of sarcoidosis supported by a spinal cord biopsy. Since involvement of the spinal cord is frequently associated with slow, progressive lesions, the diagnosis of sarcoid myelopathy is occasionally established after spinal cord biopsies are obtained in patients with suspected spinal cord tumors. NEUROPATHIC AND MYOPATHIC FORMS Peripheral nerve involvement in sarcoidosis is seen frequently as multiple mononeuropathies, mononeuritis multiplex, or polyradiculoneuropathies. Neuropathic forms of neurosarcoidosis follow subacute and relapsing remitting forms that produce a mixture of motor and sensory symptoms. A definite diagnosis of peripheral nerve involvement in sarcoidosis is difficult to achieve, whereas a biopsy of the sural nerve has a very low yield to establish the diagnosis and the presumptive diagnosis is based on indirect evidence of disease activity, clinical evolution, and response to steroid treatment. Myopathic forms on the other side appear to be relatively easy to be diagnosed because the clinical presentation involves primarily weakness and signs of focal or polymyositis. Pathologic documentation of muscle involvement can be achieved by muscle biopsy, a procedure that has a better yield in demonstrating granulomatous inflammatory lesions.
Treatment Approaches
At present, there are no controlled studies that objectively document the efficacy of the different pharmacologic approaches used in the treatment of patients
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with neurosarcoidosis. Current therapies are the result of anecdotal experiences and clinical case series of patients with systemic sarcoidosis and nervous system involvement rather than evidence from controlled trials. The main goal of treatment for neurosarcoidosis focuses on the control of the granulomatous inflammatory activity within the CNS or PNS and the neurologic manifestations derived from pathologic processes associated with sarcoid activity in the CNS or PNS. A treatment algorithm is delineated in Figure 2. Since neurosarcoidosis is a heterogenous disorder, treatment approaches should be guided by the type, clinical course, and evolution of the disease. Clinical follow-up and coordination of treatment with other clinicians (e.g., pulmonologist, endocrinologist, or internist) are highly recommended because neurologic problems in sarcoidosis are frequently associated with other systemic manifestations of the disease.
MANAGEMENT OF ACUTE MANIFESTATIONS OR EARLY STAGES In a newly diagnosed patient naive to steroid treatment or any other pharmacologic intervention for sarcoidosis, treatment of monophasic forms or early stages of meningeal, encephalitic, myelopathic, or neuromuscular forms should be initiated with steroid therapy. Oral prednisone at doses of 1 mg/kg/day during the first and second week followed by a tapering dose over the next following weeks may be effective in controlling acute symptoms. In some circumstances, such as in cases of encephalitic and aggressive meningeal forms, an initial short course of intravenous methylprednisolone, 1 gm/day for 3 to 5 days, followed by oral prednisone may be helpful in controlling some of the acute symptoms associated with these forms. A decision about continuation of steroid treatment at lower doses or use of other
Acute, subacute or monophasic forms
Relapsing-remitting forms
Chronic forms
8
Methylprednisolone 1 gr/IV/day x 3 days Consider a steroid-sparing immunomodulatory OR immunosuppressant medication WITH or WITHOUT oral prednisone
Prednisone 1 mg/kg/PO/day
Evaluation at 24 weeks Immunomodulators Hydroxycloroquine 200 mg/PO/day OR Infliximab 3 mg/kg/IV one dose week 1, 3 and 5 followed by same dose every 6 weeks (combined with methotrexate) Immunosuppressants Methotrexate 1025 mg/PO/once a week OR Cyclosporin 2.5 mg/kg/BID OR Azathioprine 50 mg/PO/TID OR Cyclophosphamide 50200 mg/PO/day AND/OR Cyclophosphamide 700 mg/body surface area/IV every month
Successful treatment: Clinical improvement of neurological symptoms + Resolution of MRI/CSF abnormalities if any before treatment
Unsuccessful treatment: No clinical improvement or persistence/worsening of neurological problems and/or persistence of MRI/CSF abnormalities
Taper dose and discontinue treatment if other systemic manifestations are quiescent
Continue treatment if other systemic manifestations are active and/or Patient evolves to relapsingremitting or chronic forms
Successful treatment
Unsuccessful treatment
Taper dose or lower maintenance dose of prednisone
Consider adding a steroid-sparing immunomodulatory or immunosuppressant medications
Follow patient and try to wean if clinical situation allows
Radiation therapy
Surgical resection if there is a tumor-like lesion
FIGURE 2. Treatment algorithm for neurosarcoidosis. CSF, Cerebrospinal fluid. Johnson: Current Therapy in Neurologic Disease (7/E)
206
Neurosarcoidosis
medications should be based on the patients clinical response, neurologic assessment, brain or spinal cord imaging, and/or other laboratory studies. In patients who respond well to the initial steroid treatment, a lower maintenance dose of prednisone, 5 to 10 mg/day, may be beneficial for avoiding relapses of the disease. In patients who continue with marked neurologic involvement despite steroid treatment or have relapse of symptoms, higher doses of prednisone are sometimes required to maintain stability and control of the clinical problems. In these patients, special consideration should be given to the potential long-term side effects associated with steroid therapy, and use of other immunomodulatory and immunosuppressant medications should be considered. MANAGEMENT OF REFRACTORY DISEASE, RELAPSING-REMITTING, AND CHRONIC FORMS Treatment of relapsing-remitting and chronic forms of neurosarcoidosis may require the use of alternate treatments that include immunomodulatory or immunosuppressive medications. The decision about use of these medications should be based on patient response to steroid therapy, adverse effects of chronic use of steroids, and clinical course of the disease. The major goal of therapy in relapsing-remitting and chronic forms of neurosarcoidosis is to limit the immune system reactivity that facilitates the development of granulomatous inflammatory lesions within the CNS or PNS. Since mechanisms of inflammation are governed by immune mediators, medications that modulate or suppress these immune reactions may be helpful in the treatment of neurosarcoidosis. Long-term use of immunosuppressant medications such as methotrexate, azathioprine, cyclophosphamide, cyclosporine, and mycophenolate mofetil have been proposed as an alternative to the chronic use of prednisone or as adjuvant to chronic steroid therapy. The selection of these medications should be based on patient individual assessment because some of these medications may have unwanted side effects. Methotrexate, 10 to 25 mg by mouth or subcutaneously once a week, is perhaps one of the most used immunosuppressants in sarcoidosis and should be prescribed in combination with folic acid, 1 mg/day by mouth. Methotrexate has potential hepatic, bone marrow, and pulmonary toxicity, and patients receiving this medication should be followed closely. Azathioprine, 50 mg orally three times a day, has been shown to be beneficial in some refractory cases, but its bone marrow, hepatic, and gastrointestinal toxicity as well as potential oncogenic property limit its use to aggressive forms of sarcoidosis. Cyclosporine, 5 mg/kg/day divided into two doses, has limited efficacy in systemic sarcoidosis but has been shown to be beneficial in some cases of neurosarcoidosis. Cyclosporine may produce considerable nephrotoxicity and has oncogenic properties that limit its use to only aggressive and serious cases of neurosarcoidosis that have failed other therapies. Cyclophosphamide, 50 to 200 mg/day orally or boluses of 700 mg/m2 monthly, has been also used but has side effects associated with cystitis, neutropenia, and potential
oncogenic properties. Mycophenolate mofetil, a relatively new immunosuppressant, has been mentioned recently as potentially useful in neurosarcoidosis. Immunomodulatory medications such as hydroxychloroquine, pentoxifylline, and, most recently, infliximab have been used in the management of neurosarcoidosis. Hydroxychloroquine, 200 mg/day orally, requires careful ophthalmologic follow-up for its association with retinopathy and may produce ototoxic, neuropsychiatric, and myopathic adverse effects. Infliximab, a humanized monoclonal antibody with effect on tumor necrosis factor function, has been shown to be useful in some cases of neurosarcoidosis, but the drug carries an increased risk of infections, allergic reactions, or exacerbation of tuberculosis. This medication should be associated with methotrexate to achieve a suppression of humoral responses. Other immunomodulatory medications such as pentoxifylline, thalidomide, and etanercept have been proposed as alternatives in the treatment of complicated forms of sarcoidosis, but their efficacy in cases of neurosarcoidosis is unknown. OTHER NONPHARMACOLOGIC THERAPEUTIC APPROACHES Treatment of hydrocephalus in neurosarcoidosis requires special attention because of the potential risk of life-threatening increase in intracranial pressure. The decision about ventriculostomy or shunting procedures should be evaluated carefully because patients with neurosarcoidosis may have an increased risk of shunt dysfunction due to infection or obstruction due to immunosuppression and inflammatory tissue reactions. Surgical resection of tumor-like dural masses or focal encephalitic lesions that produce marked mass effect or increased intracranial pressure should be considered if medical treatment with steroids is ineffective. In some cases refractory to pharmacologic treatment and/or with difficult access to surgical resection, radiation therapy may be useful in controlling inflammatory tissue reactions and mass effect. SUGGESTED READING
Baughman RP: Therapeutic options for sarcoidosis: new and old, Curr Opin Pulm Med 8:464-469, 2002. Hoitsma E, Faber CG, Drent M, et al: Neurosarcoidosis: a clinical dilemma, Lancet Neurol 3:397-407, 2004. Moller DR: Treatment of sarcoidosisfrom a basic science point of view, J Intern Med 253:31-40, 2003. Smith JK, Matheus MG, Castillo M: Imaging manifestations of neurosarcoidosis, AJR Am J Roentgenol 182:289-295, 2004. Stern BJ: Neurological complications of sarcoidosis, Curr Opin Neurol 17:311-316, 2004.
PATIENT RESOURCES
National Sarcoidosis Foundation Sarcoidosis Networking
Bells Palsy
207
Bells Palsy
Donald H. Gilden, M.D.
Definition and Clinical Diagnosis

Bells palsy (idiopathic peripheral facial palsy) is defined by the abrupt onset of unilateral weakness of upper and lower muscles of one side of the face with no apparent cause. Before diagnosing Bells palsy, consideration should be given to other causes of acquired peripheral facial weakness, even though they are much less common. Associated conditions include diabetes mellitus, hypertension, human immunodeficiency virus infection, Lyme disease, Ramsay Hunt syndrome (facial palsy with zoster oticus caused by varicella zoster virus), sarcoidosis, Sjgrens syndrome, parotid-nerve tumors, eclampsia, and amyloidosis. Peripheral facial nerve palsy has also been reported in recipients of inactivated intranasal influenza vaccine. Furthermore, the clinician should always remember that peripheral facial weakness can also be produced by a lesion of the ipsilateral facial nerve nucleus or facial nerve in the pons. However, an intrinsic pontine lesion is likely to be associated with additional neurologic symptoms and signs. The incidence of Bells palsy is 20 to 30 cases per 100,000 people per year and accounts for 60% to 75% of all unilateral facial paralysis. Both sexes are affected equally. The median age at onset is 40 years, but disease may occur at any age. The incidence is lowest in children younger than 10 years of age, increases from age 10 to 29, remains stable at ages 30 to 69, and is highest in people older than 70 years of age. Both sides of the face are involved with equal frequency. Most patients recover completely, although some have permanent disfiguring facial weakness. Poor prognostic factors include older age, hypertension, impairment of taste, pain other than in the ear, and complete facial weakness. In the first 3 days, electrical studies do not reveal any changes in involved facial muscles, whereas a steady decline in electrical activity is often noted on days 4 to 10. When excitability is retained, 90% patients recover completely; in the absence of excitability, only 20% patients recover completely. Bells palsy patients may develop hyperacusis from paralysis of the stapedius muscle, which dampens vibrations of the ear ossicles and causes sounds to be abnormally loud on the affected side; there is no hearing loss. Also, because the nervus intermedius carries parasympathetic fibers that stimulate salivation and lacrimation, patients with lesions proximal to the geniculate ganglion often have a permanent loss of taste and fail to produce tears. Rapid recognition of the latter symptom is important, since these patients require artificial tears to lubricate the cornea and may need to have the eye taped shut to prevent drying and infection. Peripheral facial weakness may be confused with hemifacial spasm, in which the corner of the mouth is drawn up and the eye is partially or completely closed due to
involuntary contraction of the risorius and orbicularis oculi muscles. After acute facial paralysis, preganglionic parasympathetic fibers that previously projected to the submandibular ganglion may regrow and enter the major superficial petrosal nerve. Such aberrant regeneration may lead to lacrimation on a salivary stimulus (so-called crocodile tears). Bells palsy rarely recurs. Recurrent or bilateral facial palsy should prompt consideration of myasthenia gravis, lymphoma, sarcoidosis, and Lyme disease. Rarely, patients with inflammatory demyelinating polyneuropathy (Guillain-Barr syndrome) present with bilateral facial palsy to the relative exclusion of extremity weakness. In immunocompetent people, Ramsay Hunt syndrome is neither recurrent nor bilateral.
Diagnostic Studies
If Bells palsy is diagnosed within 10 days, no tests are indicated unless other cranial nerve deficits develop (indicating more widespread disease), there is no recovery at 3 to 6 weeks after the onset of symptoms, or a facial twitch or spasm preceded Bells palsy (indicating continuous facial nerve irritation suggestive of a tumor). Thus, brain magnetic resonance (MR) imaging is not routinely indicated. If performed, the most common abnormality seen is contrast enhancement of the distal intracanalicular and labyrinthine segments of the facial nerve; the geniculate ganglion, as well as the proximal and distal tympanic and mastoid portions of the facial nerve, may also be involved. If the patient has complete facial paralysis after 1 week of medical treatment, electroneurography (EONG) should be performed. EONG measures the amplitude of the facial muscle compound action potential; the extent of nerve degeneration is determined by comparing the paralyzed side of the face with the normal side.
Medical Treatment (Figure 1)

Overall, 71% of untreated patients recover completely, and 84% achieve near-normal function. Thus, the 20% to 30% who do not recover fully remain the focus of treatment. Two main findings provide a rationale for early and aggressive treatment. First, for more than half a century, surgeons who have performed decompression operations on Bells palsy patients have described facial nerve swelling, a finding confirmed by MR imaging. Second, the detection of herpes simplex virus in endoneurial fluid in patients with Bells palsy has implicated the virus in the pathogenesis of the disease. The Quality Standards Subcommittee of the American Academy of Neurology recommends that early treatment with oral corticosteroids is probably effective in improving facial function outcomes in Bells palsy, that the addition of acyclovir to prednisone is possibly effective, and that insufficient evidence exists to recommend facial nerve decompression. When I see a patient with Bells palsy of less than 10 days duration, I treat him/her with oral prednisone,
208
Bells Palsy
Bell's palsy
Abrupt onset of unilateral upper and lower facial weakness with no apparent cause
Brain MRI is not routine Consider MRI if: (1) Additional cranial neuropathies or brainstem disease develops (ataxia, ophthalmoparesis, nystagmus, speech disturbance, long tract or hemisensory signs); (2) There is no recovery of facial weakness at 3 weeks; (3) A facial twitch or spasm preceded Bell's palsy.
Medical treatment If Bell's palsy is of less than 10 days' duration, treat with: oral prednisone, 1 mg/kg body weight for 7 days; no taper necessary; oral valacyclovir, 1 gm twice daily for 7 days. If complete facial paralysis is present after 1 week of medical treatment: obtain electroneurography (ENOG). If ENOG reveals more than 90% nerve degeneration, rapid referral to otolaryngologist for consideration of decompression.
doses of 800 mg. In children, the dose of prednisone and valacyclovir must be adjusted for weight. The same treatment can be given during pregnancy, although the safety of valacyclovir in pregnancy has not been established. There is no need to taper prednisone after only 1 week of treatment. Rarely, patients with Bells palsy may be candidates for surgery. The facial nerve may be compressed (and its conduction blocked) at its narrowest point, the entrance to the meatal foramen, occupied by the labyrinthine segment and geniculate ganglion. If complete facial paralysis is still present after 1 week of medical treatment, and ENOG documents 90% or more nerve degeneration, decompression may be considered, although data are lacking from clinical trials to support its use. If decompression is performed, timing is critical. The destiny of the facial nerve in Bells palsy is probably decided within the first 2 to 3 weeks after the onset of symptoms. After decompression surgery, permanent unilateral deafness may occur. Because severe degeneration of the facial nerve is probably irreversible after 2 to 3 weeks, decompression should not be performed 14 days or more after the onset of paralysis. Finally, for patients with permanent facial paralysis, various surgical procedures exist for dynamic reconstruction of the facial nerve (http://www.emedicine.com.plastic/ topic218.htm). SUGGESTED READING
FIGURE 1. Treatment of Bells palsy.
1 mg/kg/day for 7 days. Prednisone should be used cautiously in patients with diabetes, peptic ulcer disease, renal or hepatic dysfunction, or severe hypertension. Although data are lacking to show that the addition of antiviral agents speeds recovery or leads to a better long-term outcome, I also give oral valacyclovir, 1 gm twice daily for 7 days. Adherence is better with valacyclovir than with acyclovir, which requires five daily
Cawthorne T: The pathology and surgical treatment of Bells palsy, Proc R Soc Med 4:565-572, 1950. Murakami S, Mizobuchi M, Nakashiro Y, et al: Bell palsy and herpes simplex virus: identification of viral DNA in endoneurial fluid and muscle, Ann Intern Med 124:27-30, 1996. Richardson AT: Electrodiagnosis of facial palsies, Ann Otol Rhinol Laryngol 72:569-580, 1963. Sartoretti-Schefer S, Wichmann W, Valavanis A: Idiopathic, herpetic, and HIV-associated facial nerve palsies: abnormal MR enhancement patterns, AJNR Am J Neuroradiol 15:479-485, 1994.
SECTION 9
Cerebrovascular Disease
Rafael H. Llins, M.D.
at onset without a march. Migraine aura can present with transient neurologic defects, including visual loss, hemisensory loss, weakness, and aphasia. Migraine auras tend not to be maximal at onset but instead the deficits march. That is, defects start small and then increase in size or areas of involvement over minutes, typically over 10 to 30 minutes, and are often followed by a typical hemicranial pulsatile headache. Seizures, typically those with focal onset, can present with Todds paralysis, which can last from 20 minutes to 24 hours after seizure. They also tend to have marching deficits but typically march over 1 to 2 minutes. See Table 1 for the differential diagnoses related to TIAs.
Transient ischemic attack (TIA) is formally defined as a transient neurologic deficit of vascular origin that lasts less than 24 hours. In truth, most TIAs last only minutes, classically 10 to 20 minutes. Diffusionweighted magnetic resonance (MR) imaging has shown that TIAs that last longer than a few hours result in irreversible tissue damage defined radiographically as a stroke. Although it may seem to be an academic issue to discuss the duration of the deficits of a TIA, it is important to differentiate TIA from stroke. It is best to think about TIA as equivalent to unstable angina, and it should be treated equally as aggressively. This is because TIAs are deficits without permanent damage, but they define an area of risk. Because of this, the evaluation of TIA needs to be completed quickly for the same reason the work-up of unstable angina is urgent. TIAs can recur and can be followed by permanent deficits. The term ministroke is one many avoid because it suggests the problem is less severe than stroke. The argument can be made that TIAs are more important to work up quickly to avoid the permanent deficits that occur with stroke. TIAs can have a recurrent stroke rate within 48 hours and therefore expedited work-up before recurrence is important. There is debate over whether inpatient or outpatient work-ups are preferable. The speed of completion of the work-up is more important than whether it is outpatient or inpatient. If a high-quality, reliable work-up can be completed within 48 hours of the onset of the TIA, then often an inpatient work-up can be avoided. I tend to admit patients to our inpatient stroke service to expedite the work-up and act on the results quickly. The discussion that follows is primarily regarding cerebrovascular disease and is not a discussion on how to diagnose and manage transient neurologic defects of other causes. The differential diagnosis of TIAs is short but important to discuss briefly. Most TIAs present with rapid-onset neurologic deficits that are maximal
Evaluation of Patients with Transient Ischemic Attack

Once the basic neurologic examination has been completed and the other possibilities have been considered, an assessment for TIA is primarily an imaging evaluation. In general the TIA examination tends to be a stereotyped work-up. Special attention and more in-depth evaluations should be done when symptoms clearly suggest a vascular distribution. For instance, amaurosis fugax, or transient monocular blindness, is classically secondary to carotid stenosis; however, it can also occur from intracranial carotid or carotid-origin stenosis, which is often missed by regular carotid ultrasonography. Therefore, the history and presentation of the patient are vital, and classic TIA symptoms should be worked up beyond the basic evaluation when there is a high clinical index of suspicion. As a general rule, TIAs are divided into anterior and posterior circulation events. Although there can be some overlap, it is important primarily to direct how the next level of scrutiny should be done if the initial work-up is inconclusive. Anterior-circulation TIAs may present with aphasia, neglects, transient monocular blindness, isolated leg weakness, and abulia. Posteriorcirculation TIAs may present with diplopia, ataxia, dysphasia, hiccups, vertigo, and crossed cranial nerve and somatic deficits. Deficits that may be either anterior or posterior in localization are hemiplegia, visual field cuts, hemisensory loss, and dysarthria. In cases where TIA symptoms are not clearly anterior or posterior circulation, then a broad vascular examination 209
210
TABLE 1 Disorders Resembling TIA

Disorder Migraine Seizure Subdural hematoma Hypoglycemia Ischemic optic neuropathy Peripheral neuropathy Peripheral vertigo Clues to Diagnosis Symptom march followed by headache Stereotyped spells Abnormal EEG Recent head trauma Abnormal brain CT Hypoglycemic agent history Recurrent visual TIA Optic disk pallor Tinels sign at compression site Focal sensory loss, weakness Lack of other cranial nerve findings Elicitable symptoms
TIA, Transient ischemic attack; EEG, electroencephalogram.
should be performed. See Figure 1 for a stroke work-up algorithm. Work-up of TIA should evaluate for atherosclerotic stenotic, cardioembolic, or small-vessel disease. The extracranial carotid artery is a common area for atherosclerotic stenosis and TIAs. Classically, TIAs from carotid artery stenosis present with crescendo TIAs. Carotid duplex imaging is the test of choice. Confirmation with MR angiography, computed tomographic (CT) angiography, or conventional angiography is often required, especially if the carotid duplex shows moderate stenosis. The symptomatic carotid stenosis is best treated with carotid endarterectomy (CEA) if it is 70% or greater. Stenosis of 65% or less is best treated with antiplatelet agents and risk factor control. Patients who are not candidates for CEA with symptomatic stenosis and significant medical issues that preclude carotid surgery can be considered for carotid stenting by an experienced interventionalist. Large artery stenosis of anterior or posterior circulation can present with TIAs similar to carotid-source TIAs. They may also present with postural TIA, with deficits occurring with drops in blood pressure or when moving from sitting to standing. Limb-shaking TIAs are spells where either just the arm or arm and leg on the affected side has shaking movements for 10 to 30 seconds, often with position change. These are typically secondary to large-artery stenosis often in the anterior circulation. Large-artery stenosis of intracranial carotids or intracranial circulation (anterior cerebral artery, middle cerebral artery, posterior cerebral artery, basilar artery) can lead to TIA and are missed by basic TIA work-ups that do not include some form of intracranial vascular imaging like transcranial Doppler, CT angiogram, or MR angiogram. Stenosis of the origins of the vertebral artery and carotid artery also is missed by basic carotid imaging and requires focused imaging of the chest and
origin of great vessels with conventional angiography, MR angiography of the chest, or CT angiography of the chest and great vessels. Cardiac-source TIAs tend to be different than largeartery-source TIAs in presentation. They are less likely to present with stereotyped or recurrent TIA in the same vascular distribution. A large-artery TIA that is recurrent tends to just affect one hemisphere, whereas cardiac-source TIAs can affect one side, then another, and then can affect the posterior circulation. Evaluation depends on the type of TIA. TIAs that present with large-territory deficits should have a careful cardiac work-up. Cardiac work-up should begin with an electrocardiogram because the diagnosis of atrial fibrillation with TIA in a patient not on anticoagulation ends up being straightforward. Paroxysmal atrial fibrillation can be missed unless prolonged cardiac rhythm evaluation is performed. For outpatient use, a 48-hour Holter monitor picks up most instances of PAF. In general, transesophageal echocardiography (TEE) is a sensitive test for cardiac-source clot secondary to left atrial appendage clot, patent foramen ovale (PFO) septal deficits, decreased global ejection fraction, and areas of apical hypokinesia or dyskinesia, leading to clot formation. It is the most sensitive cardiac imaging test of occult cardiac-source thromboembolism. In patients with TIA secondary to large-artery stenosis or that clinically is due to lacunar disease, a transthoracic echocardiogram (TTE) is often all that is required. TTE is associated with less morbidity and is a reasonable screening test. Some authors recommend TTE for those younger than 50 years of age without cardiac disease. In general, for those patients in whom there is clinical concern for cardiac-source emboli, a TEE should be performed. Recall that aortic dissection can be a cause of stroke and can occur in the young. Both TEE and TTE are typically performed with contrast material to look for right-to-left shunts. Cardiac rhythm evaluation for 24 to 48 hours is indicated in patients with largeterritory TIA. Small-vessel-disease TIAs occur and classically tend to stutter. They may present with a lacunar syndrome such as hemisensory loss, pure motor hemiparesis, clumsy hand dysarthria, or ataxic hemiparesis syndrome. These symptoms may occur, then clear only to recur multiple times in a short period. Although technically multiple TIAs, stuttering lacune is actually a single vascular lesion that may have an entirely negative stroke work-up. Often diffusion-weighted imaging shows the lacunar stroke on repeat evaluation if initial testing is normal. Typically, with lacunar disease all testing is normal and the arterial lesion is a small vessel. On MR or CT imaging, there may be evidence of previous lacunar strokes.
Treatment
Treatment of TIA should depend on the suspected etiology of the TIA. In general, etiology-specific treatment is a better approach than escalating doses of aspirin and the addition of warfarin (Table 2).
211
Warfarin INR 2-3 or ASA
Atrial fibrillation PAF
CBC, CMP, Fasting cholesterol Homocysteine, CRP, CXR, ECG and 24-hour monitor
Neuroimaging CT/MRI
Subdural Mass lesion
Stop
Cerebrovascular imaging TCD, CTA, MRA, DSA Abnormal Normal
Yes
Symptomatic intracranial disease?
No
Carotid duplex Plus confirmatory CTA, MRA, DSA 70% stenosis 70% stenosis
Recurrent? Surgical candidate? Large vessel suspected Yes No Yes Carotid endarterectomy No Consider stenting TEE Consider stenting or angioplasty Atherosclerotic Disease Management Cardiac source Normal TTE Small vessel suspected
Normal Cardiac source PFO + ASA Warfarin INR 2-3 or ASA Consider PFO closure device PFO + ASA
FIGURE 1. Algorithm for assessment of stroke. TCD, Transcranial Doppler; CTA, CT angiography; MRA, magnetic resonance angiography; DSA, digital subtraction angiography; TTE, transthoracic echocardiogram; TEE, transesophageal echocardiogram; PAF, paroxysmal atrial fibrillation; PFO, patent foramen ovale; ASA, atrial septal aneurysm; CBC, complete blood count; CMP, comprehensive metabolic panel; CRP, C-reactive protein; CXR, chest radiograph; ECG, electrocardiogram.
The treatment of small-vessel-disease TIAs is unclear. Small-vessel disease is secondary to lipohyalinosis of small vessel with clot formation. It is typically treated with aspirin in a dosage ranging from 50 to 325 mg/day. Clopidogrel or aspirin plus dipyridamole combination may be more effective in preventing recurrent spells. Perhaps more important is medical treatment of atherosclerotic disease (see later).
TIAs from symptomatic internal carotid stenosis are treated with CEA if stenosis is 70% or greater by angiography. Stenting of symptomatic carotid stenosis has been shown to be safe and effective in patients who have contraindications to CEA. Even in good hands, the morbidity is still greater than for CEA; therefore, I do not recommend carotid stenting for patients with carotid stenosis who have no contraindications
212
TABLE 2 Treatment of TIAs

Etiology of TIA Lacunar Primary Treatment ASA , 50-325 mg Statin agents Blood pressure control Carotid endarterectomy ASA 50-325 mg Statins Warfarin* Secondary Treatment Clopidogrel 75 mg ASA + dipyridamole Angioplasty/ stenting Clopidogrel 75 mg ASA + dipyridamole PFO closure device ASA 325 mg
Atherosclerotic
Cardioembolic
*International Normalized Ratio of 2.0-3.0. TIA, Transient ischemic attack; ASA, acetylsalicylic acid; PFO, patent foramen ovale.
for surgery. In the case of large-artery stenosis from carotid-origin stenosis, vertebral-origin stenosis, and intracranial artery stenosis, warfarin has not been shown to be superior to aspirin according to the Warfarin Versus Aspirin Recurrent Stroke Study (WARSS) and the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) Trial. Stenting of largeartery stenosis has not been studied carefully in a controlled fashion, but it has been shown to be effective in observational trials. Because of the morbidity sometimes associated with the procedure, I usually recommend stenting only for clearly symptomatic arterial stenosis that has led to recurrent TIA or stroke despite maximal medical therapy. Aortic arch atherosclerotic disease is treated with warfarin when there is a mobile component. After that, antiplatelet agents and atherosclerotic medical management are probably best. TIA from cardiac source is often treated with warfarin. Patients with atrial fibrillation as a cause of TIA are typically anticoagulated with warfarin. There are numerous trials that show significant benefit of warfarin for atrial fibrillation. Adding aspirin to warfarin has not been shown to be more effective than warfarin alone. Other cardiac sources of emboli leading to TIA can be seen in left ventricular ejection fraction of 25% or less, cardiac thrombus, left atrial appendage clot, recent myocardial infarction, and areas of apical hypokinesis or dyskinesis of wall motion. Patients with these cardiac lesions are often anticoagulated to reduce the risk of recurrent TIA. PFO in association with an atrial septal aneurysm also can be treated with warfarin, although surgical closure and percutaneous closure devices also can close the right-to-left shunt. These procedures should be reserved for clear and recurrent TIAs with no other source of emboli found. Trials are pending for effectiveness of these treatments. PFO alone is probably not a significant stroke risk factor for reasons that are unclear. Medical management of atherosclerotic disease is probably the most important intervention for small- and
large-vessel TIAs. This includes aggressive treatment of hypercholesterolemia with HMG Co-A reductase inhibitor (statin) medications. The effectiveness of statin medications in preventing stroke is an issue of ongoing study. Their effectiveness does not appear to be solely because of their cholesterol-lowering effectsthey seem to reduce the inflammation associated with atherosclerotic disease. C-reactive protein, often elevated in patients with a significant atherosclerotic disease burden, is used by some to dictate whether statin medications are indicated. Hypertension control is another important intervention. Hypertension trials have shown that even modest lowering of systolic hypertension when an angiotensin-converting enzyme inhibitor and a diuretic are used is effective in preventing TIA and stroke. A systolic blood pressure of 140 mm Hg or less is probably optional, especially in those with diabetes and coronary artery disease. It is unclear at this point if advising a lower blood pressure than this is more protective. In general, weight loss improves blood pressure control, and smoking cessation, although not proved to be of short-term benefit, has significant long-term benefits in reducing atherosclerotic burden.
Conclusion
TIAs are a warning that a patient may go on to have an irreversible cerebrovascular event. They should be worked up aggressively as inpatients or within 48 hours as outpatients, and treatment should be based at least in part on the etiology of TIA. Although the use of aspirin and other antiplatelet agents is important, care should be given not to forget the role of hypertension control, cholesterol reduction with a statin, and smoking cessation in reducing recurrence of TIA and stroke. SUGGESTED READING
Albers GW: A review of published TIA treatment recommendations, Neurology 62(Suppl 6):S26-S28, 2004. Albers GW, Amarenco P, Easton J, et al: Antithrombotic and thrombolytic therapy of ischemic stroke, Chest 119:300S-320S, 2001. Coull BM, Williams LS, Goldstein LB, et al: Anticoagulants and antiplatelet agents in acute stroke, Stroke 33:1934-1942, 2002. Sacco RL: Risk factors for TIA and TIA as a risk factor for stroke, Neurology 62(Suppl 6):S7-S11, 2004. Sherman DG: Reconsideration of TIA diagnostic criteria, Neurology 62(Suppl 6):S20-S21, 2004.
213

Argye E. Hillis, M.D., M.A.
Management of acute ischemic stroke is among the most rapidly evolving domains in clinical neurology. Recent advances in neuroimaging and interventional neuroradiology have provided opportunities for new interventions to salvage tissue at risk of infarction. Although the focus of acute stroke management for most patients remains identification of the cause of the stroke to prevent subsequent strokes and prevention of complications, some patients benefit from aggressive intervention to restore blood flow to ischemic tissue. Furthermore, close management of blood pressure, glucose, and temperature can improve outcome after acute ischemic stroke. This chapter briefly covers clinical management in the first few days after stroke onset.
Pathophysiology of Ischemic Stroke

Ischemic stroke is caused by occlusion or severe stenosis of a cerebral artery, due to embolus or thrombosis, resulting in reduced cerebral blood flow (CBF) and impaired delivery of oxygen and glucose to the tissue supplied by that artery. When CBF falls from a normal rate of 50 to 55 mL/100 gm/min to below about 18 mL/100 gm/min, neuronal electrical function fails. When CBF falls below 8 mL/100 gm/min, cellular energy metabolism fails, resulting in cell death. In acute stroke, a core area of infarct (cell death) may be surrounded by a larger area of tissue where CBF falls between these two thresholds. This hypoperfused but potentially salvageable tissue is known as the ischemic penumbra. The ischemic penumbra receives enough blood to survive for a limited period, but not enough to function. Unless blood flow is restored, the ischemic penumbra is at risk for progressing to infarct owing to increased permeability of ionic membrane channels and inflammation that result in toxic accumulation of glutamate, lactate, and free radicals. The two most important principles in acute stroke management that have emerged in recent years are (1) the importance of restoring perfusion to the ischemic penumbra; and (2) the importance of intervening as rapidly as possible to protect neurons until blood flow can be restored.
Early identification allows for rapid transportation to designated stroke centers and alerting stroke teams about the expected arrival of a patient who may need immediate intervention. On arrival, mimicking conditions such as seizure, syncope, tumor, subdural hematoma, and hypoglycemia must be ruled out. These stroke mimics, which comprise about 10% to 15% of conditions originally attributed to stroke can usually be excluded with laboratory tests and/or imaging. Initial laboratory tests essential for all patients with suspected stroke on arrival to the hospital are listed in Table 1. Generally, a head computed tomographic (CT) scan is obtained immediately to rule out intracranial hemorrhage (which demands a different course of management from ischemic stroke). Additionally, evidence of early infarction involving greater than a third of the territory of the middle cerebral artery on CT is thought to indicate a high risk of hemorrhagic conversion, excluding the safe administration of thrombolytics. Early signs of infarct on CT include loss of the gray-white distinction in the cortical ribbon or lentiform nucleus and effacement of sulci in a vascular distribution. When magnetic resonance (MR) imaging is available without delay, the combination of diffusion-weighted imaging (DWI) to identify areas of acute dense ischemia or infarct, gradient-echo sequences to rule out hemorrhage, and fluid-attenuated inversion recovery (FLAIR) or T2 sequences to evaluate for old infarcts or other lesions can be used in place of CT scans. New imaging techniques have been developed for the purpose of visualizing the ischemic penumbra to identify patients who are candidates for intervention to restore blood flow (or neuroprotection). MR perfusion-weighted imaging (PWI) shows areas of delayed arrival and clearance of a bolus of contrast that may reflect hypoperfusion. The PWI abnormality minus the DWI abnormality (the diffusion-perfusion mismatch) can estimate the ischemic penumbra if appropriate thresholds of abnormality are selected. CT perfusion scans can also reveal the ischemic penumbra; areas of severe hypoperfusion correspond to infarct, whereas areas of moderate hypoperfusion surrounding the infarct correspond to tissue at risk. Although oxygen-15 positron emission tomography is the gold standard for identifying ischemic penumbra, the duration of the scan and other logistical considerations make it impractical for common use in managing acute ischemic stroke. The duration that hypoperfused tissue can survive is unknown, but likely depends on the severity and mechanism of hypoperfusion.
Management in the First Three Hours of Stroke Onset

The only therapy for restoring blood flow for which there is strong evidence of clinical benefit from randomized, double-blind, placebo-controlled trials is intravenous (IV) recombinant tissue plasminogen activator (rt-PA) given within 3 hours of onset. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study demonstrated that more
Rapid Diagnosis
Rapid intervention requires immediate diagnosis. Ideally, patients with probable acute stroke are identified by paramedics trained to identify stroke symptoms, such as abrupt onset of hemiparesis, aphasia, hemispatial neglect, homonymous hemianopia, hemisensory loss, or brainstem signs (e.g., diplopia, dysarthria, ataxia).
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TABLE 1 Diagnostic Studies for Suspected Acute Ischemic Stroke

Categories Urgent studies for all patients Specific Tests Electrolytes, glucose, blood urea nitrogen, creatinine Complete blood count Prothrombin time/international normalized ratio and activated partial thromboplastin time Head CT or MR imaging (see text) Oxygen saturation Toxicology screen and blood alcohol level Liver function tests Pregnancy test Chest Radiography Arterial blood gas (if breathing is labored) Lumbar puncture (if subarachnoid hemorrhage is considered and CT is negative for hemorrhage, or if meningitis is considered) Electroencephalogram (if seizures are suspected) Transthoracic or transesophageal echocardiogram (with bubble study if patent foramen ovale is suspected) Carotid Doppler ultrasound, MR angiogram of the neck, CT angiogram of the neck, or catheter angiogram Blood tests: RPR, ESR, homocysteine, fasting lipid profile In selected patients: Coagulopathy panel (e.g., patients with venous thrombosis or unknown etiology) TSH (e.g., patients with new-onset atrial fibrillation) MR imaging in selected patients MR angiogram of the circle of Willis, CT angiogram, or catheter angiogram Transcranial Doppler ultrasound in selected patients (with bubble study if patent foramen ovale is suspected)
Urgent studies for selected patients
Nonurgent tests to identify etiology of acute ischemic stroke
RPR, Rapid plasma reagin; ESR, erythrocyte sedimentation rate; TSH, thyroid-stimulating hormone.
rt-PAtreated patients achieved favorable clinical outcomes at 3 months and 1 year, and there was an increased mortality in the treated group. The major risk of this intervention is symptomatic intracranial hemorrhage, which occurs in about 6% of patients who receive IV rt-PA according to the established guidelines. Therefore, patients who arrive within 3 hours of stroke onset should be immediately evaluated for potential thrombolysis, based on criteria listed in Table 2. Urgent imaging studies should be completed within 25 minutes of arrival to the hospital, and the interpretation should be completed by a total of 45 minutes. Patients who meet all inclusion criteria, and none of the exclusion criteria, should be administered IV rt-PA as soon as possible, because outcome has been shown to be better with earlier administration, even within the 3-hour window. IV rt-PA is administered with a total dose of 0.9 mg/kg up to a maximum of 90 mg. The first 10% of the dose is given as a bolus over 1 minute, the remainder over 60 minutes. If the patient develops sudden neurologic deterioration, severe headache, nausea, vomiting, or acute increase in blood pressure, rt-PA should be discontinued, the airway should be protected (e.g., with intubation), and a CT scan should be obtained urgently to evaluate for hemorrhage. Following rt-PA administration, blood pressure should be monitored and controlled according to the regimen in Figure 1. Regimens for administration of rt-PA and subsequent monitoring and control of blood pressure
lend themselves to stroke pathways with preprinted nursing orders.
Investigational Interventions for Management of Acute Ischemic Stroke

Studies are currently underway to determine the safety and efficacy of additional protocols for restoring blood flow. These interventions include IV rt-PA after the 3-hour window in selective patients, intra-arterial rt-PA (alone or after a submaximal dose of IV rt-PA), thrombolectomy, angioplasty and stenting, ultrasonography in combination with rt-PA, new antiplatelet agents, and induced blood pressure elevation in selective patients. These interventions may prove to be useful only for specific patients identified with additional imaging (e.g., DWI/PWI, CT perfusion, or catheter angiogram) and may be limited to stroke centers with adequate expertise in interventional neuroradiology, neurovascular surgery, and neurocritical care. Trials of various neuroprotective agents are underway with the goal that future management of acute ischemic stroke will involve a combination of the administration of neuroprotective agents and the restoration of blood flow. Although IV heparin was once commonly used in acute ischemic stroke, no benefit of anticoagulation for
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TABLE 2 Contraindications for Intravenous Thrombolysis

Standard Contraindications Onset of symptoms > 3 hr before administration Evidence of infarct > 1/3 of middle cerebral artery territory on CT scan Evidence of intracranial hemorrhage Suspected subarachnoid hemorrhage Recent previous stroke, serious head injury, or intracranial surgery Uncontrolled hypertension (>185 mm Hg systolic or >110 mm Hg diastolic) at time of administration Active internal bleeding Seizure at stroke onset Known bleeding diathesis (e.g., heparin within 48 hr, elevated PTT or INR, platelet count < 100,000)
PTT, Partial thromboplastin time; INR, international normalized ratio.
Relative Contraindications (Warnings) Severe neurologic deficits (e.g., National Institutes of Health Stroke Scale Score > 22) Midline shift or mass effect on CT or MR imaging
improving stroke outcome has been demonstrated. However, anticoagulation may prevent recurrent stroke (and perhaps extension of stroke) in cases where there is a known embolic source of infarct, arterial dissection, or sinus thrombosis. However, in the case of embolic stroke, anticoagulation is generally delayed for at least 5 or 6 days, when a repeat CT scan is done to rule out hemorrhagic transformation of the infarct. Hemorrhage occurs when there is recanalization allowing blood flow to the infarct and so is a particular risk in embolic stroke. IV anticoagulation may worsen hemorrhagic transformation, which can lead to increased edema.
Stroke Association specify that antihypertensive medications should initially be withheld from patients who have not received thrombolytics unless systolic blood pressure rises above 220 mm Hg or diastolic blood pressure rises above 120 mm Hg. Symptomatic hypertension (e.g., associated with cardiac ischemia or congestive heart failure) should also be treated. Even in these cases, blood pressure should not be lowered precipitously, but cautiously using IV labetalol or nicardipine, aiming for an initial reduction of 10% to 15%. GLUCOSE Several studies have provided evidence that hyperglycemia is associated with worse outcome in ischemic stroke in humans, and animal studies suggest that tight glucose control may lead to better outcome. Patients with known diabetes or elevated serum glucose at admission should have glucose monitoring and sliding scale insulin to maintain glucose in the range of 80 to 120 mg/dL. TEMPERATURE There is also strong evidence that hyperthermia can worsen outcome after stroke. Close monitoring of temperature and aggressive treatment of both fever and infections are therefore essential. NUTRITION Large hemispheric strokes, bilateral strokes, or brainstem strokes can severely compromise swallowing function. Typically, thin liquids are more likely to be aspirated than thick liquids, soft solids, or purees in patients with neurogenic dysphagia. To reduce the risk of aspiration, swallowing should be assessed before allowing the patient to eat or drink by mouth. A simple bedside swallowing evaluation by observing for coughing, choking, or change in voice quality (wet-hoarse phonation) after swallowing 2 oz of water can identify patients at greatest risk for aspiration. Patients who show signs of dysphagia in this bedside assessment or
Medical Management that Improves Outcome

Whether a patient receives intervention to re-establish cerebral perfusion, careful monitoring and control of other clinical conditions related to the stroke can markedly influence outcome. For this reason, many stroke patients are being cared for in dedicated stroke units, which have now been associated with better outcomes. Whether the benefit of such units is due to protocols for treatment, closer monitoring, better communication between care providers, or specialized training of nurses and physicians is unclear. However, it is clear that close attention to the following issues can improve clinical outcome. BLOOD PRESSURE The optimum blood pressure range for patients who do not receive thrombolytics has been a matter of intense debate. Although high blood pressure is among the strongest risk factors for stroke, the best management of blood pressure in the first few days following stroke probably depends on the etiology and size of stroke. Several studies have indicated that a relatively high blood pressure in the first few days of stroke may be beneficial and that lowering blood pressure acutely may be harmful. Current guidelines from the American
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IV r-TPA 0.9 mg/kg up to 90 mg; 10% over 1 minute; remaining over 60 minutes (must be started within 3 h of onset of symptoms)
FIGURE 1. Procedures to follow in patients who meet the criteria for intravenous recombinant tissue plasminogen activator (IV r-TPA) (see Table 2). BP, Blood pressure.
Measure BP every 15 min for 2 h, then every 30 min for 6 h; then hourly for 18 h
Systolic BP <180 mm Hg and diastolic BP <105 mm Hg No Diastolic BP >140 No
Yes
Continue to monitor
Yes
IV sodium nitroprusside 0.510 mcg/kg/min IV labetalol 20 mg over 12 min, then every 10 min prn or infusion 28 mg/min until goal BP
Systolic BP >230 mm Hg or Yes diastolic BP >120 (2 readings) No Systolic BP >180 mm Hg or Yes diastolic BP >105 (2 readings)
IV labetalol 10 mg over 12 min, then every 1020 min prn or infusion 28 mg/min until goal BP
Monitor BP every 15 minutes during antihypertensive therapy
No anticoagulants or antiplatelets for 24 h
Intracranial hemorrhage suspected No
Yes
Discontinue r-TPA; stabilize patient; head CT
Follow-up head CT before starting any antiplatelet or anticoagulant
who have an absent gag reflex accompanied by dysarthria or dysphonia should have a swallowing evaluation by a speech-language pathologist prior to oral alimentation or hydration. Nutrition and fluids can be given for short periods via a nasogastric tube, but a percutaneous gastrostomy or jejunostomy tube should be considered if the patient is expected to be kept from oral intake longer than a week. OXYGEN Hypoxia can increase intracranial pressure (ICP) and worsen stroke outcome. Large strokes or brainstem strokes can cause both hypoventilation and aspiration and thus may demand intubation in the acute stage to protect the airway and prevent hypoxia. Most patients
should have pulse oximetry at least at admission. Supplemental oxygen should be given as necessary to keep oxygen saturation above 95%, except in cases of chronic obstructive lung disease (in which case oxygen saturation should be kept at the patients optimum baseline). Arterial blood gas may be required for appropriate evaluation and management.
Prevention of Complications
ELEVATED INTRACRANIAL PRESSURE The most devastating complication of stroke is increased ICP, which generally occurs only in large strokes or stroke in the posterior fossa, when there is significant edema.
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Edema typically is highest 3 to 5 days after onset of stroke. Hyperthermia, hypoxia, or hypercapnia can worsen edema and should be aggressively corrected. Elevating the head of the bed, reducing excess fluids, eliminating hypo-osmolar fluids, and eliminating any restrictions on venous outflow (e.g., tape on the neck) can be helpful. Urgent interventions to reduce ICP to prevent or reverse herniation include increasing the osmolarity of the blood with mannitol or hypertonic saline, hyperventilation to reduce PCO2 by 5 to 10 mm Hg, hypothermia, or barbiturates administered in an intensive care environment. Insertion of an intraventricular catheter to drain cerebrospinal fluid is used primarily when edema results in obstructive hydrocephalus. Benefits of hemicraniectomy or temporal lobectomy for malignant brain edema are also under investigation. SEIZURES Seizures in the first week after stroke have been reported in 4% to 43% of cases, and recurrent seizures are seen in 20% to 80% of patients. Although seizures do not alter long-term outcome, they can increase ICP and should be treated when observed. Patients with fluctuating level of consciousness should have an electroencephalogram to rule out nonconvulsive status epilepticus, which is treated with anticonvulsants. Blood levels of unbound anticonvulsants (e.g., phenytoin) should be monitored. DEEP VEIN THROMBOSIS AND PULMONARY EMBOLUS Limb paresis and immobility present a high risk for deep vein thrombosis (DVT) and pulmonary embolus. All nonambulatory patients should have DVT prophylaxis from the time of admission with subcutaneous heparin (5000 units twice a day), low-molecular-weight heparin, and/or sequential compression devices, as long as they are not anticoagulated for another reason. In addition, progressive mobility with physical therapy and occupational therapy should begin as soon as possible to prevent DVT, pulmonary embolus, contractures, and atelectasis. ASPIRATION PNEUMONIA Patients with dysphagia have a high risk of aspiration pneumonia. Oral alimentation and hydration should be undertaken only after ruling out significant aspiration (see earlier). Additionally, keeping the head elevated 45 degrees, and propping the head slightly forward in flexed position (never hyperextended), can also reduce the risk for aspiration. URINARY TRACT INFECTIONS Urinary tract infections are common in patients with neurogenic bladder due to incomplete emptying of the bladder and use of indwelling catheters for bladder incontinence. Assisting the patient to the toilet or offering a bedpan or urinal every few hours while awake can prevent the need for catheterization in many cases.
PRESSURE SORES Immobility can cause pressure sores (decubitus ulcers) in just 2 hours. The best prevention is turning immobile patients every 2 hours. Special beds that keep pressure off one place can also be helpful. Since urinary and bowel incontinence can exacerbate or infect pressure sores, urinary incontinence should be treated (see earlier), and a bowel regimen should be established using daily suppositories if necessary. Wet-to-dry dressing can be helpful to prevent worsening of pressure sores. A large number of later complications, such as depression, contractures, spasticity, and pain, require monitoring, prevention, and treatment after the first few days of stroke, but their management is beyond the scope of this chapter.
Prevention of Recurrent Stroke

Rapid evaluation of the etiology of ischemic stroke is a first step toward preventing recurrence. Tests that are frequently used to determine the most likely cause of stroke are listed in Table 1. Patients with 70% to 99% carotid stenosis as the suspected cause of stroke should be evaluated for potential carotid endarterectomy or stenting, although the procedure is generally delayed for at least 6 weeks after stroke to prevent hemorrhagic conversion or edema. After new carotid occlusion, anticoagulation for 6 weeks can prevent embolism from the thrombus. Intracranial large vessel stenosis is generally treated with antiplatelet agents, but when severe stenosis is associated with persistent symptomatic hypoperfusion, other investigational interventions described earlier may be considered. The standard secondary prevention of ischemic stroke due to intracranial large or small-vessel disease is aspirin (50 mg). Patients whose stroke occurred while on aspirin can be offered other antiplatelet medications such as clopidogrel (or dipyridamole in addition to aspirin). Evaluation and management of vasculitis and cerebral embolism are described in other chapters. Risk factor reduction is also essential. Hypercholesterolemia should be aggressively treated. High-dose statins may help reduce the risk of embolism from plaque in patients with severe atherosclerosis. Tight control of diabetes, healthy diet, smoking cessation, and treatment of drug or alcohol abuse are also important. Many of these issues can be initially addressed in the acute hospitalization and reinforced during rehabilitation or as an outpatient.
Summary
Management of acute ischemic stroke has changed radically in the last decade and is likely to continue to evolve with further progress in the domains of imaging, interventional neuroradiology, and neuroprotection. Interventions to salvage the ischemic penumbra begin as soon as possible after onset of stroke. Inpatient management to reduce complications, prevent recurrent stroke,
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and begin rehabilitation is equally important. Most patients recover substantial function in the first few days to weeks, but many will continue to improve over many years, particularly with appropriate rehabilitation. SUGGESTED READING
Adams HP Jr, Adams R J, Brott T, et al: Guidelines for the early management of patients with ischemic stroke: a scientific statement from the Stroke Council of the American Stroke Association, Stroke 34:1056-1083, 2003. Adams HP Jr, Brott TG, Crowell RM, et al: Guidelines for the management of patients with acute ischemic stroke: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association, Stroke 25:1901-1914, 1994. Biller J, Feinberg WM, Castaldo JE, et al: Guidelines for carotid endarterectomy: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association, Stroke 29:554-562, 1998. Fisher M, Albers GW: Applications of diffusion-perfusion magnetic resonance imaging in acute ischemic stroke, Neurology 52: 1750-1756, 1999. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke, N Engl J Med 333:1581-1587, 1995.
Identification of Cardiac Sources of Embolization

According to the American Heart Association guidelines, all patients being evaluated for cerebral ischemia should have a routine electrocardiogram performed (Figure 1). Additionally, 24 hours of cardiac rhythm monitoring should be performed in all patients with stroke and transient ischemic attack (TIA) admitted to the hospital. For those with a normal cardiac examination, normal electrocardiogram, no history of cardiac symptoms or disease, and brain imaging not suggestive of an embolic event, echocardiography is not likely to identify a cardiac source of embolization. Echocardiography should be performed in all others. A detailed discussion of the selection of transthoracic versus transesophageal echocardiography (TEE) is beyond the scope of this chapter.
Primary Prevention of Cardioembolism

NONVALVULAR ATRIAL FIBRILLATION AF is the most common sustained arrhythmia, affecting approximately 2 million Americans. Its prevalence increases with age, with 10% of those over 80 affected. AF accounts for approximately half of all cardioembolic strokes. Overall, the annual stroke rate of those with nonvalvular AF not treated with an antithrombotic agent is 5%, with a range of approximately 1% to 25%, depending on the individuals risk classification related to comorbidities. Patients with AF should be treated the same regardless of whether it is persistent or paroxysmal. Likewise, those with atrial flutter and those with AF should be treated equivalently. Most patients with AF require anticoagulation with a goal international normalized ratio (INR) of 2 to 3 for stroke and other thromboembolism prophylaxis. Unfortunately, studies have shown that warfarin is currently being underutilized for primary stroke prophylaxis in AF patients. Warfarin has been shown to be superior to aspirin for stroke prophylaxis, although the benefits and risks must be weighed carefully. In patients with AF, aspirin reduces stroke risk by 19%, whereas warfarin reduced it by 68%. In patients with nonvalvular AF, increased age, prior thromboembolism, hypertension, heart failure, and diabetes appear to be independent risk factors for stroke. There are several systems for scoring stroke risk related to AF. One such example is the CHADS2 score, standing for congestive heart failure, hypertension, age older than 75 years, and prior history of stroke. Each risk factor is ascribed one point, with the exception of history of stroke, to which two points are ascribed. For each point increase in the CHADS2 score, there is an approximate 1.5-fold increase in stroke rate. An understanding of AF risk factors can allow for risk stratification; however, in general, those with AF should be treated with warfarin unless there is a clear contraindication. Those who have a contraindication to
PATIENT RESOURCES
American Heart Associations Stroke Connection 7272 Greenville Avenue Dallas, TX 75231 Phone: 800-553-6321 Fax: 214-706-2139 E-mail: strokeaha@amhrt.org http://www.americanheart.org National Stroke Association 96 Inverness Drive, E., Suite 1 Englewood, CO 80112 Phone: 800-787-6537 Fax: 303-649-1328 E-mail: info@stroke.org http://www.stroke.org

Devin L. Brown, M.D., and Lewis B. Morgenstern, M.D.
Cardioembolism is typically due to thrombus formation from intracardiac blood stasis. Atrial fibrillation (AF) can lead to left atrial and, more specifically, left atrial appendage clots, whereas depressed left ventricular function due to cardiac ischemia or other causes may result in ventricular thrombi. Cardioembolism is a common cause of stroke, accounting for approximately 20% of all ischemic stroke.
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and begin rehabilitation is equally important. Most patients recover substantial function in the first few days to weeks, but many will continue to improve over many years, particularly with appropriate rehabilitation. SUGGESTED READING
Adams HP Jr, Adams R J, Brott T, et al: Guidelines for the early management of patients with ischemic stroke: a scientific statement from the Stroke Council of the American Stroke Association, Stroke 34:1056-1083, 2003. Adams HP Jr, Brott TG, Crowell RM, et al: Guidelines for the management of patients with acute ischemic stroke: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association, Stroke 25:1901-1914, 1994. Biller J, Feinberg WM, Castaldo JE, et al: Guidelines for carotid endarterectomy: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association, Stroke 29:554-562, 1998. Fisher M, Albers GW: Applications of diffusion-perfusion magnetic resonance imaging in acute ischemic stroke, Neurology 52: 1750-1756, 1999. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke, N Engl J Med 333:1581-1587, 1995.
Identification of Cardiac Sources of Embolization

According to the American Heart Association guidelines, all patients being evaluated for cerebral ischemia should have a routine electrocardiogram performed (Figure 1). Additionally, 24 hours of cardiac rhythm monitoring should be performed in all patients with stroke and transient ischemic attack (TIA) admitted to the hospital. For those with a normal cardiac examination, normal electrocardiogram, no history of cardiac symptoms or disease, and brain imaging not suggestive of an embolic event, echocardiography is not likely to identify a cardiac source of embolization. Echocardiography should be performed in all others. A detailed discussion of the selection of transthoracic versus transesophageal echocardiography (TEE) is beyond the scope of this chapter.
Primary Prevention of Cardioembolism

NONVALVULAR ATRIAL FIBRILLATION AF is the most common sustained arrhythmia, affecting approximately 2 million Americans. Its prevalence increases with age, with 10% of those over 80 affected. AF accounts for approximately half of all cardioembolic strokes. Overall, the annual stroke rate of those with nonvalvular AF not treated with an antithrombotic agent is 5%, with a range of approximately 1% to 25%, depending on the individuals risk classification related to comorbidities. Patients with AF should be treated the same regardless of whether it is persistent or paroxysmal. Likewise, those with atrial flutter and those with AF should be treated equivalently. Most patients with AF require anticoagulation with a goal international normalized ratio (INR) of 2 to 3 for stroke and other thromboembolism prophylaxis. Unfortunately, studies have shown that warfarin is currently being underutilized for primary stroke prophylaxis in AF patients. Warfarin has been shown to be superior to aspirin for stroke prophylaxis, although the benefits and risks must be weighed carefully. In patients with AF, aspirin reduces stroke risk by 19%, whereas warfarin reduced it by 68%. In patients with nonvalvular AF, increased age, prior thromboembolism, hypertension, heart failure, and diabetes appear to be independent risk factors for stroke. There are several systems for scoring stroke risk related to AF. One such example is the CHADS2 score, standing for congestive heart failure, hypertension, age older than 75 years, and prior history of stroke. Each risk factor is ascribed one point, with the exception of history of stroke, to which two points are ascribed. For each point increase in the CHADS2 score, there is an approximate 1.5-fold increase in stroke rate. An understanding of AF risk factors can allow for risk stratification; however, in general, those with AF should be treated with warfarin unless there is a clear contraindication. Those who have a contraindication to
PATIENT RESOURCES
American Heart Associations Stroke Connection 7272 Greenville Avenue Dallas, TX 75231 Phone: 800-553-6321 Fax: 214-706-2139 E-mail: strokeaha@amhrt.org http://www.americanheart.org National Stroke Association 96 Inverness Drive, E., Suite 1 Englewood, CO 80112 Phone: 800-787-6537 Fax: 303-649-1328 E-mail: info@stroke.org http://www.stroke.org

Devin L. Brown, M.D., and Lewis B. Morgenstern, M.D.
Cardioembolism is typically due to thrombus formation from intracardiac blood stasis. Atrial fibrillation (AF) can lead to left atrial and, more specifically, left atrial appendage clots, whereas depressed left ventricular function due to cardiac ischemia or other causes may result in ventricular thrombi. Cardioembolism is a common cause of stroke, accounting for approximately 20% of all ischemic stroke.
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FIGURE 1. Treatment algorithm for emboli of cardiac origin transient ischemic attack (TIA). EKG, Electrocardiogram; Afib, atrial fibrillation.
Stroke/TIA
History, exam, EKG, brain imaging, echocardiography
Cardiac source identified Risk factor modification
No cardiac source found
Antiplatelet agent, risk factor modification TIA Small infarct Large infarct
Immediate anticoagulation
Warfarin after ~2 days
Warfarin after ~710 days
Recurrence while adequately anticoagulated Assess for alternative causes, including endocarditis
No endocarditis
Endocarditis
Afib
Mechanical valve
Stop anticoagulation, start antibiotics, cardiology consult, antiplatelet agent
Add aspirin
anticoagulation should be given aspirin, 325 mg per day. Patients with lone AF (typically defined as patients younger than 60 years of age, without heart disease, without risk factors for thromboembolism, and with evidence of normal ventricular function by echocardiography) should be treated with aspirin rather than warfarin because they are at lower risk of thromboembolism. ATRIAL THROMBI Detection of an atrial thrombus without associated AF is uncommon. Those with AF should be treated as discussed earlier. Surprisingly, there are few data dictating treatment for atrial thrombi. We use warfarin to treat these patients for at least 3 months. If the thrombus has resolved, and the patient does not have AF, we then switch to antiplatelet therapy. PROSTHETIC VALVES Patients with prosthetic valves are at increased risk of cardioembolism. Even those treated with appropriate
stroke prophylactic agents have a 1% to 2% stroke risk per year for mechanical valves and a little less than 1% per year for bioprosthetic valves. Patients with mechanical valves are at high risk for cardioembolic stroke if not treated with anticoagulation. The American College of Cardiology has guidelines that should be followed for the use of anticoagulation for patients with mechanical valves, depending on the valve type and the valve position. Most require warfarin with a goal INR of 2.5 to 3.5. Patients with new bioprosthetic valves should be treated with warfarin for the first 3 months, followed by antiplatelet therapy. In patients at high risk of thromboembolism, such as those with previous thromboembolism, an ejection fraction (EF) less than 30%, or a hypercoaguable state, life-long warfarin with a goal INR of 2 to 3 is likely indicated. DEPRESSED EJECTION FRACTION Patients with depressed left ventricular function secondary to ischemic cardiomyopathy appear to be at
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an elevated risk of stroke and other thromboembolism. The degree of risk elevation appears to be proportional to the degree of left ventricular dysfunction. Those treated with warfarin may have lower stroke rates than those treated with antiplatelet therapy, although no prospective, randomized trials to assess this as a primary endpoint have yet been completed. In the Survival and Ventricular Enlargement (SAVE) trial, a prospective study where patients post-myocardial infarction (MI) with an EF less than 40% were randomized to captopril or placebo, stroke was a prespecified endpoint. The estimated cumulative rate of stroke over 5 years was 8.1%. For each 5% decrease in EF, there was an 18% increase in stroke risk. Those with an EF less than 28% had almost double the risk of those with an EF 35% to 40%. Both aspirin and warfarin were associated with lower stroke risk, with warfarin having a stronger association. The Studies of Left Ventricular Dysfunction (SOLVD), another trial in which patients were randomized to an angiotensin-converting enzyme inhibitor or placebo, showed lower mortality associated with warfarin use in those with depressed left ventricular function (EF < 35%). In patients with a depressed EF, stroke prophylactic selection should be tailored to the individual patient and performed in conjunction with the patients cardiologist. Those who have a TIA or stroke on an antiplatelet agent typically should be switched to warfarin. POST-MYOCARDIAL INFARCTION In general, patients who are post-MI have about a 1% to 2% risk of stroke per year, although the risk is likely greatest in the first few months. It seems clear that patients who are post-MI and who also have AF or a left ventricular thrombus, and those with an anterior Q wave MI, should be anticoagulated. For all others, data are somewhat conflicting. Warfarin is likely superior to aspirin in post-MI stroke prevention but is associated with a significant increase in bleeding complications. The use of warfarin post-MI should typically be reserved for those at higher risk of embolization, including those with significant cardiac wall motion abnormalities and depressed left ventricular function. We typically anticoagulate these patients for at least 3 months. Post-MI stroke prevention choices are best determined in conjunction with the patients cardiologist.
awaiting adequate anticoagulation with warfarin. The heparin should be discontinued after the patient reaches a therapeutic INR. If the patient clinically has a TIA but is found to have DWI changes consistent with parenchymal ischemia, we forego using immediate anticoagulation with heparin/ heparinoid and proceed with immediate initiation of warfarin. Patients with known protein C or protein S deficiency, theoretically, should be therapeutically anticoagulated on heparin prior to initiation of warfarin. Stroke The decision to anticoagulate a patient immediately following a stroke from a cardioembolic source requires balancing the risk of recurrent infarction with the risk of symptomatic intracerebral hemorrhage. Data from the International Stroke Trial (IST) and the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) suggest that patients not anticoagulated after a stroke associated with nonvalvular AF have a low risk of recurrent stroke within the first 14 days (well less than 1% per day). Given this low risk of recurrence, we delay anticoagulation after a new stroke. The size of the infarction (or of the individual infarctions if multiple) dictates the length of delay. Typically, we initiate warfarin after 2 to 3 days for a small infarction, and after 7 to 10 days for a large infarction, without first using heparin. Prior to full anticoagulation with warfarin, we use aspirin in these patients. The aspirin is discontinued after a therapeutic INR is achieved. MECHANICAL VALVES Some patients develop embolization from a mechanical valve despite therapeutic warfarin. For these patients, the dose of warfarin should not be escalated to exceed the recommended INR, but rather aspirin, 81 mg/day, should be added. This does increase the risk of hemorrhagic complications; however, the benefits appear to outweigh the risks. Patients with stroke and a mechanical valve require blood cultures and an evaluation for endocarditis. ENDOCARDITIS It is essential to have a high index of suspicion for endocarditis. Patients with valvular abnormalities and/or a new murmur and those with recent infections should arouse particular suspicion. Although fever and an elevated leukocyte count are suggestive of the diagnosis, it is important to recall that elderly patients may have neither sign. Patients with endocarditis and stroke are at risk for further cerebral ischemic events. The embolic material may contain bacterial vegetation, platelet-fibrin clot that has formed on the vegetation, or a combination thereof. Risk of further events is reduced by treatment with antibiotics. If a second embolic event occurs, valvular surgery may become indicated. Bacterial material may embolize to cerebral vessels and create mycotic aneurysms, which are typically distal and multiple in the middle cerebral artery branches. With rupture, the resulting subarachnoid hemorrhage can be fatal.
Secondary Prevention of Cardioembolism

ATRIAL FIBRILLATION Transient Ischemic Attack Patients who present with transient cerebral ischemia who are found in their evaluation to have a clear cardioembolic source, such as AF, require anticoagulation. If no infarction is seen on diffusion-weighted imaging (DWI), immediate anticoagulation should be undertaken, barring a contraindication, with either intravenous unfractionated heparin or low-molecular-weight heparinoid, while
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Delivery of a full antibiotic course for endocarditis can cure the aneurysms. Although these aneurysms are uncommon, we recommend cerebral angiography in patients with stroke from endocarditis who have reasonable neurologic and medical recovery, prior to discontinuation of antibiotics. Aneurysms that do not resolve with antibiotic therapy and are accessible may be amenable to surgical treatment. We do not anticoagulate patients with endocarditis secondary to the risk of intracerebral hemorrhage, but instead use an antiplatelet agent for stroke prophylaxis. PATENT FORAMEN OVALE By autopsy and TEE studies, approximately 20% to 30% of the population has a patent foramen ovale (PFO). If a PFO is to be implicated as causative, venous thrombosis with paradoxical embolization must be inferred, suggesting the need to assess for deep venous thrombosis. One study suggests that 10% of stroke patients with a PFO have a deep venous thrombosis. These patients should be treated with anticoagulation. In the PFO in Cryptogenic Stroke Study (PICSS), stroke patients who had TEEs were randomized to receive warfarin, with a goal INR of 2 to 3, or aspirin 325 mg/day. Time to recurrent stroke in those with a PFO was not different between the two treatment groups. Those with a PFO were not at a higher risk than those without a PFO in this study, regardless of the presence of an atrial septal aneurysm or the size of the PFO. As the mean age of patients in PICSS was around 59, the best agent for secondary stroke prophylaxis in younger patients with PFOs remains uncertain. OTHER There are several other more rare causes of cardioembolism, including atrial myxomas and other intracardiac tumors, and nonbacterial thrombotic endocarditis (NBTE). For these more rare causes, evidence-based recommendations are not possible. Complete resection of atrial myxomas is recommended for stroke prophylaxis and to alleviate any direct cardiac effects. For NBTE, supported by the American College of Chest Physicians consensus conferences, heparin should be used for stroke prophylaxis. Addressing the primary medical process, such as cancer or sepsis, is of course critical in this setting. SUGGESTED READING
ACC/AHA/ESC Guidelines for the Management of Patients with Atrial Fibrillation: Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients with Atrial Fibrillation) Developed in Collaboration with the North American Society of Pacing and Electrophysiology, Circulation 104:2118-2150, 2001. Anticoagulants and antiplatelet agents in acute ischemic stroke: report of the Joint Stroke Guideline Development Committee of the American Academy of Neurology and the American Stroke Association (a division of the American Heart Association), Stroke 33:1934-1942, 2002. Johnson: Current Therapy in Neurologic Disease (7/E)
Spontaneous intracerebral hemorrhage (ICH) encompasses hemorrhage in the parenchyma of the brain and may include hemorrhage into the ventricles and subarachnoid space. This accounts for approximately 15% to 20% of all strokes. The underlying cause of hemorrhage can be varied and is often divided into primary and secondary ICH. The former tends to result from the rupture of smaller vessels in patients with poorly controlled hypertension or amyloid angiopathy. The latter is more often the result of gross structural lesions such as aneurysms, arteriovenous malformations, and tumors. This chapter is a discussion of primary ICH. ICH has a significantly higher mortality rate and has not benefited from the same kind of proven advances documented for the treatment of ischemic stroke. Nonetheless, more continues to be discovered about ICH, which should ultimately lead to improved therapeutics.
Diagnosis
Clinical diagnosis is difficult because of the inability to distinguish ICH with ischemic strokes based solely on clinical symptoms. The neurologic symptoms can be identical to ischemic stroke, though there is more likelihood of headache, vomiting, and unconsciousness in the setting of ICH. The sensitivity and specificity of these clinical features are insufficient for a meaningful positive predictive value. Typically, a radiographic test is necessary to complete the diagnosis, and currently computed tomographic (CT) scanning remains the preferred initial test, because of availability, cost, familiarity, and sensitivity. Magnetic resonance (MR) imaging technology has improved significantly, and many believe that the sensitivity to detect even small amounts of subarachnoid hemorrhage approaches CT, but availability, cost, and familiarity remain issues. Besides the diagnosis of ICH, the CT scan can be used to give an initial prognosis for the patient. Care must be considered in discussions of prognosis, since these can be self-fulfilling prophecies, such that the prediction of a bad outcome can lead to limited care, which will then lead to a guaranteed bad outcome. Furthermore, these prognostic scales are based on retrospective data and do not take into account new advances in care, nor do they measure or predict the quality of life of a patient. So, in actuality, it is impossible to definitely predict a patients outcome; however, these scales remain useful at least as a measure of severity of the clinical picture. There have been several studies of prognostic factors, and the common denominators always include hematoma size and clinical condition. Other variables that have been found to influence the prognosis
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Delivery of a full antibiotic course for endocarditis can cure the aneurysms. Although these aneurysms are uncommon, we recommend cerebral angiography in patients with stroke from endocarditis who have reasonable neurologic and medical recovery, prior to discontinuation of antibiotics. Aneurysms that do not resolve with antibiotic therapy and are accessible may be amenable to surgical treatment. We do not anticoagulate patients with endocarditis secondary to the risk of intracerebral hemorrhage, but instead use an antiplatelet agent for stroke prophylaxis. PATENT FORAMEN OVALE By autopsy and TEE studies, approximately 20% to 30% of the population has a patent foramen ovale (PFO). If a PFO is to be implicated as causative, venous thrombosis with paradoxical embolization must be inferred, suggesting the need to assess for deep venous thrombosis. One study suggests that 10% of stroke patients with a PFO have a deep venous thrombosis. These patients should be treated with anticoagulation. In the PFO in Cryptogenic Stroke Study (PICSS), stroke patients who had TEEs were randomized to receive warfarin, with a goal INR of 2 to 3, or aspirin 325 mg/day. Time to recurrent stroke in those with a PFO was not different between the two treatment groups. Those with a PFO were not at a higher risk than those without a PFO in this study, regardless of the presence of an atrial septal aneurysm or the size of the PFO. As the mean age of patients in PICSS was around 59, the best agent for secondary stroke prophylaxis in younger patients with PFOs remains uncertain. OTHER There are several other more rare causes of cardioembolism, including atrial myxomas and other intracardiac tumors, and nonbacterial thrombotic endocarditis (NBTE). For these more rare causes, evidence-based recommendations are not possible. Complete resection of atrial myxomas is recommended for stroke prophylaxis and to alleviate any direct cardiac effects. For NBTE, supported by the American College of Chest Physicians consensus conferences, heparin should be used for stroke prophylaxis. Addressing the primary medical process, such as cancer or sepsis, is of course critical in this setting. SUGGESTED READING
ACC/AHA/ESC Guidelines for the Management of Patients with Atrial Fibrillation: Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients with Atrial Fibrillation) Developed in Collaboration with the North American Society of Pacing and Electrophysiology, Circulation 104:2118-2150, 2001. Anticoagulants and antiplatelet agents in acute ischemic stroke: report of the Joint Stroke Guideline Development Committee of the American Academy of Neurology and the American Stroke Association (a division of the American Heart Association), Stroke 33:1934-1942, 2002. Johnson: Current Therapy in Neurologic Disease (7/E)
Spontaneous intracerebral hemorrhage (ICH) encompasses hemorrhage in the parenchyma of the brain and may include hemorrhage into the ventricles and subarachnoid space. This accounts for approximately 15% to 20% of all strokes. The underlying cause of hemorrhage can be varied and is often divided into primary and secondary ICH. The former tends to result from the rupture of smaller vessels in patients with poorly controlled hypertension or amyloid angiopathy. The latter is more often the result of gross structural lesions such as aneurysms, arteriovenous malformations, and tumors. This chapter is a discussion of primary ICH. ICH has a significantly higher mortality rate and has not benefited from the same kind of proven advances documented for the treatment of ischemic stroke. Nonetheless, more continues to be discovered about ICH, which should ultimately lead to improved therapeutics.
Diagnosis
Clinical diagnosis is difficult because of the inability to distinguish ICH with ischemic strokes based solely on clinical symptoms. The neurologic symptoms can be identical to ischemic stroke, though there is more likelihood of headache, vomiting, and unconsciousness in the setting of ICH. The sensitivity and specificity of these clinical features are insufficient for a meaningful positive predictive value. Typically, a radiographic test is necessary to complete the diagnosis, and currently computed tomographic (CT) scanning remains the preferred initial test, because of availability, cost, familiarity, and sensitivity. Magnetic resonance (MR) imaging technology has improved significantly, and many believe that the sensitivity to detect even small amounts of subarachnoid hemorrhage approaches CT, but availability, cost, and familiarity remain issues. Besides the diagnosis of ICH, the CT scan can be used to give an initial prognosis for the patient. Care must be considered in discussions of prognosis, since these can be self-fulfilling prophecies, such that the prediction of a bad outcome can lead to limited care, which will then lead to a guaranteed bad outcome. Furthermore, these prognostic scales are based on retrospective data and do not take into account new advances in care, nor do they measure or predict the quality of life of a patient. So, in actuality, it is impossible to definitely predict a patients outcome; however, these scales remain useful at least as a measure of severity of the clinical picture. There have been several studies of prognostic factors, and the common denominators always include hematoma size and clinical condition. Other variables that have been found to influence the prognosis
222
include patient age and presence of intraventricular hemorrhage. One measure of hematoma volume is using the formula for the volume of an ellipsoid [4/3 (/2) (/2) (C/2)]; making approximation that = 3, this is simplified to: (A B C) 2 where A is the longest length of the hemorrhage, B is the largest width of the hemorrhage, and C is depth of the hemorrhage (determined by the number of CT slices in which hemorrhage is present times the slice thickness).
Yes
Acute onset of neurologic deficits
Protecting airway or GCS>8? No
Ventilation and oxygenation adequate? Yes
No
Intubate
Evaluation and Management (Figure 1)

The initial evaluation and management of the patient with ICH are the same as for any patient in the emergency or critical care setting, which starts with the ABC (airway, breathing, circulation) assessment. ABCs In reference to A, determine whether the patients airway is protected. Is there a lack of gag reflex either from depressed level of consciousness or brainstem/ cranial nerve dysfunction? Or is there an obstruction, such as the tongue or other foreign objects such as food or dentures, and so forth? Obstructions should be removed, and intubation is indicated for those patients who cannot protect their airway or will need breathing assistance. Induction should be accomplished only with short-acting anesthetics so that the clinician is able to monitor the neurologic status as quickly as possible after intubation. In reference to B, determine whether there is an impediment to breathing/gas exchange, from depressed respiratory drive, mechanical respiratory failure or lung parenchymal disease (e.g., chronic obstructive pulmonary disease), pulmonary edema, or aspiration pneumonia. Intubation and mechanical ventilation are also indicated for these patients as well. Finally, in reference to C, determine whether the circulation is adequate. Is the intravascular volume sufficient to maintain adequate blood pressure and cerebral perfusion pressure? Generally, though, most ICH patients blood pressure will be raised and in the early stage will need to be lowered. BLOOD PRESSURE A discussion of blood pressure leads to the somewhat controversial dilemma of hemodynamic management. Typically a patient with ICH has elevated blood pressure, but there had been concern in treating this blood pressure aggressively because the blood pressure may simply be a response to the acute insult, and, more important, because of the fear of decreasing collateral perfusion and worsening the presumed ischemic penumbra around the hematoma. However, in a variety of studies
Hypotension No Yes
Obtain CT or MRI to confirm ICH No Yes
IV fluids and vasopressors
End ICH algorithm
Go to part 2 of ICH algorithm
ICH seen on imaging study Yes Acute hydrocephalus?
Yes
External ventricular drainage
No Is it a cerebellar hematoma (>30 ml or GCS <14) or a large hematoma and recent, severe neurological decline? No Yes
SBP >160 or MAP >120 Yes No
Neurosurgical evacuation
IV antihypertensive infusion
Consider seizure prophylaxis Euvolemia Normothermia Normotensive Early mobilization
FIGURE 1. Algorithm for the treatment of intracranial hemorrhage (ICH). GCS, Glasgow Coma Scale.
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using single-photon emission CT (SPECT), positron emission tomography (PET), and diffusion MR imaging, no such ischemic penumbra has been demonstrated. Since chronic and acute hypertension are known risk factors for ICH, and there is high probability of early recurrent ICH and no ischemic penumbra has been proven, at our institution we believe in early blood pressure reduction. Blood pressure reduction can be accomplished in a variety of means. In an informal survey of neurointensivists, I have found that approximately half used the mean arterial blood pressure (MAP) and half used the systolic blood pressure as the measurement of choice to set patient care goals and monitoring. At our institution, we use systolic blood pressure goals of 130 to 160 mm Hg, since approximately two thirds of the MAP value is based on the diastolic blood pressure and we feel that the higher systolic blood pressure is the likely instigator in recurrent hemorrhage. MAP goals are perhaps better for those patients where consistent perfusion is more of a concern, and typical MAP goals might be in the range of 100 to 120 mm Hg. After setting the chosen goals, specific agents must be chosen to meet those goals. In Table 1 there is a list of typical antihypertensive agents and doses used in acute ICH. A caveat to the use of nitroprusside is that arterial line monitoring is recommended because of the chance of acute severe hypotension and hemodynamic instability. At our institution, we prefer intravenous infusions of nicardipine because of more consistent blood pressure response and tighter blood pressure control, compared with either nitroprusside or boluses of antihypertensive medications, such as labetalol.
VENTRICULOSTOMY AND SURGERY A severe complication of ICH is an increase in intracranial pressure (ICP), either in the acute setting because of the large size of the hematoma, or delayed ICP elevation because of perihematoma edema or because of hydrocephalus caused from either an intraventricular hemorrhage component to the ICH or from obstruction of ventricular outflow by compression of the third or fourth ventricles, depending on the location of the ICH. Obstructive hydrocephalus is fairly easily treated with external ventricular drainage; however, there may be continued compression of other brain elements that may lead to the decision of surgical evacuation of the hematoma. Though there is no evidence that evacuation of supratentorial hemorrhage can consistently lead to improved clinical outcomes, it is often attempted at most institutions with neurosurgical support. Certainly there has been successful outcome in isolated cases. In the instance of cerebellar hematoma, there is evidence that surgical evacuation will lead to improved outcome in those cases where the hematoma is larger than 40 mL or where there has been neurologic decline. INTRACRANIAL PRESSURE Though there is no concrete evidence that monitoring and treatment actually lead to an improved outcome, if ICP is to be treated, it makes sense to monitor ICP. When ICP is known, then the cerebral perfusion pressure (CPP) can be calculated as CPP = MAP ICP and hemodynamic therapy can also be modified to maintain CPP at adequate levels, typically greater than 60 mm Hg. Occasionally, blood pressure needs to be raised with hypertensive agents to meet these goals (see Table 1 for agents treating hypotension). Treatment of ICP (Table 2) consists of (1) improving venous drainage by elevating the head of the bed to 30 degrees above horizontal, (2) hyperventilation to cause vasoconstriction and decrease cerebral blood volume, (3) diuretics to decrease intravascular blood volume, and (4) hyperosmolar therapy, typically with mannitol and sometimes hypertonic saline, to maintain an elevated serum osmolarity to draw off interstitial fluid and edema from the brain into the vasculature and then excretion through the renal system. Except for raising the head of the bed, these interventions are short lived
TABLE 1 Hemodynamic Management

Drug and Type of Blood Pressure Hypertension Labetalol Esmolol Hydralazine Enalapril Nitroprusside Nicardipine Hypotension IV fluids Dopamine Phenylephrine Norepinephrine
Dosage
5-40 mg IV q 15 min or 5-200 mg/h continuous infusion 500 g/kg IV load, then 50-200 g/kg/min 10-20 mg IV q 6-8 h 0.625-1.25 mg IV q 10 min (not to exceed 5 mg/6 h) 0.5-10 g/kg/min (doses > 4g/kg/min or prolonged infusion may lead to cyanide toxicity) 5-15 mg/h IV infusion Maintain euvolemia, preferably with isotonic saline 2-20 g/kg/min IV infusion Up to 200 g as a bolus, then 2-10 g/kg/min IV infusion 0.05-0.2 g/kg/min, then titrate to effect
TABLE 2 Treatment of Elevated Intracranial Pressure

1. Raise head of bed > 30 degrees. 2. Treat hyperventilation by increasing set respiratory rate to meet PCO2 goals of 25-30 mm Hg. 3. Administer diuretic dose with furosemide (Lasix) 10 mg (in patients with adequate renal function). 4. Administer mannitol 1 gm/kg IV to meet serum osmolarity goals of 300-320 mOsm (in patients with adequate renal function).
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and should be reserved for the acutely deteriorating patient. Steroids should be avoided since they have not been found to be effective in randomized, controlled trials.
SUGGESTED READING
Broderick JP, Adams HP Jr, Barsan W, et al: Guidelines for the management of spontaneous intracerebral hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association, Stroke 30:905-915, 1999. Broderick JP, Brott TG, Duldner JE, et al: Volume of intracerebral hemorrhage: a powerful and easy-to-use predictor of 30-day mortality, Stroke 24:987-993, 1993. Qureshi AI, Tuhrim S, Broderick JP, et al: Spontaneous intracerebral hemorrhage, N Engl J Med 344:1450-1460, 2001. Tuhrim S, Horowitz DR, Sacher M, Godbold JH: Validation and comparison of models predicting survival following intracerebral hemorrhage, Crit Care Med 23:950-954, 1995.
Complications
A major complication of ICH is seizures, usually developing within 24 hours of the hemorrhage. The risk is higher when blood invades or is adjacent to the cerebral cortex, so for those patients with cortical hemorrhages or those who have had seizures, it is reasonable to begin immediate prophylactic therapy with anticonvulsants such as phenytoin or valproate that can be given intravenously or orally (Table 3). If no seizures have occurred, it is agreed to discontinue prophylactic therapy, though there is some discrepancy on the timeline, anywhere from 1 to 6 months after the ICH has been espoused. Certainly those with later seizures will need long-term therapy. Systemic factors that have been associated with poorer outcome in stroke patients are consistently dehydration, elevated serum glucose levels, and fever. So though not proven to be a causal relationship, it certainly makes sense to aggressively maintain euvolemia, euthermia, and normal serum glucose levels.

Joao A. Gomes, M.D., and Wendy C. Ziai, M.D.
Upcoming Therapies and Trials

There remains little high-level clinical trial evidence to help determine the best management of the patient with ICH. Some of the difficult issues in ICH management that are targets of active investigation include (1) a study on blood pressure management of ICH patients that stratifies patients to high, low, and normal blood pressure control; (2) minimally invasive removal of hematoma through stereotactic approaches; (3) hypothermia treatment for ICH; (4) accelerating removal of intraventricular hemorrhage through aggressive drainage and thrombolytic agents; and (5) preventing recurrent hemorrhage with recombinant VIIa factors.
TABLE 3 Seizure Prophylaxis

Drug Phenytoin Dosage Loading dose 15-20 mg/kg IV (not to exceed 50 mg/min) or orally in divided doses Maintenance 300 mg/day in divided doses Loading dose 10-20 mg PE/kg IV (not to exceed 150 mg PE/min) or IM Maintenance dose 4 to 6 mg PE/kg/day IV or IM IV loading dose 10-15 mg/kg/day (20 mg/min) Maintenance titrated to meet therapeutic goals
Fosphenytoin
Valproate
PE, Phenytoin sodium equivalent units.
Overall, craniocerebral trauma is the most common cause of subarachnoid hemorrhage (SAH), whereas aneurysmal rupture (saccular or berry) accounts for more than 80% of nontraumatic SAH. Other less common etiologies include perimesencephalic (presumably venous) hemorrhages, arterial dissections, vascular malformations, drug abuse, coagulopathies, and sickle cell disease. In this review we concentrate primarily on the management of aneurysmal SAH. The estimated annual incidence of SAH varies greatly with the population studied and with other demographic and geographic factors. In a recent meta-analysis, the pooled incidence of SAH was 10.5 per 100,000 personyears, and in the United States alone 30,000 new cases are reported every year. The relative risk of developing SAH is increased with alcohol intake, hypertension, smoking, and history of a first-degree relative with SAH. The prevalence of intracranial aneurysm in the general U.S. population is 0.5% to 1%. After an episode of aneurysmal SAH, 80% of patients reach the hospital alive, 30% die during their hospital admission, and only about 16% ultimately regain independence without cognitive deficits. Overall, fewer than 50% of independent patients return to their prior level of work after SAH. At presentation patients typically complain of a sudden-onset, severe headache (worse headache of my life), accompanied by nausea, vomiting and photophobia. In 19% of cases, however, the headache progresses gradually over minutes or rarely longer. A warning leak, called a sentinel hemorrhage, occurs in approximately 70% of patients and is usually indicated by a previous episode of milder symptoms. Alterations of consciousness, including coma (occurring in 25% of patients), and focal neurologic deficits (in 33%), are also frequent manifestations. The nonspecific nature of these symptoms leads to initial misdiagnosis in 23% to 37%
224
and should be reserved for the acutely deteriorating patient. Steroids should be avoided since they have not been found to be effective in randomized, controlled trials.
SUGGESTED READING
Broderick JP, Adams HP Jr, Barsan W, et al: Guidelines for the management of spontaneous intracerebral hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association, Stroke 30:905-915, 1999. Broderick JP, Brott TG, Duldner JE, et al: Volume of intracerebral hemorrhage: a powerful and easy-to-use predictor of 30-day mortality, Stroke 24:987-993, 1993. Qureshi AI, Tuhrim S, Broderick JP, et al: Spontaneous intracerebral hemorrhage, N Engl J Med 344:1450-1460, 2001. Tuhrim S, Horowitz DR, Sacher M, Godbold JH: Validation and comparison of models predicting survival following intracerebral hemorrhage, Crit Care Med 23:950-954, 1995.
Complications
A major complication of ICH is seizures, usually developing within 24 hours of the hemorrhage. The risk is higher when blood invades or is adjacent to the cerebral cortex, so for those patients with cortical hemorrhages or those who have had seizures, it is reasonable to begin immediate prophylactic therapy with anticonvulsants such as phenytoin or valproate that can be given intravenously or orally (Table 3). If no seizures have occurred, it is agreed to discontinue prophylactic therapy, though there is some discrepancy on the timeline, anywhere from 1 to 6 months after the ICH has been espoused. Certainly those with later seizures will need long-term therapy. Systemic factors that have been associated with poorer outcome in stroke patients are consistently dehydration, elevated serum glucose levels, and fever. So though not proven to be a causal relationship, it certainly makes sense to aggressively maintain euvolemia, euthermia, and normal serum glucose levels.

Joao A. Gomes, M.D., and Wendy C. Ziai, M.D.
Upcoming Therapies and Trials

There remains little high-level clinical trial evidence to help determine the best management of the patient with ICH. Some of the difficult issues in ICH management that are targets of active investigation include (1) a study on blood pressure management of ICH patients that stratifies patients to high, low, and normal blood pressure control; (2) minimally invasive removal of hematoma through stereotactic approaches; (3) hypothermia treatment for ICH; (4) accelerating removal of intraventricular hemorrhage through aggressive drainage and thrombolytic agents; and (5) preventing recurrent hemorrhage with recombinant VIIa factors.
TABLE 3 Seizure Prophylaxis

Drug Phenytoin Dosage Loading dose 15-20 mg/kg IV (not to exceed 50 mg/min) or orally in divided doses Maintenance 300 mg/day in divided doses Loading dose 10-20 mg PE/kg IV (not to exceed 150 mg PE/min) or IM Maintenance dose 4 to 6 mg PE/kg/day IV or IM IV loading dose 10-15 mg/kg/day (20 mg/min) Maintenance titrated to meet therapeutic goals
Fosphenytoin
Valproate
PE, Phenytoin sodium equivalent units.
Overall, craniocerebral trauma is the most common cause of subarachnoid hemorrhage (SAH), whereas aneurysmal rupture (saccular or berry) accounts for more than 80% of nontraumatic SAH. Other less common etiologies include perimesencephalic (presumably venous) hemorrhages, arterial dissections, vascular malformations, drug abuse, coagulopathies, and sickle cell disease. In this review we concentrate primarily on the management of aneurysmal SAH. The estimated annual incidence of SAH varies greatly with the population studied and with other demographic and geographic factors. In a recent meta-analysis, the pooled incidence of SAH was 10.5 per 100,000 personyears, and in the United States alone 30,000 new cases are reported every year. The relative risk of developing SAH is increased with alcohol intake, hypertension, smoking, and history of a first-degree relative with SAH. The prevalence of intracranial aneurysm in the general U.S. population is 0.5% to 1%. After an episode of aneurysmal SAH, 80% of patients reach the hospital alive, 30% die during their hospital admission, and only about 16% ultimately regain independence without cognitive deficits. Overall, fewer than 50% of independent patients return to their prior level of work after SAH. At presentation patients typically complain of a sudden-onset, severe headache (worse headache of my life), accompanied by nausea, vomiting and photophobia. In 19% of cases, however, the headache progresses gradually over minutes or rarely longer. A warning leak, called a sentinel hemorrhage, occurs in approximately 70% of patients and is usually indicated by a previous episode of milder symptoms. Alterations of consciousness, including coma (occurring in 25% of patients), and focal neurologic deficits (in 33%), are also frequent manifestations. The nonspecific nature of these symptoms leads to initial misdiagnosis in 23% to 37%
225
of patients. Findings on physical examination include nuchal rigidity, papilledema, subhyaloid hemorrhage, cranial nerve palsy (especially cranial nerves III and VI), bilateral leg weakness, abulia, nystagmus, hemiparesis, ataxia, aphasia, and neglect. The three baseline variables that best predict poor outcome after SAH are neurologic status of the patient on admission, age, and amount of subarachnoid blood on the initial computed tomographic (CT) scan. Several clinical and radiologic grading scales have been proposed, and the most commonly used in routine practice are shown in Tables 1 to 3. These scales have some prognostic value (i.e., an SAH with a grade V in the Hunt-Hess scale has an estimated mortality of close to 100%) and to some extent can help dictate further management. They are, however, far from perfect because they include subjective terminology, they have undocumented or imperfect interobserver reliability, the prognostic value may not be the same for all of the elements included, and they fail to consider the presence of reversible conditions such as hydrocephalus that may initially suggest a worse prognosis. In the past, rebleeding was a major cause of morbidity and mortality following the initial hemorrhage. With the current practice of early aneurysm clipping, the incidence of rebleeding is more limited and vasospasm and delayed ischemic deficits have become the most significant and feared complications following SAH. Although classically the presence of thick clot on the initial CT scan was considered a major determinant of vasospasm, this view has been recently challenged. The pathophysiology of cerebral vasospasm is currently not fully understood, but both inflammation and endothelial dysfunction seem to play a major role in its development. The management of patients with SAH remains a major challenge for physicians involved in the care of these patients. In this review we focus on the initial management of patients after SAH (i.e., the acute phase up to the time of aneurysm clipping), and then review the management of various complications associated with SAH.
General Management
Noncontrast CT scanning of the brain has a sensitivity of 85% to 90% for the diagnosis of SAH. The location of clot on CT scan can be indicative of the location of the ruptured aneurysm. If the CT result is negative for SAH, a lumbar puncture is mandatory to look for the presence of blood or xanthochromia in the cerebrospinal fluid (CSF). Four-vessel cerebral angiography remains the gold standard for detection of aneurysms, although 10% to 30% of cases may not reveal an aneurysm, and repeat angiography should be performed in 1 to 2 weeks (10% to 20% of cases are then positive). Helical CT angiography provides multiplanar views or three-dimensional images that have a sensitivity of 77% to 97% (specificity, 87% to 100%) and is a reasonable alternative for patients who cannot tolerate an angiogram and require surgery. Initial stabilization of patients with SAH requires admission to a monitored critical care setting. After assessing the basic ABCs (airway, breathing, circulation), one of the earliest interventions that relieves patient distress and may control hypertension and agitation is adequate pain control. Oral or rectal acetaminophen or intravenous (IV) short-acting narcotics such as fentanyl can be used until pain control is achieved. The sedating effect of narcotic agents may limit their use in patients with impaired consciousness and/or higher SAH grades. Although frequent neurologic assessments are required during this period, excessive stimulation should be reduced to a minimum. If the patient requires intubation, general anesthetic induction should be used to blunt the hemodynamic stress of laryngoscopy. Adequate IV access is also mandatory, and although peripheral venous lines are usually sufficient in the early stages, central venous access is often required, particularly if the patient requires hypertonic fluids or prolonged use of vasopressor agents. The presence of a central venous line also helps with hemodynamic monitoring and the assessment of fluid status by continuous measurement of central venous pressure. Fever in this setting is a common occurrence and may play a role in the pathophysiology of cerebral vasospasm. Experimental data suggest that fever is associated with worse outcomes after brain trauma or ischemia; therefore, it is important to aggressively maintain normothermia. Although adequate microbiologic cultures should be obtained, including CSF in patients with
TABLE 1 Hunt-Hess Grading Scale for Subarachnoid Hemorrhage*

Grade 1 2 3 4 5 Criteria Asymptomatic or minimal headache and slight nuchal rigidity Moderate-to-severe headache, nuchal rigidity, no neurologic deficit other than cranial nerve palsy Drowsiness, confusion, or mild focal deficit Stupor, moderate-to-severe focal deficit (hemiparesis); vegetative disturbances Deep coma, decerebrate posturing
TABLE 2 World Federation of Neurological Surgeons Grading Scale for Subarachnoid Hemorrhage
Grade 1 2 3 4 5 Criteria GCS GCS GCS GCS GCS score score score score score 15, no motor deficit 13-14, no motor deficit 13-14, with motor deficit 7-12, with or without motor deficit 3-6, with or without motor deficit
*Significant comorbidity raises the Hunt-Hess score by 1 point.
GCS, Glasgow Coma Scale.
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TABLE 3 Fisher Grading Scale for Subarachnoid Hemorrhage

Grade 1 2 3 4 Criteria No subarachnoid blood detected on CT scan Diffuse subarachnoid blood or vertical layer <1 mm thick Localized clot in subarachnoid space and/or vertical layer >1 mm thick Intracerebral or intraventricular clot in absence of significant subarachnoid blood
intraventricular catheters or following craniotomy, fever in these patients may occur without any identifiable infectious etiologies (central fever). Oral or rectal acetaminophen and surface cooling techniques (i.e., cooling blankets, ice packs, and alcohol rubs) are routinely used to maintain core body temperature below 37.5C. Intravascular cooling catheters have also been successfully used for this purpose; however, cost and potential side effects due to their invasive nature may limit their widespread use. Nimodipine, a calcium channel blocker, has been shown to improve outcomes in patients with SAH, but it is unclear if it does so by decreasing vasospasm or through other neuroprotective mechanisms. We routinely start nimodipine at 60 mg every 4 hours (or 30 mg every 2 hours if hypotension is induced with the larger dose), and continue treatment for 3 weeks. IV nimodipine is available in some countries. The incidence of rebleeding from the aneurysm during the first 24 hours is likely underestimated. It ranges from 4% to as high as 15%. During the first 2 weeks about 20% of patients experience an episode of rebleeding, which is a major factor contributing to poor outcome. In the past, administration of antifibrinolytic agents (epsilon aminocaproic acid) was associated with a decreased rate of rebleeding, but at the expense of an increased risk of ischemic complications. More recently, activated recombinant factor VII has been tested in a small cohort of patients. No episodes of rebleeding were documented, but the trial was stopped pending the adjudication of a thrombotic complication. In retrospective studies, up to 20% of patients had at least one seizure during the first 2 weeks following SAH, whereas only 6% to 8% developed late seizures and epilepsy. Persistent postoperative neurologic deficits, loss of consciousness for more than 1 hour at ictus, subdural hematoma, and cerebral infarction were associated with the development of epilepsy. All patients should receive seizure prophylaxis with an IV bolus of phenytoin or fosphenytoin (20 mg/kg) on arrival to the hospital, and therapeutic levels (15 to 20 ng/dL) should be maintained throughout their admission. Common side effects such as skin rash, hypotension during the infusion, hyponatremia, and drug fever should be monitored for. Valproate is also a reasonable alternative if phenytoin is contraindicated and is available in an IV formulation. In uncomplicated cases the antiepileptic agent can be stopped after the first month but may be continued
longer if there is a high likelihood of developing late epilepsy, for example, after cerebral infarction or brain abscess. Because of the ability of corticosteroids to suppress inflammation, inhibit prostanoid actions, and prevent lipid peroxidation, their use has been tested extensively in SAH, particularly as a means of preventing vasospasm. In a trial involving 22 patients, those treated with corticosteroids were twice as likely to have an excellent outcome and half as likely to die. Unfortunately these results have not been replicated, and despite a reasonable rationale for their use, good clinical data are lacking. In our unit patients are treated with dexamethasone 4 mg every 6 hours IV in the perioperative period, but rarely for more than a few days. The rationale is for control of pain and inflammation. Between 10% and 34% of patients with SAH develop hypovolemia associated with a negative sodium balance, known as cerebral salt wasting. Fluid restriction in patients with hyponatremia and SAH is associated with an increased risk of cerebral ischemia. Therefore, maintaining normal intravascular volume is an important strategy to prevent the development of delayed ischemic deficits. Two nonrandomized studies support this view and advocate the daily intake of at least 3 L of fluid. Normal saline is usually the fluid of choice, and if a central line is in place, the central venous pressure should be maintained between 8 and 12 cm H2O. Fludrocortisone is sometimes used to promote sodium and water retention, particularly if cerebral salt wasting has developed (see later). Another important consideration is hemoglobin and hematocrit levels. To optimize oxygen delivery to brain tissue, the hemoglobin level should be kept between 10 and 11 gm/dL and hematocrit should be in the 30% to 34% range. Blood transfusions should be used as needed, but consideration should also be given to recombinant erythropoietin for patients with severe anemia. Blood transfusion thresholds in the SAH population have recently been challenged in view of lower hemoglobin thresholds used in other intensive care unit populations where blood transfusion may be an independent predictor of worse outcome. Arterial hypertension is a common occurrence in this initial period and may be the result of anxiety, pain, increased intracranial pressure, or agitation. On the one hand, uncontrolled hypertension can theoretically lead to rerupture of the aneurysm, whereas aggressive blood pressure lowering may compromise cerebral perfusion pressure, particularly if elevated intracranial pressure is present. Although the optimal range of blood pressure in this setting is unknown, in an observational study, lowering blood pressure did not reduce the rate of rerupture but increased the risk of cerebral ischemia. Our usual practice is to maintain a systolic blood pressure below 160 mm Hg prior to aneurysm clipping or coiling (diastolic blood pressure, < 80 mm Hg, and mean arterial pressure [MAP] < 110 mm Hg), and to treat aggressively only if end organ damage is evident. The preferred IV agents include labetalol, hydralazine, and nicardipine. The latter has the added advantage of reducing the incidence of vasospasm.
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The respiratory status of the patient should be assessed periodically, supplemental oxygen provided as required, and the airway secured if there is evidence of aspiration, neurogenic pulmonary edema with compromised oxygenation, or poor mental status with inability to protect the airway. Baseline chest radiograph and arterial blood gases should be obtained and repeated if the patient status changes. Adequate prophylaxis for pulmonary embolism should be instituted with compressive stockings and sequential compression devices initially and subcutaneous heparin after the aneurysm has been secured. An effective bowel regimen is paramount to prevent stress ulcers and avoid constipation, particularly in patients taking narcotic analgesics. Proton pump inhibitors, H2 blockers, or sucralfate, and a variety of medications to keep a regular bowel schedule should be implemented early. Nausea should also be aggressively treated with the standard medications (i.e., metoclopramide, prochlorperazine, dolasetron, or ondansetron). Patients should not be fed for the first 24 to 48 hours in preparation for surgery or endovascular interventions. Patients with inadequate swallowing mechanisms should have a nasogastric or orogastric tube placed and tube feeds started postoperatively to provide adequate nutrition. Concentrated feeds with less free water and higher sodium content may be preferable for these patients.
Complications
Angiographic vasospasm is documented in about 60% of patients following SAH but becomes symptomatic in only half of them. Ultimately, delayed ischemic deficits develop in about 16% of subjects with SAH. Typically, vasospasm has its onset 3 to 5 days following the initial bleed, peaks at 7 to 10 days, and resolves spontaneously over 2 to 4 weeks. Vasospasm is a proliferative vasculopathy that results from a variety of vasoactive mediators including oxyhemoglobin, free radicals, prostaglandins, decreased action of nitric oxide, inflammatory immune mediators, and vasoconstrictive peptides such as endothelin. The clinical manifestations of vasospasm include decreased responsiveness, abulia, focal neurologic deficits including paraparesis, and apraxia. Without adequate supportive care, the result is mortality in 30% and disability in 35% of patients. The best predictor of vasospasm is the amount of blood detected on head CT scan (Fisher grade) within the first 3 days after SAH. Structural complications should be ruled out by CT scan when vasospasm is suspected. Although conventional angiography is considered the gold standard for the diagnosis of vasospasm, daily screening of cerebral blood flow (CBF) velocities in the large arteries comprising the circle of Willis by means of transcranial Doppler (TCD) ultrasound is routinely performed in an attempt to detect it. Overall, the sensitivity of TCD for detecting vasospasm ranges from 65% to 80%, with velocities less than 120 cm/sec having a negative predictive value of 94% and greater than 200 cm/sec
a positive predictive value of almost 90%. Unfortunately, most CBF velocities during vasospasm actually fall in the range between 120 and 200 cm/sec, making TCD somewhat less useful. The ratio of the mean velocity of the middle cerebral artery to the mean velocity recorded in the extracranial carotid artery (Lindegaard index [LI]) helps differentiate hyperemia (LI < 3) from vasospasm (LI > 3). An increment in mean CBF velocities by more than 50 cm/sec in a 24-hour period is considered a specific marker of vasospasm. The combination of hypervolemia, hemodilution, and hypertension (triple-H therapy) was first introduced in the 1970s and remains the mainstay of therapy for cerebral vasospasm, even though its effectiveness has never been documented in a randomized, controlled trial. In the presence of arterial narrowing, cerebral autoregulation is impaired and blood flow may become pressure dependent. This is the rationale for blood pressure augmentation in symptomatic vasospasm. It is also thought that hemodilution decreases blood viscosity and enhances blood flow through spastic blood vessels. Besides aggressive hydration with IV normal saline with a target central venous pressure of 8 to 12 cm H2O, the use of vasopressor agents is recommended for ongoing symptoms suggestive of cerebral ischemia. Phenylephrine is usually the first agent of choice, but development of reflex bradycardia may limit its use. MAP is usually increased by 20% up to a MAP of 140 mm Hg, and the patient is reassessed frequently. Pulmonary edema and myocardial infarction are the main complications associated with this therapy, and daily chest radiographs and electrocardiograms should be obtained in all patients. Some groups advocate the routine insertion of a pulmonary artery catheter to guide therapy, never allowing the pulmonary capillary wedge pressure to exceed the calculated colloid oncotic pressure. Increasing cardiac output independent of blood pressure has also been used successfully to increase CBF and treat vasospasm following SAH. This is usually achieved by using primarily inotropic agents such as dobutamine and has the added advantage of being potentially beneficial in the setting of cardiac dysfunction. If maximal medical therapy fails to produce clinical improvement after 2 to 4 hours, an angiogram should be obtained and endovascular interventions considered. Percutaneous transluminal angioplasty has been advocated as an effective and relatively safe procedure to mechanically dilate large intracranial vessels increasing distal CBF (rarely vessel rupture or dissection can occur), but no controlled trials have documented its value. If the spasm is diffuse or present in smaller arterial branches, the infusion of papaverine, verapamil, or nicardipine is then considered, but their effect tends to be short lasting. Hyponatremia occurs in as many as 30% of patients with SAH and is often associated with intravascular volume depletion and cerebral ischemia. In most instances this is due to cerebral salt wasting (CSW), a syndrome thought to be mediated by a natriuretic factor that is released as a consequence of the initial brain insult as well as decreased rennin and aldosterone. It is most commonly seen in aneurysms involving the
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anterior cerebral artery complex and typically peaks in the first 7 to 10 days. It manifests as natriuresis, hyponatremia, and hypovolemia. CSW needs to be differentiated from the syndrome of inappropriate antidiuretic hormone (SIADH) secretion. In the latter, there are no signs of dehydration because patients are usually euvolemic or slightly hypervolemic. Serum uric acid concentration (decreased in SIADH), plasma osmolality (decreased in SIADH), and CVP (increased or normal in SIADH) may also help differentiate between these two conditions. Volume repletion and maintenance of a positive sodium balance are the cornerstones of therapy. Multiplying the deficit in sodium concentration by the total body water (TBW) helps estimate the amount of sodium required to achieve normonatremia, as shown in the following equation: Na+ replacement = (ideal Na+ measured Na+) TBW Oral sodium chloride tablets (2 gm every 6 hours), 2% or 3% hypertonic saline (when serum Na+ < 130), and fludrocortisone (a mineralocorticoid agent) all are useful in correcting the sodium deficit. Although a rapid decrease in sodium plasma levels can lead to cerebral edema, overtly aggressive correction of hyponatremia (>20 mEq/L per day) can lead to central pontine myelinolysis. Fluid restriction is contraindicated in patients with vasospasm. Hydrocephalus following SAH can be either noncommunicating (usually acute) or communicating (typically subacute or delayed). Usually patients develop decline in alertness, confusion, disorientation, and inattention. In the acute period if the CT scan shows enlarged ventricles, an intraventricular catheter is inserted to drain CSF and relieve symptoms, but the pop-off (the set pressure above which CSF would drain) is set at a high level (15 to 20 mm Hg) to avoid changes in the transmural differential pressure across the aneurysm wall and to prevent sagging of the brain against the floor of the anterior cranial fossa, which may theoretically lead to rerupture. Once the aneurysm is secured (clipped), this is no longer a consideration and the pop-off can be lowered to optimize treatment of hydrocephalus. In instances of communicating (nonobstructive) hydrocephalus, lumbar drain insertion for continuous CSF drainage or serial large volume lumbar punctures are less invasive options. If these interventions are unsuccessful and chronic hydrocephalus develops, ventriculoperitoneal or ventriculopleural shunts are required. It is estimated that about 20% of patients following SAH require a ventriculoperitoneal shunt within the first 30 days. Although not all aneurysms necessarily require treatment, in the setting of SAH, the predicted natural history of the aneurysm is a 50% risk of rerupture in the subsequent 6 months. Rupture of an aneurysm that has previously bled has a significantly higher mortality risk (75%), usually justifying the risks of intervention. The goal of surgical management of aneurysms is to isolate the aneurysm fully from the intracranial circulation to remove the risk of rehemorrhage. This can be accomplished through a craniotomy with direct
visualization of the aneurysm that is clipped, or occasionally trapped or wrapped for less favorable aneurysms. Endovascular obliteration of aneurysms is performed by an interventional team and involves insertion of thrombogenic wire coils into the aneurysm that are detached from the guide wire and left in place. Occasionally balloons or stents are used with the coils. Endovascular treatment, although less invasive than direct surgery, is currently limited by specific aneurysm characteristics such as neck-to-dome ratio and aneurysm location. In addition, this technique achieves complete aneurysm obliteration in only about 60% to 70% of cases, making recurrence a potential risk. SUGGESTED READING
McKhann GM II, Le Roux PD: Perioperative and intensive care unit care of patients with aneurysmal subarachnoid hemorrhage, Neurosurg Clin North Am 9:595-613, 1998. Treggiari-Venzi M, Suter PM, Romand J: Review of medical prevention of vasospasm after aneurysmal subarachnoid hemorrhage: a problem of neurointensive care, Neurosurgery 48:249-262, 2001. van Gijn J, Rinkel GJE: Subarachnoid hemorrhage: diagnosis, causes, and management, Brain 124:249-278, 2001.

Vascular malformations of the brain, such as aneurysms, cavernous malformations, and arteriovenous malformations (AVMs) and fistulas, are complicated to manage. Patients presenting with hemorrhage due to a vascular malformation are some of the sickest in the hospital, with high risk of serious complications and short-term mortality rates approaching 50%. For those whose lesions are discovered for other reasons (e.g., incidentally or in the work-up of seizures, headache, or focal neurologic symptoms), it is difficult to balance the risk of complications from surgical or endovascular treatment with the expected natural history if left untreated; the balance between risk and benefit turns on a dime, at least as we understand it today. Given all these issues, management by a multidisciplinary team is essential. A fully complemented team includes a vascular or intensive-care neurologist, a vascular neurosurgeon, and a neurointerventionalist. Since these specialists are biased to exaggerate the benefits of their own approach, a balanced team is essential in making the best decisions, particularly given the scarcity of evidence and necessary reliance on judgment and experience. Several studies have shown that outcomes are better at centers that treat more patients with these conditions and provide
228
anterior cerebral artery complex and typically peaks in the first 7 to 10 days. It manifests as natriuresis, hyponatremia, and hypovolemia. CSW needs to be differentiated from the syndrome of inappropriate antidiuretic hormone (SIADH) secretion. In the latter, there are no signs of dehydration because patients are usually euvolemic or slightly hypervolemic. Serum uric acid concentration (decreased in SIADH), plasma osmolality (decreased in SIADH), and CVP (increased or normal in SIADH) may also help differentiate between these two conditions. Volume repletion and maintenance of a positive sodium balance are the cornerstones of therapy. Multiplying the deficit in sodium concentration by the total body water (TBW) helps estimate the amount of sodium required to achieve normonatremia, as shown in the following equation: Na+ replacement = (ideal Na+ measured Na+) TBW Oral sodium chloride tablets (2 gm every 6 hours), 2% or 3% hypertonic saline (when serum Na+ < 130), and fludrocortisone (a mineralocorticoid agent) all are useful in correcting the sodium deficit. Although a rapid decrease in sodium plasma levels can lead to cerebral edema, overtly aggressive correction of hyponatremia (>20 mEq/L per day) can lead to central pontine myelinolysis. Fluid restriction is contraindicated in patients with vasospasm. Hydrocephalus following SAH can be either noncommunicating (usually acute) or communicating (typically subacute or delayed). Usually patients develop decline in alertness, confusion, disorientation, and inattention. In the acute period if the CT scan shows enlarged ventricles, an intraventricular catheter is inserted to drain CSF and relieve symptoms, but the pop-off (the set pressure above which CSF would drain) is set at a high level (15 to 20 mm Hg) to avoid changes in the transmural differential pressure across the aneurysm wall and to prevent sagging of the brain against the floor of the anterior cranial fossa, which may theoretically lead to rerupture. Once the aneurysm is secured (clipped), this is no longer a consideration and the pop-off can be lowered to optimize treatment of hydrocephalus. In instances of communicating (nonobstructive) hydrocephalus, lumbar drain insertion for continuous CSF drainage or serial large volume lumbar punctures are less invasive options. If these interventions are unsuccessful and chronic hydrocephalus develops, ventriculoperitoneal or ventriculopleural shunts are required. It is estimated that about 20% of patients following SAH require a ventriculoperitoneal shunt within the first 30 days. Although not all aneurysms necessarily require treatment, in the setting of SAH, the predicted natural history of the aneurysm is a 50% risk of rerupture in the subsequent 6 months. Rupture of an aneurysm that has previously bled has a significantly higher mortality risk (75%), usually justifying the risks of intervention. The goal of surgical management of aneurysms is to isolate the aneurysm fully from the intracranial circulation to remove the risk of rehemorrhage. This can be accomplished through a craniotomy with direct
visualization of the aneurysm that is clipped, or occasionally trapped or wrapped for less favorable aneurysms. Endovascular obliteration of aneurysms is performed by an interventional team and involves insertion of thrombogenic wire coils into the aneurysm that are detached from the guide wire and left in place. Occasionally balloons or stents are used with the coils. Endovascular treatment, although less invasive than direct surgery, is currently limited by specific aneurysm characteristics such as neck-to-dome ratio and aneurysm location. In addition, this technique achieves complete aneurysm obliteration in only about 60% to 70% of cases, making recurrence a potential risk. SUGGESTED READING
McKhann GM II, Le Roux PD: Perioperative and intensive care unit care of patients with aneurysmal subarachnoid hemorrhage, Neurosurg Clin North Am 9:595-613, 1998. Treggiari-Venzi M, Suter PM, Romand J: Review of medical prevention of vasospasm after aneurysmal subarachnoid hemorrhage: a problem of neurointensive care, Neurosurgery 48:249-262, 2001. van Gijn J, Rinkel GJE: Subarachnoid hemorrhage: diagnosis, causes, and management, Brain 124:249-278, 2001.

Vascular malformations of the brain, such as aneurysms, cavernous malformations, and arteriovenous malformations (AVMs) and fistulas, are complicated to manage. Patients presenting with hemorrhage due to a vascular malformation are some of the sickest in the hospital, with high risk of serious complications and short-term mortality rates approaching 50%. For those whose lesions are discovered for other reasons (e.g., incidentally or in the work-up of seizures, headache, or focal neurologic symptoms), it is difficult to balance the risk of complications from surgical or endovascular treatment with the expected natural history if left untreated; the balance between risk and benefit turns on a dime, at least as we understand it today. Given all these issues, management by a multidisciplinary team is essential. A fully complemented team includes a vascular or intensive-care neurologist, a vascular neurosurgeon, and a neurointerventionalist. Since these specialists are biased to exaggerate the benefits of their own approach, a balanced team is essential in making the best decisions, particularly given the scarcity of evidence and necessary reliance on judgment and experience. Several studies have shown that outcomes are better at centers that treat more patients with these conditions and provide
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multidisciplinary care, so transfer should be considered if local expertise is limited.
Unruptured Intracranial Aneurysms

Unruptured intracranial aneurysms are common, with a prevalence estimated at greater than 1% among adults. Most are asymptomatic, incidentally discovered in a work-up for unrelated headache, vertigo, or other neurologic symptoms. Some headaches and focal neurologic signs are produced by aneurysms, particularly when large aneurysms compress neighboring nerves or brain, but these represent fewer than half those discovered. As more data have become available from large cohort studies, such as the International Study of Unruptured Intracranial Aneurysms (ISUIA), treatment decisions about incidentally discovered aneurysms have gotten much more complicated. We previously treated all unruptured aneurysms, motivated by the devastating consequences of subarachnoid hemorrhage from aneurysm rupture and confident that results of surgery and endovascular treatment were favorable. However, recent data suggest that the risks of treatment are not inconsequential and that, for many aneurysms, the risk of rupture is much lower than expected. Furthermore, results of endovascular therapy have been improving and, in the short term, appear better than for surgery, although long-term occlusion remains a concern. Now we are much more careful about who gets referred for an intervention. The first questions are, who should have the aneurysm treated and who can be followed medically? This is a rapidly evolving area with new data published monthly, but the chart represents our interpretation of the best data available today (Figure 1). The decision is based on a number of factors that affect natural history and surgical risk. These include aneurysm size and location, history of subarachnoid hemorrhage from a different aneurysm, age, and whether the aneurysm is producing symptoms. The bottom line is that most aneurysms probably should be treated; however, intervention is not justified in patients with no history of subarachnoid hemorrhage with asymptomatic aneurysms smaller than 7 mm in diameter (in the anterior circulation but not in the posterior communicating artery). The risk of rupture is so low in that group that treatment would need to be nearly completely without complications to justify it. Given the preponderance of evidence supporting greater safety of endovascular therapy, even with limited information on long-term follow-up, we generally favor endovascular coil embolization over surgical clipping. Still, there are many in whom surgery is the best option. Patients best treated with surgical clipping include those with a strong preference for a single treatment procedure, those with aneurysms with wide necks or arising from the middle cerebral artery, and those in whom follow-up is questionable. In addition, other particular characteristics of an aneurysm on imaging may reveal that it is not safely treated by endovascular
therapy, which can only be determined by a neurointerventionalist reviewing the images or attempting treatment. For difficult cases, representatives of endovascular therapy, neurology, and vascular neurosurgery converge in the angiography suite to discuss the best approach to treatment. After endovascular therapy, we generally recommend a follow-up angiogram at 6 months. Subtotal occlusion or recanalization is common and often necessitates further attempts at placing coils. Follow-up angiography is continued about every 6 months until the aneurysm appears completely and stably occluded. For those receiving surgery, a postoperative angiogram is recommended because incomplete occlusion may occur, necessitating further treatment or closer follow-up. If an aneurysm is completely occluded by surgical clipping on a postoperative angiogram, we generally do not perform further angiography or other vascular imaging during follow-up. For those not treated invasively, we generally recommend either computed tomographic (CT) angiography or magnetic resonance angiography 1 year after first diagnosis. If the aneurysm is stable in appearance, the duration between images can be rapidly increased (e.g., year 3, year 6, year 12). Since the literature suggests that most aneurysms expand suddenly before rupturing, the usefulness of follow-up imaging, beyond reassurance of the patient and physician, is questionable. Regardless of how the aneurysm is treated, we recommend secondary prevention through reduction of risk factors. This includes smoking cessation counseling and careful control of blood pressure. We do not recommend cessation of strenuous exercise or straining.
Ruptured Aneurysms
Subarachnoid hemorrhage from ruptured aneurysms is devastating, with 50% mortality and 30% major morbidity. Much of the mortality is due to the initial hemorrhage and its resultant elevation in intracranial pressure. Management can be divided into acute stabilization, treatment of the aneurysm to prevent another rupture, and treatment of complications. An acute head CT scan confirms the diagnosis in most patients and identifies whether hydrocephalus is present, which should be treated by placement of an extraventricular drain. If there is no hydrocephalus or once it is treated with drainage, we generally lower the blood pressure (but maintain a cerebral perfusion pressure of at least 70 mm Hg) in an attempt to reduce risk of rehemorrhage. To reduce the risk of symptomatic vasospasm, we immediately initiate nimodipine 60 mg every 4 hours in all patients. Patients are lightly sedated, and any early complications, such as seizures or aspiration pneumonia, are treated. Patients with any intraparenchymal blood are treated with phenytoin (17 mg/kg load followed by 100 mg every 8 hours) as prophylaxis at least until 24 hours after the aneurysm is treated, and those presenting with seizures are continued on anticonvulsants at least for the duration of the acute hospitalization.
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Unruptured intracranial aneurysm
No
SAH from another aneurysm
Yes
FIGURE 1. Treatment algorithm for unruptured intracranial aneurysms. This simplistic flowchart undervalues important characteristics that are likely to influence treatment decisions, including characteristics of the aneurysm other than size, patient age, the presence of symptoms from the aneurysm, and overall patient preference. Rigid application of this algorithm would be inappropriate. Treatment decisions are complex and require input from the patient and a multidisciplinary team. SAH, Subarachnoid hemorrhage; PCom, posterior communicating artery; Post Circ, posterior circulation.
<7 mm
Maximal diameter
7 mm
Location
Post circ or Pcom
Treatable with coil embolization
No
Other anterior circ Follow medically
Yes Endovascular coil embolization Surgical clipping
Although they debated in the past, most experts now agree that a ruptured aneurysm should be occluded as soon as possible. The risk of rehemorrhage is substantial in the first few days and the benefit of delaying surgery or endovascular treatment in terms of reduced complications appears to be limited. Thus, we perform angiography in all patients as soon as possible to confirm the location and define the anatomy of the aneurysm, and we strive to occlude all ruptured aneurysms within 24 hours of arrival. Similar to evidence for treatment of unruptured aneurysms, the data favor selection of coil embolization for treatment of most patients, with the same factors determining treatment modality as discussed earlier. A recent randomized trial also confirmed that patients treated with coil embolization were less likely to die or have major disability 1 year later compared to those treated with surgical clipping. Therefore, we typically prepare patients for possible coil embolization at the time of the initial angiogram. (We plan a consultation between the interventionalist, the treating neurologist, and our vascular neurosurgeon during imaging in the angiography suite so that all can contribute to the final treatment plan.) Complications from vasospasm, hyponatremia, fever/ infection, and heart failure are common after subarachnoid hemorrhage. Vasospasm is particularly devastating and difficult to manage. We maintain euvolemia with intravenous normal saline. We typically perform transcranial Doppler ultrasound daily in patients within 2 weeks of aneurysmal subarachnoid hemorrhage. At the earliest signs of vasospasm, detected as an increase in blood flow velocities, we induce hypertension
with phenylephrine (Neo-Synephrine) at a dose adjusted to maintain a main arterial pressure greater than 110 mm Hg. If the patient becomes symptomatic from vasospasm, blood pressure is elevated further and the patient is taken to the angiography suite where vasospastic vessel segments are treated with angioplasty or, for distal segments, with vessel-directed intra-arterial verapamil at a dose of 1 to 8 mg per vessel. Angioplasty generally produces an immediate and lasting improvement in blood flow, but response to verapamil is unreliable and more transient, so induced hypertension is generally continued. Hyponatremia from cerebral salt wasting should not be managed with fluid restriction since this may exacerbate vasospasm. Rather, it generally responds to supplemental sodium. We generally begin with oral sodium chloride at 1 to 2 gm three times a day and add 3% intravenous sodium chloride at 10 to 50 mL/h when oral repletion is inadequate. Although central fever is common after subarachnoid hemorrhage, infectious causes must be ruled out. We use antibiotics when fever occurs with either an elevation in white blood cell count or with a reduction in blood pressure, at least until cultures come back negative. We treat fever aggressively with antipyretics and cooling blankets since it is likely that fever itself worsens outcomes. Neurogenic heart failure may result in hypotension or respiratory compromise. We avoid diuresis in these patients given the risk of exacerbating vasospasm with hypovolemia, and we often continue to use pressors in spite of heart failure, changes on electrocardiogram, or
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even troponin elevation. It is rare that heart failure or evidence of myocardial injury is due to coronary artery disease in these patients, so the usual protocols for managing myocardial infarction are generally inappropriate. Heart failure generally improves over the first few days without specific therapy.
Arteriovenous Malformations
Although brain AVMs are rarer than aneurysms, their management is equally complex. Like aneurysms, they present with hemorrhage (usually intraparenchymal, sometimes with subarachnoid or intraventricular extension), seizures, or headaches, or they are detected incidentally in the work-up of other symptoms. Also, the management of those presenting with hemorrhage is quite different from those presenting with other symptoms, primarily because the short-term risk of hemorrhage is great after presentation with a hemorrhage (3% in the first month and 6% in the first year) compared with those presenting for other reasons (0.5% in the first month and 3% in the first year). As with aneurysms, the decision to follow the patient medically or treat with surgical resection or radiosurgery
is complicated and based, in part, on the subsequent risk of hemorrhage (Figure 2). Unfortunately, the evidence guiding these decisions is sparse, but several large-scale studies are underway and trials are planned. Although other scales have been developed, the Spetzler-Martin scale (scale in Figure 2) is the best studied, predicts risk of surgical complications well, and is important in considering the treatment options. We perform catheter angiograms in all patients with probable AVMs. This is essential for planning treatment. During angiography, we convene a multidisciplinary team to plan treatment. If surgical resection is considered the best option, we generally proceed with embolization of feeding vessels to reduce blood flow to the AVM. Also, since some studies have suggested that risk of hemorrhage is greater in those with an aneurysm associated with the AVM, we often attempt to treat any aneurysms with embolization if surgical resection is not planned. We do not consider embolization definitive treatment of an AVM, although there are rare instances when endovascular therapy is adequate to completely and permanently eliminate the AVM. Radiosurgery is an excellent choice for small AVMs that are high risk for surgery, but reduction in risk of hemorrhage is delayed 1 to 3 years after treatment.
FIGURE 2. Treatment algorithm for brain arteriovenous malformations. Evidence useful in guiding treatment decisions is sparse but is growing rapidly. This should be considered a loose framework and is not meant to substitute for detailed discussions between the patient and members of a multidisciplinary team. Other important characteristics of the patient or the arteriovenous malformation are likely to influence treatment decisions.
Spetzler-Martin grading scale [Total points from each category] Size <3 cm 36 cm >6 cm Location Arteriovenous malformation Noneloquent Eloquent Deep venous drainage Not present Present Hemorrhage Yes Spetzler-Martin score <4 0 1 0 1 1 2 3
No
No
Yes
Spetzler-Martin score <3
Yes
Surgical excision
No
Maximal diameter
<3 cm
Radiosurgery
3 cm
Follow medically
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Giant Cell Arteritis and CNS Vasculitis National Stroke Association http://www.stroke.org Brain Aneurysm Foundation http://www.bafound.org
Cavernous Malformations
An even rarer form of intracranial vascular malformation, these generally present with intraparenchymal hemorrhage or seizures, or they are discovered incidentally. The risk of first symptomatic hemorrhage is probably less than 1% per year, but the risk of recurrent hemorrhage is probably closer to 3% per year. However, the consequences of hemorrhage are generally more minor compared to AVMs. We generally do not recommend treatment for asymptomatic cavernous malformations. Cavernous malformations can be treated only with surgery and the risk of complications is strongly dependent on location. Consultation with a vascular neurosurgeon is essential in cases with prior symptomatic hemorrhage or with seizures due to the cavernous malformation.

This chapter reviews the diagnosis and treatment of both giant cell arteritis (GCA) and cerebral vasculitis.
Arteriovenous Fistulas
Arteriovenous fistulas are particularly rare and complex. They may present with cranial bruit/pulsatile tinnitus, headache, symptoms of raised intracranial pressure, focal neurologic symptoms from venous ischemia, or intraparenchymal hemorrhage. They tend to grow and become more unstable over time, so treatment is generally indicated. Endovascular therapy is often the best option: the fistula can usually be completely eliminated without complication by occlusion of the involved arteries, veins, or sinuses. For those who cannot be treated via an endovascular approach, surgery may be effective and is generally fairly safe. SUGGESTED READING
Bederson JB, Awad IA, Wiebers DO, et al: Recommendations for the management of patients with unruptured intracranial aneurysms, Circulation 102:2300-2308, 2000. Halim AX, Johnston SC, Singh V, et al: Longitudinal risk of intracranial hemorrhage in patients with arteriovenous malformation of the brain within a defined population, Stroke 35:1697, 1702, 2004. Johnston SC, Higashida RT, Barrow DL, et al: Recommendations for the endovascular treatment of intracranial aneurysms: a statement for healthcare professionals from the Committee on Cerebrovascular Imaging of the American Heart Association Council on Cardiovascular Radiology, Stroke 33:2536-2544, 2002. Molyneux A: International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial, Lancet 360:1267-1274, 2002. Ogilvy CS, Stieg PE, Awad I, et al: Recommendations for the management of intracranial arteriovenous malformations: a statement for healthcare professionals from a special writing group of the Stroke Council, American Stroke Association, Circulation 103:2644-2657, 2001. Wiebers DO, Whisnant JP, Huston J III, et al: Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment, Lancet 362:103-110, 2003.
Giant Cell Arteritis

EPIDEMIOLOGY GCA is a large-vessel vasculitis that typically affects older individuals, with an average age in the 60s or 70s, and an incidence that rises with age. Women are affected about three times more frequently than men, and whites have a higher rate than other racial groups. CLINICAL MANIFESTATIONS Typically, the symptoms of GCA develop gradually over a few weeks or months; however, some of the ocular manifestations (reviewed later) can have an abrupt or acute onset. The systemic features of GCA include a low-grade fever in up to half of individuals, with fatigue, myalgias, and weight loss (Figure 1). Polymyalgia rheumatica overlaps with GCA, occurring in about one half of patients, and GCA occurs in about 15% of patients with polymyalgia rheumatica. Other systemic features include tenosynovitis and distal extremity edema, nonproductive cough, or sore throat. Aortic aneurysm or dissection may occur in about 5%. The most common neurologic symptom is a new-pattern headache that develops in two thirds of patients. The headache tends to be frontal or frontotemporal, superficial, and associated with scalp tenderness. Thickening or tenderness of the scalp arteries may be described, and rarely scalp necrosis occurs. Jaw claudication is a stiffness of the muscles of mastication, usually developing after several minutes of chewing. Narrowing of the subclavian and axillary arteries can lead to arm claudication in 5% and may occur independently of any cranial involvement. The most dreaded and dramatic symptom is partial or complete loss of vision in one or both eyes, which affects 15% to 20%. The visual loss results from retinal ischemia from occlusion or thrombosis of the posterior ciliary arteries supplying the optic nerve. The ophthalmic artery can also be affected, either by vasculitis or by microemboli. Unlike the other symptoms that develop over weeks or months, visual
PATIENT RESOURCES
American Stroke Association http://www.strokeassociation.org
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Giant Cell Arteritis and CNS Vasculitis National Stroke Association http://www.stroke.org Brain Aneurysm Foundation http://www.bafound.org
Cavernous Malformations
An even rarer form of intracranial vascular malformation, these generally present with intraparenchymal hemorrhage or seizures, or they are discovered incidentally. The risk of first symptomatic hemorrhage is probably less than 1% per year, but the risk of recurrent hemorrhage is probably closer to 3% per year. However, the consequences of hemorrhage are generally more minor compared to AVMs. We generally do not recommend treatment for asymptomatic cavernous malformations. Cavernous malformations can be treated only with surgery and the risk of complications is strongly dependent on location. Consultation with a vascular neurosurgeon is essential in cases with prior symptomatic hemorrhage or with seizures due to the cavernous malformation.

This chapter reviews the diagnosis and treatment of both giant cell arteritis (GCA) and cerebral vasculitis.
Arteriovenous Fistulas
Arteriovenous fistulas are particularly rare and complex. They may present with cranial bruit/pulsatile tinnitus, headache, symptoms of raised intracranial pressure, focal neurologic symptoms from venous ischemia, or intraparenchymal hemorrhage. They tend to grow and become more unstable over time, so treatment is generally indicated. Endovascular therapy is often the best option: the fistula can usually be completely eliminated without complication by occlusion of the involved arteries, veins, or sinuses. For those who cannot be treated via an endovascular approach, surgery may be effective and is generally fairly safe. SUGGESTED READING
Bederson JB, Awad IA, Wiebers DO, et al: Recommendations for the management of patients with unruptured intracranial aneurysms, Circulation 102:2300-2308, 2000. Halim AX, Johnston SC, Singh V, et al: Longitudinal risk of intracranial hemorrhage in patients with arteriovenous malformation of the brain within a defined population, Stroke 35:1697, 1702, 2004. Johnston SC, Higashida RT, Barrow DL, et al: Recommendations for the endovascular treatment of intracranial aneurysms: a statement for healthcare professionals from the Committee on Cerebrovascular Imaging of the American Heart Association Council on Cardiovascular Radiology, Stroke 33:2536-2544, 2002. Molyneux A: International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial, Lancet 360:1267-1274, 2002. Ogilvy CS, Stieg PE, Awad I, et al: Recommendations for the management of intracranial arteriovenous malformations: a statement for healthcare professionals from a special writing group of the Stroke Council, American Stroke Association, Circulation 103:2644-2657, 2001. Wiebers DO, Whisnant JP, Huston J III, et al: Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment, Lancet 362:103-110, 2003.
Giant Cell Arteritis

EPIDEMIOLOGY GCA is a large-vessel vasculitis that typically affects older individuals, with an average age in the 60s or 70s, and an incidence that rises with age. Women are affected about three times more frequently than men, and whites have a higher rate than other racial groups. CLINICAL MANIFESTATIONS Typically, the symptoms of GCA develop gradually over a few weeks or months; however, some of the ocular manifestations (reviewed later) can have an abrupt or acute onset. The systemic features of GCA include a low-grade fever in up to half of individuals, with fatigue, myalgias, and weight loss (Figure 1). Polymyalgia rheumatica overlaps with GCA, occurring in about one half of patients, and GCA occurs in about 15% of patients with polymyalgia rheumatica. Other systemic features include tenosynovitis and distal extremity edema, nonproductive cough, or sore throat. Aortic aneurysm or dissection may occur in about 5%. The most common neurologic symptom is a new-pattern headache that develops in two thirds of patients. The headache tends to be frontal or frontotemporal, superficial, and associated with scalp tenderness. Thickening or tenderness of the scalp arteries may be described, and rarely scalp necrosis occurs. Jaw claudication is a stiffness of the muscles of mastication, usually developing after several minutes of chewing. Narrowing of the subclavian and axillary arteries can lead to arm claudication in 5% and may occur independently of any cranial involvement. The most dreaded and dramatic symptom is partial or complete loss of vision in one or both eyes, which affects 15% to 20%. The visual loss results from retinal ischemia from occlusion or thrombosis of the posterior ciliary arteries supplying the optic nerve. The ophthalmic artery can also be affected, either by vasculitis or by microemboli. Unlike the other symptoms that develop over weeks or months, visual
PATIENT RESOURCES
American Stroke Association http://www.strokeassociation.org
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FIGURE 1. Frequency of systemic symptoms in giant cell arteritis. (Data from Hayreh, Ocular Manifestations of GCA. Am J Ophthalmol 1998 Nov; 126(5):742-744.)
Headache Anorexia/weight loss Jaw claudication Malaise Myalgia Fever Abnormal temporal artery Scalp tenderness Neck pain Anemia 0 20 40 60 80 100
involvement typically has an abrupt onset with a painless partial field defect in one eye. This may progress to total blindness over hours and is a true neurologic emergency. If untreated, the second eye is likely to become involved within 7 to 10 days. Occult GCA refers to biopsy-proven GCA in patients presenting only with visual loss and, in some series, accounts for about 20% of cases. Thus, the absence of systemic symptoms does not exclude GCA. The different forms of visual involvement are reviewed in the following section. Nonocular central nervous system (CNS) ischemia can include transient ischemic attacks, vertigo, hearing loss, and stroke that usually results from vasculitis affecting the great vessels rather than from intracranial vasculitis. Examination should include a search for tender or thickened superficial temporal or other scalp arteries, which may be visibly swollen and erythematous; bruits over the carotid, axillary, or supraclavicular areas; and tenosynovitis. Ocular Manifestations of GCA Ocular manifestations of GCA include anterior ischemic optic neuropathy (AION) (76%), posterior ischemic optic neuropathy (PION) (6%), central retinal artery occlusion (CRAO) (13%), cilioretinal artery occlusion (25%), ophthalmic artery occlusion, and amaurosis fugax (26%), diplopia (7%), and ophthalmoplegia. Amaurosis fugax can be the only presenting visual symptom, suggesting that amaurosis fugax in persons older than 50 years of age should be considered a red flag for GCA. Other relatively rare but reported ocular manifestations include tonic pupil, Horners syndrome, ocular hypotony, chronic uveitis, episcleritis and scleritis, conjunctivitis, visual hallucinations, posterior chiasmal field loss, cortical blindness, and ocular ischemic syndrome. Of these diverse ocular manifestations, however, AION is clearly the most common, and the main clinical issue is differentiating AION from atherosclerotic or nonvasculitic causes of visual loss. Hayreh and associates have defined various features that can reliably differentiate vasculitic from nonvasculitic visual loss as follows: Vasculitic AION patients usually have worse visual loss than those with nonvasculitic AION.
Chalky white optic disk swelling is identified during the acute phase of vasculitic AION in about two thirds of eyes but is rare in a typical nonvasculitic AION. Optic disk swelling associated with cilioretinal artery occlusion is also strongly suggestive of a vasculitic AION but is uncommon in nonarteritic AION. Fluorescein angiography can define posterior ciliary artery occlusion in AION, which is another point of distinction from a nonvasculitic AION. DIFFERENTIAL DIAGNOSIS The symptoms, findings, or histopathology of polyarteritis nodosa, Wegeners granulomatosis, Takayasus arteritis, and other vasculitides can overlap with those of GCA; however, the distribution of lesions, histopathology, and organ involvement usually differs. Occasionally, however, these forms of necrotizing vasculitis can involve the temporal artery, mimicking GCA. Rarely, nonvasculitic disorders can mimic some of the major findings in GCA. For example, jaw or arm claudication occurs in patients with amyloidosis, and Lyme disease can mimic some of the systemic features of GCA. Laboratory Diagnosis The most helpful diagnostic abnormality with GCA is a very high erythrocyte sedimentation rate (ESR), which often reaches 100 mm/h (Table 1). A useful cut-off criterion for a normal ESR is less than 30 mm/h in men and less than 35 mm/h in women, with a sensitivity and specificity of 92%. Other acute-phase reactants may also be elevated, particularly C-reactive protein (CRP). Unlike ESR, CRP is not influenced by age, sex or anemia. Normal values are less than 0.5 mg/dL, and typically in GCA CRP is elevated by approximately 10-fold. The sensitivity and specificity of CRP in detecting GCA are 100% and 79% to 83%, respectively. Frequently a normochromic anemia is detected, with a reactive thrombocytosis. The leukocyte count and serum creatinine are usually normal, although microscopic hematuria occurs in one third of patients. Modest elevations in aspartate transaminase or alkaline phosphatase occur in 25% of patients. Fever, weight loss,
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TABLE 1 Diagnosis of Giant Cell Arteritis (GCA)

Considerations in a patient > 50 yr with the following: New-pattern headache with tenderness or decreased pulse in the superficial temporal artery Abrupt visual loss Symptoms of polymyalgia rheumatica Unexplained fever or anemia High erythrocyte sedimentation rate (>50 mm/h) High level of serum C-reactive protein (>2.5 mg/dL) Confirmation with the following: Arterial biopsy revealing a necrotizing arteritis with a predominance of mononuclear cells or a granulomatous process with multinucleated giant cells
Modified from: Hayreh SS, Podhajsky PA, Raman R, Zimmerman B: Giant cell arteritis: Validity and reliability of various diagnostic criteria. Am J Ophthalmol 1997 Mar;123(3):285-296.
specificity for GCA but relatively low sensitivity (50%). The results of ultrasonography have yet to change my recommendations for obtaining a diagnostic biopsy. Fluorescein fundus angiography is a helpful test to diagnose GCA early during a presentation with visual loss, revealing occlusion of one or more of the posterior ciliary arteries. TREATMENT The treatment of choice for GCA is systemic corticosteroids, which should always be carefully supervised by a practitioner experienced in the various manifestations of GCA and the potential complications of long-term corticosteroids. Intravenous (IV) methylprednisolone therapy (1000 mg/day for 3 to 5 days) should be used for high-risk patients presenting with acute visual symptoms including amaurosis fugax, monocular complete loss of vision, and early signs of involvement in the second eye. The objective is to try to prevent further visual loss. For all other patients with suspected GCA, prednisone 1 mg/kg/day orally should be initiated, with the aim of suppressing the vasculitis over several weeks of therapy, and then permitting a slow taper. Failure of corticosteroid therapy usually results from an overly rapid taper of prednisone. The fall in ESR and CRP values is the most helpful and reliable indicator, with CRP usually falling more rapidly than ESR, and CRP values normalizing within 2 to 3 weeks. High-dose steroids should then be maintained for 4 to 6 weeks, and then a slow taper begun. It can take many months to reach a low maintenance level of prednisone that adequately suppresses ESR and CRP, and the taper has to be individualized for each patient. Most patients with GCA continue to require small long-term maintenance doses in the 5- to 10-mg/day range for years. I avoid alternate-day prednisone, even though in other neurologic conditions it may be useful to reduce steroid complications. I usually recommend a proton pump inhibitor for most patients to prevent gastritis and peptic ulceration (omeprazole 20 mg twice daily). Trimethoprimsulfamethoxazole (Bactrim single-strength daily) should also be used for prophylaxis against Pneumocystis pneumoniae. Bone density should be determined with DEXA scan in all patients who will use corticosteroids on a long-term basis, and vitamin D and calcium should be prescribed. Daily low-dose aspirin is also recommended, although its benefits have not been proved to prevent retinal or cerebral ischemia in GCA. The role of steroid-sparing regimens is still debated, and both cyclosporine-azathioprine or cyclosporinemethotrexate combinations have been suggested as steroid-sparing regimens in steroid-refractory cases. One randomized, multicenter trial did not support the adjunctive use of methotrexate to control disease activity or to decrease the cumulative dose and toxicity of corticosteroids. However, alternate-day corticosteroids were used in this study, and I recommend methotrexate (starting with 0.15 mg/kg per week, up to a maximum of 0.25 mg/kg per week or 15 mg) with daily prednisone (at the lowest possible dose to control ESR and CRP) in patients who have not responded to steroids alone.
ESR greater than 85 mm/h, or a hemoglobin level less than 11 gm/dL reflect a strong initial systemic inflammatory reaction, and patients with these parameters tend to have greater and longer corticosteroid requirements, experience more disease flares during corticosteroid therapy, and have higher levels of interleukin 6 and tumor necrosis factor (TNF)-alpha than patients with weaker systemic acute-phase responses. Patients with a weaker acute phase inflammatory response appear to have a higher risk of developing cranial ischemic events and should thus be monitored closely for the development of cranial ischemic events. Temporal artery biopsy is mandatory in all cases of suspected GCA, except for those with a clinical diagnosis of pure polymyalgia rheumatica, who rarely have a positive temporal artery biopsy. Biopsy should be performed urgently (within 1 week), but the initiation of steroids should never be delayed (Figure 2). The yield is higher if a tender or swollen segment of the superficial temporal artery (STA) can be identified for biopsy, because inflammatory involvement is frequently patchy. It is critical to biopsy a sufficiently long (3- to 5-cm) segment of the temporal artery. Although bilateral temporal artery biopsy is recommended by some, the incremental increase in diagnostic yield is only 3% to 15%, especially if the clinical likelihood is low. In practice, I recommend sequential STA biopsies only if the suspicion of GCA is high and the initial biopsy is negative. The inflammatory infiltrate resolves only slowly over weeks even after initiation of steroids, so delaying the biopsy does not usually affect the histopathologic diagnosis. Hayreh has identified the following features as predictive of a negative biopsy: normal or only mildly elevated ESR (<40 mm/h), the absence of jaw claudication, the absence of STA tenderness, and the presence of synovitis. Various other diagnostic techniques have been proposed as useful in the diagnosis of GCA, but none have yet supplanted biopsy, which is considered the gold standard. Ocular pneumoplethysmography can detect reduced ocular blood flow and color-duplex ultrasound examination of the STA can detect stenoses, occlusions, and hypoechoic halo surrounding the lumen of the vessel. This last feature is thought to have a high
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Clinical suspicion of GCA High Low Review alternative causes ESR CRP Low High
Begin corticosteroids Stat ESR CRP Schedule TAB
Vision loss or transient symptoms Yes No Unilateral TAB Stop
Consider alternate causes for elevations in ESR CRP
Yes
No Unilateral TAB
IV steroids
Positive Bx: Strong inflammatory systemic response*
Positive Bx: Weak systemic inflammatory response*
Negative
Negative Low
Positive
Clinical suspicion?
Rx as GCA Remains high
Rx as GCA; monitor closely for relapse
Rx as GCA; Consider antiplatelet therapy Monitor closely for cranial ischemia
Consider contralateral TAB Review alternative causes
Positive
Negative No Clinical suspicion remains high
* Strong inflammatory response: fever, weight loss, ESR 85, Hgb <11.0 TAB = temporal artery biopsy
Yes Rx as GCA
FIGURE 2. Management of giant cell arteritis (GCA). ESR, Erythrocyte sedimentation rate; CRP, C-reactive protein; TAB, temporal artery biopsy; Bx, biopsy. (Modified from Lee AG, Brazis PW: Temporal arteritis and central nervous system vasculitis. In Johnson RT, Griffin JW, McArthur JC, editors: Current therapy in neurologic disease, ed 6, St. Louis, 2002, Mosby, 224.)
Folic acid (1 mg/day) should be used with methotrexate to prevent oral ulceration and anemia. For patients who remain uncontrolled with prolonged corticosteroids, or combination regimens, the newer anti-TNF-alpha agents infliximab and etanercept have been occasionally reported as useful adjunctive therapies. I have not personally used these agents, and their use remains experimental.
CNS Vasculitis
TERMINOLOGY CNS vasculitis can be classified as primary (primary angiitis of the CNS [PACNS]) when there is no underlying systemic disease or triggering condition present.
I prefer the term PACNS to indicate a small- or mediumsized vasculitis affecting both arteries and veins in the parenchyma and leptomeninges. When pathologically confirmed, the term histologically defined angiitis of the CNS (HDACNS) can be used, and when angiographically defined, angiographically defined angiitis of the CNS (ADACNS). This latter subgroup tends to manifest a milder disease course and is occasionally termed benign angiopathy (as opposed to angiitis) of the CNS (BACNS). Because the course is not always benign, I prefer to avoid this terminology. Obviously, this distinction is probably an artificial one, reflecting differences in disease course and prognosis rather than true pathophysiologic variability. Other alternative terminologies, which should probably no longer be used, include isolated angiitis of the CNS (IACNS), or granulomatous angiitis of the CNS (GACNS), which
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highlights a pathologic feature of the disease seen in a subset of cases. Other primary CNS vasculitides, which are not discussed here, include Cogans syndrome (nonsyphilitic interstitial keratitis and bilateral audiovestibular deficits), Susacs syndrome (a microangiopathy affecting young women with involvement of brain, retina, and inner ear), Eales disease (primary retinal vasculitis), and primary spinal cord arteritis. Secondary vasculitis of the CNS is more common and can be one part of a variety of systemic illnesses including generalized autoimmune diseases such as systemic lupus erythematosus (SLE), Sjgrens syndrome, and a variety of systemic vasculitides such as Wegeners granulomatosis, polyarteritis nodosa, and others (Table 2). Intravascular lymphoma can mimic PACNS. Secondary CNS vasculitis can also be caused by a reaction to drugs such as amphetamines, heroin, cocaine, and over-thecounter cold preparations containing sympathomimetics such as ephedrine (recently banned by the U.S. Food and Drug Administration [FDA]) and phenylpropanolamine. EPIDEMIOLOGY OF CNS VASCULITIS The epidemiology of cerebral vasculitis has not been systematically studied. There is a slight male predominance (4:3) for PACNS, and the mean age is 42 years, but the range is very wide and young children and the elderly can be affected. In contrast, patients with ADACNS tend to be young women, often those with previous histories of migraines. These patients often have had heavy nicotine or caffeine use, over-the-counter cold remedies or appetite suppressants, and oral contraceptive or estrogen replacement therapy, but the precise relationship (if any) of these exposures to the development of ADACNS remains unclear. Some viral infections have been linked to the development of CNS vasculopathy. Herpes zoster (HZ) varicella has clearly been associated with a cerebral vasculopathy and
delayed contralateral hemiplegia developing after HZ ophthalmicus (cerebral angiitis). These patients tend to be older than PACNS patients. Human immunodeficiency virus (HIV) has been associated with a cerebral vasculopathy, particularly in children; however, it remains unclear whether this is a direct effect of HIV on the vessels. Other infectious agents commonly associated with cerebral vessel involvement include Aspergillus, syphilis, borrelia burgdorferi, Bartonella, typhus, Rocky Mountain spotted fever, and tuberculosis. CLINICAL FEATURES OF PACNS The clinical manifestations of PACNS include a wide range of neurologic symptoms and signs, such as nonspecific headache, focal weakness, seizures, intracranial hemorrhage, confusion, disorders of memory and cognition, and altered consciousness (Table 3). HDACNS tends to present more commonly with diffuse encephalopathy than does ADACNS. HDACNS patients are more likely to develop symptoms subacutely over months (with a mean of 170 days in one series), whereas an acute presentation is more typical of ADACNS (with a mean of 46 days in one series). Without treatment, patients with PACNS tend to have a progressively downhill course that is usually fatal. The spinal cord can be involved by transverse myelitis, spinal cord stroke, or hemorrhage. Most of these symptoms and signs are nonspecific and can overlap or mimic other conditions. These include atherosclerotic strokes, Lyme disease, viral encephalitides, brain tumor, tuberculosis and fungal meningitis, histoplasmosis, migraine, and multiple sclerosis. SLE, Wegeners granulomatosis, and polyarteritis nodosa cause CNS vasculitis or vasculopathy frequently, but scleroderma, Sjgrens syndrome, Behets disease, or rheumatoid arthritis are unusual causes. Cerebral amyloid angiopathy both can mimic PACNS and coexist. Disseminated intravascular
TABLE 2 Classification and Selected Clinical Features of Vasculitis

Type Polyarteritis nodosa Wegeners granulomatosis Temporal (giant cell) arteritis Takayasus arteritis Primary angiitis of the CNS Hypersensitivity vasculitis* Vasculitis with connective tissue disease (e.g., SLE, rheumatoid arthritis) Churg-Strauss syndrome Lymphomatoid granulomatosis Buergers disease Cogans syndrome Behets syndrome Vasculitis associated with malignancy Relapsing polychondritis Vessels Involved Small muscular arteries Small and medium arteries; veins Large elastic arteries Aorta and main branches Arterioles, capillaries Capillaries, venules Small muscular arteries, capillaries; venules Small and medium arteries, veins Small arteries Arterioles, veins Aorta, arterioles Arterioles, veins Capillaries, veins Arterioles Target Tissues Kidney, nerve, gut, heart Sinus, lung, kidney Eye; brain less common Heart, brain, skeletal muscle Brain Skin, kidney, gut, nerve Skin, lung, kidney Skin, lung, brain Skin, digits, muscles Eye, cochlea, heart Mouth, genitals, eye, brain Skin Ear, trachea, eye
*Includes serum sickness, Henoch-Schnlein purpura, and cryoglobulinemia. CNS, Central nervous system; SLE, systemic lupus erythematosus. (Modified from Hellmann DB: Vasculitis. In Stobo JD, Traill TA, Hellman DB, et al, editors: The principles and practice of medicine, ed 23, New York, 1996, McGraw-Hill Medical, 216.)
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TABLE 3 Cerebral Vasculitis: Suggested Clinical Patterns of Presentation that Might Facilitate Recognition
Primary Finding Acute or subacute encephalopathy Intracranial mass lesion Superficially resembling atypical multiple sclerosis (MS plus) in phenotype Symptoms Associated with Finding Headache and an acute confusional state progressing to drowsiness and coma Headache, drowsiness, focal signs and (often) raised intracranial pressure Relapsing-remitting course and features such as optic neuropathy and brainstem episodes, but also accompanied by other features less common in multiple sclerosis (e.g., seizures, severe and persisting headaches, encephalopathic episodes or hemispheric strokelike episodes)
Adapted from Scolding NJ, Jayne DR, Zajicek JP, et al: Cerebral vasculitis: Recognition, diagnosis, and management, Q J Med 90:61-63, 1997.
lymphoma also can mimic PACNS and requires biopsy for exclusion. Unlike other vasculitides, in PACNS systemic symptoms such as fever, weight loss, arthralgias, or myalgias are uncommon. Serologic evidence of inflammation or detectable autoantibodies are typically absent. DIAGNOSIS OF PACNS (TABLE 4) In PACNS, the cerebrospinal fluid (CSF) is frequently abnormal, with nonspecific elevations in protein and a mononuclear pleocytosis, but is normal frequently enough to be useful only to exclude other conditions. Oligoclonal bands may be detectable but are not specific. In one series, lumbar puncture was abnormal in about half of cases with angiographically proven PACNS, with a sensitivity of only 53%. Noninvasive tests have limited sensitivity and specificity in the diagnosis of PACNS. Magnetic resonance (MR) imaging is the most sensitive neuroimaging test and is abnormal in more than 80% of patients with PACNS. MR imaging had a sensitivity of 75% in one series but can be normal even in cases of PACNS when the angiogram is positive. The radiologic appearance of PACNS can range from scattered supratentorial and infratentorial FLAIR hyperintensities, areas of hemorrhage, diffuse-weighted positive areas of infarction, or leptomeningeal enhancement. In a careful comparison of MR imaging and angiograms, Pomper and colleagues found that all patients with angiographically confirmed CNS vasculitis had abnormalities on MR studies, with an average of four detectable lesions. In order of frequency, lesions were located in the subcortical
white matter, cortical gray matter, deep gray matter, deep white matter, and cerebellum. Only 65% of MR lesions were evident on angiograms; 44% of the lesions revealed on angiograms were detected by MR. This only modest correlation between the two imaging modalities suggests that both should always be performed because they provide different information about CNS vasculitis. FLAIR and diffusion-weighted scans should always be performed since these sequences increase the sensitivity in PACNS. The diagnosis of PACNS is uncommon when both the lumbar puncture and the MR imaging study are normal. MR angiograms are not sufficiently sensitive at this time to recommend in place of conventional angiograms, especially since they typically do not display the vessels most affected in PACNS. However, the resolution of the technique is improving rapidly, and recent experience suggests that MRA may disclose multiple focal or diffuse vessel narrowing, irregularities of vessel diameter or stenosis, or even occlusion. Currently, I do not recommend supplanting conventional angiography with MR angiography. The morbidity from angiogram is about 0.2%-1.0% for permanent injury. A typical angiographic appearance in PACNS shows beading with alternating stenosis and dilation. The middle and anterior cerebral arteries are most commonly affected. The appearance, however, suggests the diagnosis but is not always specific and can easily be mimicked by severe hypertension, atherosclerotic changes, or the effects of radiation, amphetamine, or cocaine. Hellman and coworkers have studied the sensitivity of the angiogram and found that it appears to range from 50% to 80%. Cerebral biopsy is warranted, even in the presence of a highly suspicious angiogram. Even though the quoted sensitivity of brain biopsy is only 75%, brain biopsy is essential in most adults with suspected PACNS to both secure the underlying diagnosis of vasculitis and to rule out mimicking conditions. The only exception is a patient with mild neurologic deficits and a relatively acute presentation who thus likely fits the ADACNS category and who could therefore be managed without biopsy. In one series of 61 consecutive patients suspected of having PACNS biopsies disclosed PACNS in 22 (36%), alternative diagnoses in 24 (39%), and were nondiagnostic in 15 (25%). Clinical indicators and angiography do not usually predict the histologic finding of PACNS.
TABLE 4 Criteria that Establish the Diagnosis of PACNS

Clinical picture of headaches and multifocal neurologic deficits present for at least 6 months, unless the onset is devastating Cerebral angiography demonstrating several areas of segmental arterial narrowing Exclusion of systemic malignancy, inflammation, or infection Leptomeningeal/parenchymal biopsy demonstrating vascular inflammation and to exclude infection, atherosclerosis, and neoplasia
PACNS, Primary angiitis of the central nervous system.
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Attention to detail in planning the biopsy is critical to maximize the diagnostic yield: (1) lesions identified on MR imaging should be biopsied whenever feasible; (2) leptomeningeal tissue should be obtained along with parenchyma; and (3) a blind biopsy not guided by an identifiable MR lesion should include both leptomeninges and cortex from the nondominant frontal or temporal lobes. Although the gold standard is histologic confirmation, a recent review (1992) by Calabrese and associates (see Suggested Reading) suggests that nearly one in four biopsy procedures results in a false-negative outcome. TREATMENT OF PACNS The optimal therapy of PACNS has not been systematically established, and most patients are treated with prednisone and cyclophosphamide based on a small uncontrolled series from 1983. HDACNS cases with a fulminant or progressive course should be treated with high-dose IV corticosteroids (15 mg/kg IV methylprednisolone or 3 mg/kg IV dexamethasone) for 5 days, followed by oral prednisone 1 mg/kg/day. Patients with HDACNS require aggressive therapy with high doses of prednisone and cyclophosphamide. Currently recommended doses include prednisone, 1 mg/kg/day, and cyclophosphamide, 2 mg/kg/day; the prednisone dosage is maintained until the disease is brought under control clinically, then tapered off. The cyclophosphamide is continued for about 1 year after clinical control has been achieved. Doses of the latter drug should be adjusted to keep the total white blood cell count higher than 3000 to 4000 and the absolute neutrophil count higher than 1000 to 1500. These drugs are generally administered for 6 to 12 months and require meticulous follow-up to assess benefit and avoid side effects. Intermittent pulses of IV cyclophosphamide may be used in patients who are unable to reliably take daily oral cyclophosphamide or who are at high risk of hemorrhagic cystitis or bladder cancer (stones, frequent infections, indwelling catheters). For patients with normal renal function, I recommend an initial dose of cyclophosphamide of 750 mg/m2 of body surface area (BSA). To reduce toxicities, this initial dose should be reduced to 500 mg/m2 BSA in obese patients or those older than 70 years of age. The side effects of corticosteroids include obesity and a cushingoid appearance, hyperglycemia, thinning of skin and bones, orogenital candidiasis, glaucoma and cataracts, peptic ulceration and gastric irritation, and an increased risk of infections such as P. pneumoniae, Listeria monocytogenes meningitis, tuberculosis, and cryptococcal meningitis. In utero exposure to corticosteroids is to be avoided, especially during the first trimester, because of the increased risk of cleft palate. The FDA rates the risk of prednisone in pregnancy as B (no evidence of human risk). The side effects of cyclophosphamide include neutropenia, transaminitis or drug-induced hepatitis, rarely cardiomyopathy or pulmonary fibrosis, increased risk of infections, bladder cancer, and hemorrhagic cystitis. The latter complication may be reduced by hydration, treatment of infections, and the use of
monthly pulse cyclophosphamide with mercaptoethane sulfonate (mesna [Mesnex]) to prevent hemorrhagic cystitis by reacting with acrolein and other urotoxic metabolites of oxazaphosphorines to form stable, nonurotoxic compounds. The dose of mesna is expressed as a percentage of the cyclophosphamide dose: as a continuous infusion 20% IV immediately prechemo, then 50% to 100% with chemo, then 25% to 50% for 12 hours following chemotherapy. During pregnancy there have been reports of intrauterine growth restriction, delayed development, premature closure of cranial sutures, blepharophimosis, ear abnormalities, abnormal number or shape of digits, and coronary artery abnormalities. There may also be an increased risk of carcinoma for children exposed in utero. Breastfeeding should be avoided while taking cyclophosphamide. The FDA rates the risk of cyclophosphamide use in pregnancy as D (positive risk during pregnancy). Cyclophosphamide can have significant drug interactions with drugs that induce hepatic microsomal enzymes
TABLE 5 Specific Monitoring Checklist for the Safe Use of Corticosteroids and Cyclophosphamide for Therapy of PACNS
Frequency of Administration Corticosteroids Daily Factors to Monitor
Weekly Bimonthly Annually PRN
Self-check for fever, GI bleeding, or infections: PCP prophylaxis with Bactrim (single-strength daily) and calcium/vitamin D. Maintain birth control measures. (Alternatives for Bactrim-allergic patients: dapsone or aerosolized pentamidine monthly) Weights, instruct patients to self-check for orogenital candidiasis Vital signs, CBC, chemistry panel, fasting glucose or HgbA1C Ophthalmology check for cataracts and glaucoma, DEXA scan for bone density, PPD for tuberculosis After trauma, with infections or surgery: consider additional doses of stress corticosteroids
Cyclophosphamide Daily Self-check for fever, oral ulcerations, hematuria, or infections: PCP prophylaxis with Bactrim. Maintain birth control measures. Take cyclophosphamide in morning with full glass of water, and empty bladder before sleeping Monthly Vital signs, CBC/differential, chemistry panel, transaminases, and urinalysis prior to surgery; warn anesthesiologist about prolonged neuromuscular blockade with succinylcholine
PACNS, Primary angiitis of the central nervous system; GI, gastrointestinal; PCP, Pneumocystis carinii pneumonia; CBC, complete blood count; HgbA1C, hemoglobin A1C; PPD, purified protein derivative.
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(e.g., barbiturates, phenytoin, rifampin, alcohol), which can accelerate the metabolism of cyclophosphamide into its active metabolites, in turn increasing both the pharmacologic and toxic effects. By contrast, drugs that inhibit the hepatic metabolism (e.g., corticosteroids, antimalarials, allopurinol, tricyclic antidepressants) slow the conversion of cyclophosphamide to its active metabolites, and thus may decrease both therapeutic and adverse effects. Tricyclic antidepressants and other anticholinergic agents reduce bladder emptying and can prolong bladder exposure to the toxic metabolite acrolein. Cyclophosphamide reduces plasma pseudocholinesterase activity; thus, coadministration or subsequent use of succinylcholine may lead to prolonged neuromuscular blockade. Cyclophosphamide has negative effects on fertility both in women and men and can induce premature menopause. Sperm can be banked or eggs stored prior to the initiation of cyclophosphamide. Table 5 lists the minimum monitoring by patient and physician required for patients receiving these agents. The treatment of ADACNS is similarly not well defined, and it is unclear whether these patients require as intensive a regimen of immunosuppressive agents as patients with HDACNS. Some have advocated treatment with calcium channel blockade and shorter courses of prednisone, but again, treatment should be individualized based on response and situation. Unproven treatments for PACNS include (plasmapheresis), mycophenolate, or IV gamma globulin. Neurologists who do not use immunosuppressive agents regularly should consult with a practitioner who does. Blood tests for blood cell count and liver function should be checked monthly, and the patients should be instructed to monitor temperatures daily for signs of infection. Precautions for maintaining bone density and preventing P. carinii pneumonia were discussed earlier.
One of the most difficult aspects of managing PACNS is judging when to reduce (or increase) the immunosuppressive regimen. Unlike the situation in GCA, there are no serologic markers that can be followed, and even serial CSF analysis or cranial MR imaging is insensitive to changes. Ultimately, clinical judgment has to prevail based on the neurologic symptoms and signs. SUGGESTED READING
Calabrese LH, Duna GF, Lee JT: Vasculitis in the central nervous system, Arthritis Rheum 40:1189-1201, 1997. Calabrese LH, Furlan AJ, Gragg LA, et al: Primary angiitis of the central nervous system: diagnostic criteria and clinical approach, Cleve Clin J Med 59:293-306, 1992. Hayreh SS, Podhajsky PA, Raman R, Zimmerman B: Giant cell arteritis: validity and reliability of various diagnostic criteria, Am J Ophthalmol 123(3):285-296, 1997 Mar. Hunder GG, Bloch DA, Michel BA, Stevens MB, et al: The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum 33:1122-1128, 1990. Meskimen S, Cook TD, Blake RL Jr: Management of giant cell arteritis and polymyalgia rheumatica, Am Fam Physician 61: 2061-2068, 2000. Pomper MG, Miller TJ, Stone JH, Tidmore WC, et al: CNS vasculitis in autoimmune disease: MR imaging findings and correlation with angiography. American Journal of Neuroradiology 20(1):75-85, 1999. Stone JH, Pomper MG, Roubenoff R, Miller TJ, et al: Sensitivities of noninvasive tests for central nervous system vasculitis: a comparison of lumbar puncture, computed tomography, and magnetic resonance imaging. J Rheumatol 21(7):1277-1282, 1994.
PATIENT RESOURCES
Johns Hopkins Vasculitis Center http://vasculitis.med.jhu.edu/typesof/cns.html http://www.blackandwhite.org/savvy/index.shtml A Savvy Vasculitis: The Medzine for Contact, Info, and Opinion http://www.niams.nih.gov/hi/topics/polymyalgia
SECTION 10
Trauma
Anthony S. Burns, M.D., and Michael E. Selzer, M.D., Ph.D.
8 hours of injury. It is administered as an intravenous bolus (30 mg/kg) over 15 minutes, followed by a 45-minute pause, then a continuous drip (5.4 mg/kg/hr) for 23 hours. The National Acute Spinal Cord Injury Study (NASCIS) III advocated 48 hours, but this practice is not as widespread. NEUROLOGIC ASSESSMENT Spinal cord injury (SCI) affects approximately 11,000 U.S. residents annually and has a prevalence of 250,000. There is a 4:1 male-to-female ratio, and the average age at injury is 32.6 years. Acute treatment focuses on supportive care and the prevention of secondary complications. A thorough neurologic assessment should be performed as soon as possible. The accepted instrument is the International Standards for the Neurological Classification of SCI devised by the American Spinal Injury Association (ASIA) (http://www.asia-spinalinjury.org/home/index.html) in 1982 and adopted by the International Spinal Cord Society in 1992. Assessment involves evaluating clinical completeness, assigning motor and sensory scores, assigning motor and sensory levels, and designating an ASIA impairment grade (Figure 1). RESPIRATORY DYSFUNCTION All individuals with complete SCI above C3 will be ventilator dependent. Below C3, most will become ventilator independent, but many require temporary ventilator support. Cervical injuries not initially intubated should be followed with vital capacities every 6 to 8 hours during the first few days. Intubation should be performed for rapidly diminishing vital capacities or values consistently below 10 to 15 mL/kg of ideal body weight. In cervical and high thoracic injuries, expiratory flow rates are inadequate for coughing. Sympathetic innervation to the lungs is compromised, but vagal parasympathetic innervation remains intact. This results in airway hyper-reactivity and increased secretion production, requiring bronchodilators, mucolytic agents (i.e., guaifenesin), chest physiotherapy, and assisted coughing. The latter involves either compressing the costophrenic margin or exerting upward pressure inferior to the xyphoid process timed with expiration. The In-Exsufflator (J.H. Emerson Co., Cambridge, MA) is a device that rapidly generates positive pressures of +40 mm Hg followed by a rapid reversal of airflow to 40 mm Hg accompanied by the removal of airway secretions. Most patients prefer it to endotracheal suctioning, and it can be attached to an endotracheal or tracheotomy tube or used with a mouthpiece. Incentive spirometry 241
Acute Medical Management

IMMOBILIZATION/SPINE STABILITY Care of traumatic SCI begins in the field. The patient should be immobilized on a board, the spine in natural alignment, the cervical spine immobilized with sand bags or similar devices, and the patient transported immediately to a level-1 trauma center with SCI expertise. Sixteen model SCI centerswith capabilities for acute medical management, rehabilitation, and lifelong followupare funded by the National Institute for Disability and Rehabilitation Research (http://www.ncddr.org/ rpp/hf/hfdw/mscis/map.html). In the emergency department, medical stability should be assessed and resuscitation performed. The entire spine should be surveyed by radiograph and, if possible, computed tomography (CT), to identify regions of mechanical instability. Magnetic resonance (MR) imaging should be performed if there are neurologic deficits or suspected ligamentous injuries. Consultation should be obtained promptly from a spine surgeon. A Rotorest bed, which employs belts/straps and bolsters, can be used temporarily to achieve spine immobilization. The turning feature provides postural drainage for pulmonary secretions while avoiding pressure sores. Time spent in this bed should be minimized. METHYLPREDNISOLONE Although the efficacy of methylprednisolone treatment has been questioned, most trauma centers continue to administer it to patients presenting within
242
STANDARD NEUROLOGICAL CLASSIFICATION OF SPINALCORD INJURY MOTOR

LIGHT TOUCH PIN PRICK
SENSORY
KEY SENSORY POINTS
C2 C3
KEY MUSCLES
0 = absent 1 = impaired 2 = normal NT = not testable

C2 C3 C4 T2 C5 T2
C4
C5
S 3 S45 C6
T1
T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 Palm L1
T1 C6
L 2 S2 L 3 L 3 S2
L 2
Palm
L2
L2
C6
C7 C8 7 C6
C8 C7
L3 Dorsum L 4 S1 L 4 S1
L3 Dorsum
L4 L5 L5 L5
L4 L5
*Key Sensory Points

S1 S1 S1
C2 C3 C4 C5 C6 C7 C8 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 L4 L5 S1 S2 S3 S4-5

Any anal sensation (Yes/No) + +
(56) (56)
C2 C3 C4 Elbow flexors C5 Wrist extensors C6 Elbow extensors C7 Finger flexors (distal phalanx of middle finger) C8 Finger abductors (little finger) T1 T2 0 = total paralysis T3 1 = palpable or visible contraction T4 2 = active movement, T5 gravity eliminated T6 3 = active movement, T7 against gravity T8 4 = active movement, T9 against some resistance T10 5 = active movement, T11 against full resistance T12 NT = not testable L1 Hip flexors L2 Knee extensors L3 Ankle dorsiflexors L4 Long toe extensors L5 Ankle plantar flexors S1 S2 S3 Voluntary anal contraction (Yes/No) S4-5
TOTALS
+
MOTOR SCORE
TOTALS
= =
(max: 112) (max: 112)
(MAXIMUM) (50)
(50)
(100)
PIN PRICK SCORE LIGHT TOUCH SCORE
(MAXIMUM) (56) (56)
COMPLETE OR INCOMPLETE?
Incomplete = Any sensory or motor function in S4-S5
NEUROLOGICAL LEVEL
The most caudal segment with normal function
SENSORY MOTOR
ZONE OF PARTIAL PRESERVATION ASIA IMPAIRMENT SCALE

Caudal extent of partially innervated segments
SENSORY MOTOR
2000 Rev.
This form may be copied freely but should not be altered without permission from the American Spinal Injury Association.
FIGURE 1. Standard neurologic classification of spinal cord injury.
243
Trauma
should also be employed in ventilator-independent patients.
rehabilitation setting. If the neurologic deficits are minimal and the patient will be discharged home, adequate bladder emptying should be documented by checking two or three postvoid residuals. PRESSURE ULCER PREVENTION Pressure ulcers are devastating but largely preventable. Risk is assessed at admission using the Braden scale (range, 6 to 23). Patients with complete paralysis score as high risk (< 12 points) and warrant a low-airloss mattress. All paralyzed patients must be turned/ repositioned every 2 hours. Special attention must be paid to dependent areas, especially the heels, sacrum, scapulae, occiput, and greater trochanters. Adequate nutrition is crucial, and weekly determination of albumin/prealbumin can help direct therapy. Once a pressure ulcer is present, obtain wound care consultation promptly.
DEEP VEIN THROMBOSIS PROPHYLAXIS AND CARDIOVASCULAR COMPLICATIONS

Deep vein thrombosis (DVT) and pulmonary embolism are among the most feared acute complications. Without prophylaxis, most individuals with complete motor paralysis develop DVT. According to Paralyzed Veterans of America guidelines (http://www.pva.org/ res/cpg/sci_index.htm), individuals with significant weakness should be given subcutaneous heparin 5000 units twice daily. In cases of complete paralysis, low-molecularweight heparin is preferable. Prophylaxis should continue for the duration of hospitalization or 2 months in uncomplicated cases3 months if additional risk factors are present, such as leg fractures, prior thrombosis, cancer, heart failure, obesity, or age older than 70 years. Pharmacotherapy should be supplemented with intermittent pneumatic leg compression for the first 2 weeks and compression stockings thereafter. If pharmacologic prophylaxis is contraindicated, the legs should be screened weekly by ultrasound and placement of an inferior vena cava filter should be considered in high-risk cases. Because cervical injuries lead to autonomic imbalance with parasympathetic dominance, patients are susceptible to vagal episodesbradycardia, transient third-degree heart block, or even asystole. Episodes can be triggered by benign events such as endotracheal suctioning or repositioning. Atropine reverses the vagal symptomatology and should be kept at the bedside. The episodes rarely persist beyond 3 to 6 weeks. If they do, or become life threatening, a pacemaker should be implanted. Acute neurogenic hypotension can also occur and should be managed with pressors, not fluids. NEUROGENIC BOWEL AND BLADDER DYSFUNCTION Gut transit times are prolonged in SCI, often resulting in severe constipation or impaction. Volitional control of defecation is often lost. A neurogenic bowel program should be initiated when enteral nutrition is started. A reasonable program includes one capsule of docusate sodium (stool softener) two or three times a day, two tablets or 15 mL of liquid senna (promotility agent) at noon, and a bisacodyl suppository nightly. Stool softener can be excluded in subjects on liquid nutrition (i.e., gastrostomy tube) and an enema can be substituted for the suppository if more than 2 days have passed without a significant stool. In patients with cauda equina or conus medullaris injuries, an enema should be substituted for the suppository. Stress ulcer prophylaxis also must be administered (e.g., ranitidine 300 mg at bedtime). Urinary retention is common early in SCI. An indwelling catheter should be maintained and urine output monitored until the patient is transferred to a
Mobilization and Rehabilitation

INITIAL MOBILIZATION Physical therapy (PT) and occupational therapy (OT) should be consulted as soon as range-of-motion (ROM) exercises for the extremities are medically feasible, even in the intensive care unit. Early involvement by PT/OT also provides ongoing education to the patient and family regarding the injury and the rehabilitation process. Upright positioning in bed and sitting should be initiated as soon as adequate spine stabilization is achieved. The spine surgeon should provide specific instructions regarding precautions. This is particularly important when bracing is involved (e.g., whether the brace is required when supine or sitting in bed). Precautions, such as allowed ROM and weight bearing, also must be specified for accompanying extremity injuries. To avoid orthostatic hypotension, the head of the bed should be gradually elevated to 70 to 90 degrees while monitoring blood pressure before sitting or standing. Compression stockings (thigh or knee high) or ace wrappings diminish blood pooling in the legs. An elastic abdominal binder can be employed in early stages to counteract pooling in splanchnic vessels. If conservative measures fail, midodrine, an alpha-adrenergic agonist, or fludrocortisone, an aldosterone-like mineralocorticoid, can be used. INPATIENT REHABILITATION/ OUTPATIENT FOLLOW-UP Early consultation should be obtained from a medical rehabilitation specialist, who can assist with assessing injury severity, managing medical issues specific to SCI, and decision making about rehabilitation. Most patients benefit from inpatient rehabilitation in a Commission on the Accreditation of Rehabilitation Facilities (CARF)-accredited SCI program. Less intensive options are subacute and skilled nursing facilities. 10
244
TABLE 1 Regimen for Acute Autonomic Dysreflexia

Sit patient up at 90 degrees. Monitor blood pressure q 3 min. Check urine collection system or catheterize the bladder using lidocaine gel. Look for source of noxious stimulation. Examine rectum with topical anesthetic and remove feces. If systolic blood pressure > 170 mm Hg, apply 1 inch of transdermal nitroglycerin ointment (Nitropaste) above spinal level. If no change, give nifedipine 10 mg; repeat in 10 min as needed; monitor for hypotension. Start IV fluids if there is no change. If hypertension and symptoms persist, give nitroglycerin 0.4 mg sublingual or hydralazine 10 mg IV. If no change, give diazoxide 100 mg or labetalol 20 mg IV for a longer effect. For prophylaxis, give prazosin 5 mg PO up to tid.
Adapted from Dobkin BH: The clinical science of neurologic rehabilitation, ed 2, New York, 2003, Oxford University Press.
AUTONOMIC DYSREFLEXIA Patients with a neurologic level above T7 are at risk for life-threatening episodes of hypertension (autonomic dysreflexia). Other signs and symptoms include severe headache, increased spasticity, sweating, blurred vision, nasal congestion, piloerection, facial flushing, bradycardia, and general apprehension. Any noxious stimulus can trigger episodes, but the leading causes are bladder distention and bowel impaction. A good regimen for treating acute autonomic dysreflexia is given in Table 1. SUGGESTED READING
Dobkin BH: The clinical science of neurologic rehabilitation, ed 2, New York, 2003, Oxford University Press. Lin VW, Cardenas DD, Cutter NC, et al: Spinal cord medicine: principles and practice, New York, 2003, Demos.
PATIENT RESOURCES
National Spinal Cord Injury Association 8300 Coleville Road, Suite 551 Silver Spring, MD 20910 http://www.spinalcord.org
Following inpatient rehabilitation, outpatient followup is important. CARF-accredited programs must have a mechanism for long-term follow-up. Individuals with cervical or high thoracic injuries are at increased risk for pulmonary complications and should be vaccinated for Pneumococcus every 10 years and influenza annually.
National Spinal Cord Injury Hotline 2200 Kernan Drive Baltimore, MD 21207 Email: scihotline@aol.jcom The Miami Project to Cure Paralysis P. O. Box 016960, Mail Locator R-48 Miami, FL 33101 http://www.miamiproject.miami.edu
Long-Term Management
In addition to the complications discussed earlier, many issues become prominent once patients are home, including urologic complications, spasticity, chronic pain, sexual dysfunction, and autonomic dysreflexia. The reader is referred to specialized texts such as those listed in Suggested Reading at the end of this chapter. UROLOGIC AND SEXUAL DYSFUNCTION Voiding abnormalities, such as detrussor-sphincter dyssynergy, high-pressure voiding, and ureteral reflux, can be clinically asymptomatic. Therefore, injured individuals should be screened annually by a rehabilitation specialist or urologist. Men can have brief, reflexive erections with stimulation. Ejaculation is often retrograde or absent. Sildenafil strengthens and prolongs erections in SCI. Because of susceptibility to hypotension, a dosage of 25 mg should be tried before advancing to 50 mg. Male fertility often declines rapidly after SCI. Within the first year, it is reasonable to obtain and freeze semen for future use. Ejaculation can be induced by either vibratory or electrical stimulation. Women with SCI can become pregnant, and impaired lubrication is addressed with artificial supplements.

Peripheral nerve injury may result from sudden crushing blunt forces, stretch, transsection, or chronic compression. When confronted with a peripheral nerve injury, the physician must locate the precise site of the lesion, determine its severity, evaluate for spontaneous regeneration, and confirm the mechanism of injury and how much time has elapsed since the injury.
Determining the Site of the Lesion

The lesion should be localized to the spinal nerve root, plexus, nerve, or one of its branches, and there may be more than one lesion. One can determine the distance from the site of the injury to its target end organs. Spontaneous recovery from peripheral nerve injury is both time and distance dependent. Nerve fibers regenerate at a rate of approximately 1 mm/day. Earlier and
244
TABLE 1 Regimen for Acute Autonomic Dysreflexia

Sit patient up at 90 degrees. Monitor blood pressure q 3 min. Check urine collection system or catheterize the bladder using lidocaine gel. Look for source of noxious stimulation. Examine rectum with topical anesthetic and remove feces. If systolic blood pressure > 170 mm Hg, apply 1 inch of transdermal nitroglycerin ointment (Nitropaste) above spinal level. If no change, give nifedipine 10 mg; repeat in 10 min as needed; monitor for hypotension. Start IV fluids if there is no change. If hypertension and symptoms persist, give nitroglycerin 0.4 mg sublingual or hydralazine 10 mg IV. If no change, give diazoxide 100 mg or labetalol 20 mg IV for a longer effect. For prophylaxis, give prazosin 5 mg PO up to tid.
Adapted from Dobkin BH: The clinical science of neurologic rehabilitation, ed 2, New York, 2003, Oxford University Press.
AUTONOMIC DYSREFLEXIA Patients with a neurologic level above T7 are at risk for life-threatening episodes of hypertension (autonomic dysreflexia). Other signs and symptoms include severe headache, increased spasticity, sweating, blurred vision, nasal congestion, piloerection, facial flushing, bradycardia, and general apprehension. Any noxious stimulus can trigger episodes, but the leading causes are bladder distention and bowel impaction. A good regimen for treating acute autonomic dysreflexia is given in Table 1. SUGGESTED READING
Dobkin BH: The clinical science of neurologic rehabilitation, ed 2, New York, 2003, Oxford University Press. Lin VW, Cardenas DD, Cutter NC, et al: Spinal cord medicine: principles and practice, New York, 2003, Demos.
PATIENT RESOURCES
National Spinal Cord Injury Association 8300 Coleville Road, Suite 551 Silver Spring, MD 20910 http://www.spinalcord.org
Following inpatient rehabilitation, outpatient followup is important. CARF-accredited programs must have a mechanism for long-term follow-up. Individuals with cervical or high thoracic injuries are at increased risk for pulmonary complications and should be vaccinated for Pneumococcus every 10 years and influenza annually.
National Spinal Cord Injury Hotline 2200 Kernan Drive Baltimore, MD 21207 Email: scihotline@aol.jcom The Miami Project to Cure Paralysis P. O. Box 016960, Mail Locator R-48 Miami, FL 33101 http://www.miamiproject.miami.edu
Long-Term Management
In addition to the complications discussed earlier, many issues become prominent once patients are home, including urologic complications, spasticity, chronic pain, sexual dysfunction, and autonomic dysreflexia. The reader is referred to specialized texts such as those listed in Suggested Reading at the end of this chapter. UROLOGIC AND SEXUAL DYSFUNCTION Voiding abnormalities, such as detrussor-sphincter dyssynergy, high-pressure voiding, and ureteral reflux, can be clinically asymptomatic. Therefore, injured individuals should be screened annually by a rehabilitation specialist or urologist. Men can have brief, reflexive erections with stimulation. Ejaculation is often retrograde or absent. Sildenafil strengthens and prolongs erections in SCI. Because of susceptibility to hypotension, a dosage of 25 mg should be tried before advancing to 50 mg. Male fertility often declines rapidly after SCI. Within the first year, it is reasonable to obtain and freeze semen for future use. Ejaculation can be induced by either vibratory or electrical stimulation. Women with SCI can become pregnant, and impaired lubrication is addressed with artificial supplements.

Peripheral nerve injury may result from sudden crushing blunt forces, stretch, transsection, or chronic compression. When confronted with a peripheral nerve injury, the physician must locate the precise site of the lesion, determine its severity, evaluate for spontaneous regeneration, and confirm the mechanism of injury and how much time has elapsed since the injury.
Determining the Site of the Lesion

The lesion should be localized to the spinal nerve root, plexus, nerve, or one of its branches, and there may be more than one lesion. One can determine the distance from the site of the injury to its target end organs. Spontaneous recovery from peripheral nerve injury is both time and distance dependent. Nerve fibers regenerate at a rate of approximately 1 mm/day. Earlier and
245
Trauma
more complete recovery is associated with shorter distances between the site of nerve injury and the target end organ. Thus, injuries at the root level are associated with worse prognoses than those at the plexus and peripheral nerves. The criteria used to distinguish root injury from peripheral nerve (or plexus) injury are outlined in Table 1, and a brachial plexus lesion serves as an example. The clinical approach to localizing a peripheral nerve injury is to determine which muscles (motor nerves) and cutaneous areas (sensory and sympathetic nerves) are involved and then to combine this knowledge with knowledge of the anatomy of the nervous structures involved. It is important to examine the entire course of an affected nerve for bone, joint, or other abnormalities that may be causing nerve damage. Local tenderness of the nerve or a positive Tinels sign (paresthesias/dysesthesias produced along the normal distribution of the injured nerve when that nerve is tapped or palpated) or both may help localize the injury site. The maximal Tinels response occurs at the growth cone or regenerating tip of the nerve. Further, the distal progression of the Tinels sign may serve as an assay for the progression of regeneration. MOTOR NERVES A lesion of the motor fibers of a peripheral nerve may manifest as weakness, clumsiness, paralysis, or muscle atrophy. The pain associated with nerve injury may be so severe that changes in strength, at least initially, can
TABLE 1 Features that Distinguish Cervical Root Lesions from Brachial Plexus Lesions
Cervical Root Lesion (Proximal to DRG) Paroxysms of severe pain Horners syndrome Signs of myelopathy (pyramidal signs, sensory level) Tinels sign Sensory nerve action potentials Somatosensory evoked potentials EMG: paraspinals, rhomboids, serratus, spinatii Histamine skin flare CT-myelography/ MR pseudomeningocele ++++ Present with C8-T1 May be present Absent Normal Absent Abnormal Normal Present
Brachial Plexus Lesion + Absent Absent May be present Reduced/absent Absent Normal Absent Absent
go unnoticed by the patient. A systematic examination of individual muscles should be performed; we recommend using Aids to the Examination of the Peripheral Nervous System (see Suggested Reading) as an anatomic guide for examination and localization. The British Medical Council (MRC) scale is used to grade muscle strength, both initially and at follow-up. The pattern of motor deficit aids in localizing the lesion. More proximal lesions (root, plexus level) tend to produce deficits that are more widespread than those from lesions to peripheral nerves. However, since there is often considerable overlapping innervation provided by adjacent roots or components of the plexus, the degree of impairment of a single muscle produced by a proximal lesion may be less than that which would result from a lesion to the peripheral nerve that innervates that muscle. Each major peripheral nerve has a sequence of muscular innervation from proximal to distal sites that helps pinpoint the area of injury. For example, from proximal to distal the radial nerve supplies the triceps in the arm, the brachioradialis in the elbow region, the extensor digitorum communis in the mid-forearm, and the extensor indicis in the distal forearm. Muscles should be examined for atrophy, fasciculations, and loss of reflexes. With any lower motor neuron lesion, the muscle undergoes atrophy, and if it is not innervated over 18 to 24 months, it may be replaced by fibrosis. Contractures of the tendon occur when a muscle is unopposed by the antagonist muscle and there is no passive stretching performed. Disuse atrophy, which is less severe than denervation atrophy, may result when a patient does not move an extremity because of pain or because of internal or external fixation placed for associated bone or joint injuries. Muscle strength, however, is relatively preserved with disuse atrophy. If more than a few months have elapsed since injury, a lack of atrophy in a weak muscle may indicate an upper motor neuron etiology. Motor nerve conduction studies (NCSs) reveal reduction and eventual loss of compound muscle action potential (CMAP) amplitudes in muscles distal to the peripheral nerve lesion. A time course for loss of amplitudes can be predicted, depending on the distance of the injury from the recording site on the muscle and the degree and severity of the injury (Figure 1). Two to three weeks after injury, needle electromyographic (EMG) examination will reveal abnormal spontaneous activity in the form of fibrillation potentials and positive sharp waves. If the peripheral nerve injury is complete, no motor unit potentials (MUPs) will be recruited in the target muscles; if the injury is partial, volitional MUPs will be detected by EMG, but they will show reduced recruitment. Needle EMG is also helpful in documenting newly formed motor units, an indication that at least some recovery is occurring. SENSORY NERVES Injury to the sensory component of a peripheral nerve can cause abnormal sensations (paresthesias), increased sensitivity (e.g., hyperalgesia to pinprick, brushing/cooling allodynia, pain), diminished sensation (hypesthesia), or total loss of sensation (anesthesia) in the distribution
10
EMG, Electromyography; DRG, dorsal root ganglion.
246
Time since nerve injury
<1 wk 12 wk
>2 wk
NCS
EMG
NCS
EMG
NCS
EMG
Stimulate proximal to lesion
MUPs in muscles distal to lesion
Stimulate distal to lesion
Stimulate distal to lesion
Fibs and positive sharp waves
No response distally
Response present distally
Absent
Present (recruitment reduced)
No response
Reduced response
Normal response
Absent
No response
Reduced response
Normal response
Present
Absent
Complete lesion
Incomplete lesion
Complete lesion
Incomplete lesion
Complete lesion
Incomplete lesion
Neurapraxia
Complete lesion
Incomplete lesion
Complete lesion
Incomplete lesion
Neurapraxia
Axonotmesis Neurotmesis
Neurapraxia
Neurapraxia Axonotmesis Neurotmesis
Neurapraxia Axonotmesis Neurotmesis
Absent
Complete lesion
Incomplete lesion
FIGURE 1. Electrophysiologic assessment of peripheral nerve injuries. NCS, Nerve conduction studies; EMG, electromyography; MUP, motor unit potential.
247
Trauma
of the affected nerve. Following complete distal peripheral nerve injury, a small area of total anesthesia is generally surrounded by areas of either hypesthesia or increased sensitivity, the latter representing a zone of overlap between the injured and adjacent intact nerves. Because of overlap, the sensory loss is rarely as extensive as is expected from the anatomic distribution of the injured nerve. If the lesion is distal to the dorsal root ganglia (DRG), the sensory axon is disconnected from the cell body in the DRG and will undergo wallerian degeneration; sensory NCSs reveal reduction of sensory nerve action potential (SNAP) amplitudes. Loss of SNAP amplitude lags behind reductions in motor amplitudes by 2 or 3 days. Conversely, if the lesion is proximal to the DRG (i.e., at the root level), the axon remains connected to the cell body, no wallerian degeneration takes place in sensory fibers, and SNAP will be normal. Sensory NCSs, therefore, help the physician to discriminate between a root lesion and a more distal lesion (see Table 1). SYMPATHETIC NERVES Sympathetic function may be altered after nerve injury, and such dysfunction also helps localize the lesion. For example, injury to the C8 or T1 roots interrupts sympathetic innervation to the head resulting in Horners syndrome (ptosis, myosis, and anhidrosis). Patients seldom note local areas of reduced sweating but may complain of discoloration, altered temperature, or skin turgidity.
Establishing Severity of Nerve Injury

Complete nerve lesions interrupt all sensory, motor, and sympathetic functions distal to the site of nerve injury. If clinical or electrophysiologic tests indicate preserved function distal to the injury site, the lesion is classified as
partial or incomplete. Each of these two types of injuries are further classified as neurapraxia, axonotmesis, and neurotmesis (Table 2). The mildest form of nerve injury results when a stretch or pressure injury distorts the myelin overlying the nodes of Ranvier and produces focal conduction block. This type of injury, with conduction block but without wallerian degeneration, is referred to as neurapraxia, or class 1 injury. An example is the transient sensation of numbness or pins and needles in an extremity after lying or sitting in a certain position for a prolonged period. There can be some demyelination in this injury prolonging the time of recovery; however, a complete return of function is anticipated. Moderate nerve injuries interrupt the axons continuity and result in wallerian degeneration but leave the endoneurium intact. These lesions are referred to as axonotmesis, or class 2 injury. Since the neural connective tissue structures remain intact, the potential for spontaneous regeneration is retained. However, if the endoneurium is interrupted, the potential for spontaneous regeneration is greatly reduced, and the lesion is called neurotmesis. Neurotmesis can be further divided into class 3, 4, and 5 injuries: class 3 injuries disrupt axons and endoneurium but preserve fascicular orientation; class 4 injuries disrupt the perineurium; and class 5 injuries disrupt the epineurium and result in a loss of continuity of the entire nerve trunk. In axonotmesis, the Schwann cells still line the endoneurial tubes and guide regenerating axons back into the end organs. In neurotmesis, regenerating axons escape the disrupted endoneurial tubes and branch freely within a disorganized mass of fibroblasts forming a neuroma. If the perineurium and epineurium remain intact (class 3 and 4), neuromas may form within the nerve (neuroma-in-continuity). Class 5 injuries result in the formation of neuroma at the end of the proximal nerve stump. Lesions are often mixed, and neurapraxia and axonotmesis may coexist.
10
TABLE 2 Classification of Nerve Injuries

Neuropraxia Class Part of nerve affected: interruption of axoplasmic flow Myelin Axon Schwann cell basal lamina and connective tissue Mechanism Clinical examination 1 Yes Yes No No External compression Motor deficit usually > sympathetic or sensory loss Axonotmesis 2 Yes Yes Yes No Traction/stretch/contusion Variable loss of motor, sensory, and sympathetic function Neurotmesis 3-5 Yes Yes Yes Yes Laceration/severe traction Complete sensory and motor loss distally
Electrophysiology
248
Similarly, the severity of injury may vary across fascicles in an injured nerve.
Time Elapsed Since Nerve Injury

Nerve conduction and EMG findings may vary depending on the time from injury. Three time phases can be identified: (1) an acute phase, within the first week of injury; (2) the period 1 to 2 weeks after injury; and (3) the period beyond 2 weeks (see Figure 1). NCS findings may also be influenced by the site of the injury, the distance between the injury site and recording site, and the type of fibers affected. During the first week of injury, sensory and motor NCS in the distal nerve stump remain normal, even with severe nerve injuries. It has been shown that CMAP amplitudes can continue to be recorded for up to 7 days after the injury and sensory amplitudes for up to 10 days. Thus, in the acute phase, NCS cannot distinguish between neurapraxia, axonotmesis, or neurotmesis. However, in the first week of injury, NCS may help establish whether the lesion is complete or incomplete. The nerve is stimulated proximal to the site of the nerve injury and the response is recorded from the nerve or muscle distal to the injury site: if there is a response, the lesion is incomplete; if there is no response, the lesion is complete. Similarly, on needle EMG examination of the innervated muscles distal to the nerve injury, volitional motor units will be absent if the lesion is complete. If any volitional motor units can be recorded, one can assume that the lesion is incomplete. A further advantage of studying nerve conduction in the first week of injury is to establish a baseline value. On serial nerve conductions, if the sensory and motor amplitudes improve or remain unchanged, one can conclude that the lesion is neurapraxic. If amplitudes progressively fall, the conclusion is that wallerian degeneration has begun and the injury is class 2 or worse. During the second phase (1 to 2 weeks), if axonal discontinuity has occurred (injury classes 2 to 5), then NCSs show evidence of axonal loss first in the motor fibers and later in the sensory fibers. Therefore, stimulation of the injured nerve distal to the injury site shows reduced or absent SNAP and/or CMAP responses if the lesion is axonotmetic or neurotmetic but normal responses if the lesion is neurapraxic. Needle EMG may not detect any abnormal spontaneous activity during this phase. The interpretation of volitional MUPs resemble those seen during the first week of injury. During the third phase ( 2 weeks after injury), NCS findings resemble those in the second phase, with absent (in complete injuries) or reduced SNAP/CMAP amplitudes (in incomplete injuries in the distal nerve stump). NCS findings become established by the second week, but EMG findings become established just beyond the second week after injury. It is during the third phase that NCS and EMG studies are most reliable in classifying the severity of the lesion, localizing the lesion, and suggesting a prognosis. We therefore recommend waiting 3 weeks after injury before getting an electrophysiologic evaluation. In axonotmesis and
neurotmesis, needle EMG shows abnormal spontaneous activity in the form of fibrillation potentials and positive sharp waves in the denervated muscle fibers. These EMG findings are length dependent, being seen earlier in muscles closer to the lesion than in those farther away from the lesion. As in the earlier two phases, volitional EMG activity either shows no units or a reduced recruitment of motor units, depending on the severity of the lesion.
Mechanism of Injury
The mechanism of injury is critical in determining the severity of the injury, its management, and its prognosis. Table 3 shows the common modes of injury for the peripheral nerves most often injured. The mechanisms of injury can be classified as follows: injuries due to laceration; stretch, traction, or contusion; ischemia; and acute compression. NERVE LACERATION Common causes of nerve laceration include from knife wounds, glass, propeller and fan blades, chainsaws, bullets, fractured bones, or surgical instruments. These injuries usually result in neurotmesis and are followed by wallerian degeneration. By their location, many peripheral nerves are particularly vulnerable, but virtually any nerve is susceptible to such injuries. Nerve transsection injuries of this kind are often good candidates for early surgical repair. STRETCH, TRACTION, AND CONTUSION Stretch, traction, and contusion may be associated with fractures, motor vehicle accidents, birth, and bullets. The degree of injury is determined by the magnitude of the insult and the length of time that the deforming force has to inflict its damage. Hence the severity of injury may vary from transient, neurapraxic damage to neurotmesis. Stretch or traction of a mixed nerve results in numbness or paresthesias, with or without weakness. Severe stretch and traction injuries are difficult to treat because the intrafunicular rupture of nerve fibers occurs over considerable lengths (or at multiple locations) of the nerve. Therefore, even if the lesion is in continuity (axonotmesis), regenerating fibers may have difficulty navigating through long lengths of fibrosis to their targets. Nerve injuries associated with closed fractures or dislocations may be missed in the acute setting due to preoccupation with the bone or joint injury that often dominates the clinical picture. IATROGENIC INJURIES Examples of iatrogenic injuries include injection injuries commonly seen in the sciatic nerve at the buttock or in the radial nerve in the lateral upper arm. Generally the patient complains of electric shock-like sensations at the time of the injection. The spinal accessory nerve is at risk during cervical lymph node biopsy or resection in the posterior triangle of the neck. Nerve injuries may also
TABLE 3 Mechanisms of Nerve Injury for Peripheral Nerves

Trauma
Peripheral Nerve Facial Spinal accessory
Common Modes of Injury Traction/contusion*: temporal bone fractures, blunt trauma, GSW Laceration: stab wounds Iatrogenic: during ear surgery, parotid surgery, acoustic neuroma surgery Iatrogenic: surgery in the posterior triangle of the neck, e.g., lymph node resection, carotid endarterectomy cyst removal Laceration: stab wounds Traction/contusion: blunt injuries Stretch/traction/contusion: MVA, motorcycle accidents, GSW, shoulder fracture/dislocations, contact sports (stingers and burners), birth injury Laceration: stab wounds Iatrogenic: improper positioning during anesthesia, excessive sternal retraction (cardiac surgery) External compression: prolonged compression during narcotic coma, excessive supraclavicular pressure from weight of heavy backpack Stretch/traction/contusion: traction injuries in falls, MVA, motorcycle accidents, fracture of scapula; intensive exercise such as weightlifting, repair work on ceiling, associated with rotator cuff tear Stretch/traction/contusion: traction injury (accidents), direct blows (contact sports), overuse of shoulder (chopping, weightlifting) Iatrogenic: during surgeryfirst rib resection, thoracotomy, axillary lymph node resection Stretch/traction/contusion: fracture humerus, crutch use, missile wounds, posterior interosseous nervefracture or dislocation of radius (Monteggia fracture) External compression: pressure from head of a sleeping person; tight handcuffs, wristwatches, or plaster casts Laceration: axilla, wrist Iatrogenic: upper arm (tourniquets, injections) Stretch/traction/contusion: fractures or dislocations of shoulder, crutch palsy Iatrogenic: injection injury Stretch/traction/contusion: rarely damaged alone but involved with brachial plexus injuries or axillary nerve after shoulder dislocation; sudden or violent extension of forearm with strenuous exercise; sensory branch injured at the elbow by carrying heavy objects supported at the elbow crease, e.g., strap of a handbag Iatrogenic: venipuncturesensory branch injured at the elbow Lacerations: upper arm or wrist Stretch/traction/contusion: fracture of humerus, GSW, crutches, tourniquet, rifle sling palsy; anterior interosseous damage by fractures at elbow External compression: pressure from head of a sleeping partner External compression: at axilla, upper arm, elbow, wrist (prolonged bicycle riding), or hand lacerations Stretch/traction/contusion: penetrating injuries, dislocation/fracture of elbow, fractures at wrist or distal radius Iatrogenic: improper position during anesthesia Stretch/traction/contusion: fracture of pelvic girdle, GSW Iatrogenic: hematomas in patients on anticoagulants; during parturition compressed against rim of pelvis by fetal head of forceps Iatrogenic: stretch during lithotomy position for childbirth, or vaginal hysterectomy; other surgical procedures (abdominal hysterectomy, renal transplant, hernia repair, hip arthroplasty, femoral artery cannulation, angioplasty, hip operations) Laceration: stab wounds Stretch/traction/contusion: GSW, hematoma, abscesses, fractures of pelvis or femur External compression: gymnasts and dancers performing hyperextension hip exercises Iatrogenic: injured by the fetal head or forceps during prolonged or difficult labor; during hip replacement Stretch/traction/contusion: blunt sports injuries, car seat belts Iatrogenic: external pressure during anesthesia; during operation for harvesting iliac bone crest graft; lower abdominal surgeries, misplaced injections Stretch/traction/contusion: traumapelvic and hip joint fractures or dislocations, GSW Laceration: stab wounds Iatrogenic: hip surgery; arthroscopic surgery, total hip replacement, gluteal injections External compression: coma; prolonged sitting in lotus position, on bicycles Stretch/traction/contusion: closed tibial fracture, trauma at the ankle Laceration: in the popliteal fossa Iatrogenic: pressure during anesthesia, bedridden patients, improper casts External compression: coma, sleep, prolonged squatting; deep peroneal nerve-anterior compartment syndrome; excessive exercise, soft tissue trauma, hemorrhage Laceration: skate blade in hockey players Stretch/traction/contusion: fractures of femur, tibia, or fibula; ankle inversion injury and minor athletic trauma in runners; blunt injury (contact sports)
Brachial plexus
Suprascapular Long thoracic Radial
Axillary Musculocutaneous Median
10
Ulnar
Lumbosacral plexus Femoral
Obturator Lateral cutaneous Sciatic Tibial Peroneal
Mechanisms in boldface type represent the most frequently seen modes of injury for that particular nerve. GSW, Gunshot wound; MVA, motor vehicle accident.
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occur during surgical procedures owing to the patient being in the same position for prolonged periods, from retractors used during surgery, from tight plaster casts, and so on. Iatrogenic injuries need to be recognized and dealt with in a timely and professional manner. ISCHEMIA AND ACUTE COMPRESSION Tourniquets or a surgical patients maintenance of a constant position can compress nerves; however, damage generally results from mechanical distortion rather than from ischemia per se. Mild compression leads to paranodal or segmental demyelination (neurapraxic injury); more severe compression for longer periods produces crush, which can also damage the axon. Most palsies associated with focal compression due to anesthesia, coma, drug narcosis, undisturbed sleep of the fatigued, intoxication, or improper application of plaster casts fall into this category. In acute compressive neuropathies, muscle weakness is far more striking than sensory loss. Brachial plexus, radial, ulnar, sciatic, and peroneal nerves are particularly vulnerable. The prognosis is good for compressive injuries; most compression injuries are managed nonoperatively. Compartment syndromes occur when the pressure within a confined space increases such that compression or ischemic injury results. The anterior compartment of the lower leg is a common site of involvement and can lead to peroneal nerve palsy. Compartment syndromes are often missed until irreversible damage has occurred. Diagnosis rests with clinical examination and measurement of pressures. Early fasciotomy is indicated to prevent progressive wallerian degeneration in compartment syndrome. OTHER MODES OF INJURY Other modes of injury include thermal, electrical, and irradiation injuries. In patients with severe thirddegree burns, long lengths of nerve are often involved,
which necessitates nerve grafts or tendon transfers. Concomitant damage to soft tissues and muscles worsens the prognosis. Electrical injury, like thermal injury, may involve long nerve segments with extensive damage, resulting in a poor prognosis. Irradiation injuries in the brachial or lumbosacral plexus need to be distinguished from direct neoplastic infiltration. Imaging and electrophysiologic studies are often helpful. EMG may show myokymic discharges specific for radiation-induced injuries. The upper brachial plexus is more likely to be affected by irradiation, whereas the lower brachial plexus is more commonly infiltrated or compressed by cancer.
Therapy
Management of a nerve lesion requires precise localization of the injury, confirmation of time interval since injury, and definition of the nature and severity of the injury. Surgical procedures for nerve injuries are presented in Table 4. We recommend the stepwise approach to management shown in Figure 2 and discussed in the following sections. COMPLETE VERSUS INCOMPLETE INJURIES If the clinical and electrophysiologic examinations suggest a complete injury, and if the mechanism of injury is known to be a sharp laceration, then surgical repair should be considered within 24 hours. An endto-end suture is the traditional method of choice for repairing a transected nerve. Recently we have begun to use fibrin glue as a substitute for epineural sutures. Fibrin glue shortens the duration of the procedure and produces less intraneural scar than do nerve sutures. At follow-up visits, the physician evaluates for evidence of nerve regeneration. Tinels sign should progress
TABLE 4 Peripheral Nerve Surgical Procedures

Procedure External neurolysis Internal neurolysis End-to-end repair Nerve grafts Neurorrhaphy Neurotization Nerve transfer Split repair Resection of neuroma Description Dissection of nerve free from the surrounding and investing tissues, including scar; required prior to all peripheral nerve procedures Separation of the nerve into its individual fascicles; performed when injury is more severe to one portion of the nerve than to others; may be followed by split repair Generally performed to coapt nerves that have been transected or for lesions in continuity that are relatively short Use of healthy nerve to bridge the gap between a distal nerve stump and proximal stump of the injured nerve or a donor nerve; required for relatively long lesions in continuity Joining together of two parts of a divided nerve; includes end-to-end repair, and nerve grafts Regeneration of axons into tissues such as a distal nerve stump or a motor end plate; may occur spontaneously or result from end-to-end repair, nerve grafting, or nerve transfer Use of proximal healthy nerves (donor nerves) to reinnervate distal stump of injured nerve Repair of select fascicles after internal neurolysis Some injuries result in a painful neuroma; treatment involves resection of the neuroma and relocation of the proximal nerve stump away from scar tissue to location where it will be protected from mechanical stimulation (in muscle or bone)
Peripheral Nerve Injury FIGURE 2. Algorithm for the management of peripheral nerve injuries. NCS, Nerve conduction studies; EMG, electromyography; MUP, motor unit potential. Complete No sensory or motor function No motor units in muscles
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Trauma
Peripheral nerve injury
Incomplete
Mixed (fascicular injury)
Laceration or open injury (neurotmesis)
Closed injury (neurapraxia or neurotmesis)
Neurorrhaphy as soon as possible
NCS and EMG at 3 wk
NCS and EMG at 3 wk
NCS and EMG at 3 wk
Neurapraxia
Axonotmesis
MUPs in all innervated muscles
MUPs absent in some innervated muscles
Follow at 1 mo intervals
Follow monthly for 3 mo
10
Spontaneous recovery No evidence of recovery of function distally Spontaneous recovery No progress Spontaneous recovery
Surgery: Neurorrhaphy or neurolysis
Surgery: Neurorrhaphy or neurolysis
distally at the expected rate of 1 inch of regeneration per month. Early evidence of reinnervation can be seen by EMG changes in muscles closest to the nerve repair site. Distal progression of muscle reinnervation should mirror that of Tinels progression at about 1 inch per month. For complete injuries caused by contusion, stretch, traction, or compression, we suggest waiting 3 weeks and then performing NCSs to determine whether the lesion is neurapraxic or axonotmetic. Lack of muscle denervation with loss of muscle power indicates a neurapraxic injury. Approximately 80% of closed injuries recover spontaneously because these lesions are in continuity. If neurapraxic, a return of function can be expected provided care is taken to ensure that no ongoing compressive injury is occurring. Axonotmetic injuries should be followed at 1- to 3-month intervals. An advancing Tinels sign in the distribution of the injured nerve indicates that the nerve is in continuity and justifies postponement of surgery. Lack of advancing Tinels sign or failure of muscle to show EMG evidence of reinnervation at the expected time course suggests neurotmetic injury and need for surgical exploration.
TIMING OF SURGERY The stepwise approach just described is useful when the physician sees a patient immediately after the patient has been injured, but this approach must be altered if the physician first sees the patient weeks or months after the injury. As mentioned, for clean lacerations of nerve, end-to-end nerve suturing or gluing should be performed as soon as local conditions are judged favorable for repair. Delays within the first few months of injury may necessitate nerve grafts that offer less chance of success. The chances of a successful recovery of motor function decline after 6 months, although severed axons retain their capacity to sprout for several years. The critical period for muscle reinnervation is about 18 to 24 months. Beyond this period, denervated muscles atrophy irreversibly and are replaced by connective tissue. After 18 to 24 months, tendon transfers are the preferred treatment for nerve injuries. No such time limits exist for the restoration of sensory function. INTRAOPERATIVE MONITORING Intraoperative electrophysiologic techniques have proved especially useful in the management of closed
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nerve injuries. Axonal continuity is established by the technique of intraoperative stimulation and recording across the area on injury. If compound nerve action potentials are present, external neurolysis is performed. If action potentials are absent, an internal neurolysis is then performed in the nonconducting region of the nerve. A neuroma in continuity is often identified. The nerve is then resected both proximal and distal until a healthy fascicular anatomy is identified. The gap is spanned by application of nerve cable grafts. When there is a question of nerve root avulsion, the use of proximal recordings can be of value. A stimulating electrode is placed on the nerve in question followed by an attempt at recording an averaged somatosensory potential from the contralateral cerebral hemisphere. Because of confounding issues such as level or type of anesthetic being employed, it is best to have access to a control nerve to ensure the system is functioning.
are helpful. Fortunately, regeneration pain is often self-limited and ceases once reinnervation is complete. NEUROPATHIC PAIN Severe pain may arise in the distribution of the injured nerve. Patients may experience spontaneous shooting electrical pains or hypersensitivity to stimulation of the skin in the distribution of the injured nerve. First-line therapy consists of anticonvulsants, tricyclic antidepressants, and strong analgesics. If the pain is refractory to pharmacologic treatment, surgical repair may be needed. AVULSION PAIN Avulsion of nerve roots may lead to the development of severe pain in the distribution of the injured nerve root. The pain is described as constant burning or crushing pain with paroxysmal burning or shooting pain. The unpredictable nature of the shooting pains often adds much distress. Nonoperative treatment consisting of extensive physical rehabilitation and polypharmacy is often required. The natural history of the avulsion pain is that about one half of patients are pain free or able to cope with their pain within 1 year, and most are pain free within 3 years. Unfortunately, avulsion-related pain can become exceedingly severe and bring a patient to suicide. Refractory pain can be managed by making a series of lesions at the dorsal root entry zone of the traumatized spinal cord (DREZ procedure). PAINFUL NEUROMAS When an axon is severed, the proximal end will form sprouts that attempt to grow down the distal endoneurial tube. If the forward progress of regenerating sprouts is blocked, they form a tangled mass of nerve fiber and connective tissue, a neuroma. A small proportion of these become pain generators. If medication management fails, surgical resection is performed with placing the proximal end away from sources of trauma. BONES, JOINTS, AND CONTRACTURES A nerve injury, even when uncomplicated by extensive soft tissue damage or wound infection, may be followed by changes in the bones, joints, and tendon sheaths of the affected limb. Changes are most common at and below the wrist and ankle. In adult bones, osteoporosis sets in; in growing bones, bone growth may be altered. In either case, arthritic changes, joint stiffness, or deformity may follow. Maintaining range of motion of joints, muscles, and tendons is of utmost importance. Patients should be educated as to the passive and active range of motion of the paralyzed joint. While awaiting nerve recovery and muscle activity, the patient must be engaged in an aggressive stretching program. Splints and other mechanical appliances in addition to physical and occupational therapy can be used to help with maintenance of musculoskeletal integrity.
Complications after Injury

PAIN A patient may develop pain after nerve injury due to several different mechanisms. COMPLEX REGIONAL PAIN SYNDROME Partial nerve injury may lead to the development of complex regional pain syndrome (CRPS) previously referred to as reflex sympathetic dystrophy. The pain is usually burning in quality (causalgia) and disproportionately severe with respect to the extent of injury. The pain often persists well after the injury has been presumed to have healed. If not treated early and aggressively, the pain often expands outside of the boundaries of the area of injured tissue. Allodynia to light touch and cooling are common symptoms. The skin may be warm and red or cold and cyanotic. Over time, the skin may have a smooth, glossy appearance with loss of skin folds and wrinkles. Excessive sweating is common. Decreased range of motion due to swelling and pain may eventually lead to permanent joint stiffness and contractures. Muscle wasting, osteoporosis, and tapering of the distal digits may occur in severe cases. Sympathetic block or sympathectomy in combination with physical therapy often relieves these symptoms (see Chapter 17). DENERVATION AND REGENERATION PAIN During the acute phase of nerve injury, patients may experience pain due to muscle denervation, joint stiffness, and/or contracture formation. The use of analgesics, awareness of the possibility of contracture, and the avoidance of prolonged immobilization are usually all that are necessary to manage these pains. As the nerve regenerates, paresthesias or dysesthesias may travel in the direction of regeneration. If such symptoms are bothersome, tricyclic antidepressants and anticonvulsants (gabapentin [Neurontin], pregabalin)
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Trauma
SKIN AND SUBCUTANEOUS TISSUE Loss of protective sensation increases the risk for tissue damage due to burn or noxious chemicals. Trophic changes are uncommon unless the injury is severe. Injuries occurring in the median, ulnar, sciatic, and particularly the tibial component are the most likely to give rise to trophic changes. They are confined to the hand or foot and, in particular, to the digits. If the injury is complete, the skin becomes cold and cyanotic, the digital pads become atrophic and deformed, and the nails become brittle. If the injury is partial and irritative, causalgia and severe vasomotor disturbances add to the trophic changes. Treatment should aim to avoid recurrent trauma to insensate structures. DEPRESSION Loss of function, pain, or the slow process of recovery may be quite distressing for patients. Many patients
develop depression, which may magnify their degree of suffering. Care must be taken to identify psychological symptoms and obtain appropriate mental health consultations. SUGGESTED READING
Aids to the examination of the peripheral nervous system, London, 1986, Bailliere Tindall. Chaudhry V, Glass JD, Griffin JW: Wallerian degeneration in peripheral nerve disease, Neurol Clin 10:613-627, 1992. Kline DG, Hudson AR: Nerve injuries: operative results for major nerve injuries, entrapments, and tumors, Philadelphia, 1995, WB Saunders. Sunderland S: Nerve injuries and their repair, New York, 1991, Churchill Livingstone.
10
SECTION 11
Neoplastic Disease
Kaleb Yohay, M.D., and Kenneth Cohen, M.D., M.B.A.
stereotaxy, and endoscopy have improved extent of resection and reduced surgical morbidity though infection, hemorrhage, and neurologic dysfunction remain significant. In many instances, surgical resection is limited by anatomy or extent of disease. Surgery cannot be used to eliminate or treat invasive disease that may have expanded beyond the visible borders of a tumor or in the setting of disseminated disease. Radiation therapy can be used to treat macroscopic tumor and/or local or disseminated microscopic tumor. It frequently follows attempted surgical resection of the primary tumor. The use of conformal field radiation allows the delivery of higher doses of radiation to the target area while limiting exposure of adjacent structures and other organs. Despite improvements, the side effects of radiation therapy can be severe, particularly in the youngest of children. Chemotherapy can also be useful in the treatment of some brain tumors. It is used almost always in conjunction with surgery, radiation, or both. Chemotherapy can be useful in treating primary and disseminated disease. It can be used to help delay radiation therapy or reduce the total radiation dosage needed and in some instances can be used prior to definitive surgery to facilitate surgical resection. Chemotherapeutic agents carry the risk of significant side effects including immunosuppression, mucositis, increased risk of secondary malignancy, cognitive changes, neuropathy, and seizures. New therapies and modes of delivery for brain tumors are being explored, including gene therapies, other molecular techniques, and localized administration of radioactive, chemotherapeutic, or biologic agents. Corticosteroids are useful in decreasing peritumoral edema and can quickly and effectively reduce symptoms related to swelling. We typically use dexamethasone 1 to 2 mg every 4 to 6 hours or a total daily dose of 1 to 1.5 mg/kg to a maximum of 32 mg/day. The use of corticosteroids should be considered in any patient with symptomatic edema and also may be used in many patients for several days preceding planned surgical resection. Common side effects of corticosteroids include gastrointestinal bleeding (generally requiring the use of an acid-reducing agent), hypertension, hyperglycemia, and behavioral changes. In addition, steroids can have the unintended effect of decreasing the permeability of the blood-brain barrier, theoretically reducing the efficacy of chemotherapy. 255
Brain tumors are the most common solid malignancy of childhood, with an annual incidence of approximately 3.9 cases per 100,000 person-years according to data from the Central Brain Tumor Registry of the United States (CBTRUS). Each year, approximately 3000 children within the United States are newly diagnosed with a primary brain tumor. Though improvements in diagnosis and treatment have resulted in overall improvement in survival, morbidity and mortality remain high. The overall survival rate at 5 years following diagnosis for children with a primary malignant brain tumor is approximately 63%. Brain tumors in children differ from those in adults in several key ways. Tumors are more likely to be infratentorial in location (see Table 1 for types of tumors based on location). Brain tumors in children are much more varied in terms of histopathologic type and grade resulting in more diverse treatment regimens and outcome. Central nervous system (CNS) dissemination is common. Treatments for tumors in children must be significantly modified according to age to minimize the long-term impact these therapies can have on the developing nervous system.
General Principles
The treatment of brain tumors in children relies on a combination of surgery, chemotherapy, and radiation therapy. For most brain tumors, surgical resection is the mainstay of therapy. Surgery alone can be curative for selected tumor types when gross total resection (GTR) is achieved. Surgery enables histologic diagnosis and symptomatic control. Surgical debulking of a tumor may improve efficacy of chemotherapy or radiation therapy. Improvements in surgical techniques and technology including intraoperative neuroimaging, frameless
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TABLE 1 Differential Diagnosis by Tumor Location

Location Hemispheric Tumor Type Astrocytoma PXA PNET Ependymoma Ganglioglioma Oligodendroglioma DNT DIG AT/RT Meningioma Craniopharyngioma Pituitary adenoma Germinoma Astrocytoma NGGCTs Pineocytoma Pineoblastoma Germinoma NGGCTs AT/RT Pineal cyst Choroid plexus papilloma Choroid plexus carcinoma SEGA Astrocytoma Meningioma PNET Colloid cyst Ependymoma Oligodendroglioma Pilocytic astrocytoma Medulloblastoma Ependymoma Diffuse pontine glioma Vestibular schwannoma AT/RT
Sellar/suprasellar
Pineal region
Intraventricular/periventricular
agents and other medications. Some of the newer anticonvulsants can provide excellent seizure control with fewer drug interactions. In particular, for long-term seizure control we frequently use levetiracetam at a starting dose of 10 mg/kg/day divided twice-daily, increasing by about 10 mg/kg per week to a goal of 40 mg/kg/day. Levetiracetam offers several advantages including excellent tolerability, no drug-drug interactions, and a broad spectrum of seizure control. For acute seizure control, drugs that allow rapid loading such as fosphenytoin, valproic acid, and phenobarbital may be necessary. The duration of anticonvulsant therapy must be individually tailored to the patients circumstances. We generally continue antiepileptic therapy in patients with known seizures for at least a 2-year seizure-free interval after surgical resection, though there are no specific data to suggest the most efficacious duration of therapy. Tumors are frequently associated with signs and symptoms of raised intracranial pressure. This occurs as a result of direct mass effect, peritumoral edema, or ventricular obstruction and hydrocephalus. For a discussion on the management of increased intracranial pressure, see Brain Metastases chapter. Therapies for specific tumors vary from institution to institution and trial to trial. Most children in the United States being treated for cancer are treated on cooperative group, multi-institutional, or single-institution studies. As such, treatment regimens are constantly changing, especially with regard to radiation therapy or chemotherapy dosing and/or specific therapeutic agents used.
Specific Therapies
PILOCYTIC ASTROCYTOMAS/LOW-GRADE FIBRILLARY ASTROCYTOMAS Astrocytomas make up approximately one third of brain tumors in childhood. Unlike adults, low-grade astrocytomas, including pilocytic and fibrillary astrocytomas (World Health Organization [WHO] grades 1 and 2), predominate. Pilocytic astrocytomas make up about 10% of supratentorial astrocytomas and 85% of cerebellar astrocytomas. Pilocytic astrocytomas can occur throughout the neuraxis but have particular predilection for the cerebellum, cerebral hemispheres, thalamus and basal ganglia, the optic pathway (including the chiasm and hypothalamic region), and brainstem (dorsal exophytic brainstem glioma). Tumors with features of a low-grade astrocytoma on neuroimaging may potentially be followed expectantly on serial scans without resorting to surgical intervention, particularly if resection would carry a high risk of morbidity because of the tumors location. Magnetic resonance (MR) spectroscopy sometimes can be helpful in distinguishing between low- and high-grade neoplastic processes. For low-grade astrocytomas that show progression on serial imaging or that cause symptoms that cannot be effectively managed medically, surgery is the mainstay of therapy. For low-grade astrocytomas in locations conducive to GTR, outcomes are excellent with greater than 90% long-term progression-free survival.
Infratentorial (brainstem, cerebellum, and cerebellopontine angle)
PXA, Pleomorphic xanthoastrocytoma; PNET, primitive neuroectodermal tumor; DNT, dysembryoplastic neuroepithelial tumor; DIG, desmoplastic infantile ganglioglioma; AT/RT, atypical teratoid/rhabdoid tumor; NGGCTs, nongerminomatous germ cell tumors; SEGA, subependymal giant cell astrocytoma.
Seizures are a common complication of brain tumors in children. Seizures associated with tumors are most likely to be partial in onset, with or without secondary generalization. Despite the high incidence of seizures in patients with brain tumors, particularly supratentorial tumors, the benefit of the use of anticonvulsants for the prevention of a first seizure is uncertain. Some studies in adults have shown some benefit of short-term perioperative use of antiepileptic drugs, whereas others have not. In a child with a brain tumor and seizures, several factors must be taken into account in choosing the appropriate anticonvulsant, including the age of the patient, the type of seizure, the rapidity with which seizure control must be obtained, the route of administration, and potential interactions with chemotherapeutic
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Neoplastic Disease
Subtotal resection can be useful in reducing symptoms and prolonging survival, but the incidence of progression is variable. Chemotherapy is commonly used in instances of recurrence, followed by radiation therapy if necessary. For tumors in locations that make resection impossible without significant morbidity, such as the optic pathways, thalamus, or hypothalamus, radiation therapy or chemotherapy may be used as the primary mode of treatment. Stereotactic radiosurgery may also prove to be an effective treatment for some unresectable tumors or tumor recurrences (Figure 1). Optic pathway gliomas are low-grade astrocytomas originating within the optic nerves, chiasm, or optic radiations. These tumors have a variable natural history ranging from no progression to aggressive progression or occasionally regression. Patients with optic pathway glioma and neurofibromatosis (NF)-1 tend to have a more benign course. Generally, conservative management with serial neuroimaging and ophthalmologic examination is preferred. However, surgery is considered in instances of significant proptosis or visual loss and particularly in unilateral tumors located anterior to the optic chiasm. Chemotherapy has been shown to be effective and is commonly used in symptomatic patients younger than 5 years of age, in whom radiation therapy would carry a high risk of associated morbidities. Radiation therapy is more commonly used in older children who have had a partial resection or progression after surgery and/or chemotherapy. ANAPLASTIC ASTROCYTOMAS/ GLIOBLASTOMA MULTIFORME High-grade astrocytomas (WHO grades 3 and 4) are less common in children. Treatments to date have been disappointing in providing cure or significant survival benefit
to most of these children. Because of the infiltrative nature of the tumors, GTR is uncommon. Maximal surgical resection does provide some survival benefit, particularly for patients with anaplastic astrocytomas. Adjunctive therapy with radiation therapy and/ or chemotherapy may provide some additional modest improvement. Other treatment modalities are being explored, including interstitial brachytherapy with radioisotope seeds implanted into the tumor bed, highdose chemotherapy with autologous stem cell rescue, radiosensitizers, localized administration of chemotherapeutic agents in implanted polymers, and various gene and molecular therapies. BRAINSTEM GLIOMAS Brainstem tumors are relatively common in children, making up 10% to 25% of all childhood brain tumors. There are distinct subtypes of brainstem tumors with widely divergent natural histories, prognoses, and treatments. They are characterized by their location (medullary, pontine, midbrain, tectal), whether they are diffuse or focal, and whether they are intrinsic or exophytic. The most common brainstem tumor is the diffuse intrinsic pontine glioma. These tumors typically present with a fairly brief clinical history, with weakness, gait problems, and cranial nerve findings. They most commonly occur in children aged 6 to 10 years. Histologically, these tumors are fibrillary astrocytomas. Diffuse pontine gliomas respond poorly to treatment and survival is usually less than 18 months. Biopsy is not necessary if the clinical course and neuroimaging are consistent with a diffuse pontine glioma. Treatment is palliative with focal radiation therapy with or without chemotherapy.
11
FIGURE 1. Treatment algorithm for astrocytomas. WHO, World Health Organization; GBM, glioblastoma multiforme; XRT, radiation therapy. Pilocytic astrocytoma (WHO 1)
Astrocytomas
Fibrillary astrocytoma (WHO 2)
Anaplastic astrocytoma GBM (WHO 34) Best resection Chemoradiotherapy + adjuvant chemotherapy
Surgical resection if feasible
Consider observation with interval scans
Surgical resection
Observation with interval scans
If progression
Observation with interval scans
If progression consider chemotherapy vs. XRT
If progression consider chemotherapy vs. XRT
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Dorsally exophytic and focal brainstem tumors tend to be pilocytic astrocytomas and to respond well to surgical resection when technically feasible. Adjunctive chemotherapy or radiation therapy is generally reserved for recurrent or progressive disease. EPENDYMOMAS Ependymomas make up about 10% of childhood brain tumors. About two thirds of ependymomas are infratentorial. Ependymomas have a propensity for seeding the neuraxis, with reports of metastatic rates ranging from 5% to 20%. Evaluation should include MR imaging of the entire neuraxis and cerebrospinal fluid (CSF) cytopathology. Infratentorial ependymomas are typically located in association with the ventricular system, whereas supratentorial ependymomas tend to be located within the parenchyma. The peak incidence in children is around 4 to 5 years of age with a moderate male predominance. Maximal surgical resection is critical to the outcome for patients with ependymoma. Survival rates for patients after GTR range from 50% to 70% and less than 40% after subtotal resection. For supratentorial tumors with nonanaplastic pathology that are resectable with a wide margin and with no evidence of metastatic disease, adjuvant therapy may not be necessary (Figure 2). Adjuvant radiation therapy is used for all infratentorial tumors, for subtotally resected supratentorial tumors, for those with anaplastic histology, or in the setting of neuraxis dissemination. In young children where the morbidity from radiation therapy is high, radiation dose may be modified or even be deferred with the use of
adjuvant chemotherapy. Chemotherapeutic regimens have included standard agents such as cisplatin, etoposide, vincristine, and cyclophosphamide (or other oxazaphosphorines) in various combinations. Salvage therapy is generally palliative in nature. MEDULLOBLASTOMA Medulloblastomas make up about 20% of all CNS tumors in children. The peak incidence is in children 5 to 9 years of age, with 70% diagnosed prior to the age of 20. Three fourths of medulloblastomas arise within the midline of the cerebellum; the remainder arise in the cerebellar hemispheres. Patients typically present with signs of raised intracranial pressure, ataxia, and cranial nerve deficits. Medulloblastomas have a propensity for seeding the CNS, which impacts prognosis and treatment, so complete CNS imaging with contrast-enhanced MR scanning should be part of the initial evaluation. Cytologic examination of the CSF should be performed preoperatively or 10 to 21 days following surgery. Treatment consists of surgical resection, chemotherapy, and local and craniospinal radiation (Figure 3). The goal of surgery is maximal resection without causing severe neurologic sequelae. GTR is associated with better outcomes. For treatment stratification, patients are divided into standard-risk or high-risk patients based on the extent of resection and presence or absence of neuraxis dissemination. Increasingly, a variety of other risk factors have been identified including histologic subtypes (e.g., large cell, anaplastic variants) and molecular markers (e.g., c-Myc or Trk-C expression). The extent
Ependymoma
Supratentorial GTR
Infratentorial M0 disease
Infratentorial M+ disease
FIGURE 2. Treatment algorithm for ependymoma. GTR, Gross total resection; STR, subtotal resection; M0, localized disease; M+, neuraxis dissemination or metastases; CSI, craniospinal irradiation; XRT, radiation therapy.
Nonanaplastic histology
Anaplastic histology
GTR
STR
Consider CSI Adjuvant chemotherapy
Observation
Focal irradiation
Focal XRT to region of tumor only
Neoadjuvant chemotherapy
Second look surgery for attempted GTR
Focal XRT to region of tumor only
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FIGURE 3. Treatment algorithm for medulloblastoma. GTR, Gross total resection; STR, subtotal resection; M0, localized disease; M+, neuraxis dissemination or metastases; CSI, craniospinal irradiation; XRT, radiation therapy; BMT, bone marrow transplant.
Medulloblastoma
Standard risk: GTR(<1.5 cm3 residual), M0 disease
High risk: STR, M+ disease
Young children
Older children
3600 cGY CSI 3240 cGY tumor bed boost Adjuvant chemotherapy +/ BMT
Options include: Chemo alone +/ BMT or chemo + focal XRT
2340 cGY CSI 3240 cGY tumor bed boost Adjuvant chemotherapy
of adjuvant chemotherapy depends on patient age and associated risk factors at the time of diagnosis and treatment. Five-year survival rates range from 50% to 80% overall. Younger patients tend to have a poorer prognosis, in part related to the desire of most practitioners to avoid craniospinal irradiation. CRANIOPHARYNGIOMA Craniopharyngiomas are low-grade neoplasms that arise from remnants of Rathkes pouch. They are the most common nonglial brain tumor of childhood accounting for more than 5% of all intracranial tumors. There are two types of craniopharyngioma, of which the adamantimous type is much more common in childhood, with a peak incidence around age 5 to 9 years. The squamous papillary type rarely occurs in children. Endocrine dysfunction frequently occurs, with about 75% of the children having growth hormone deficiency at time of presentation. Hypothyroidism, diabetes insipidus, adrenal insufficiency, increased intracranial pressure, and/or visual changes are often present. Surgical resection remains the mainstay of therapy, despite the fact that the cystic and adherent nature of these tumors often makes surgical resection difficult or impossible. When complete resection is not achieved, adjuvant radiation therapy is used. Intralesional therapy with radioisotopes or infusion of bleomycin has been helpful in recurrent or progressive cystic tumors. Despite therapy, recurrence rates are as high as one third by 10 years. GERM CELL TUMORS Germ cell tumors (GCTs) account for 3% of childhood brain tumors. They are thought to be derived from embryonic cell rests located in the midline of the brain. These tumors typically arise in midline structures, located most often in the suprasellar or pineal regions.
They are twice as common in boys. Because of differential response to treatment, GCTs are divided into germinomas and nongerminomatous GCTs. Germinomas make up about half of all GCTs. Suprasellar GCTs usually present with visual field defects, diabetes insipidus, early or delayed puberty, or growth arrest. Tumors located in the pineal region more commonly present with signs and symptoms of elevated intracranial pressure. If a GCT is suspected on the basis of neuroimaging, CSF should be examined for the presence of malignant cells as well as biochemical markers (alpha-fetoprotein, beta-human chorionic gonadotropin, placental alkaline phosphatase), which may be helpful in establishing a diagnosis and useful in gauging response to therapy, particularly of the nongerminomatous GCTs. In addition, neuroimaging of the entire neuraxis should be performed because of the propensity for metastasis. Imaging should be performed prior to the lumbar puncture or surgery. In germinomas, where CSF tumor markers are generally noninformative, surgical resection and histopathologic evaluation is necessary for diagnosis, though maximal surgical resection may not be required for good outcome. Historically, treatment centered on radiation therapy, but more recently, combination therapy with neoadjuvant chemotherapy and reduced doses of radiation therapy is used (Figure 4). Though malignant in character, cure for germinomas is usual. Nongerminomatous GCTs (except mature teratomas) require maximal surgical resection, with neoadjuvant chemotherapy, radiation therapy, and consideration of high-dose therapy with stem cell rescue. Chemotherapeutic agents used include combination therapy with etoposide, cisplatin, cyclophosphamide, and vincristine or other combinations. High-dose chemotherapy with stem cell rescue has also been used. Mature teratomas can be treated with GTR alone. The prognosis for yolk sac tumors, embryonal carcinomas, and choriocarcinomas is poor with frequent recurrence and dissemination.
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Glioma
Germ cell tumors
Glioma
Surgical resection
Germinoma
NGGCT (except mature teratomas)
XRT alone vs. neoadjuvant chemotherapy and reduced dose XRT (response based)
Neoadjuvant chemotherapy and XRT +/ BMT
FIGURE 4. Treatment algorithm for germ cell tumors. NGGCT, Nongerminomatous germ cell tumor; XRT, radiation therapy; BMT, bone marrow transplant.
Summary
Brain tumors in children are variable in type, presentation, treatment, and outcome. Despite advances in therapy, outcomes are variable, with certain tumors having an excellent prognosis and others being near uniformly fatal. Morbidity of current therapies can be substantial, and efforts are ongoing to reduce the toxicity of current therapies while exploring novel therapeutic strategies. SUGGESTED READING
CBTRUS: Statistical report: primary brain tumors in the United States, 1995-1999, Chicago, 2002, Central Brain Tumor Registry of the United States. Saran F: Recent advances in paediatric neuro-oncology, Curr Opin Neurol 15:671-677, 2002.
PATIENT RESOURCES
The Childhood Brain Tumor Foundation 20312 Watkins Meadow Drive Germantown, MD 20876 Phone: 301-515-2900 http://www.childhoodbraintumor.org Childrens Brain Tumor Foundation (CBTF) 274 Madison Avenue, Suite 1301 New York, New York 10016 http://www.cbtf.org Pediatric Brain Tumor Foundation of the United States 302 Ridgefield Court Asheville, NC 28806 Phone: 828-665-6891 http://www.pbtfus.org
Approximately 30,000 patients are diagnosed with primary brain tumors each year in the United States. More than 17,000 of these tumors are malignant, and, of these, more than 60% are classified as gliomas. Although malignant brain tumors constitute approximately 2% of cancer diagnoses, they require special considerations both in treatment and patient management. The eloquent structures in the brain must be considered along with unique aspects of glioma tumor biology. The staging of primary brain tumors does not use the conventional TNM staging system that assists in the treatment planning and prognosis for nearly all other solid tumors. Because malignant gliomas rarely spread outside the central nervous system, the N component (nodal metastases) and the M component (distant metastases) would almost always have a value of zero. As a consequence, malignant gliomas are staged on the basis of their histologic grade. Tumor designation begins with grade 2 in most classification schemas, including the most popular World Health Organization (WHO) grading system. Grade 1 is reserved for noninfiltrating tumors, such as juvenile pilocytic astrocytomas, that are often cured by surgical resection. Grade 2 gliomas demonstrate increased cellularity, often with only mild degrees of pleomorphism and rare mitotic figures. Grade 3 neoplasms are marked by extensive pleomorphism and increased cellularity with mitotic figures but no necrosis. Grade 4 tumors are characterized by necrosis and include marked increases in cellularity and pleomorphism. Recently, some classification schemas, including the WHO, have permitted a diagnosis of grade 4 to be made only on the basis of vascular proliferation being present without a definitive finding of necrosis. This recent change in diagnostic criteria has not, however, been universally accepted. Although histologic grade remains the most important prognostic factor, survival varies within discrete grades. A wide range of outcomes has been reported, but most studies report survival of patients with grade 4 gliomas to be in the 10- to 12-month range, grade 3 having a 2- to 4-year range and grade 2 having a 5- to 8-year range. Other important prognostic factors include performance status and age at diagnosis (45 or 50 years of age as the separating point), with younger age being a more favorable prognostic indicator. Additional factors have been variably associated with outcome, such as extent of surgical resection, improved prognosis with seizures as the initial presenting feature, and tumor location with superficial tumors having the best prognosis. Recently, attention has been focused on finding molecular markers that can be used to further define individual prognoses within histologic grades and predict response or resistance to specific treatments. The prognostic importance and prediction
260
Glioma
Germ cell tumors
Glioma
Surgical resection
Germinoma
NGGCT (except mature teratomas)
XRT alone vs. neoadjuvant chemotherapy and reduced dose XRT (response based)
Neoadjuvant chemotherapy and XRT +/ BMT
FIGURE 4. Treatment algorithm for germ cell tumors. NGGCT, Nongerminomatous germ cell tumor; XRT, radiation therapy; BMT, bone marrow transplant.
Summary
Brain tumors in children are variable in type, presentation, treatment, and outcome. Despite advances in therapy, outcomes are variable, with certain tumors having an excellent prognosis and others being near uniformly fatal. Morbidity of current therapies can be substantial, and efforts are ongoing to reduce the toxicity of current therapies while exploring novel therapeutic strategies. SUGGESTED READING
CBTRUS: Statistical report: primary brain tumors in the United States, 1995-1999, Chicago, 2002, Central Brain Tumor Registry of the United States. Saran F: Recent advances in paediatric neuro-oncology, Curr Opin Neurol 15:671-677, 2002.
PATIENT RESOURCES
The Childhood Brain Tumor Foundation 20312 Watkins Meadow Drive Germantown, MD 20876 Phone: 301-515-2900 http://www.childhoodbraintumor.org Childrens Brain Tumor Foundation (CBTF) 274 Madison Avenue, Suite 1301 New York, New York 10016 http://www.cbtf.org Pediatric Brain Tumor Foundation of the United States 302 Ridgefield Court Asheville, NC 28806 Phone: 828-665-6891 http://www.pbtfus.org
Approximately 30,000 patients are diagnosed with primary brain tumors each year in the United States. More than 17,000 of these tumors are malignant, and, of these, more than 60% are classified as gliomas. Although malignant brain tumors constitute approximately 2% of cancer diagnoses, they require special considerations both in treatment and patient management. The eloquent structures in the brain must be considered along with unique aspects of glioma tumor biology. The staging of primary brain tumors does not use the conventional TNM staging system that assists in the treatment planning and prognosis for nearly all other solid tumors. Because malignant gliomas rarely spread outside the central nervous system, the N component (nodal metastases) and the M component (distant metastases) would almost always have a value of zero. As a consequence, malignant gliomas are staged on the basis of their histologic grade. Tumor designation begins with grade 2 in most classification schemas, including the most popular World Health Organization (WHO) grading system. Grade 1 is reserved for noninfiltrating tumors, such as juvenile pilocytic astrocytomas, that are often cured by surgical resection. Grade 2 gliomas demonstrate increased cellularity, often with only mild degrees of pleomorphism and rare mitotic figures. Grade 3 neoplasms are marked by extensive pleomorphism and increased cellularity with mitotic figures but no necrosis. Grade 4 tumors are characterized by necrosis and include marked increases in cellularity and pleomorphism. Recently, some classification schemas, including the WHO, have permitted a diagnosis of grade 4 to be made only on the basis of vascular proliferation being present without a definitive finding of necrosis. This recent change in diagnostic criteria has not, however, been universally accepted. Although histologic grade remains the most important prognostic factor, survival varies within discrete grades. A wide range of outcomes has been reported, but most studies report survival of patients with grade 4 gliomas to be in the 10- to 12-month range, grade 3 having a 2- to 4-year range and grade 2 having a 5- to 8-year range. Other important prognostic factors include performance status and age at diagnosis (45 or 50 years of age as the separating point), with younger age being a more favorable prognostic indicator. Additional factors have been variably associated with outcome, such as extent of surgical resection, improved prognosis with seizures as the initial presenting feature, and tumor location with superficial tumors having the best prognosis. Recently, attention has been focused on finding molecular markers that can be used to further define individual prognoses within histologic grades and predict response or resistance to specific treatments. The prognostic importance and prediction
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of response related to the finding of allelic loss of heterozygosity (LOH) of chromosomes 1p and 19q in anaplastic oligodendroglioma have been relatively recent areas of interest. Initial reports indicate that tumors with the classic histologic features of anaplastic oligodendroglioma containing the 1p and 19q allelic loss have a nearly 100% response to both chemotherapy and radiation and a markedly prolonged survival compared to histologically similar tumors without these chromosomal changes. The prognostic importance of other markers, such as overexpression of the epidermal growth factor receptor, has not been as definitive.
The presenting symptoms of a primary brain tumor are typically classified as generalized or focal. Headache, often the consequence of increased intracranial pressure from mass effect, and seizures are considered to be generalized symptoms, whereas deficits such as weakness, language dysfunction, or sensory loss are focal in nature. Seizures are a more common presenting feature in the lower grade tumors, whereas headache is more prevalent in patients with faster growing, high-grade tumors. Focal loss of neurologic function tends to be insidious with low-grade tumors, a consequence of their slower rate of growth. Acute events such as hemorrhage markedly alter the tempo of symptom onset regardless of tumor grade. Brain imaging, most commonly by magnetic resonance (MR) imaging both with and without gadoliniumbased contrast material, is used to evaluate the brain parenchyma. MR imaging has better resolution and is more sensitive for nonenhancing infiltrating tumors than traditional computed tomography (CT). However, CT scanning is better at imaging calcifications and bone structures. Although exceptions exist, high-grade tumors typically demonstrate contrast enhancement, whereas low-grade tumors tend to display no enhancement. Intermediate-grade neoplasms (i.e., anaplastic astrocytoma) tend to have patchy or no visible enhancement. Often the region of enhancement represents the most malignant component of a large tumor. The enhancing region is thus usually the optimal target of tissue sampling for diagnosis. Functional imaging, such as MR spectroscopy and positron emission tomography provide biochemical or physiologic data. Currently, these technologies have not proved useful in determining tumor grade, because there is overlap in their respective functional parameters. Functional imaging is therefore more commonly used when a distinction between treatment-related necrosis and recurrent tumor is needed. After discovery of a mass lesion, tissue is almost always required before appropriate treatment can be initiated. Exceptions to this rule are infiltrating brainstem glioma in children and similar lesions in adults, although in adults the histologic grade and natural history of the tumor can be quite varied. Therefore, whenever possible, a tissue sample should be obtained from brainstem tumors in adults.
The decision to perform a diagnostic biopsy or tumor resection is complex. Several factors, including tumor location, the patients overall physical status encompassing general health, number of lesions, and presence of significant mass effect, midline shift, or herniation, need to be considered. Biopsy, either open or using a stereotactic technique, is well tolerated with a low morbidity and short hospital stay. However, virtually none of the tumor burden is lessened, and sampling errors in the typically small sample is a critical issue, particularly for lower grade tumors. One study compared the diagnostic accuracy of biopsy with resection and found that 60% of diagnoses changed when a subsequent (within 4 weeks) resection was performed after a biopsy. However, tumor resection is a major operative procedure with increased risk of postoperative complications. Given the infiltrative nature of the cancer, temporary or permanent neurologic worsening remains an issue. Advances in neurosurgical technique, particularly intraoperative mapping and monitoring, have facilitated more complete resections while decreasing operative morbidity.
Supportive Care
Symptom management is a major component of the care required for patients with primary brain tumors. Corticosteroid treatment is often initiated after a mass lesion has been found by imaging studies. Dexamethasone is most commonly used because of its potent impact on edema and minimal mineralocorticoid effects. Equivalent doses of other corticosteroids can be equally effective but are less frequently used. Attempts should be made to reach the lowest effective dose because of the strong dose-to-toxicity relationship of this group of medications. Often, patients require the prophylactic use of H2 blockers to combat steroid-induced gastrointestinal symptoms such as gastritis. Dose reduction of corticosteroids in patients with brain tumors should be gradual because a rapid taper can result in rebound edema that quickly compromises neurologic function. Additionally, patients who have been on prolonged courses of corticosteroids should be evaluated for endogenous adrenal function or placed on physiologic doses of cortisone. Seizures are a major concern for patients with supratentorial tumors. As mentioned earlier, patients with lower grade tumors are more likely to present with seizures, and a higher incidence of seizures (70% to 80%) has been reported for low-grade tumors over the course of the illness. The seizure rate is lower in patients with higher-grade tumors, but it is more difficult for them to recover function after seizures. Although there is a nearly uniform consensus on the need for anticonvulsant treatment for patients with documented seizures, controversy exists about using anticonvulsants prophylactically. The several randomized trials of prophylactic anticonvulsant use in patients with brain tumors have been flawed by small patient populations and the lack of adequate monitoring of anticonvulsant levels. A meta-analysis of these studies performed by a consensus panel concluded that there are no data to
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Glioma
support the use of anticonvulsant prophylaxis. Newer anticonvulsants with better side effect profiles and no requirement for monitoring blood levels may prove to be more effective agents for prophylaxis in this patient population. Finally, the classic anticonvulsants such as phenytoin, carbamazepine, and phenobarbital can enhance the activity of cytochrome P450 enzymes in the liver, increasing the metabolism and clearance of some chemotherapeutic agents. Therefore, careful consideration of concurrent medications is required when contemplating the choice and dosing of chemotherapy for patients with brain tumors. Developing thromboembolic disease is a major concern for patients with primary brain tumors. Although the incidence over the course of the illness for patients with glioblastoma has been reported to be as high as 35% to 40%, prophylactic anticoagulation has not been recommended because of the risk of intracranial hemorrhage. A retrospective review showed that the rate of intratumoral hemorrhage did not increase in patients taking anticoagulants, but the severity of hemorrhage was greater. Once a deep vein thrombosis or pulmonary embolus has been diagnosed, patients without ongoing or prior intratumoral hemorrhage can be anticoagulated. Low-molecular-weight heparin and intravenous, nonfractionated heparin have been used successfully. No initial bolus should be used for administering intravenous heparinization. Instead, the anticoagulation should be allowed to gradually increase. Warfarin is often instituted after heparin use. A minimum of 3 days of heparin is recommended before initiating warfarin to avert the risk of transient hypercoagulation. Most studies use an international ratio (INR) of two to three times laboratory control as the desired level. The risk of recurrent thrombosis remains throughout the illness; therefore, most patients are maintained on chronic anticoagulation. The use of inferior vena cava filters is more controversial, with some physicians using them only for patients with hemorrhagic tumors, and others using them for all patients with pulmonary embolus to prevent additional passage of clot to the lungs. Studies confirm that, in the absence of systemic anticoagulation, the filters will clot within 4 to 6 weeks and venous collaterals will form, providing an alternative path for subsequent emboli.
Treatment
The treatment of primary brain tumors requires a multidisciplinary approach with consideration of the incurable nature of the disease and the potential for treatment to cause neurologic toxicity and deleteriously impact quality of life. Treatment regimens vary according to histologic category and tumor grade (Figure 1). GLIOBLASTOMA The treatment of glioblastoma almost always includes radiation therapy. Extensive evaluation has concluded that local field irradiation is equally effective and causes
less neurologic toxicity than whole-brain irradiation. Most treatment protocols use a fractionated schedule of 180 to 200 cGy to a total dose of approximately 60 Gy. Conformal planning, reducing exposure to surrounding brain, is the most common technology used. Other approaches, such as intensity-modulated radiation therapy, radiosurgery, and implantation of radiation into the tumor bed, have not shown improvement over conventional radiation treatment to date. Investigations in these areas continue in an effort to increase the radiation dose to the tumor while minimizing exposure to the surrounding normal brain parenchyma. Frequently, after completing radiation treatment, patients with glioblastoma are treated with systemic chemotherapy, often referred to as adjuvant chemotherapy. Overall survival and the progression-free benefit of this treatment has been modest. However, in a large randomized trial, a recent regimen that combined lowdose chemotherapy with the oral alkylating agent temozolomide and irradiation, followed by additional months of adjuvant temozolomide, demonstrated a survival advantage over irradiation alone. The treatment was well tolerated with only rare complications related to the addition of the chemotherapy. Therefore, it is likely that this regimen will be widely adopted. Chemotherapy (BCNU)-impregnated polymer in the form of a wafer also has been shown to improve survival in patients with newly diagnosed glioblastoma. A randomized, double-blind study compared surgery with implantation of the chemotherapy wafer to a group of patients undergoing surgery but with empty polymers. Both groups then received radiation therapy. A statistically significant improvement in survival was reported for patients receiving the chemotherapy-containing polymer. Thus far, no studies have compared a systemic chemotherapy strategy with wafer treatment to determine the optimal treatment for patients with newly diagnosed glioblastoma, so definitive guidelines have not been established. Some patients elect to undergo radiation therapy only, reserving the wafer and temozolomide as potential treatments at the time of tumor recurrence. At recurrence, various conventional chemotherapy treatments are used, including the nitrosoureas, BCNU and CCNU as well as chemotherapies such as irinotecan, carboplatin, or cisplatin and etoposide. Select patients may benefit from a tumor resection, reducing tumor mass and burden. Reoperation also permits the placement of chemotherapy-impregnated polymer wafers. Patients with recurrent glioblastoma are also encouraged to participate in approved clinical trials. ANAPLASTIC ASTROCYTOMA The treatment principles for anaplastic astrocytoma are similar to those for glioblastoma. Radiation therapy is a component of nearly all regimens. Because a concurrent chemotherapy-radiation therapy trial using temozolomide has not been performed in this group of patients, the benefit of this approach, although proved for glioblastoma, has not been established for anaplastic astrocytoma. Similarly, the use of the chemotherapyimpregnated wafer has not been tested for treating
Glioma
263
Neoplastic Disease
Brain mass detected (likely to be a primary brain tumor)
Maximal surgical debulking of tumor mass
FIGURE 1. A, Treatment approach algorithm for patients with a newly diagnosed glioma and glioblastoma. B, Anaplastic glioma (AG) algorithm. C, Low-grade glioma algorithm. GBM, Glioblastoma multiforme; AG, anaplastic glioma; LOH, loss of heterozygosity; PCV, procarbazine; BCNU, carmustine; CCNU, bincristine.
Frozen section during resection
GBM
Grade of tumor uncertain
Consider placement of BCNU wafers
Await final pathology
Yes
No
GBM
AG
Low-grade glioma
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Fractionated external beam radiotherapy Concurrent fractionated radiation plus daily temozolomide (75 mg/m2) See AG algorithm See low-grade glioma algorithm
A
ANAPLASTIC GLIOMA Anaplastic oligodendroglioma Anaplastic mixed oligostrocytoma Anaplastic astrocytoma Complete surgical resection Yes Observe Fractionated radiation therapy No Fractionated external beam radiotherapy LOW-GRADE GLIOMA
Chromosome analysis for 1p 19q LOH
LOH present
LOH absent
PCV or temozolomide
Adjuvant chemotherapy with BCNU/CCNU or temozolomide
Response
Progression
Observe
Fractionalized radiation therapy
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anaplastic tumors. Patients with anaplastic astrocytoma demonstrate a higher rate of response to systemic chemotherapies than those with glioblastoma multiforme. Although the use of adjuvant chemotherapy after radiation is prevalent, its benefit has not been proved. LOW-GRADE ASTROCYTOMA The treatment of low-grade astrocytoma is controversial. Most investigators concur with serial observation in young patients (< 40 years of age) who have undergone extensive tumor resection. Older patients or patients with extensive residual tumor often undergo extensive radiation therapy. Studies confirm that time to tumor growth is prolonged compared to untreated patients. However, most studies found that overall survival did not improve significantly. Chemotherapy is not widely used for low-grade astrocytoma. Reports of small series of patients treated with chemotherapy vary widely in the regimen used and response rate. Therefore, chemotherapy is often reserved for recurrent disease. OLIGODENDROGLIOMAS The optimal treatment for oligodendrogliomas is rapidly evolving. The recent discovery of the prognostic and predictive treatment response related to allelic chromosomal loss has dramatically impacted therapeutic decisions. Preliminary reports suggest that anaplastic oligodendrogliomas demonstrating classic histopathology with fried egg cellular morphology and a chicken wire vascular pattern that concurrently demonstrate allelic LOH of the 1p and 19q chromosome arms have nearly a 100% response rate to chemotherapy and/or radiation therapy. Nonclassic tumors without the same allelic loss have a response rate only in the range of 15% to 30%. Survival mirrors the marked difference in response. As a consequence of these dramatic findings, evaluation of chromosomes in oligodendroglial tumors is universal, and most centers base treatment decisions on these findings. Of note, although a small percentage of anaplastic astrocytomas demonstrate the 1p 19q LOH, this finding does not predict response or prognosis in the former as for oligodendroglial tumors. Similar chromosomal changes have been noted in low-grade oligodendroglial tumors, although few studies have evaluated their importance in these tumors. Because preliminary reports suggest that there is an association between these chromosomal perturbations and an increase in treatment response, patients with low-grade oligodendrogliomas containing the 1p and 19q LOH are being treated with chemotherapy as the initial treatment. Radiation therapy is reserved for recurrence, based on the rationale that delaying the use of radiation therapy postpones the risk of radiation-induced neurotoxicity. No formal studies have compared this chemotherapy approach with the more traditional radiation therapy regimen. Radiation therapy is still recommended for tumors that do not demonstrate 1p and 19q chromosomal changes.
Future Directions
New treatments are clearly needed to impact the poor prognosis that persists for patients with high-grade primary brain tumors. Innovative approaches, including immunotherapies, gene therapies, and targeted therapies that block specific signal transduction pathways, are being actively investigated. Immunotherapies initially focused on antibody strategies, but with the exception of intracavitary delivery strategies for a limited group of patients, delivery of the antibody to the tumor has been problematic. Newer investigations have focused on vaccine strategies, including dendritic cell stimulation. Gene therapy approaches have also been limited by inefficient delivery. Initial work in this area focused on direct injection into the tumor bed of retrovirus or adenovirus containing the herpes virus thymidine kinase gene. Successful transfection of tumor cells would lead to cell death after treatment with ganciclovir. Unfortunately, gene delivery was still inefficient and a large randomized phase III trial failed to prove the benefit of this approach. New gene therapy approaches include the use of genetically engineered neural stem cells to deliver genes or replication-competent virus to deliver genes or effect direct tumor cell death via viral-mediated cell lysis. Early clinical trials are underway using the latter approach. New molecules that specifically block signal transduction pathways are currently undergoing extensive analysis. These include drugs that block angiogenesis (vascular endothelial growth factor receptor), proliferation, tumor cell invasion and survival (epidermal growth factor receptor), cell survival (platelet-derived growth factor receptor), as well as different inhibitors of downstream signaling molecules such as AKT, Ras, Raf kinase, and mTOR. Clinical trials are now focusing on determining the optimal biologic dose of these agents and determining effective combinations because results from single-agent studies have been disappointing.
Conclusions
Malignant primary brain tumors present continuing challenges in patient care as well as finding effective therapies. Management issues include the progressive loss of neurologic function, seizures, long-term consequences of medications such as corticosteroids, issues related to rehabilitation, and the high incidence of thromboembolic disease. Response to treatment is often modest and transient for most patients, and the prognosis remains grim. The recent discovery of the prognostically important chromosomal changes in the oligodendroglial tumors has generated enthusiasm that molecular classification will ultimately permit customized treatment for patients with brain tumor, improving response and sparing them from unnecessary treatment. Extending molecular profiling efforts will ultimately permit optimal selection of signal transduction inhibitors tailored to individual tumors. These promising avenues of basic and clinical research provide hope for major therapeutic advances in the near future.
Brain Metastases
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SUGGESTED READING
Behin A, Hoang-Xuan K, Carpentier AF, Delatter JY: Primary brain tumors in adults, Lancet 361:323-331, 2003. Kitange GJ, Templeton BA, Jenkins RB: Recent advances in the molecular genetics of primary gliomas, Curr Opin Oncol 15: 197-203, 2003. Parney IF, Chang SM: Current chemotherapy for glioblastoma, Cancer J 9:149-156, 2003. Tremont-Lukas IW, Gilbert MR: Advances in molecular therapies in patients with brain tumors, Cancer Control 10:125-137, 2003.
in the brain. However, the signs and symptoms related to cerebral metastatic lesions may be extremely varied, and the suspicion of brain metastases should be raised in all patients with known systemic cancer in whom new neurologic findings develop.
Diagnosis
The best diagnostic test for brain metastases is contrast enhanced magnetic resonance (MR) imaging. If the clinical history is typical and lesions are multiple, usually there is little doubt surrounding the diagnosis. However, it is important that metastases be distinguished carefully from primary brain tumors (benign or malignant), abscesses, cerebral infarction, and hemorrhages. Other diagnostic tests, such as arteriography or biopsy, may be needed to establish the diagnosis firmly.
PATIENT RESOURCES
The American Brain Tumor Association 2720 River Road Des Plaines, IL 60018 Phone: 800-886-2282 http://www.abta.org/ The National Brain Tumor Federation 22 Battery Street, Suite 612 San Francisco, CA 94111-5520 Phone: 415-834-9970 http://www.braintumor.org/ Information web site http://www.virtualtrials.com/
Treatment
Corticosteroids, radiation therapy, surgical therapy, and radiosurgery all have an established place in management. In addition, chemotherapy is useful in some patients with chemosensitive tumors. There are several things to be considered when determining the best treatment for each patient, including the extent of systemic disease, neurologic status at diagnosis, and the number and site of metastases. Regardless of treatment, brain metastases are associated with a poor prognosis. Untreated patients have a median survival of only about 4 weeks. Nearly all untreated patients die as a direct result of the brain tumor, with increasing intracranial pressure leading to obtundation and terminal cerebral herniation. Almost all patients with brain metastases should be started on corticosteroid (steroid) therapy at diagnosis. The usual dose is dexamethasone, 4 mg, four times a day. Patients with small, completely asymptomatic lesions may not need steroids; however, steroids may reduce the side effects of cranial radiation therapy and are rarely harmful for short periods. The mechanism of action of corticosteroids is not completely understood, although a reduction in the edema surrounding the metastatic tumors is a frequent finding. The beneficial effects of steroids are noticeable within 6 to 24 hours after the first dose and reach maximum effect in 3 to 7 days. The median survival time of patients treated with steroids alone is approximately 2 months. Seizures occur in about 25% of patients with brain metastases and are the presenting complaint in 10% to 15% of patients. Randomized studies have shown that prophylactic anticonvulsants do not reduce the frequency of first seizures in patients with newly diagnosed brain metastases. Therefore, anticonvulsants should be given only to patients who have actually had seizures and should not be given routinely to all patients when brain metastasis is diagnosed. Conventional radiation therapy is the treatment of choice for most patients with brain metastases. This is because more than three fourths have multiple
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Brain Metastases
Brain metastases are tumors that originate in tissues outside the brain and spread secondarily to involve the brain. Although the development of brain metastases still usually indicates a poor prognosis for the patient, advances in treatment have made it possible to reverse most of the symptoms and give patients a meaningful extension of life. For most patients with cerebral metastases, treatment will prevent death from causes related to the brain metastases. Metastases to the brain are the most common intracranial tumors in adults and outnumber primary brain tumors by at least 10:1 and affect 20% to 40% of cancer patients. Most tumor cells are carried to the brain by the blood, almost always through the arterial circulation. Metastases do not appear randomly in the brain but are usually found in the area of the gray-white junction. This is due to a change in the size of blood vessels at that pointthe narrowed vessels act as a trap for tumor emboli. Brain metastases may be single or multiple. About three fourths of patients have multiple brain metastases at diagnosis. More than two thirds of patients with brain metastases have some neurologic symptoms during the course of their illness. More than 80% of brain metastases are discovered sometime after the diagnosis of systemic cancer has been made. The clinical presentation of brain metastases is similar to that of other mass lesions
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SUGGESTED READING
Behin A, Hoang-Xuan K, Carpentier AF, Delatter JY: Primary brain tumors in adults, Lancet 361:323-331, 2003. Kitange GJ, Templeton BA, Jenkins RB: Recent advances in the molecular genetics of primary gliomas, Curr Opin Oncol 15: 197-203, 2003. Parney IF, Chang SM: Current chemotherapy for glioblastoma, Cancer J 9:149-156, 2003. Tremont-Lukas IW, Gilbert MR: Advances in molecular therapies in patients with brain tumors, Cancer Control 10:125-137, 2003.
in the brain. However, the signs and symptoms related to cerebral metastatic lesions may be extremely varied, and the suspicion of brain metastases should be raised in all patients with known systemic cancer in whom new neurologic findings develop.
Diagnosis
The best diagnostic test for brain metastases is contrast enhanced magnetic resonance (MR) imaging. If the clinical history is typical and lesions are multiple, usually there is little doubt surrounding the diagnosis. However, it is important that metastases be distinguished carefully from primary brain tumors (benign or malignant), abscesses, cerebral infarction, and hemorrhages. Other diagnostic tests, such as arteriography or biopsy, may be needed to establish the diagnosis firmly.
PATIENT RESOURCES
The American Brain Tumor Association 2720 River Road Des Plaines, IL 60018 Phone: 800-886-2282 http://www.abta.org/ The National Brain Tumor Federation 22 Battery Street, Suite 612 San Francisco, CA 94111-5520 Phone: 415-834-9970 http://www.braintumor.org/ Information web site http://www.virtualtrials.com/
Treatment
Corticosteroids, radiation therapy, surgical therapy, and radiosurgery all have an established place in management. In addition, chemotherapy is useful in some patients with chemosensitive tumors. There are several things to be considered when determining the best treatment for each patient, including the extent of systemic disease, neurologic status at diagnosis, and the number and site of metastases. Regardless of treatment, brain metastases are associated with a poor prognosis. Untreated patients have a median survival of only about 4 weeks. Nearly all untreated patients die as a direct result of the brain tumor, with increasing intracranial pressure leading to obtundation and terminal cerebral herniation. Almost all patients with brain metastases should be started on corticosteroid (steroid) therapy at diagnosis. The usual dose is dexamethasone, 4 mg, four times a day. Patients with small, completely asymptomatic lesions may not need steroids; however, steroids may reduce the side effects of cranial radiation therapy and are rarely harmful for short periods. The mechanism of action of corticosteroids is not completely understood, although a reduction in the edema surrounding the metastatic tumors is a frequent finding. The beneficial effects of steroids are noticeable within 6 to 24 hours after the first dose and reach maximum effect in 3 to 7 days. The median survival time of patients treated with steroids alone is approximately 2 months. Seizures occur in about 25% of patients with brain metastases and are the presenting complaint in 10% to 15% of patients. Randomized studies have shown that prophylactic anticonvulsants do not reduce the frequency of first seizures in patients with newly diagnosed brain metastases. Therefore, anticonvulsants should be given only to patients who have actually had seizures and should not be given routinely to all patients when brain metastasis is diagnosed. Conventional radiation therapy is the treatment of choice for most patients with brain metastases. This is because more than three fourths have multiple
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Brain Metastases
Brain metastases are tumors that originate in tissues outside the brain and spread secondarily to involve the brain. Although the development of brain metastases still usually indicates a poor prognosis for the patient, advances in treatment have made it possible to reverse most of the symptoms and give patients a meaningful extension of life. For most patients with cerebral metastases, treatment will prevent death from causes related to the brain metastases. Metastases to the brain are the most common intracranial tumors in adults and outnumber primary brain tumors by at least 10:1 and affect 20% to 40% of cancer patients. Most tumor cells are carried to the brain by the blood, almost always through the arterial circulation. Metastases do not appear randomly in the brain but are usually found in the area of the gray-white junction. This is due to a change in the size of blood vessels at that pointthe narrowed vessels act as a trap for tumor emboli. Brain metastases may be single or multiple. About three fourths of patients have multiple brain metastases at diagnosis. More than two thirds of patients with brain metastases have some neurologic symptoms during the course of their illness. More than 80% of brain metastases are discovered sometime after the diagnosis of systemic cancer has been made. The clinical presentation of brain metastases is similar to that of other mass lesions
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metastases at diagnosis, which usually makes surgical or other focal treatment ineffective. There remains no consensus on the optimum radiation dose and schedule for the treatment of brain metastases. Currently, typical radiation treatment schedules for brain metastases consist of short courses (7 to 15 days) of whole-brain radiation therapy (WBRT) with relatively high doses per fraction (200 to 400 cGy/day) with total doses in the range of 3000 to 5000 cGy. These schedules minimize the duration of treatment while still delivering adequate amounts of radiation to the tumor. Giving a boost dose of conventional radiation to the tumor along with WBRT is no better than WBRT alone in preventing neurologic recurrences or increasing survival. WBRT increases the median survival to 3 to 6 months. Data from large retrospective studies have shown that more than half of patients treated with WBRT die of progressive systemic cancer and not from their brain metastases. Conventional surgery has an established place in the management of brain metastases. There have been three prospective, randomized trials assessing the value of surgical removal of single brain metastases. In a prospective, randomized trial performed at the University of Kentucky, 48 patients with known systemic cancer were treated with either biopsy of the suspected brain metastasis plus WBRT or complete surgical resection of the metastasis plus WBRT. There was a statistically significant increase in survival in the surgical group (10 vs. 4 months). In addition, the time to recurrence of brain metastases, freedom from death due to neurologic causes, and duration of functional independence were significantly longer in the surgical group. A second randomized study, conducted as a multi-institutional trial in the Netherlands, contained 63 evaluable patients. Patients were randomized to either complete surgical resection plus WBRT or WBRT alone. Survival was significantly longer in the surgical group (10 vs. 6 months). There was also a nonsignificant trend toward longer duration of functional independence in the surgically treated patients. A third randomized trial, conducted in Canada by Mintz and associates (see Suggested Reading), failed to find a benefit from surgical treatment. In that study, 84 patients were randomized to receive radiation therapy alone or surgery plus radiation therapy. No difference was found in overall survival; the median survival was 6.3 months in the radiation therapy alone group and 5.6 months for the surgical group. There was also no difference in causes of death or quality of life. It is unclear why the results from the Canadian study differed from the other two trials. In all three studies, the control arms (the radiation-alone arms) had median survivals in the 3- to 6-month rangewithin the expected range for patients treated with radiation therapy alone. The major difference in the studies was the poor outcome obtained in the surgical arm of the Canadian trial. That study contained a higher proportion of patients with extensive systemic disease and lower performance scores. Differences in patient selection in the Canadian trial may well have contributed to its failure to detect a significant benefit from the addition of surgical therapy. Also, the Canadian health care system sometimes discourages aggressive and expensive treatment
for patients with disseminated cancer. It is possible that these factors (i.e., selection/philosophy) resulted in more patients dying of their systemic cancer before a longterm benefit of surgery was seen. Although the data supporting surgery for single brain metastases were derived from relatively small, randomized trials that were not uniformly positive, the results have generally been interpreted to show that surgical resection is beneficial in selected patients. The value of surgery in the management of multiple metastases remains to be demonstrated. It is difficult to draw firm conclusions regarding the efficacy of surgery for multiple metastases from the studies published to date. Current practice is to treat multiple metastases with WBRT alone. Surgery is sometimes performed on patients with multiple metastases who have one lifethreatening brain lesion (e.g., a large compressive cerebellar lesion). The intent of surgery in these cases is to remove the single life-threatening lesion and to treat the remaining tumors with WBRT. A point of controversy has been whether postoperative radiation therapy needs to be given as WBRT (as opposed to focal irradiation) or whether radiation therapy is even necessary at all after a complete resection of a single metastasis. There is no doubt that radiation therapy, when given as the only treatment for brain metastases, results in longer survival. Postoperative WBRT is thought to be beneficial because there may be residual disease in the tumor bed or at distant microscopic sites in the brain. However, brain metastases tend to be discrete masses that are theoretically capable of being removed totally, and so postoperative WBRT may not be necessary. Retrospective studies that examined the role of postoperative radiation therapy in the management of single brain metastasis failed to answer the question because of conflicting results. Only one randomized trial has addressed the question of postoperative radiation therapy. In that study, 95 patients who had single brain metastases that were completely resected (as determined by postoperative MR scans) were randomized to postoperative WBRT (50.4 Gy) or to observation with no further treatment of the brain metastasis (until recurrence). Recurrence of tumor anywhere in the brain was significantly less frequent in the radiation therapy group than in the observation group (18% vs. 70%). Postoperative radiation therapy prevented brain recurrence at the site of the original metastasis (10% vs. 46%) and at other sites in the brain (14% vs. 37%). As a result, patients in the radiation therapy group were less likely to die of neurologic causes than patients in the observation group (6 [14%] of 43 who died vs. 17 [44%] of 39). However, there was no significant difference between the two groups in overall survival or the time patients remained functionally independent. The lack of difference in overall survival and quality of life may be explained by the fact that of the 32 patients in the observation group who had recurrence of brain metastases, 29 (91%) received WBRT at recurrence. This diluted the effect of WBRT given immediately postoperatively by most likely improving survival and quality of life in the observation group. Based on the best current evidence, adjuvant WBRT with conventional surgery (and stereotactic radiosurgery)
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is clearly the treatment of choice. There is no doubt that WBRT substantially reduces the recurrence of brain metastases. The side effects of WBRT have been overstated in the past and are in the acceptable range. On the other hand, the side effects of recurrent brain metastases are unacceptable and far outweigh any potential problems associated with WBRT. Therefore, adjuvant WBRT should almost always be given in conjunction with surgery (or radiosurgery). Stereotactic radiosurgery, a method of delivering intense focal irradiation using a linear accelerator (LINAC) or a multiple cobalt 60 sources (gamma knife), has an established place in the management of brain metastases. Radiosurgery does not replace conventional radiation therapy to the brain but instead offers a substitute for surgical therapy in patients with lesions less than 3 cm in diameter. The role of radiosurgery in the treatment of multiple metastases has recently been the subject of three randomized trials. The first randomized trial on the subject was reported by Kondziolka and colleagues. This study contained only 27 patients and used nonstandard endpoints. As a result, it was uninterpretable. A second study reported by Chougule and coworkers contained methodologic errors that made it impossible to draw firm conclusions from the data. The Radiation Therapy Oncology Group (RTOG) reported the results of a randomized study involving patients with multiple brain metastases and single brain metastases. This study (RTOG 9508) contained 333 evaluable patients who were randomized to treatment with either WBRT (37.5 Gy) plus radiosurgery or WBRT (37.5 Gy) alone. In patients with multiple metastases, there was no significant difference in failure rates in the brain: 21% in the radiosurgery arm and 37% in the WBRT-alone arm. There was also no significant difference in survival of the two groups (median, 5.3 months for radiosurgery and 6.7 months for WBRT alone). Most noteworthy was the lack of difference between the proportions of patients in each group who died of neurologic causes (33% radiosurgery vs. 35% WBRT alone). Lower post-treatment Karnofsky scores and steroid dependence were more common in the WBRT alone patients. Nevertheless, for multiple brain metastases, this was a completely negative trial with regard to the major endpoints of tumor control in the brain, prevention of death due to neurologic causes, and overall survival. For patients with single metastases, there was a significant survival advantage favoring radiosurgery (median, 4.9 vs. 6.5 months). This study established the efficacy of radiosurgery for the treatment of single brain metastases but did not support its use for multiple brain metastases. Although chemotherapy has not yet emerged as a standard of therapy for patients with brain metastases, evidence has been accumulating that chemotherapy may have a role in the treatment of selected patients. Chemotherapy has been used in the treatment of brain metastases from a variety of primary tumors, but results are generally modest. However, brain metastases from certain highly chemosensitive tumors (e.g., breast, small cell lung cancer, germ cell tumors) have been
treated effectively with chemotherapy. More recently, temozolomide, a new oral chemotherapeutic agent, has shown some promise in the treatment of metastases. However, chemotherapy is rarely the primary therapy for most patients and is seldom the only therapy. At present, a reasonable use for chemotherapy for brain metastases would be in those patients with small, asymptomatic tumors from primaries that are known to be chemosensitive. If progression occurs with the patient receiving chemotherapy alone, more definitive treatment with surgery, radiosurgery, or radiation therapy may be given. SUGGESTED READING
Andrews DW, Scott CB, Sperduto PW, et al: Whole-brain radiotherapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial, Lancet 363:1665-1672, 2004. Berk L: An overview of radiotherapy trials for the treatment of brain metastases, Oncology 9:1205-1219, 1995. Mintz AH, Kestle J, Gaspar L, et al: A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with single cerebral metastasis, Cancer 78:1470-1476, 1996. ONeill BP, Iturria NJ, Link MJ, et al: A comparison of surgical resection and stereotactic radiosurgery in the treatment of solitary brain metastases, Int J Radiat Oncol Biol Phys 55:1169-1176, 2003. Patchell RA: The management of brain metastases, Cancer Treat Rev 29:533-540, 2003. Patchell RA, Regine WF: The rationale for adjuvant whole-brain radiation therapy with radiosurgery in the treatment of single brain metastases, Technol Cancer Res Treat 2:111-116, 2003. Patchell RA, Tibbs PA, Regine WF, et al: Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial, JAMA 280:1485-1489, 1998. Patchell RA, Tibbs PA, Walsh JW, et al: A randomized trial of surgery in the treatment of single metastases to the brain, N Engl J Med 322:494-500, 1990. Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al: Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery, Ann Neurol 33:583-590, 1993.
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PATIENT RESOURCES
American Brain Tumor Association 2720 River Rd., Suite 146 Des Plaines, IL 60018 Phone: 800-886-2282 Fax: 847-827-9918 E-mail: info@abta.org http://www.abta.org/ The Brain Tumor Society 84 Seattle St. Boston, MA 02134-1245 Phone: 800-770-8287 Fax: 617-783-0340 E-mail: info@tbts.org http://www.tbts.org/ The Healing Exchange BRAIN TRUST MIT-Kendall 425743 Cambridge, MA 02142-0014 Phone: 617-623-0066 Fax: 617-623-2203 E-mail: info@braintrust.org http://www.braintrust.org/ National Brain Tumor Foundation 785 Market St., Suite 1600 San Francisco, CA 94103 Phone: 800-934-2873 Fax: 415-284-0209 E-mail: nbtf@braintumor.org http://www.braintumor.org/
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Heinrich Elinzano, M.D., and John Laterra, M.D., Ph.D.
Epidural Spinal Cord Compression

The most common cause of acute myelopathy in the middle to late decades of life is epidural spinal cord compression (ESCC) from metastatic carcinoma. Clinically evident epidural metastasis is estimated to occur in 3% to 7% of cancer patients. Most cases arise from metastasis to a vertebral body. A smaller percentage arise from the posterior pedicles. Progressive tumor growth results in compression of the dural sac and its contents (spinal cord, cauda equina, and nerve roots). If untreated, metastatic spinal cord compression can lead to progressive pain, paralysis, sensory loss, and sphincter dysfunction. This is a neurologic emergency since early diagnosis and prompt management are strong predictors of favorable neurologic outcome. ETIOLOGY It is thought that tumor cells gain access to the spine and spinal canal via the valveless venous system known as Batsons plexus that drains the skull and the spine and anastomoses with veins that drain the breasts, thoracic, abdominal, and pelvic organs. Arterial seeding of vertebral bodies is another route implicated in metastasis to the spine. Once the vertebral bodies are involved, direct extension of the tumor may occur and compress the spinal canal directly or by extruded bony fragments from involved vertebral bodies in the epidural space. Irreversible spinal cord injury ultimately results from direct compression, venous hypertension and edema, ischemia, and infarction. Most systemic cancer has the potential to metastasize or spread contiguously to the spine and spinal epidural space. There is a strong correlation between the incidence of the tumor and its tendency for spinal involvement. About 50% of ESCC in adults arise from breast, lung, or prostate cancer. Although most cases of ESCC are clinically suspected and eventually diagnosed in patients known to have cancer, 20% of ESCC cases arise as initial manifestation of cancer. Suspicion warrants immediate investigation to rule in or rule out ESCC. SIGNS AND SYMPTOMS Pain is the most common symptom of ESCC, and it may precede the diagnosis by days to even several months. Pain can be local, radicular, or both, depending on the
extent of tumor involvement of the spine, the spinal canal and its contents, and/or the neural foramen. It may occur at any level and is frequently aggravated by recumbency. This feature of the pain may be due to increased epidural venous distention in recumbency. Motor weakness is the most common sign followed by sensory abnormality, reflex changes, spinal tenderness, and autonomic dysfunction (bowel/bladder). Weakness can progress rapidly to paralysis in hours or days. Patients who are plegic at presentation have a substantially poorer prognosis for future ambulation (0 to 25%) compared with those who are ambulatory on initial presentation (60% to 100%). EVALUATION ESCC should be suspected in patients with known cancer who present with back pain even if myeloradiculopathic signs and/or autonomic dysfunction are absent. A detailed neurologic examination is absolutely critical to determine whether there is segmental radiculopathy, myelopathy, or autonomic dysfunction attributable to the spinal cord. More than half of spinal epidural metastases arise in the thoracic spine and about a third in the lumbosacral region, reflecting the relative proportion of bone volume in each of these spinal regions. The exact localization of the lesion within the spinal axis is less important than early diagnosis and immediate management. Neuroimaging studies of the whole spine should be completed as soon as possible to confirm any clinical suspicion of ESCC and also to detect multilevel involvement. Suspected ESCC is a true neurologic emergency, and magnetic resonance (MR) imaging should be completed within 3 to 6 hours, if possible. MR imaging is the modality of choice since MR is both highly sensitive and specific with an overall diagnostic accuracy of 95% in detecting ESCC. About a third of patients with back pain and known bone metastasis can have radiographic evidence of ESCC by gadolinium MR imaging despite a normal neurologic examination. Plain films of the spine and technetium bone scan are helpful ancillary tests in directing plan of care. Myelography and CT scanning are the imaging modalities of choice if MR imaging is unavailable or contraindicated. Myelography can acutely exacerbate neurologic deficits in the presence of complete spinal subarachnoid block due to pressure shifts, and to minimize this, only a small volume of cerebrospinal fluid (CSF) should be removed for cells, protein, and cytology. THERAPY The overall survival of patients with ESCC is typically dictated by the natural history and total body burden of the underlying primary cancer despite the fact that ESCC itself carries significant morbidity to the cancer patient. The goal of treatment therefore is to improve the patients quality of life by eliminating pain and preserving or improving motor, sensory, and autonomic functions. In addition to early diagnosis and prompt management of ESCC, the success of treatment also
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depends on the extent of epidural disease and patient performance status at diagnosis. Tumor histology and chemo-radioresponsiveness of the tumor as well as the time between diagnosis of the underlying primary tumor and the appearance of ESCC are other important prognostic factors. There are three specific treatments for ESCC: glucocorticoids, surgery, and radiation therapy. Chemohormonal modalities are used mainly as adjunctive therapy. An algorithm of early diagnosis and treatment of patients with ESCC is presented in Figure 1. This algorithm is presented as a general guide to the management of
ESCC, and it is by no means a rigid flow chart to be adhered to in all circumstances. It is recommended that the entire clinical situation dictate ones plan of action keeping in mind that ESCC is a neurologic emergency. Glucocorticoids Glucocorticoids play an important role in the initial treatment plan by reversing vasogenic edema and local mass effect. Glucocorticoids can also have direct cytotoxic effects on cancer cells, particularly lymphoma. The clinical impact of this cytotoxic effect on overall neurologic outcome is not known. Glucocorticoids have been shown to improve neurologic outcome in animal models and in a randomized clinical study comparing patients treated with radiation alone or radiation plus dexamethasone. It is imperative that glucocorticoid therapy is started as soon as clinical and radiographic diagnosis of ESCC is made. When clinical suspicion is very high, glucocorticoid therapy can be administered emergently while awaiting diagnostic neuroimaging studies. In addition to reducing spinal cord compression, glucocorticoids improve pain due to vertebral bone metastasis and neural compression, thus providing rapid symptomatic relief for the patient. Dexamethasone is the most commonly used glucocorticoid for ESCC. Methylprednisolone has also been used; however, there is no randomized study comparing the two. Although there is no definite consensus as to the most appropriate glucocorticoid dose for ESCC, aggressive therapy is recommended in patients with severe or progressive neurologic deficits and/or cord compression by imaging studies. In this circumstance, patients should receive dexamethasone, 100 mg intravenously, followed by an initial maintenance dose of 10 to 20 mg intravenously every 6 hours. Patients thought to be at low risk for acute decompensation can be initially treated with lower daily doses. A phase II trial has shown good posttreatment ambulation outcome in patients with minimally symptomatic ESCC, that is, no neurologic deficit or with only signs of radiculopathy and no extensive spinal metastasis or spinal instability on MR imaging or CT scan treated with radiation therapy alone and no steroids. Therefore, glucocorticoids prior to radiation therapy may not be necessary in asymptomatic, nonparetic, and ambulatory patients without radiographic evidence of spinal cord compression. As expected, the acute side effects such as anxiety, insomnia, psychosis, and hyperglycemia can result from high dose glucocorticoid regimens. Surgery Although several studies in the past have reported similar results using surgery plus radiation therapy or radiation therapy alone in patients with ESCC, a recent randomized trial showed that radical decompressive surgery prior to radiation therapy can have significant benefits over radiation therapy alone. Surgery prior to radiation therapy improved ambulation and reduced steroid and narcotic requirements. These results reflect the trend toward more aggressive tumor resection via vertebral corpectomy (the most common site of epidural spinal cord metastasis) and spine stabilization rather
EPIDURAL SPINAL CORD COMPRESSION ALGORITHM Back pain myeloradiculopathy
Plain films of the spine
Osteolysis and/or osteosclerosis vertebral spinal fracture or collapse Yes No Bone scan (MRI in radiculopathy patients) MRI or CT Positive Negative
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ESCC Yes No Analgesics and close follow-up
Moderate to high dose glucocorticoids
Radiotherapy surgery in 24 hrs chemo-hormonal therapy
Neurologic progression Yes Surgery in patients submitted to radiotherapy alone No Continue radiotherapy or postoperative radiotherapy
FIGURE 1. Algorithm of early diagnosis and therapy in patients with metastatic spinal cord compression. ESCC, Epidural spinal cord compression. (Adapted from Maranzano E, Trippa F, Chirico L, et al: Management of metastatic spinal cord compression, Tumori 89:469-475, 2003.) Johnson: Current Therapy in Neurologic Disease (7/E)
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than posterior decompressive laminectomy. Neurosurgical evaluation should therefore be carried out as soon as possible in patients with acceptable long-term prognosis. Surgery may also be required in patients with spinal instability, bony compression on the contents of the spinal canal and/or neural foramen, or radioresistant tumor. Other indications for surgery include a need to establish a tissue diagnosis (CT-guided percutaneous vertebral biopsy can be an alternative to open surgery) and progressive disease within a previously radiated field. Obviously, the patients performance status, life expectancy, and extent of systemic tumor burden are important factors in considering aggressive surgical options. Radiation Therapy Nearly all patients receive radiation therapy either alone or following decompressive surgery. There is a tendency to initiate radiation therapy alone as the treatment of choice because of its efficacy in preventing tumor progression and neurologic damage and the difficulty in emergently assembling the multidisciplinary surgical team required for vertebral corpectomy. The degree of functional limitation when radiation therapy is instituted, size of the extramedullary mass, extent of CSF obstruction, and tumor radiosensitivity are important factors affecting neurologic outcome following radiation therapy. Radiation therapy alone is in fact effective in most cases of ESCC from highly radioresponsive tumors such as multiple myeloma, germ cell tumors, or lymphoproliferative tumors. Radiation doses are influenced by tumor type and radiosensitivity of normal spinal cord. Typical radiation doses consist of 2500 to 3600 cGy delivered in 10 to 15 fractions. Some studies have shown efficacy and good spinal tolerance to hypofractionated radiation therapy. Radiation portals are centered on the site of epidural compression and normally include two vertebral segments above and below disease margins. This is based on the fact that over half of epidural recurrences are located within two vertebral bodies of the site of the initial compression. In the setting of postoperative treatment, radiation therapy is usually initiated about 7 to 10 days following surgery. Experience suggests that highly localized ablative radiation therapy using frameless image-guided methodologies (e.g., Cyber Knife) can be an alternative to conventional fractionated radiation therapy when tumor volumes are relatively low and tumor margins are well demarcated from the spinal cord. Radiation-induced myelopathy is an important complication of spinal radiation. Radiation injury appears most often within the first year following treatment but can also occur years later. It may present subacutely or as a chronic progressive process. Radiation myelopathy is believed to result from white matter and vascular damage. It is radiation dose dependent, with an incidence of approximately 5% for 4500 cGy administered in standard daily 180- to 200-cGy fractions. Other factors that increase the risk of radiation-induced myelopathy include young patient age, accelerated hyperfractionated radiation schedules, treatment volume, and concurrent
use of chemotherapeutic agents. Radiation-induced brachial or lumbar plexopathy also occurs in about 10% of patients who received conventional radiation therapy to the spine using ports that include these structures. Chemohormonal Therapy Chemotherapy administered alone or in combination with radiation therapy may be an option in patients with chemosensitive tumors who are either poor surgical candidates or have recurrent disease after already receiving maximal spinal irradiation. There are no randomized, controlled studies employing chemotherapy with radiation therapy or using chemotherapy in the neoadjuvant setting prior to planned surgical or radiation therapy. Nonrandomized studies and case reports describe some success in chemosensitive tumors such as lymphoma, breast cancer, germ cell tumors, small cell lung carcinoma, myeloma, and neuroblastoma. Hormonal therapy can play a palliative role in hormone-naive patients with ESCC from breast or prostate cancer. REHABILITATION The management of ESCC should be a multidisciplinary team approach. It is important to involve spinal cord rehabilitation physicians early even in the acute setting since they make helpful recommendations regarding the general care of patients with spinal cord dysfunction. They will also eventually assume a significant role in the rehabilitation of these patients, who can survive a year or more following ESCC depending on the stage of the primary tumor. General supportive care measures should include adequate pain control with judicious use of nonsteroidal anti-inflammatory drugs, narcotic analgesics, and membrane-stabilizing agents. Appropriate attention should be paid to associated medical issues such as respiratory, gastrointestinal, nutrition, deep vein thrombosis prophylaxis, neurogenic bowel and bladder, skin, orthostasis, heterotopic ossification, spasticity, autonomic dysreflexia, and hypercalcemia with the assistance of the spinal cord injury physicians. Physical and occupational therapy evaluation should be initiated as soon as the immediate medical and surgical issues are addressed.
Leptomeningeal Metastasis
Cancer metastasizes to the leptomeninges in about 5% of all cancer patients. Leptomeningeal is rarely the first sign of cancer. The presence of cancer cells in the leptomeninges or in the CSF is generally referred to as leptomeningeal metastasis (LM), or alternatively as neoplastic meningitis. LM is also called leptomeningeal carcinomatosis or carcinomatous meningitis when cancer metastasizes from a solid carcinoma, leukemic meningitis from leukemia, or lymphomatous meningitis from lymphoma. The frequency of LM is increasing, as more cancer patients are surviving longer from improved systemic cancer therapy. Although LM can arise from almost any solid systemic tumor, breast carcinoma, lung carcinoma,
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and melanoma are the most common primary solid cancers that metastasize to the leptomeninges. Leukemias such as acute lymphoblastic leukemia and acute myelocytic leukemia and lymphomas represent most of the hematologic malignancies that cause neoplastic meningitis. Rarely, lymphoma can be isolated to the leptomeninges without parenchymal or systemic involvement, a condition known as primary leptomeningeal lymphoma. Of the primary central nervous system (CNS) tumors, primary CNS lymphoma, medulloblastoma, and malignant glioma are the more common tumors that spread to the leptomeninges. Tumor cells gain access to the leptomeninges via several mechanisms. They can spread through vascular structures such as the arachnoid vessels and venous Batsons plexus as well as through perineural/perivascular lymphatics. Direct extension of tumors from vertebral/ paravertebral structures, epidural, intradural, and intraparenchymal areas is another common mechanism of cancer spread to the leptomeninges. Escape from the subependymal/choroid plexus area and iatrogenic dissemination during surgery for intracranial parenchymal tumors may also occur. Once tumor cells are in the subarachnoid space, they can spread to any region of the neuraxis via CSF flow pathways. The most common areas of bulky deposition of CSF tumor cells are the basal cistern, posterior fossa, and the cauda equina. SIGNS AND SYMPTOMS Because of the potential for widespread involvement of the neuraxis by leptomeningeal cancer, patients can present with multifocal neurologic signs and symptoms. This is in fact the clinical hallmark of LM. LM causes symptoms by compression or irritation of adjacent brain parenchyma and nerve roots resulting in focal neurologic signs. Focal or localizing neurologic deficits such as cranial neuropathy (most commonly cranial nerves III, IV, VI, VII, and VIII that pass through the basal cistern), radiculomyelopathies, and cauda equina syndrome are commonly seen. Tumor cell deposits may block CSF flow causing hydrocephalus and increased intracranial pressure. Less commonly, vascular compromise by the tumor cell deposits leads to ischemia and stroke. Thus, a patient may also present with nonlocalizing symptoms such as those associated with increased intracranial pressure and pain from spinal, radicular, or meningeal irritation. Although less common, seizures occur as a result of ischemia or direct cortical infiltration of tumor cells. Rarely, the suspicion of LM is based on MR imaging findings of leptomeningeal contrast enhancement in patients with minimal or no neurologic symptoms or signs. EVALUATION Diagnostic evaluation for LM should be performed as soon as there are signs and symptoms suggestive of leptomeningeal involvement. MR imaging of the brain and spine with and without contrast can be a sensitive noninvasive test to corroborate the suspicion of LM. MR imaging sensitivity depends on the extent of disease at the time of imaging. The typical radiographic
appearance of LM is linear, nodular, or diffuse leptomeningeal enhancement involving the ventricular surface, cranial nerves, or spinal nerve roots. Leptomeningeal enhancement may be seen in non-neoplastic processes such as infection and head injury or from intracranial hypotension after a recent lumbar puncture (LP). A definitive diagnosis requires identification of cancer cells within the CSF. CSF examination should be performed when safe, and CSF should be obtained as close to the level of neurologic dysfunction as possible to optimize yield. In addition to CSF cytology, routine CSF studies should be done to rule out other non-neoplastic processes. The risk of LM is less than 2% when all parameters (opening pressure, cell count, protein, glucose, cytopathology) are normal. A minimum of three separate LPs should be performed if an initial nondiagnostic evaluation reveals nonspecific abnormalities (i.e., elevated cell count, elevated protein, low glucose). The probability of identifying neoplastic cells increases with the volume of CSF sent for cytopathology and with the number of LPs performed. Repeated CSF sampling may have to be done because cytology is reported to be positive in only 74% to 91% of cases after three LPs. Other CSF studies that are not routinely done but can sometimes be helpful in the histologic diagnosis of LM include flow cytometry, immunohistochemistry, testing for tumor markers, and polymerase chain reaction. Flow cytometry to detect small numbers of monoclonal cell population is required when leukemic or lymphomatous meningitis is suspected. Tumor markers in the CSF may aid in the diagnosis of LM but they are not very sensitive or specific. Polymerase chain reaction of tumor specific gene products can occasionally be used successfully to detect LM. It is important, however, that if there is a high index of clinical suspicion of LM and neuroimaging and CSF cytology studies are negative, close clinical, neuroimaging, and CSF cytology monitoring should be performed to confirm the diagnosis. Occasionally empirical treatment is initiated based on strong clinical findings despite negative cytopathology. Leptomeningeal and/or brain biopsy may be required to establish a diagnosis in patients with positive neuroimaging, negative CSF cytopathology, and no known systemic cancer. THERAPY LM is a serious neurologic complication of cancer because it is associated with significant morbidity and mortality. LM usually occurs in patients with widely disseminated and progressive disease. The treatment for LM is palliative for most patients. Early diagnosis and treatment not only aim to control pain, preserve neurologic function, and improve quality of life but to prolong survival. Unlike ESCC where the impact of treatment on patient survival is questionable and the main predictors of outcome are typically the type of tumor and extent of systemic tumor burden, treating LM can improve survival and prolong quality of life. Median survival of patients with LM is increased from 4 to 6 weeks in untreated patients to 3 to 6 months following multimodality therapy. Progressive multifocal neurologic dysfunction is usually the cause of death in these patients.
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An algorithm for LM as adapted from the National Comprehensive Cancer Network (NCCN) is presented in Figure 2. Once the diagnosis of LM is made, the NCCN guidelines recommend stratifying patients according to risk status. Depending on the risk status of the patient, one may either initiate symptomatic treatment and supportive care or proceed with more aggressive treatment. Poor-risk patients include those with poor performance status; multiple, serious, fixed neurologic deficits; and extensive systemic disease with few treatment options. Good-risk patients are treated with intrathecal chemotherapy. Indium-111-DPTA CSF flow studies via subcutaneous reservoir with ventricular catheter are necessary prior to initiating intrathecal chemotherapy. If there is a block to CSF flow, radiation therapy is used to reverse the block prior to instituting intrathecal chemotherapy. Initiation of chemotherapy, however, should not be excessively delayed for CSF flow studies, especially in patients who have LM from chemoresponsive tumors such as small cell lung carcinoma or lymphoma. Symptomatic Treatment or Supportive Care Symptoms of LM from compression and/or irritation of cranial nerves and spinal nerve roots, obstruction of CSF pathways, and increased intracranial pressure should be addressed as soon as possible since treatment rarely reverses existing deficits. Medical decompressive therapy with steroids is used for symptoms and signs related to vasogenic edema. There is no definite guideline as to the appropriate steroid dosage, but a typical dose is 16 mg/day in four divided doses. Higher doses can be considered for patients with rapidly progressive neurologic deficits attributable to vasogenic edema. Cranial neuropathy and radiculopathy from LM usually fail to improve with steroid therapy. Antiepileptic drugs are used for patients with seizures. If possible, newer antiepileptic drugs such as levetiracetam that do not induce the cytochrome P450 enzyme system are preferred in patients expected to receive chemotherapy. Radiation Therapy Radiation therapy is directed at bulky disease identified by imaging and symptomatic sites (skull base for multiple cranial neuropathies and lumbosacral spine for cauda equina syndrome) and to reverse sites of obstruction to CSF flow. In some patients, intrathecal chemotherapy can be initiated only once CSF flow is re-established following radiation therapy. The radiation therapy course is usually shortened for most patients with LM. The total dose of radiation is often between 2400 and 3000 cGy in about 10 fractions over 2 weeks. Radiation therapy may also be used for relief or stabilization of focal symptoms such as cranial neuropathies and/or pain due to tumor bulk compression of neural structures. Chemotherapy Intrathecal chemotherapy is required to halt progression of leptomeningeal disease and to prevent reseeding
following radiation therapy for bulky disease. It can be given intrathecally via LP or preferably through an Ommaya reservoir and ventricular catheter in patients expected to receive a prolonged course of therapy. The response to chemotherapy in patients with LM is dependent not only on the relative chemosensitivity of the primary tumor but also on how well the drug is distributed in the neuraxis. Therefore, to maximize the benefit of intrathecal chemotherapy, patency of CSF pathways should be established with an indium-111-DPTA CSF flow study prior to treatment. Intrathecal therapy is administered as initial induction intrathecal chemotherapy and then as postinduction or maintenance chemotherapy. Intrathecal administration via LP is typically used initially with subsequent doses administered via intraventricular Ommaya reservoir. Administration via Ommaya reservoir is more reliable and convenient than via LP. Induction chemotherapy is given for 4 weeks, and then response to treatment is evaluated, preferably by lumbar CSF cytology. If CSF cytology is negative, induction intrathecal chemotherapy is continued for 4 more weeks and then postinduction or maintenance intrathecal chemotherapy is given once per month. CSF cytology monitoring is recommended every 2 months thereafter. If CSF cytology is positive after initial induction intrathecal chemotherapy, induction intrathecal chemotherapy is either continued for 4 more weeks using the same chemotherapy drug or treatment using an alternate drug is initiated with reassessment by CSF cytology in 4 weeks. If CSF cytology remains positive and there is clinical and radiographic progression of LM, patients are managed as poor-risk-status patients. Methotrexate, cytarabine, and thiotepa are the most commonly used intrathecal chemotherapeutic agents. Methotrexate, a dihydrofolate reductase inhibitor that interferes with DNA synthesis, is typically used as firstline therapy. It has activity against hematologic cancers, breast cancer, and, to a lesser extent, other solid tumors that cause LM. Inductive methotrexate consists of 10 to 12 mg intrathecally twice a week. Leucovorin (folinic acid) 10 mg every 12 hours for six doses is given to prevent bone marrow suppression from methotrexate. The risk of leukoencephalopathy, a delayed complication of intrathecal methotrexate, increases with the duration of treatment, cumulative dose, and concurrent radiation exposure. Cytarabine (cytosine arabinoside), a synthetic pyrimidine nucleoside, is commonly used for hematologic tumors and has less activity against solid tumors. Inductive cytarabine is 50 mg intrathecally twice a week or every 2 weeks as a slow-release formulation (liposomal cytarabine). There is a higher response rate to the slow-release formulation based on delayed time to neurologic progression and improvement in Karnofsky performance status. Thiotepa, an alkylating agent, is a second-line drug for those who do not respond to or cannot tolerate intrathecal methotrexate. It has activity against leukemia and breast cancer. It is initially given as 10 mg intrathecally twice a week. In unique circumstances, systemic chemotherapy may be used for treatment of LM. As in intrathecal chemotherapy, the response to systemic chemotherapy in patients with LM ultimately depends on the type and
NCCN 1.2003 CARCINOMATOUS/LYMPHOMATOUS MENINGITIS ALGORITHM DIAGNOSIS Poor Riska: Low KPS Multiple, serious, fixed neurologic deficits Extensive systemic disease with few treatment options Supportive care, which may include analgesics, anticonvulsants, and/or RT to symptomatic sites RISK STATUS TREATMENT
EVALUATION
Signs and symptoms suggestive of leptomeningeal disease Good Risk: High KPS No fixed neurologic deficits Minimal systemic disease Reasonable systemic treatment options, if needed Initial intrathecal or intraventricular chemotherapyb + RT to bulk disease, symptomatic sites + analgesics and/or anticonvulsants as appropriate Obtain CSF flow scan via subcutaneous reservoir with ventricular catheter
Physical exam with careful neurologic evaluation MRI of brain and spine CSF exam (if safe)
Positive CSF cytology OR Positive radiologic findings with supportive clinical or CSF findings in a patient known to have a malignancy OR Positive signs and symptoms with supportive CSF or radiologic findings in a patient known to have a malignancy
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PRIMARY TREATMENT CSF cytology negative Continue induction intrathecal for 1 month POSTINDUCTION THERAPY Maintenance intrathecal chemotherapy 1 wk per mo Monitor CSF every 2 mo Reassess CSF from site where CSF cytology was originally positive or from lumbar region if CSF cytology was originally negative CSF cytology positive Patient clinically stable or improving and there is no evidence of clinical or radiologic progression of leptomeningeal disease Continue induction intrathecal chemotherapy for 4 wk OR Consider switching intrathecal drugs for 4 wk Negative cytology Cytology continually positive and/or evidence of clinical or radiologic progression of leptomeningeal disease Evidence of clinical or radiologic progression of leptomeningeal disease See treatment for poor risk Repeat CSF flow scan Normal flow Flow abnormalities See pathway for Normal flow, above Treat as poor risk
Normal flow
Induction intrathecal chemotherapy for 4 wk
CSF flow scan
Flow abnormalities
RT to sites of obstruction intrathecal chemotherapy
a b
Patients with exceptionally chemosensitive tumors, e.g., SCLC, lymphoma: may be treated. Initiation of chemotherapy should not be delayed for flow study.
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FIGURE 2. National Comprehensive Cancer Network practice guideline for carcinomatous/lymphomatous meningitis (LM). A, Shows the initial evaluation for LM and the treatment pathway. B, Shows how cerebrospinal fluid (CSF) flow studies may be used to help guide treatment and how to assess response. KPS, Karnofsky performance status; RT, radiation therapy. (Adapted from the National Comprehensive Cancer Network [NCCN] guidelines 1.2003 Central Nervous System Cancers Guideline, The Complete library of NCCN clinical practice guidelines in oncology [CD-ROM].)
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extent of underlying primary tumor. Although systemic chemotherapy is not dependent on CSF flow, the distribution of the drug in the nervous system is dependent on the drugs ability to penetrate the blood-brain barrier. Systemic chemotherapy is used occasionally for LM due to leukemia and lymphoma. The response of LM arising from solid tumors is limited since LM is usually a manifestation of advanced disease and systemic chemotherapy options have been optimized already by then. Surgery Surgery is often used as a supportive measure or in certain cases for tissue diagnosis. Placement of a ventriculoperitoneal shunt can relieve obstructive hydrocephalus when present. Shunting can provide immediate and marked improvement of clinical symptoms due to increased intracranial pressure. The risk of seeding the peritoneum with tumor cells through ventriculoperitoneal shunts is not well defined and should not contraindicate shunt placement. Intrathecal chemotherapy can be given through ventriculoperitoneal shunts equipped with an on-off valve in patients who can tolerate having the shunt temporarily off to allow intrathecal chemotherapy to circulate in the CSF. SUGGESTED READING
Kesari S, Batchelor TT: Leptomeningeal metastasis, Neurol Clin North Am 21:25-66, 2003. Maranzano E, Trippa F, Chirico L, et al: Management of metastatic spinal cord compression, Tumori 89:469-475, 2003. National Comprehensive Cancer Network (NCCN): Central nervous system cancer guidelines. In The complete library of NCCN oncology practice guidelines [CD-ROM], Rockledge, PA, 2004. (To view most recent version of the guidelines, go online to http:// www.nccn.org/.) Schiff D: Spinal cord compression, Neurol Clin North Am 21:67-86, 2003.
subsequently tested by examining the patients sera for anti-CNS antibodies, which led to the first identification of a neuronal-specific antibody in 1964. Since then, this hypothesis has been demonstrated in a few syndromes of the neuromuscular junction and nerve and has been suggested in many other syndromes. The current concept is that the expression of neuronal proteins by a cancer triggers an antitumor immune response that in some patients affects the nervous system. Virtually any type of tumor and any part of the nervous system can be involved, producing a large variety of syndromes (Table 1). In association with these syndromes are frequent immune responses to an expanding number of antigens expressed by the underlying cancer and the nervous system (onconeuronal antigens) (Table 2). The frequency of PND varies with the type of syndrome, tumor, and techniques used for the diagnosis. Although some syndromes such as Lambert-Eaton myasthenic syndrome (LEMS) affects approximately 3% of patients with small cell lung cancer (SCLC), the frequency of many PNDs is estimated to be less than 1:1000 patients with cancer. In contrast, if mild or subclinical neuropathies are considered, about 15% of patients with malignant monoclonal gammopathies (i.e., myeloma, Waldenstrms macroglobulinemia) develop electrophysiologic abnormalities compatible with paraneoplastic neuropathy. There are several general concepts that apply to most paraneoplastic syndromes, including the following: The neurologic symptoms often develop at early stages of cancer when the presence of the tumor is not known, or they herald the recurrence of a tumor considered in remission. Symptoms develop rapidly and evolve subacutely in a matter of days, weeks, or a few months. Diagnostic delays are important, and most patients have severe or irreversible deficits by the time treatment is considered. There are only a few animal models of the neurophysiologic abnormalities occurring in some PND. These include LEMS, myasthenia gravis, and neuromyotonia, all of which are directly mediated by antibodies to cell surface antigens, such as ion channels or receptors, and all affect the peripheral nervous system. There are no animal models for PND of the CNS; therefore, although there are robust data supporting an immune-mediated pathogenesis, the mechanism of neuronal injury in these disorders remains speculative. There is evidence that treatment of the tumor is a cornerstone in the management of PND, with increasing recognition of the importance of immunologic therapies (immunomodulation, immunosuppression) at early stages of the neurologic disease.

For many years the terms remote effects of cancer on the nervous system and paraneoplastic neurologic disorder (PND) were used to describe neurologic disorders that occur by unclear pathogenic mechanisms in patients with cancer. In the mid 1950s the observation that many of these patients had extensive inflammatory infiltrates in the central nervous system (CNS) led to proposition that the infiltrating lymphocytes were the cause rather than the result of the neuronal degeneration. The hypothesis of an immune-mediated pathogenesis was
Concepts with Implications for Therapy

Data from recent studies and personal experience suggest that several general concepts on PND need to be revised. First, in comparison with past series of patients
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extent of underlying primary tumor. Although systemic chemotherapy is not dependent on CSF flow, the distribution of the drug in the nervous system is dependent on the drugs ability to penetrate the blood-brain barrier. Systemic chemotherapy is used occasionally for LM due to leukemia and lymphoma. The response of LM arising from solid tumors is limited since LM is usually a manifestation of advanced disease and systemic chemotherapy options have been optimized already by then. Surgery Surgery is often used as a supportive measure or in certain cases for tissue diagnosis. Placement of a ventriculoperitoneal shunt can relieve obstructive hydrocephalus when present. Shunting can provide immediate and marked improvement of clinical symptoms due to increased intracranial pressure. The risk of seeding the peritoneum with tumor cells through ventriculoperitoneal shunts is not well defined and should not contraindicate shunt placement. Intrathecal chemotherapy can be given through ventriculoperitoneal shunts equipped with an on-off valve in patients who can tolerate having the shunt temporarily off to allow intrathecal chemotherapy to circulate in the CSF. SUGGESTED READING
Kesari S, Batchelor TT: Leptomeningeal metastasis, Neurol Clin North Am 21:25-66, 2003. Maranzano E, Trippa F, Chirico L, et al: Management of metastatic spinal cord compression, Tumori 89:469-475, 2003. National Comprehensive Cancer Network (NCCN): Central nervous system cancer guidelines. In The complete library of NCCN oncology practice guidelines [CD-ROM], Rockledge, PA, 2004. (To view most recent version of the guidelines, go online to http:// www.nccn.org/.) Schiff D: Spinal cord compression, Neurol Clin North Am 21:67-86, 2003.
subsequently tested by examining the patients sera for anti-CNS antibodies, which led to the first identification of a neuronal-specific antibody in 1964. Since then, this hypothesis has been demonstrated in a few syndromes of the neuromuscular junction and nerve and has been suggested in many other syndromes. The current concept is that the expression of neuronal proteins by a cancer triggers an antitumor immune response that in some patients affects the nervous system. Virtually any type of tumor and any part of the nervous system can be involved, producing a large variety of syndromes (Table 1). In association with these syndromes are frequent immune responses to an expanding number of antigens expressed by the underlying cancer and the nervous system (onconeuronal antigens) (Table 2). The frequency of PND varies with the type of syndrome, tumor, and techniques used for the diagnosis. Although some syndromes such as Lambert-Eaton myasthenic syndrome (LEMS) affects approximately 3% of patients with small cell lung cancer (SCLC), the frequency of many PNDs is estimated to be less than 1:1000 patients with cancer. In contrast, if mild or subclinical neuropathies are considered, about 15% of patients with malignant monoclonal gammopathies (i.e., myeloma, Waldenstrms macroglobulinemia) develop electrophysiologic abnormalities compatible with paraneoplastic neuropathy. There are several general concepts that apply to most paraneoplastic syndromes, including the following: The neurologic symptoms often develop at early stages of cancer when the presence of the tumor is not known, or they herald the recurrence of a tumor considered in remission. Symptoms develop rapidly and evolve subacutely in a matter of days, weeks, or a few months. Diagnostic delays are important, and most patients have severe or irreversible deficits by the time treatment is considered. There are only a few animal models of the neurophysiologic abnormalities occurring in some PND. These include LEMS, myasthenia gravis, and neuromyotonia, all of which are directly mediated by antibodies to cell surface antigens, such as ion channels or receptors, and all affect the peripheral nervous system. There are no animal models for PND of the CNS; therefore, although there are robust data supporting an immune-mediated pathogenesis, the mechanism of neuronal injury in these disorders remains speculative. There is evidence that treatment of the tumor is a cornerstone in the management of PND, with increasing recognition of the importance of immunologic therapies (immunomodulation, immunosuppression) at early stages of the neurologic disease.

For many years the terms remote effects of cancer on the nervous system and paraneoplastic neurologic disorder (PND) were used to describe neurologic disorders that occur by unclear pathogenic mechanisms in patients with cancer. In the mid 1950s the observation that many of these patients had extensive inflammatory infiltrates in the central nervous system (CNS) led to proposition that the infiltrating lymphocytes were the cause rather than the result of the neuronal degeneration. The hypothesis of an immune-mediated pathogenesis was
Concepts with Implications for Therapy

Data from recent studies and personal experience suggest that several general concepts on PND need to be revised. First, in comparison with past series of patients
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TABLE 1 Paraneoplastic Syndromes of the Nervous System

Location of the Pathology Brain, cranial nerves, and retina Paraneoplastic Neurologic Disorders Classic Cerebellar degeneration Limbic encephalitis Opsoclonus-myoclonus Cancer-associated retinopathy Melanoma-associated retinopathy Sensory neuronopathy Lambert-Eaton myasthenic syndrome Dermatomyositis Nonclassic Epilepsia partialis continua (focal cortical encephalitis) Hypothalamic encephalitis Brainstem encephalitis Chorea Parkinsonism Optic neuritis Necrotizing myelopathy Subacute motor neuronopathy Stiff-person syndrome Myasthenia gravis Sensorimotor neuropathy Neuromyotonia Polymyositis Necrotizing myopathy
Spinal cord Dorsal root ganglia Neuromuscular junction Peripheral nerves or muscle*
Multiple levels
Encephalomyelitis
*Reviewed by Rudnicki SA, Dalmau J: Paraneoplastic syndromes of the spinal cord, nerve, and muscle, Muscle Nerve 23:1800-1818, 2000.
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TABLE 2 Antibodies, Paraneoplastic Syndromes, and Associated Cancers

Antibody Syndrome Associated Cancers SCLC, other Gynecologic, breast Breast, gynecologic, SCLC Hodgkins lymphoma SCLC, thymoma, other Germ cell tumors of testis, other solid tumors Breast SCLC SCLC Hodgkins lymphoma SCLC SCLC Melanoma
Well-Characterized Paraneoplastic Antibodies* Anti-Hu (ANNA-1) PEM including cortical, limbic, brainstem encephalitis, PCD, myelitis; sensory neuronopathy; autonomic dysfunction Anti-Yo (PCA-1) PCD Anti-Ri (ANNA-2) PCD, brainstem encephalitis, opsoclonus-myoclonus Anti-Tr PCD Anti-CV-2/CRMP-5 PEM, PCD, chorea, peripheral neuropathy, uveitis Anti-Ma proteins Limbic, hypothalamic, brainstem encephalitis (infrequently PCD) Anti-amphiphysin Stiff person syndrome, PEM Anti-recoverin Cancer-associated retinopathy Partially Characterized Paraneoplastic Antibodies* Anti-Zic-4 PCD mGluR-1 PCD ANNA-3 Various PNDs of the CNS PCA-2 Various PNDs of the CNS Anti-bipolar cells of Melanoma-associated retinopathy the retina Antibodies that Occur with and without Cancer Association Anti-VGCC LEMS, PCD Anti-AChR Myasthenia gravis Anti-VGKC Peripheral nerve hyperexcitability (neuromyotonia), limbic encephalitis Anti-nAChR Autonomic neuropathy
SCLC Thymoma Thymoma, others SCLC, others
*Well-characterized antibodies are those directed against antigens whose molecular identity is known or that have been identified by several investigators. Patients with antibodies to Ma-2 are usually men with testicular cancer. Patients with additional antibodies to other Ma proteins are men or women with a variety of solid tumors. Other antibodies reported in a few or isolated cases include antibodies to tubby-like protein and the photoreceptor-specific nuclear receptor. PEM, Paraneoplastic encephalomyelitis; PCD, paraneoplastic cerebellar degeneration; SCLC, small cell lung cancer; LEMS, Lambert-Eaton myasthenic syndrome; VGCC, voltage-gated calcium channel; VGKC, voltage-gated potassium channel; AChR, acetylcholine receptors; nAChR, neuronal acetylcholine receptors.
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with PND of the CNS in which most treatments were considered ineffective, several recent studies suggest that there is a role for immunotherapy even for the most aggressive syndromes. The treatment approach in these studies is similar to that used in the prior studies (i.e., plasma exchange, chemotherapy) but the clinical outcome is better. This is explained, in part, by an increased awareness of PND by clinicians and the development of techniques (i.e., panels of serologic tests, body positron emission tomography [PET]) that allow a prompt diagnosis of both the neurologic disorder and the tumor. As a result, immunologic and oncologic treatments are initiated at earlier stages of the PND and cancer, when the neurologic deficits are not fully established or are partially reversible. A second concept that requires revision is the extensive belief that the paraneoplastic immunity is clinically effective in controlling tumor growth. The possible implications are obvious: a clinically effective antitumor immune response would argue against the use of immunotherapy because this would favor tumor growth. Although there is no doubt that many PND associate with antibodies and sometimes cytotoxic T-cell responses to antigens expressed by the tumor, evidence from large series of patients indicate that the oncologic outcome is not substantially different from that of patients without PND. To assess this issue one needs to analyze all evidence-based data avoiding the bias caused by selection of PND patients as the best reportable cases. This bias has favored the reports of patients with PND and atypical tumor behavior, such as slow growth or apparent regression, over reports of patients without PND and similar unusual oncologic outcomes. There are only two clinical series, both in patients with SCLC, suggesting that antitumor immunity could be clinically effective. One study of 170 patients with SCLC without PND demonstrated that 16% of the patients harbored low titers of anti-Hu antibodies. This study showed that the presence of anti-Hu antibodies at diagnosis of SCLC was a strong and independent predictor of complete response to treatment. This feature accounted for the association between anti-Hu antibodies and longer survival. Of note, the study did not demonstrate that the better outcome of the patients with anti-Hu antibodies was due to effective antitumor immunity but that the tumor was more chemoresponsive than the tumors of patients without anti-Hu antibodies. The second study showed that SCLC patients with LEMS survived longer than SCLC patients without LEMS; however, in most LEMS patients the neurologic symptoms preceded the tumor diagnosis, suggesting a lead time bias of early tumor diagnosis and treatment due to increased surveillance. Additional data suggesting effective antitumor immunity comes from a few reports of spontaneous tumor regression in patients with PND. Careful analysis of these reports shows that some of the patients underwent tumor resection or treatment with low-dose chemotherapy, suggesting that the tumor regression was likely treatment induced. Therefore, despite the demonstration that some patients with PND develop cytotoxic T-cell responses to tumor antigens, the oncologic outcome in studies
comprising hundreds of patients with antibody-associated PND does not significantly differ from that of patients without PND. In addition, studies that examined whether immunotherapy favored tumor growth did not identify a change in tumor behavior. By and large these studies suggest either, that the efficacy of the antitumor immune response is minimal or that the cancer usually overcomes the antitumor immune effect. In summary, the two factors that in my opinion have been critical in improving the outcome of PND are the increased clinical awareness that leads to prompt detection and treatment of the underlying tumor (or tumor recurrence), and the more frequent use of immunotherapy at early stages of the neurologic disease.
Diagnosis of PND and Tumor

Criteria for the diagnosis of PND have recently been reported (Table 3). These criteria include two levels of evidence, definitive and probable, and are based on information provided by the type of syndrome (classic or nonclassic), detection of paraneoplastic antibodies (typical or atypical), and identification of the underlying tumor. In addition to facilitating the diagnosis of PND, these criteria will serve to better define groups of patients for clinical trials. TYPE OF SYNDROME Some PNDs are more characteristic than others and can be considered classic syndromes, because they usually associate with cancer or the clinical features readily
TABLE 3 Diagnostic Criteria of Paraneoplastic Neurologic Disorder (PND)

PND Status Definite Associated Criteria 1. Classic syndrome with cancer diagnosed within 5 yr of neurologic symptom development 2. Nonclassic syndrome that resolves or significantly improves after cancer treatment 3. Nonclassic syndrome with cancer diagnosed within 5 yr of neurologic symptom development and positive antineuronal antibodies 4. Neurologic syndrome (classic or not) without cancer and with wellcharacterized antineuronal antibodies 1. Classic syndrome with high risk of cancer, without antineuronal antibodies 2. Neurologic syndrome (classic or not) without cancer and with partially characterized antineuronal antibodies 3. Nonclassic syndrome with cancer diagnosed within 2 yr of neurologic symptom development, without antineuronal antibodies
Possible
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evoke a paraneoplastic origin. Other disorders (nonclassic) are less characteristic and occur more frequently without cancer association, requiring a more extensive differential diagnosis than the classic syndromes. Classic and nonclassic syndromes are listed in Table 1. ANTINEURONAL ANTIBODIES Patients suspected to have a PND should be examined for antineuronal antibodies in their serum and cerebrospinal fluid (CSF). These antibodies preferentially associate with restricted histologic types of tumors (see Table 2). Therefore, in addition to supporting the diagnosis of PND, the presence of antineuronal antibodies focuses the search of the cancer to specific organs. Wellcharacterized antineuronal antibodies are those directed against antigens whose molecular identity is known or have been identified by several investigators. Partially characterized antibodies are those whose target antigens are unknown or when the clinical experience is limited. Because the serum of cancer patients without PND may contain antineuronal antibodies, detection of antineuronal antibodies does not preclude ruling out other complications of cancer, particularly if the syndrome is not a classic PND. For syndromes of the peripheral nervous system, the only two paraneoplastic antibodies of consideration are anti-Hu and anti-CV2. The detection of anti-Hu in patients with peripheral neuropathy (usually sensory neuronopathy) is an indicator of dorsal root ganglionitis. Anti-CV2 antibodies are present in a few patients with paraneoplastic sensorimotor neuropathy; these antibodies often occur in association with anti-Hu. IDENTIFICATION OF THE TUMOR The discovery of an occult neoplasm in association with a particular neurologic syndrome remains the gold standard of diagnosing PND. In about 70% of patients the tumor is demonstrated by computed tomography (CT) of the chest, abdomen, or pelvis. If the CT scan is negative, a whole-body fluorodeoxyglucose (FDG)-PET uncovers the tumor in approximately 90% of the patients. In patients with CT abnormalities that are not easily accessible to biopsy or surgery, FDG-PET may demonstrate smaller but more accessible lesions (i.e., axillary or supraclavicular adenopathies not detected by CT). Despite the sensitivity of FDG-PET scan, I have seen patients with antibody-positive limbic encephalitis and microscopic testicular tumors that escaped FDG-PET detection. For this reason, testicular ultrasound should be considered in young men (< 45 years of age) with limbic encephalitis. FDG-PET also helps evaluate tumors of the bone marrow (e.g., myeloma), but the experience of FDGPET for sclerotic myeloma is limited. A radiologic skeletal survey or magnetic resonance (MR) imaging study should be considered in patients with peripheral neuropathy of unknown etiology, usually with features resembling chronic inflammatory demyelinating neuropathy. In the appropriate context of a suspected PND, the detection of several serologic cancer markers (CA125, CA 15-3, alfa-fetoprotein, carcinoembryonic antigen)
strongly supports the presence of cancer and may direct the search to a specific organ. Patients with classic PND or with nonclassic PND but positive antineuronal antibodies, whose tumor is not found, need close clinical and radiologic surveillance. A common practice is to repeat evaluations every 6 months (i.e., body CT or FDG-PET). In 80% of the patients the cancer manifests within the first year of the PND; if no tumor is identified, routine evaluations for at least 5 years are warranted. OTHER TESTS CSF findings consistent with PND of the CNS include mild pleocytosis, elevated protein levels, intrathecal synthesis of immunoglobulins, and oligoclonal bands. In paraneoplastic encephalitis (i.e., cortical, limbic, brainstem) the MRI shows abnormal T2-weighted or FLAIRabnormalities in approximately 70% of the patients. In general, CSF and MR imaging studies help rule out other cancer-related or unrelated neurologic complications such as metastasis and infections of the CNS. With the exception of the detection of antineuronal antibodies, there are no specific CSF findings that confirm the diagnosis of PND. For paraneoplastic neuropathies, immunofixation and electrophoresis may demonstrate a monoclonal band that leads to further diagnostic tests to rule out plasma cell dyscrasia, myeloma, Waldenstrms macroglobulinemia, or B-cell malignancy.
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Treatment of PND of the Peripheral Nervous System

There are an extensive number of disorders of the peripheral nerve, neuromuscular junction, and muscle caused by paraneoplastic mechanisms (see Table 1). Immune mechanisms are involved in many but not all of these disorders. Most patients with paraneoplastic neuropathies do not harbor antineuronal antibodies; therefore, an immune-mediated etiology is inferred by the subacute development of symptoms, pleocytosis, or increased proteins in the CSF or the presence of inflammatory infiltrates on nerve biopsy. Electrophysiologic findings are usually compatible with a mixed axonaldemyelinating neuropathy or, less frequently, with a predominant demyelinating neuropathy. These neuropathies usually develop before or by the time of the cancer diagnosis. Plasmapheresis, intravenous immunoglobulin (IVIg), and immunosuppression can be rewarding treatments in neuropathies of subacute onset and predominant demyelinating features. In contrast, predominant axonal neuropathies can occur at any time during the course of the neoplastic disease; they are typical of patients with osteolytic myeloma and can occur in advanced stages of solid tumors, lymphomas, and leukemias. Paraneoplastic axonal neuropathies are poorly responsive to immunotherapy; a reasonable approach is symptomatic or supportive care along with treatment of the tumor. Table 4 lists the main PND of
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TABLE 4 Treatment of Paraneoplastic Syndromes of the Peripheral Nervous System*

Syndrome Syndromes that Often Respond to Treatment Lambert-Eaton myasthenic syndrome Myasthenia gravis Dermatomyositis Neuropathy (osteosclerotic myeloma) Syndromes that May Respond to Treatment Neuromyotonia Guillain-Barr (Hodgkins) Vasculitis of nerve and muscle Neuropathy with MAG antibodies (Waldenstrms macroglobulinemia) Subacute neuropathy with demyelinating features in association with solid tumors Syndromes that Usually Do Not Respond to Treatment Neuropathy of multiple myeloma Predominant axonal neuropathy of solid tumors Subacute necrotizing myopathy
*For all PNS initial treatment should focus on detecting and treating the tumor. Immunosuppression includes steroids or azathioprine. IVIg, Intravenous immunoglobulin.
Treatment
3,4-diaminopyridine, IVIg, plasma exchange, immunosuppression Plasma exchange, IVIg, immunosuppression Immunosuppression, IVIg Focal treatment of sclerotic lesion, radiation, chemotherapy Plasma exchange, IVIg Plasma exchange, IVIg Steroids, cyclophosphamide Plasma exchange, IVIg, rituximab, immunosuppressants (chlorambucil, cyclophosphamide, or fludarabine) Corticosteroids, IVIg
Supportive care Supportive care Corticosteroids
the peripheral nervous system and the recommended treatments. LEMS, myasthenia gravis, neuromyotonia, and some types of autonomic neuropathy are directly mediated by antibodies to ion channels or cell membrane receptors (see Table 2). These disorders usually respond to plasma exchange, IVIg, and immunosuppressive therapies. Aside from treating the tumor, the therapeutic strategies for these syndromes are similar to those used for the nonparaneoplastic form of the disorders. Inflammatory myopathies, such as dermatomyositis and less often polymyositis, can occur as paraneoplastic manifestations of cancer. There are no specific antibodies or serologic markers of paraneoplasia. Although the cancer-related mechanisms that lead to immune activation against muscle antigens are unclear, the downstream effects causing inflammatory muscle injury are similar to the nonparaneoplastic forms of these disorders. Therefore, aside from treating the tumor, it is reasonable to treat these syndromes as one would treat the nonparaneoplastic disorders.
Treatment of PND of the Central Nervous System

The treatment of PND of the CNS is complicated by (1) the lack of animal models; (2) the involvement of cytotoxic T-cell mechanisms that can make these disorders resistant to strategies used for antibody-mediated disorders; (3) the rapid progression of symptoms and narrow window for intervention to prevent irreversible
neurologic deficits; and (4) the logistics of combining oncologic and immunosuppressive therapies in patients with poor clinical condition. Keeping these considerations in mind, a general treatment approach is proposed in Figure 1. A major effort should be the prompt diagnosis and treatment of the tumor. Because the simultaneous use of chemotherapy and some immunosuppressants may result in significant toxicity, two levels of immunologic intervention are suggested. Patients with progressive PND who are receiving chemotherapy should be considered for immunosuppression or immunomodulation that may include oral or IV corticosteroids, IVIg, or plasma exchange. Patients with progressive PND who are not receiving chemotherapy should be considered for more aggressive immunosuppression that may include oral or IV cyclophosphamide, tacrolimus, cyclosporine, or rituximab. Although there is no compelling evidence than any of these immunosuppressants is better than another for patients with PND, I favor the use of corticosteroids, IVIg, and cyclophosphamide. The syndromes that most often respond to treatment are opsoclonus-myoclonus in children with neuroblastoma and, less frequently, in adults with solid tumors; limbic encephalitis in patients with SCLC without antiHu antibodies (some of whom may have anti-VGKC antibodies); limbic encephalitis in young patients with testicular tumors and anti-Ma2 antibodies; and stiff person syndrome associated with anti-amphiphysin antibodies. Clinical trials with homogeneous groups of patients (i.e., same antibody, same PND) assessing the proposed treatment design and immunosuppressants should be the focus of future studies.
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Neoplastic Disease
PND of the CNS
Tumor known
No tumor known
Tumor newly diagnosed
Tumor in remission
Tumor recurrence Yes Neurologic symptom progression at the time of PND diagnosis No Neurologic symptom progression at the time of PND diagnosis Yes; KPS50 No
No
Yes; KPS<50*
Supportive care
Treat the tumor and/or supportive care
Treat tumor + immunosuppressantsA
11
Improvement or stabilization of PND
Progression of PND ImmunosuppressantsA and/or immunosuppressantsB
KPS<50*
Supportive care
Improvement or stabilization of PND
Progression of PND
Supportive care
A B
May include IVIg, and/or intravenous or oral steroids, and/or plasma exchange. May include cyclophosphamide and/or rituximab, or tacrolimus. Variable efficacy (class 45 level of evidence) has been reported for IVIg, steroids, plasma exchange or protein-A IgG absorption, cyclophosphamide, and rituximab.
* Because patients with limbic encephalitis or opsoclonus/myoclonus may show dramatic improvement with immunosuppression, patients with these two disorders and KPS<50 may be considered for immmunosuppression.
FIGURE 1. Recommended approach to treatment of paraneoplastic neurologic disorder (PND) of the central nervous system (CNS). KPS, Karnofsky performance status; IVIg, intravenous immunoglobulin.
SUGGESTED READING
Albert ML, Austin LM, Darnell RB: Detection and treatment of activated T cells in the cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration, Ann Neurol 47:9-17, 2000. Bataller L, Graus F, Saiz A, Vilchez JJ: Clinical outcome in adultonset idiopathic or paraneoplastic opsoclonus-myoclonus, Brain 124:437-443, 2001. Dalmau J, Graus F, Villarejo A, et al: Clinical analysis of anti-Ma2associated encephalitis, Brain 127:1831-1844, 2004. Johnson: Current Therapy in Neurologic Disease (7/E)
Graus F, Dalmau J, Rene R, et al: Anti-Hu antibodies in patients with small cell lung cancer: association with complete response to therapy and improved survival, J Clin Oncol 15:2866-2872, 1997. Graus F, Keime-Guibert F, Rene R, et al: Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients, Brain 124: 1138-1148, 2001. Graus F, Delattre JY, Antoine JC, et al: Recommended diagnostic criteria for paraneoplastic neurologic syndromes, J Neurol Neurosurg Psychiatry 75:1135-1140, 2004.
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Remote Effects of Cancer: Treatment of Paraneoplastic Neurologic Syndromes Vernino S, ONeill BP, Marks RS, et al: Immunomodulatory treatment trial for paraneoplastic neurological disorders, Neurooncol 6:55-62, 2004.
Keime-Guibert F, Graus F, Fleury A, et al: Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone, J Neurol Neurosurg Psychiatry 68:479-482, 2000. Maddison P, Newsom-Davis J, Mills KR, Souhami RL: Favourable prognosis in Lambert-Eaton myasthenic syndrome and small cell lung carcinoma, Lancet 353:117-118, 1999. Rojas I, Graus F, Keime-Guibert F, et al: Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies, Neurology 55:713-715, 2000. Rosenfeld MR, Dalmau J: Current therapy of paraneoplastic syndromes, Curr Treat Options Neurol 5:69-77, 2003. Rudnicki SA, Dalmau J: Paraneoplastic syndromes of the spinal cord, nerve, and muscle, Muscle Nerve 23:1800-1818, 2000.
PATIENT RESOURCES
Program in Clinical Neuro-Oncology and Paraneoplastic Neurological Syndromes at the University of Pennsylvania http://pennhealth.com/neuro/services/neuro_onc/ PNSEuronet Concerted Action on Paraneoplastic Neurological Diseases http://www.pnseuronet.org/about/
SECTION 12
Movement Disorders
Parkinsons Disease
Benjamin L. Walter, M.D., and Jerrold L. Vitek, M.D., Ph.D.
include autonomic insufficiency, difficulty with articulation, frequent urination, seborrhea, dysphagia, constipation, and ill-defined sensory complaints often reported as a deep aching sensation that in some patients may be quite painful. PD occurs most commonly in older patients, but it is not infrequent in younger adults and, although rare, may occur in juveniles. With younger patients, dystonic symptoms are more common. About 15% of cases are familial.
Description
Parkinsons disease (PD) is a progressive neurodegenerative disorder whose pathologic hallmark is loss of dopaminergic neurons in the substantia nigra pars compacta. The cardinal motor signs of PD are tremor, rigidity, bradykinesia/akinesia, and a gait disorder characterized by a flexed posture and short, shuffling steps. The diagnosis is made clinically by noting at least two of these characteristic motor signs in addition to a clear-cut response to antiparkinsonian medications. Patients may also develop postural instability and freezing, a phenomenon characterized by a sudden inability to continue or initiate movement. Decreased associated movements (masked facies, decreased eye blink, and reduced arm swing) are common early signs of PD. Hypophonia; micrographia; and difficulty with fine motor control (buttoning buttons, handling utensils, shaving or applying makeup), getting out of a chair, or rolling over in bed at night are common early complaints of PD patients. Some PD patients may present with early morning foot or toe dystonia. Motor complications in the form of unpredictable on-off periods (motor fluctuations) and drug-induced involuntary movements (dyskinesia or dystonia) occur later in the disorder, are associated with long-term drug therapy, and pose a significant challenge for the clinician who must try to maintain the therapeutic response in a progressively more narrow therapeutic window. Nonmotor symptoms are also common in PD. Depression occurs in approximately 50% of patients with PD and may present at any time in the course of the disease. Visual and rarely auditory hallucinations can also occur in association with antiparkinsonian medication in patients who have had PD for many years. Dementia is not typical in early idiopathic PD but may develop in the later stages of the disease. Other symptoms that may develop or be associated with PD
Differential Diagnosis
To appropriately guide the therapeutic approach to treatment of PD, one must differentiate idiopathic PD from parkinson-plus syndromes (diffuse Lewy body disease [DLBD], progressive supranuclear palsy [PSP], multisystem atrophy, and corticobasal-ganglionic degeneration [CBGD]) and secondary parkinsonism. Secondary forms of parkinsonism may result from medications, stroke (vascular parkinsonism), or other lesions involving the basal ganglia circuitry. The most telling signs of idiopathic PD are asymmetric symptoms and a robust response to medications without dementia, hallucinations, autonomic symptoms, or pyramidal signs. Although atypical parkinsonian disorders may respond to antiparkinsonian medication, the response is usually not as robust, and it generally does not persist beyond a few years. Early occurrence of orthostatic hypotension, dysphagia, and incontinence is more suggestive of multisystem atrophy. Patients who have significant signs of dementia, hallucinations, or fluctuating delirium at presentation or in the first few years of the disease may have DLBD. Impairment of vertical gaze (particularly downgaze), early balance problems and falls, and axial (predominantly neck) greater than appendicular rigidity is suggestive of PSP. Patients with asymmetric symptoms but with apraxia, alien limb phenomenon, and myoclonus have a high likelihood of having CBGD. Fluorodeoxyglucose positron emission tomography (FDG-PET) studies may aid in discerning idiopathic PD from parkinsonism in difficult cases by noting the hypermetabolic activity that occurs in the striatum in patients with idiopathic PD versus the hypometabolic pattern that typifies parkinsonian syndromes. 281
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Neuroprotective Medical Therapy

Neuroprotective treatment should ideally be initiated as soon as there is suspicion that the patient has PD. Many medications have been studied as putative neuroprotective strategies; unfortunately, there are limited data supporting neuroprotective options. The best evidence to date exists for coenzyme Q10 (CoQ10) and rasagiline (Agilect). A pilot study suggests that CoQ10 may slow the progression of symptoms and a trend toward better benefit with higher doses when 300, 600, and 1200 mg per day were compared to placebo. No significant side effects were found. CoQ10 may be started at one or two 300-mg tablets orally (PO) once or twice a day. Patients should understand that this study has not yet been substantiated. CoQ10 is a supplement and is therefore available over-the-counter. Rasagiline, a new monoamine oxidase B inhibitor, has been shown to improve symptoms in early PD and has shown some potential in slowing disease progression. It is expected to be available in 2005. Although there is some suggestion from recent studies that dopamine agonists and/or carbidopa/levodopa (Sinemet) may also be neuroprotective (rather than neurotoxic), the data in support of this are controversial and require further study.
400 to 600 mg. Use of catechol O-methyltransferase (COMT) inhibition extends the duration of action of levodopa and provides a smoother effect, which may also help prevent the occurrence of dyskinesias. The current trend is to begin medical therapy with a dopamine agonist in younger patients with normal cognitive function, whereas carbidopa/levodopa entacapone is used for initial therapy in older patients (> age 75 years) or in patients with impaired cognition. The choice for initial therapy, therefore, depends on the patients overall medical condition, potential drug interactions, age, cognitive status, and cost considerations. Although initial approaches may vary, the common philosophy is to administer the minimal dose of antiparkinsonian medication(s) necessary to adequately control the motor symptoms and return the patient to an acceptable level of function. CARBIDOPA/LEVODOPA Sinemet is a combination of carbidopa/levodopa and is available in immediate and controlled-release (CR) preparations. The immediate release preparation is available as 10/100, 25/100, and 25/250 mg tablets. The CR form of Sinemet exists in two preparations: Sinemet 25/100 and 50/200. To begin medical therapy with Sinemet, start at a low dose of 25/100, one tablet PO twice a day, increasing as necessary to three times a day, or Sinemet 50/200 CR, one tablet PO bid. This approach is effective for most patients; however, there are some patients who are particularly sensitive to Sinemet in whom a smaller dose may be equally therapeutic. Alternatively, some patients may require a larger dose. The dose should be titrated to the individual patients requirements and varies from patient to patient. The bioavailability of levodopa in Sinemet CR is approximately 70% of that in the regular formulation. Accordingly, when switching a patient from one preparation to the other, it is important to remember that 70 mg of levodopa given as a short-acting preparation is equivalent to 100 mg of levodopa in the CR preparation (Table 1). As the disease progresses, gastrointestinal absorption becomes more erratic, which has a greater impact on the consistency of response in the CR preparations and patients may need to be switched to shorter intervals of the immediate release Sinemet or to Stalevo. Carbidopa/levodopa is also available as a sublingual dissolvable tablet (Parcopa). It is available as 10/100, 25/100, and 25/250 form and has the same pharmacologic properties as immediate-release Sinemet. It is useful for patients who have sudden off symptoms and want a pill they can carry with them that can be taken when needed without water. A combination tablet of carbidopa/levodopa/ entacapone is available as Stalevo 50, 100, and 150 that contains 50, 100, and 150 mg of levodopa, respectively. Each tablet also contains 200 mg of the COMT inhibitor entacapone. Due to the addition of the entacapone, each milligram of levodopa is 1.3 times as effective as 1 mg of regular-preparation Sinemet, and it has a longer duration of action (see Table 1). One can start patients on Stalevo 50 PO three times a day and increase as
Symptomatic Medical Therapy

GENERAL APPROACH TO THERAPY Most clinicians choose to begin symptomatic medical therapy when the motor symptoms lead to significant functional compromise interfering with work performance, or leading to difficulties in activities of daily living. Medical treatment (Figure 1) typically involves the use of drugs to replace striatal dopamine (carbidopa/ levodopa), or drugs that have dopaminergic properties (e.g., dopamine agonists including pramipexole dihydrochloride [Mirapex], ropinirole hydrochloride [Requip], pergolide mesylate [Permax], and bromocriptine mesylate [Parlodel]). Some studies have suggested that starting with a dopamine agonist alone and adding carbidopa/levodopa only when adequate control with the agonist is no longer possible may delay the development of motor fluctuations and drug-induced dyskinesias. This has been suggested to be due to (1) a smoother, more continuous stimulation of dopaminergic receptors with agonists due to their longer half-life; (2) potential neurotoxic effects of levodopa; or (3) use of relatively lower therapeutically equivalent doses of agonists in these studies. Thus, particularly for younger patients, who better tolerate dopamine agonists, these medications are often used before levodopa preparations. The Earlier Versus Later LevoDOPA (ELLDOPA) trial, however, has at least allayed previous concerns that levodopa contributes to the progression of the disease and potentially suggests that it could slow disease progression. As such, an alternative therapeutic approach is to start medical therapy with carbidopa/ levodopa entacapone and add a dopamine agonist once the dose of carbidopa/levodopa reaches approximately
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Neuroprotective strategies
Dopamine agonist
Carbidopa/levodopa +/ COMT inhibitor
Carbidopa/levodopa +/ COMT inhibitor
Dopamine agonist
Amantadine
Shorten interval of levodopa/ carbidopa
Liquid levodopa/ carbidopa
Apokyn
Parcopa
Surgery
FIGURE 1. Illustration of the typical strategies employed to manage the symptom progression and the development of motor complications in Parkinsons disease (PD). As neuroprotective agents become available, they should be used once there is suspicion the patient has PD. Most younger patients (<75 years of age) are started on a dopamine agonist (left); however, initial therapy may also be started with levodopa/carbidopa and a catechol-O-methyltransferase (COMT) inhibitor and may be better tolerated in older patients (right). Levodopa may be added to the agonist (left) after increasing the agonist has reached its therapeutic limit. In some patients started on levodopa (right), an agonist can be added once the patient has early wearing off. Once dyskinesias are problematic, some patients may benefit from amantadine. Various strategies are then employed, when significant motor complications develop using frequent doses of short-acting medications, and some patients eventually may need surgery.
12
necessary. It is important to recognize that the total daily dose of entacapone should not exceed 1600 mg, or eight tablets of Stalevo of any strength. Entacapone is associated with a 5% incidence of diarrhea and rarely may need to be discontinued if this is severe. The most common side effects of Sinemet are nausea and hypotension, which occur predominantly as the result of the peripheral conversion of levodopa to dopamine. A minimum of 75 mg/day of carbidopa is required to prevent the peripheral conversion of levodopa to dopamine. This requirement and the sensitivity of patients to the peripheral effects of dopamine, however, may vary significantly from patient to patient. Thus, for
patients who experience nausea following the administration of Sinemet or Sinemet CR, the patient may take the medication with meals or these patients may receive a supplement of the commercially available drug Lodosyn (carbidopa), which is a pure carbidopa preparation. These patients should receive pretreatment of one 25-mg tablet three times a day for several days prior to restarting treatment with Sinemet. If patients still complain of nausea, they should take the medication with meals or take their medications with ginger preparations, because ginger has an antiemetic property. In treating nausea in these patients, prochlorperazine (Compazine) and metoclopramide (Reglan) should be
TABLE 1 Relative Equivalence of Dopamimetic Medications

Medication Trade Name and Strength Apokyn 0.1 mL (1 mg) Dostinex 1.5 mg Mirapex 1 mg Parlodel 5 mg Permax 1 mg Requip 1 mg Sinemet 10/100 Sinemet 25/100 Sinemet CR 25/100 Sinemet CR 50/200 Stalevo 100 Generic Name Apomorphine Cabergoline Pramipexole dihydrochloride Bromocriptine Pergolide mesylate Ropinerole Carbidopa/levodopa Carbidopa/levodopa Carbidopa/levodopa, controlled release Carbidopa/levodopa, controlled release Carbidopa/levodopa/entacapone Levodopa Equivalence* 100 100 100 100 100 20 100 100 65 130 130 T {1/2} 40 min 65 hr 8 hr 6 hr 12-27 hr 4 hr 2 hr
*Expressed in clinically equivalent milligrams of levodopa.
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avoided because they have dopaminolytic properties and can worsen the symptoms of PD. DOPAMINE AGONISTS At present, most movement disorder specialists begin therapy with a dopamine agonist. Depending on the patients cognitive status and general medical condition, however, as discussed earlier, medical therapy may also begin with Sinemet or Stalevo. In such cases, a dopamine agonist may be added once the requirement for levodopa is greater than 400 to 600 mg (600 to 800 mg of CR). Pergolide, ropinirole, or pramipexole all provide similar benefits, although patients may be differentially sensitive to the side effects of these medications. Ropinirole and pramipexole, both predominately D2 agonists, should also be started at low doses and titrated to effect. Ropinirole is usually started at 0.25 mg PO three times a day, whereas pramipexole may be started at 0.125 mg PO three times a day. The maximal total daily dose of ropinirole is generally around 24 mg, whereas that for pramipexole is 4.5 mg. If tolerated, some patients may receive significant benefit from higher doses. Pergolide, a D1, D2 receptor agonist may be started at a dose of 0.05 mg PO bid and titrated to effect using a three- to four-times-daily dosing schedule. The maximum dose is 6 mg/day in divided doses. Pergolide rarely can cause retroperitoneal fibrosis and cardiac valvulopathy. Parlodel is used less commonly but may be useful for patients who do not tolerate other dopamine agonists. If a particular preparation does not provide adequate benefit or is associated with intolerable side effects, a switch is made to another agonist. The dose is titrated upward slowly in patients who are prone to develop side effects. COMT INHIBITORS COMT inhibitors augment the response of levodopa by slowing the breakdown of dopamine and are available for supplemental use in association with Sinemet or in a combined formulation with levodopa/carbidopa (Stalevo). The two COMT inhibitors available are entacapone (Comtan) and tolcapone (Tasmar). Entacapone is dispensed as one 200-mg tablet taken with each dose of levodopa/carbidopa. One should not exceed 1600 mg of entacapone per day. Entacapone may discolor the urine, turning it orange, and patients should be informed of this prior to starting the medication. The usual dose of tolcapone is 100 to 200 mg PO three times a day taken 6 hours apart. A small number of patients taking tolcapone developed liver failure; therefore, patients on tolcapone should have liver function tests monitored every 2 to 4 weeks. There is also a 15% incidence of diarrhea that may necessitate discontinuation of the medication. Both medications are effective in prolonging the duration of action of levodopa/carbidopa. Tolcapone, although a more potent COMT inhibitor, is more problematic to prescribe due to its risk of rare hepatic failure and the requirement for frequent blood work. Patients who are beginning to develop wearing off may respond to the addition of a
COMT inhibitor instead of increasing the dose of levodopa. When adding a COMT inhibitor to treat motor fluctuations, one should concomitantly titrate down the dose of Sinemet to prevent the development of druginduced dyskinesia. AMANTADINE Amantadine (Symmetrel), an antiviral drug, has a variety of pharmacologic properties and is also used in the treatment of PD. It is a partial dopamine agonist, may decrease dopamine reuptake, and has antiglutamatergic and anticholinergic properties. It is particularly useful for the treatment of drug-induced dyskinesias and motor fluctuations. The typical dose is a 100-mg capsule taken two or three times per day. Some patients may benefit from up to four tablets per day. The antidyskinetic property of amantadine is particularly helpful for patients with disabling drug-induced dyskinesias. A small percentage of patients may develop pedal edema or livedo reticularis. As with all the antiparkinsonian medications, in higher doses amantadine may be associated with confusion and hallucinations. This appears more commonly in older patients. Reducing the dose may be helpful in some of these patients; in others, the medication may have to be discontinued. Patients should be tapered off amantadine gradually. Rarely, patients who have been on amantadine chronically may develop delirium as a result of amantadine withdrawal. ANTICHOLINERGICS Anticholinergic medications also may be used in the treatment of PD. They are primarily effective for tremor, but some patients report improvement in rigidity as well. The improvement in rigidity may, in part, be due to the associated improvement in tremor. Younger patients for whom tremor is the predominant and most disabling symptom should be given a trial of anticholinergic medication prior to starting levodopa/carbidopa or a dopamine agonist. Older individuals are less likely to tolerate anticholinergics without confusion and memory impairment; therefore, dopaminomimetic medications may be preferable to anticholinergics in these patients. Several anticholinergic medications may be tried. Ethopropazine hydrochloride (Parsitan) is often better tolerated than other anticholinergics and can be started at 25 mg taken once or twice a day and increased slowly to effect. If patients show a response to ethopropazine, they generally respond at dosages in the range of 25 to 50 mg three or four times per day. If ethopropazine fails to provide improvement, other anticholinergic medications, (e.g., trihexyphenidyl hydrochloride [Artane] or benztropine mesylate [Cogentin]) may be tried. For benztropine, one should begin in small doses (0.5 to 1 mg daily), titrated upward by 0.5 to 1 mg every 2 to 3 days to either improvement in tremor or the development of side effects (blurred vision, dry mouth, urinary retention, and confusion or memory disturbances). Trihexyphenidyl should be initiated slowly beginning with 1 to 2 mg/day, titrated up by 1 to 2 mg every 2 to 3 days until tremor relief or intolerable side effects
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are reached. The maximum dose is 15 mg/day. Some patients may need to start at lower doses and use a slower titration schedule.
Treatment of Motor Complications

WEARING OFF (END-OF-DOSE) PHENOMENON Over time, patients symptoms become more severe, and they begin to develop wearing off phenomenon, (i.e., where symptoms return before the next dose of medication). When this occurs, one can increase the dose of medication, decrease the time interval between doses, add an agonist, or begin a COMT inhibitor to minimize the amount of off time. There should be a small amount of time prior to the next dose that the patient notes some loss of effect because this indicates that one is not giving the patient more medication than is needed. Overmedicating may predispose patients to earlier or more severe development of drug-induced dyskinesias and/or motor fluctuations. Selegiline (Eldepryl) and rasagiline are both effective in reducing off time. Selegiline may be started at 5 mg PO twice a day but should not be given late in the day due to an amphetamine metabolite that can lead to insomnia in some patients. Rasagiline may be started at 0.5 mg to 1 mg PO daily. DRUG-INDUCED DYSKINESIAS Excessive involuntary movements associated with chronic use of antiparkinsonian drug therapy are called drug-induced dyskinesias. These movements generally occur after 3 to 5 years of antiparkinsonian drug therapy and may occur at the peak serum levels of levodopa or dopaminergic medications (peak-dose dyskinesias) or while the drug level is peaking and/or falling (biphasic dyskinesias). The goal of treatment for patients with peak-dose dyskinesias is to prevent the peak levels of dopamine in the brain that lead to the dyskinetic movements. This is accomplished by administering levodopa at smaller doses and adding a COMT inhibitor or dopamine agonist or by reducing the dose while increasing the frequency of dosing. This approach allows a more continuous delivery of levodopa, reducing the peaks and troughs of serum levodopa levels, and maintains patients within the therapeutic window for a longer period. Patients with drug-induced dyskinesias receiving CR preparations may obtain better control of serum levodopa levels by switching to short-acting levodopa/carbidopa preparations because the shorter halflife makes it easier to adjust the serum level of levodopa. If dyskinesias cannot be controlled adequately without an unacceptable worsening in parkinsonian motor signs by adjusting the dose of levodopa or dopamine agonist, amantadine may be added (see Figure 1). If this is not effective, small doses of a liquid Sinemet preparation may be tried at short intervals, adjusting the dose as necessary. Liquid Sinemet can be prepared by crushing ten 10/100 tablets of levodopa/carbidopa and 500 mg of
vitamin C in 1 L of water. This will produce a 1 mg levodopa/mL solution, and should be made fresh daily. With biphasic dyskinesia, the therapeutic strategy is to either (1) keep the blood level just above that where the patient develops dyskinesias by increasing the dose or frequency of administration or (2) reduce the dose to keep the patient just below this level. ON-OFF PHENOMENON (MOTOR FLUCTUATIONS) For patients with on-off phenomenon, the goal of therapy is to smooth out the levels of antiparkinsonian medications by giving longer-acting medications, such as dopamine agonists or COMT inhibitors. For particularly brittle patients, liquid Sinemet can be given. Patients may sip 50 mL of a 1 mg/mL levodopa solution every hour, adjusting the dose or dosing interval as necessary to minimize the development of dyskinesias and motor fluctuations while maximizing the amount of on time. CR formulations of carbidopa/levodopa should usually be discontinued because their effect becomes more difficult to control as the disease progresses. For some patients a low-protein diet (dietary protein is minimized during the day and taken as one or two meals toward the end of the day) may also reduce motor fluctuations. The avoidance of dietary protein allows a more predictable response to levodopa because certain amino acids compete with transport of levodopa across the blood-brain barrier and hinder intestinal absorption. Rescue therapy may be needed for patients with frequent on/off fluctuations, particularly in those who have gait freezing. Options include keeping a vial of liquid Sinemet nearby or on their person, crushing or chewing a single 25/100 tablet of carbidopa/levodopa, also using injectable apomorphine (Apokyn) or sublingual dissolvable carbidopa/levodopa (Parcopa). Prior to routine use, a test dose of Apokyn should be initiated in a clinic setting while observing for side effects and checking orthostatic blood pressures before administration and every 20 minutes afterward for the first hour. Improvement in motor symptoms, induction of intolerable dyskinesias, and nausea should also be monitored during the initial administration. To prevent nausea commonly associated with the administration of apomorphine, trimethobenzamide (Tigan) should be started at 300 mg PO three times a day beginning also 3 days prior to the first administration of apomorphine.
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Treatment of Nonmotor Symptoms

SLEEP DISORDERS Sleep disorders are common in parkinsonian patients, particularly excessive daytime sleepiness, insomnia, sleep fragmentation, rapid eye movement, sleep behavior disorder and restless legs syndrome. Poor sleep may exacerbate parkinsonian motor signs due to the excessive fatigue and daytime sleepiness experienced by these patients. The scope of this problem has only
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recently been appreciated by movement disorder specialists. (See Table 2 for the approach to treatment of sleep disorders in these patients). MOOD DISORDERS Depression occurs in approximately 50% of patients with PD but is often overlooked. Given its significant negative impact on parkinsonian motor signs and quality of life, patients should be assessed for depression at each visit. If depression is suspected, one may opt to wait before adjusting antiparkinsonian medications until the
depression is adequately treated because successful treatment of depression is almost always associated with a concurrent improvement in parkinsonian motor signs. Table 2 provides a list of medications used to treat depression. Escitalopram (Lexapro) is well tolerated with good efficacy and minimal side effects in most patients. Other selective serotonin reuptake inhibitors (SSRIs) are also effective and include paroxetine (Paxil), sertraline (Zoloft), and fluoxetine (Prozac). Buproprion (Wellbutrin) is a good choice in sexually active patients due to a low risk of sexual side effects, and it also has a dopaminergic effect and may benefit motor symptoms.
TABLE 2 Medications for Treating Nonmotor Symptoms Associated with Parkinsons Disease
Treatment/Generic Drug (Trade Name) Standardize sleep schedule Zolpipidem (Ambien) Zaleplon (Sonata) Temazepam (Restoril) Quetiapine (Seroquel) Modafinil (Provigil) Clonazepam (Klonopin) Pramipexole (Mirapex) Ropinerole (Requip) Clonazepam (Klonopin) Bupropion (Wellbutrin XR) Escitalopram (Lexapro) Flucoxetine (Prozac) Paroxetine (Paxil) Sertraline (Zoloft) Venlafaxine (Effexor XR) Paroxetine (Paxil) Sertraline (Zoloft) Buspirone (Buspar) Clonazepam (Klonopin) Reduce antiparkinsonian medications Quetiapine (Seroquel) Clozapine (Clozaril) Rivastigmine (Exelon) Donepezil (Aricept) Memantine (Namenda) Speech therapy (Lee Silverman technique) Tolterodine (Detrol LA) Oxybutynin (Ditropan XL) Tamsulosin (Flomax) Doxazosin (Cardura) Sildenafil (Viagra) Vardenafil (Levitra) Salty foods Support hose Fludrocortisone (Florinef) Midodrine (Proamatine) NSAID (ibuprofen, naproxen) Hycosamine sulfate (Levsin) Artificial tears Dosage Initial 5 mg PO qhs 5 mg PO qhs 7.5 mg PO qhs 12.5-25 mg PO qhs 100 mg PO qd 0.5 mg PO qhs 0.125 PO qhs 0.25 PO qhs 0.5 mg PO qhs 150 mg PO qam 10 mg PO qd 10-20 mg PO qd 10-20 mg PO qd 50 mg PO qd 37.5-75 mg PO qd 10-20 mg PO qd 50 mg PO qd 5 mg bid-tid 0.25 bid 12.5-50 mg PO qhs 12.5-50 mg PO qhs 1.5 mg PO bid 5 mg PO qhs 5 mg PO qd 2 mg PO qd 5 mg PO qd 0.4 mg PO qd 1 mg PO qd 25 mg PO 2.5-5 mg PO 0.1-0.2 mg PO qd 2.5 mg PO tid 0.125 mg PO tid Range per Day 5-10 mg PO qhs 5-10 mg PO qhs 7.5-30 mg PO qhs 25-300 mg PO qhs 100-400 mg qd 0.5-2 mg PO qhs 0.125-1.5 PO qhs 0.25-4 PO qhs 0.5-2 mg PO qhs 150-450 mg PO qam 10-20 mg PO qd 10-20 mg PO qd-bid 10-50 mg PO qd 50-200 mg PO qd 37.5-225 mg PO qd 10-50 mg PO qd 50-200 mg PO qd 20-60 mg daily divided in two or three doses 0.25-0.5 mg bid 12.5-300 mg 12.5-200 mg tid 3-6 mg PO bid 5-10 mg PO QHS 5-10 mg PO bid 2-4 mg PO qd 5-15 mg PO qd 0.4-0.8 mg PO qd 1-4 mg PO qd 25-50 mg 2.5-10 mg PO
Symptom Insomnia
Excessive daytime sleepiness Periodic leg movements REM sleep behavior disorder Depression
Anxiety
Hallucinations
Dementia Speech disorder Hyperactive bladder Hypoactive bladder Sexual dysfunction Orthostatic hypotension
2.5-30 mg 0.125-1.5 mg
Sialorrhea Dry eyes

NSAID, Nonsteroidal anti-inflammatory drug.
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Venlafaxine hydrochloride (Effexor) is well tolerated and may be more useful in patients with daytime sleepiness. Patients with insomnia may do well with mirtazapine (Remeron) or Nortriptyline (Pamelor). Electroconvulsive therapy should be considered in patients in whom an adequate response cannot be obtained with antidepressant medication alone. HALLUCINATIONS Hallucinations may be precipitated in parkinsonian patients by the administration of any of the antiparkinsonian medications. These are generally associated with higher doses of medication and occur more commonly in older patients and those with more advanced disease, depression, or compromised cognitive function. No patient with PD, however, is immune to this side effect. Amantadine and anticholinergic medications make patients particularly prone to hallucinations and should be the first medications to be discontinued when such complications occur. If hallucinations persist, dopamine agonists may need to be reduced or discontinued, and sometimes levodopa/carbidopa may not be tolerated. In patients in whom the required reduction in antiparkinsonian medication to prevent hallucinations leads to unacceptable worsening in parkinsonian motor signs, atypical antipsychotics may be administered to reduce or prevent their development. These agents have less affinity for the dopamine D2 receptor and thus are less likely to aggravate the extrapyramidal motor and cognitive symptoms of PD. Quietepine (Seroquel) should be the first-line agent for hallucinations in PD and may be started at 12.5 to 25 mg at bedtime. It can be slowly increased to a three-times-daily schedule, totaling up to 300 mg/day (see Table 2). If quietepine is ineffective, clozapine (Clozaril) can be implemented at doses of 12.5 to 25 mg/day and slowly increased. Weekly complete blood counts must be followed because this medication can cause neutropenia. Indeed, the use of these particular antipsychotic medications may allow one to reinstitute levodopa or a dopamine agonist at levels higher than previously tolerated. In PD patients, typical antipsychotics such as haloperidol and risperidol should be avoided due to their nonselective dopaminolytic effects. COGNITIVE IMPAIRMENT Mild cognitive difficulties are common in PD, occurring in up to 80% of patients, and often involve decreased verbal fluency, visuomotor and visuospatial processing, and executive function. Approximately 40% of PD patients develop dementia. In patients with parkinsonism and early dementia, a diagnosis of atypical PD including Lewy body diseases should be considered. With sudden cognitive deterioration, infection, drug toxicity, or depression should be considered. PD patients developing cognitive difficulties may need to be weaned from anticholinergic medications, selegiline, amantadine, and dopamine agonists. Galantamine (Exelon) or donepezil (Aricept) may improve cognition in some PD patients. Memantine (Namenda) is a newer medication
approved for Alzheimers disease that is a NMDA receptor antagonist, which some clinicians have begun to use to treat dementia in PD patients. AUTONOMIC DISORDERS Hyperactive bladder is common in PD and results in frequency, urgency, and urge incontinence. Patients may respond to tolterodine (Detrol, Detrol LA), or oxybutynin (Ditropan). Tolterodine is generally better tolerated, resulting in less confusion in PD patients. Occasionally, PD patients may develop hypoactive bladder with difficulty initiating urination and incomplete bladder emptying. These patients may respond best to doxazosin (Cardura) or tamsulosin (Flomax). Caution should be used in patients with orthostatic hypotension. In patients with new-onset urgency and incontinence, a urinary tract infection should be ruled out and when in doubt urologic consultation can be helpful. Sexual dysfunction is common in patients with PD or with the use of SSRIs. When these medications cannot be modified, one may choose to start sildenafil (Viagra) or vardenafil (Levitra). Occasionally, PD patients may have testosterone deficiency with decreased energy, impotence, and loss of sexual interest that may respond to testosterone replacement. Orthostatic hypotension is common early in atypical PD and may present in advanced idiopathic PD patients particularly when on higher doses of dopamimetic therapy. Antihypertensive medications may need to be reduced or eliminated, and patients may need to be encouraged to use support stockings and sleep with the head elevated at 30 degrees. Fludrocortisone (Florinef) can be started at 0.1 mg PO daily, and eventually dopaminergic medications should be reduced starting with agonists, and amantadine followed by levodopa/carbidopa. The patients medical record should be examined for other offending agents, including anticholinergics and quietepine. If fludrocortisone is ineffective, midodrine (Proamatine) can be added at 2.5 mg daily and increased to a maximum of 10 mg daily divided into a three-times-daily dosage schedule. It should be given during active hours when the patient is out of bed to minimize supine hypertension.
12
Surgical Therapy
Patients with PD whose motor symptoms can no longer be adequately controlled by medical therapy are candidates for surgical therapy. Surgical procedures for PD consist of ablative procedures (thalamotomy, pallidotomy) and stimulation procedures (thalamic, pallidal, subthalamic). Neurotransplantation is considered experimental and has not yet proved to be effective in randomized, double-blinded, clinical trials. THALAMOTOMY Thalamotomy is effective for the treatment of parkinsonian tremor. Lesions are generally placed in the cerebellar receiving area, ventralis intermedius (Vim). If the lesion is extended more anteriorly into the basal
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ganglia receiving area, ventralis oralis posterior and ventralis oralis anterior, (Vop and Voa, respectively), thalamotomy may also improve rigidity and druginduced dyskinesias. It is not effective, however, for bradykinesia, freezing, postural instability, or the gait disorder associated with PD. Bilateral thalamotomy is associated with an unacceptably high incidence of speech problems. This usually manifests in the form of aphasia, dysarthria, or dysphonia. The incidence of speech problems following bilateral thalamotomy varies from 30% to 50%. In light of currently available methods employing deep brain stimulation (DBS), bilateral thalamotomy is not recommended unless alternative approaches (i.e., DBS) are contraindicated. Owing to the lack of efficacy for bradykinesia and potential worsening of gait with thalamic surgery, subthalamic nucleus (STN) or globus pallidus (GPi) stimulation is more commonly recommended. PALLIDOTOMY Pallidotomy is effective for all the cardinal motor signs of PD including tremor, rigidity, bradykinesia, as well as motor fluctuations and drug-induced dyskinesias and dystonia. It may also improve axial symptoms including gait, balance and freezing. The improvement in axial symptoms following unilateral pallidotomy, however, is less consistent than that for appendicular symptoms with many patients losing their benefit 6 months to 2 years after unilateral pallidotomy. To gain consistent benefit for axial symptoms bilateral procedures are required; however, bilateral pallidotomy, as currently performed at most centers, is associated with an unacceptably high incidence of hypophonia, the severity of which may vary significantly from patient to patient. Some centers have also reported urinary incontinence and cognitive decline associated with bilateral pallidotomy; however, this is most likely secondary to lesions encroaching on more anteromedial nonmotor portions of the internal segment of the GPi or to complications associated with the procedure. Two common reasons for failure of patients to improve following pallidotomy are 1) the patient does not have idiopathic PD, but instead a parkinsonian syndrome, or 2) the lesion(s) are placed outside of the sensorimotor territory of GPi. DEEP BRAIN STIMULATION Deep brain stimulation in the GPi or the STN is effective for the treatment of all the cardinal motor signs of PD. Two subcortical sites, the internal segment of the globus pallidus (GPi) and the STN, are current targets for DBS therapy. The average improvement in the off medication/on stimulation state following bilateral DBS in the STN or GPi is approximately 40%-60%. Although some centers support the use of DBS in the STN for midline symptoms and DBS in the GPi for patients with dyskinesias, both procedures are effective in treating both types of symptoms. DBS in either STN or GPi may be associated with a reduction in the
required dose of antiparkinson medications. Patients with significant depression or anxiety should be well controlled before considering surgery and may be at higher risk for exacerbation following surgery. DBS can be performed safely and effectively bilaterally, either as a staged procedure or simultaneously. Simultaneous bilateral procedures may be associated with a higher incidence of postoperative confusion. Based on the patients symptoms, unilateral implantation may give the patient enough benefit to preclude or at least delay the necessity for a second implantation on the other side. Patients may require bilateral DBS if axial symptoms are severe or if they have severe appendicular symptoms bilaterally. Thalamic DBS is currently recommended only for the treatment of parkinsonian or essential tremor. Given the likelihood of PD patients to develop additional motor symptoms over time, pallidotomy or DBS in either the STN or the GPi may be a better approach for PD. PATIENT RESOURCES
American Parkinson Disease Association 1250 Hylan Blvd., Suite 4B Staten Island, NY 10305-1946 Phone: 800-223-2732 Fax: 718-981-4399 http://www.apdaparkinson.com/ Parkinsons Disease Foundation 1359 Broadway, Suite 1509 New York, NY 10018 Phone: 800-457-6676 Fax: 212-923-4778 http://www.pdf.org/
Essential Tremor
Michael H. Pourfar, M.D., and Elan D. Louis, M.D., M.S.
Overview
Essential tremor (ET) is the most common adult-onset movement disorder in the general population. The prevalence is 0.4% to 6% and may be as high as 22% in the elderly. People with mild disease may live with their tremor for many years without seeking medical counsel; therefore, its prevalence is likely underestimated. For those with more severe disease, however, the degree of disability belies its oft added designation as benign ET. ET is characterized primarily by a rhythmic 4- to 12-Hz kinetic (i.e., present during volitional movements) tremor that generally affects the arms. In more severe cases, the tremor may also be present during sustained arm extension (i.e., postural tremor). Other features that support the diagnosis are (1) a progressive increase
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ganglia receiving area, ventralis oralis posterior and ventralis oralis anterior, (Vop and Voa, respectively), thalamotomy may also improve rigidity and druginduced dyskinesias. It is not effective, however, for bradykinesia, freezing, postural instability, or the gait disorder associated with PD. Bilateral thalamotomy is associated with an unacceptably high incidence of speech problems. This usually manifests in the form of aphasia, dysarthria, or dysphonia. The incidence of speech problems following bilateral thalamotomy varies from 30% to 50%. In light of currently available methods employing deep brain stimulation (DBS), bilateral thalamotomy is not recommended unless alternative approaches (i.e., DBS) are contraindicated. Owing to the lack of efficacy for bradykinesia and potential worsening of gait with thalamic surgery, subthalamic nucleus (STN) or globus pallidus (GPi) stimulation is more commonly recommended. PALLIDOTOMY Pallidotomy is effective for all the cardinal motor signs of PD including tremor, rigidity, bradykinesia, as well as motor fluctuations and drug-induced dyskinesias and dystonia. It may also improve axial symptoms including gait, balance and freezing. The improvement in axial symptoms following unilateral pallidotomy, however, is less consistent than that for appendicular symptoms with many patients losing their benefit 6 months to 2 years after unilateral pallidotomy. To gain consistent benefit for axial symptoms bilateral procedures are required; however, bilateral pallidotomy, as currently performed at most centers, is associated with an unacceptably high incidence of hypophonia, the severity of which may vary significantly from patient to patient. Some centers have also reported urinary incontinence and cognitive decline associated with bilateral pallidotomy; however, this is most likely secondary to lesions encroaching on more anteromedial nonmotor portions of the internal segment of the GPi or to complications associated with the procedure. Two common reasons for failure of patients to improve following pallidotomy are 1) the patient does not have idiopathic PD, but instead a parkinsonian syndrome, or 2) the lesion(s) are placed outside of the sensorimotor territory of GPi. DEEP BRAIN STIMULATION Deep brain stimulation in the GPi or the STN is effective for the treatment of all the cardinal motor signs of PD. Two subcortical sites, the internal segment of the globus pallidus (GPi) and the STN, are current targets for DBS therapy. The average improvement in the off medication/on stimulation state following bilateral DBS in the STN or GPi is approximately 40%-60%. Although some centers support the use of DBS in the STN for midline symptoms and DBS in the GPi for patients with dyskinesias, both procedures are effective in treating both types of symptoms. DBS in either STN or GPi may be associated with a reduction in the
required dose of antiparkinson medications. Patients with significant depression or anxiety should be well controlled before considering surgery and may be at higher risk for exacerbation following surgery. DBS can be performed safely and effectively bilaterally, either as a staged procedure or simultaneously. Simultaneous bilateral procedures may be associated with a higher incidence of postoperative confusion. Based on the patients symptoms, unilateral implantation may give the patient enough benefit to preclude or at least delay the necessity for a second implantation on the other side. Patients may require bilateral DBS if axial symptoms are severe or if they have severe appendicular symptoms bilaterally. Thalamic DBS is currently recommended only for the treatment of parkinsonian or essential tremor. Given the likelihood of PD patients to develop additional motor symptoms over time, pallidotomy or DBS in either the STN or the GPi may be a better approach for PD. PATIENT RESOURCES
American Parkinson Disease Association 1250 Hylan Blvd., Suite 4B Staten Island, NY 10305-1946 Phone: 800-223-2732 Fax: 718-981-4399 http://www.apdaparkinson.com/ Parkinsons Disease Foundation 1359 Broadway, Suite 1509 New York, NY 10018 Phone: 800-457-6676 Fax: 212-923-4778 http://www.pdf.org/
Essential Tremor
Michael H. Pourfar, M.D., and Elan D. Louis, M.D., M.S.
Overview
Essential tremor (ET) is the most common adult-onset movement disorder in the general population. The prevalence is 0.4% to 6% and may be as high as 22% in the elderly. People with mild disease may live with their tremor for many years without seeking medical counsel; therefore, its prevalence is likely underestimated. For those with more severe disease, however, the degree of disability belies its oft added designation as benign ET. ET is characterized primarily by a rhythmic 4- to 12-Hz kinetic (i.e., present during volitional movements) tremor that generally affects the arms. In more severe cases, the tremor may also be present during sustained arm extension (i.e., postural tremor). Other features that support the diagnosis are (1) a progressive increase
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in tremor amplitude over time (years); (2) the spread of tremor over time (years) to also involve the head (neck) and voice; (3) acute reduction in tremor amplitude in response to ethanol; (4) presence of other family members with ET; and (5) absence of other neurodegenerative diseases. The diagnosis remains clinical, and it should be appreciated that these features do not paint a complete picture of the clinical diversity of ET. For example, an intentional component to the kinetic tremor and complaints of unsteadiness and difficulty with tandem gait are common. Subclinical cognitive changes and differences in personality profile have been reported in patients with ET in comparison with age-matched controls. There is also a subset of ET patients, perhaps as many as 20%, which eventually develops a resting tremor of the arms. However, the concomitant presence of bradykinesia or rigidity, dystonic posturing, or taskspecific tremor should raise clinical suspicions of other disorders (Table 1). Although many physiologic aspects of ET are being illuminated, its causes remain elusive. Indeed, even whether it constitutes a single disease entity or, rather, a family of diseases remains controversial. What does seem clear at present is that ET is generated by rhythmic alternating firing of agonist and antagonist muscles, likely as the result of an abnormal central pacemaker. The olivocerebellar-thalamocortical circuit, in particular, has been implicated. The pathology is not well understood, but increased bilateral blood flow to the cerebellum on positron emission tomographic studies suggests that the cerebellum is involved. A reduction in the cerebellar N-acetyl-aspartate-to-creatine ratio, a marker of reduced neuronal viability, also supports a central role for the cerebellum. The improvement of symptoms following stimulation of the thalamic Vim nucleus, which receives input from the cerebellum, provides further support for this notion. The genetics of ET have likewise been a challenge to unravel. A positive family history can be identified in 17% to 100% of cases, with a first-degree relative of an ET case having a five-fold increased likelihood of having ET than a first-degree relative of a control subject. Twin studies, however, demonstrate only 60% to 63% disease concordance among monozygotic twins, making
it likely that environmental factors play a role in disease etiology. Linkage studies have identified two chromosomal loci on chromosomes 2p and 3q, indicating that ET is genetically heterogeneous.
Treatment Overview
The first question should be whether the symptoms are disabling or embarrassing enough to merit treatment. The question is even more pertinent with ET in that most treatments are often only partially successful and can be accompanied by side effects. More aggressive surgical modalities, although generally more effective, are not without potentially significant risks. Severity of tremor can vary within affected individuals in a given ET family as well as in a given individual over time. In general, severity tends to increase slowly over decades, though there may be subsets such as those with onset after age 60 years or those without head tremor who progress more rapidly. There does not seem to be a significant clinical response to treatment when comparing those with and those without family histories of ET. As a general rule, however, the more severe the tremor, the less likely the chance that oral medications alone will provide sufficient long-term control of tremor. Concerning head and voice tremor, treatment response is generally less robust than is treatment response of arm tremor. The choice of what and when to start should be tailored to the individual patient, though a general algorithm is provided as a guide (Figure 1).
12
Nonpharmacologic Treatment Options

For patients with mild tremors who desire tremor reduction but do not want or tolerate oral medications, biofeedback techniques have been modestly successful. The use of peripheral mechanical loading such as the use of wrist weights has little effect on tremor frequency but can dampen the amplitude of tremor. Weighted utensils also have been used to dampen the tremor when it interferes with eating.
TABLE 1 Questions for Generating a Differential to Essential Tremor

1. Is action tremor present? Check to see if tremor is present with volitional movements (kinetic) and with maintenance of posture (postural). Check if tremor is ethanol responsive. Review family history. 2. Is patient younger than 40 years old or does the patient have other involuntary movements (e.g., dystonia)? Rule out Wilsons disease. 3. Is tremor only present with specific activities or is dystonic posturing also present? Consider task-specific or dystonic tremor (e.g., primary writing tremor or head tremor with torticollis). 4. Is tremor only in the legs or trunk when the patient is standing? Consider orthostatic tremor. 5. Is tremor also present at rest, or does the patient also have rigidity and bradykinesia? Consider Parkinsons disease. 6. Is patient on medications associated with tremor (e.g., prednisone, valproate)? Consider drug-related tremor. 7. Is tremor accompanied by symptoms of hyperthyroidism (e.g., heat intolerance, palpitations)? Consider thyroid disease. 8. Is the tremor variable and of low amplitude? Consider enhanced physiologic tremor. 9. Are there any other significant neurologic findings (e.g., cerebellar speech, cranial nerve abnormalities, spasticity, chorea)? Consider alternate diagnoses (primary cerebellar processes, e.g., spinocerebellar ataxias, posterior fossa tumors, multiple sclerosis, Huntingtons disease).
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Diagnosis of ET
PROPRANOLOL Several beta blockers, including sotalol and metoprolol, appear to be effective in the management of ET, but propranolol, a nonselective antagonist, has been the most consistently studied and is more effective than relatively selective beta1-antagonists. The efficacy of propranolol appears to be mediated by peripheral and possibly central mechanisms of action, although these are not well understood. Propranolol can be given as a standard or long-acting formulation. Initial dosing with the standard formulation typically begins with 10 to 20 mg per day, titrating weekly, as tolerated, to as high as 320 mg per day, with an average being 120 mg per day. Between 45% and 75% of patients report a benefit from propranolol as compared with placebo. The response is less satisfactory in the treatment of voice and head tremor. In general, side effects are mild to moderate but can occur in over half of patients. Fatigue, depression, orthostatic changes in blood pressure, impotence, and exercise intolerance are among the more common side effects. Some of these side effects do not habituate with time and require lowering the dosage or changing to alternative therapies. Other contraindications include severe asthma and heart block. PRIMIDONE Primidone is a parent compound of phenobarbital and 2-ethyl-2-phenylmalonamide (PEMA). Its mechanism of action in controlling tremor is not completely understood, but its acute effect is thought to be partly due to the parent compound, which is not fully metabolized to PEMA and phenobarbital. Phenobarbital, along with primidone, is thought to contribute to the chronic antitremor effect. Primidone and propranolol have been compared head to head in several clinical trials and their efficacy is similar, although there is some evidence that primidone is better tolerated in long-term management. A drawback, however, is a relatively common acute adverse reaction including nausea, vomiting, or ataxia, which can occur in more than 20% of patients starting on the drug and that usually requires the
Predominantly affecting limbs
Predominantly affecting voice or head
If mild consider biofeedback, wrist weights or limited alcohol in appropriate patient
If requires treatment consider propranolol or primidone
If requires more aggressive treatment consider treatment with propranolol or primidone (see comparative box)
If suboptimal consider botulinum toxin injections
If suboptimal, consider combination or alternative oral medications +/ botulinum
If suboptimal and debilitating consider thalamic surgery (DBS > thalamotomy)
If remains uncontrolled consider thalamic surgery (DBS > thalamotomy)
FIGURE 1. General treatment algorithm for essential tremor (ET). DBS, Deep brain stimulation.
Pharmacologic Treatment Options

The long-standing stalwarts of ET therapy have been the beta blocker propranolol and the antiepileptic primidone (Table 2). Because their efficacy is roughly equivalent, the decision of which to start should be guided by side effect profile and tolerability as well as the possible coexisting need for either an antihypertensive or antiepileptic medication.
TABLE 2 Comparison between Propranolol and Primidone in the Treatment of Essential Tremor
Variables Contraindications Starting dose Target dose Adverse effects Acute Chronic Efficacy Necessary follow-up Propranolol Asthma, unstable CHF, diabetes, AV block 10-20 mg/day Average of 120-320 mg 8%, mostly fatigue 12-66%, fatigue, impotence, depression, bradycardia Range from 45-75% efficacy vs. placebo Blood pressure and heart rate; no laboratory studies necessary Primidone Porphyria, phenobarbital allergy 25 mg qhs Average of 750-1000 mg 22-32% fatigue, can have severe nausea, vomiting, ataxia Very low percentage, mostly fatigue Range from 60-75% efficacy vs. placebo CBC every 6-12 mo
CBC, Complete blood count; CHF, congestive heart failure; AV, atrioventricular.
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discontinuation of the drug. The usual starting dose is 25 mg at bedtime, increasing slowly by 25 mg per week in three divided doses up to 100 mg per day and then increasing by 50 mg increments up to 1000 mg per day with an average dose being 750 mg per day. Studies have demonstrated a 60% to 75% improvement in tremor amplitude compared with placebo. Like propranolol, however, primidone is often less effective in the management of voice and head tremor than in limb tremor. With the notable exception of the acute toxic reaction described earlier and fatigue, primidone is generally well tolerated with a low incidence of adverse symptoms 1 year into use. It should not be given to patients with an allergic reaction to phenobarbital or patients with porphyria. Because of rare cases of granulocytopenia and red blood cell hypoplasia, a complete blood count is recommended every 6 months to 1 year. OTHER PHARMACOLOGIC OPTIONS In the event that both propranolol and primidone are effective but provide suboptimal relief, combination of the two has proved to be of benefit in some cases. In patients who do not benefit from either medication or whose response is suboptimal, add-on or alternative pharmacotherapy is a reasonable next step. Medications that enhance gamma aminobutyric acid (GABA)-ergic function have demonstrated efficacy in the treatment of ET. Gabapentin proved superior to placebo in two of three trials. It is usually slowly titrated from a dose of 300 mg per day to up to 1800 to 2400 mg divided three times per day. Alprazolam, at doses from 0.75 to 2.75 mg per day, also has shown benefit but is frequently limited by sedation, and there is the potential for abuse. Other medications have shown variable success. Topiramate has recently been the subject of study and has demonstrated efficacy in ET. It is started at 25 mg per day with increments of 25 mg per week up to 100 mg per day as twice-daily dosing, followed by 50 mg increments up to 400 mg per day. In one study, side effects occurred in 32% of patients compared with 10% on placebo. These side effects included paresthesias, weight loss, fatigue, and memory difficulties. Flunarizine and nimodipine, both calcium channel blockers, have occasional benefit, whereas nifedipine, also a calcium channel blocker, appears to worsen ET. These medications are generally well tolerated, with orthostasis being a potential side effect requiring attention. Theophylline and clozapine have also been reported to be of benefit but are of questionable usefulness given their cumbersome potential side effect profiles. The list of additional medications that have been anecdotally associated with improvement is protean, but controlled trials (or lack of) have not consistently corroborated an effect. Formally condoning the use of ethanol for tremor improvement has been controversial because of concerns of dependence and abuse. In an appropriately screened patient, however, moderate situational use of ethanol can provide transient benefit. An ethanol analog 1-octanolis currently in trials and appears to provide the benefit of ethanol without the abuse potential.
Treatment with Botulinum Toxin Injections

Botulinum toxin binds to the presynaptic acetylcholine receptor and thus blocks gamma motor and muscle spindle efferent activity in the targeted muscle. Because ET is characterized by abnormal near synchrony of agonist and antagonist muscle activity, botulinum toxin can be used against one or both of the paired muscle groups to weaken and thus peripherally dampen the tremor. It is usually suboptimal for management of limb tremor because doses sufficient to diminish tremor often cause undesirable, albeit transient, limb weakness. When given for limb tremor, it is generally injected into both the extensor and flexor carpii radialis muscles in doses ranging from 15 to 100 units with the stronger flexors usually receiving a slightly higher dose. Its greatest advantage, however, is for head and voice tremor, both of which are less effectively managed with oral medications. For head tremor, 40 to 400 units are injected into the involved sternocleidomastoid, splenii, and scalene muscles. Pure vertical or horizontal movements are easier to treat than those with more complex directional components, but all require fine-tuning over successive 3- to 4-month intervals until the optimal sites and doses are achieved. Voice tremor is frequently helped with 0.6- to 15-unit injections to the vocal cords. Patients often complain of transient breathiness and dysphagia, but more significant side effects are rare if the injections are performed by an experienced hand under electromyographic guidance.
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Surgical Treatment
For those individuals with severe tremors, medications alone rarely provide satisfactory, long-term control. For this group, surgery is often the most effective means of tremor reduction. Lesioning the thalamus has been performed for tremor control for more than half a century. The procedure produces prolonged and significant improvement in tremors of the contralateral limb, but side effects (especially dysarthria) can be severe, particularly when this procedure is performed bilaterally. For this reason, thalamotomies have been largely superseded by stimulation techniques using electrodes in the Vim nucleus of the thalamus. The mechanisms of action remain controversial, but its efficacy has been repeatedly demonstrated with as high as 90% improvement ratings reported. Severe side effects include perioperative intracranial bleeding, hemiparesis, and death. In experienced centers these occur in less than 1% of cases, but the potential does necessitate more conservative initial medication trials as well as appropriate patient selection. Hardware malfunctions and infections can lead to later complications and revisions in as many as 25% of patients. Stimulation itself can cause numerous untoward symptoms including paresthesias, dystonia, dizziness, dysarthria, and gait disturbances, but these often respond to adjustments in stimulation parameters. Deep brain stimulation is most
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consistently effective in improving limb tremors but can lead to improvement in axial, head, and voice tremor as well. SELECTED READING
Deuschl G, Wenzelburger R, Loffler K, et al: Essential tremor and cerebellar dysfunction: clinical and kinematic analysis of intention tremor, Brain 123:1568-1580, 2000. Dogu O, Sevim S, Camdeviren H, et al: Prevalence of essential tremor: door-to-door neurological exams in Mersin Province, Turkey, Neurology 61:1804-1807, 2003. Gulcher JR, Jonsson P, Kong A, et al: Mapping of a familial essential tremor gene, FET1, to chromosome 3q13, Nat Genet 17:84-87, 1997. Louis ED: Clinical practice: essential tremor, N Engl J Med 345: 887-891, 2001. Louis ED: Essential tremor, Lancet Neurol 4:100-110, 2005. Louis ED, Ottman R: How familial is familial tremor? genetic epidemiology of essential tremor, Neurology 46:1200-1205, 1996. Louis ED, Ottman R, Hauser WA: How common is the most common adult movement disorder? estimates of the prevalence of essential tremor throughout the world, Mov Disord 13:5-10, 1998.
Symptomatic Treatments
MOTOR IMPAIRMENT The focus of therapy for motor abnormalities in HD has traditionally been on the control of chorea. However, chorea may not cause serious disability, and antichoreic therapy is beset with adverse effects. In fact, disease progression and pursuant functional decline are associated with a natural reduction of chorea and the emergence of dystonia. Dopaminergic blockade with typical antipsychotics, such as haloperidol, have been the mainstay of treatment for chorea. However, the impact of these medications on swallowing, speech, spontaneous movements, and gait may impair function out of proportion to any improvement in chorea. Therefore, the treatment of chorea should be reserved only for those individuals with severe chorea that interferes with activities of daily living, gait, and balance or is socially isolating. Figure 1 details the treatment approaches to chorea in HD. Amantadine appears to be a well-tolerated medication for treating chorea and is a useful first-line agent for disabling chorea in HD. The presynaptic monoamine depleting agent tetrabenazine, not available in the United States, is an effective agent for chorea management. Its use is limited by the need to import it from Canada and the risk of depression and parkinsonism as side effects. However, if tetrabenazine does become available in the United States, it may ultimately be considered a first- or second-line agent in patients without comorbid depression or parkinsonian features. Depression is not an absolute contraindication for the use of tetrabenazine as long as the depression is treated and closely followed. Atypical antipsychotics may be considered, particularly in individuals with comorbid psychosis, agitation, or irritability. Finally, typical antipsychotics such as haloperidol can be considered in patients with severe chorea where other agents have failed or are poorly tolerated. Some patients with an akinetic-rigid or parkinsonian variant of HD may benefit from dopaminergic therapy. Generally a carbidopa/levodopa preparation started at 25/100 mg daily and increased weekly by 25/100 mg to 25/100 mg three times daily. The dose can ultimately be increased to 300 mg of levodopa three times daily. Unlike in Parkinsons disease, levodopa does not appear to be associated with dyskinesia or worsening chorea in HD. Physical therapy and occupational therapy may be useful in patients with relatively well-preserved cognitive function and gait, balance, and fine motor difficulties. Speech therapists are useful in assessing swallowing function and making recommendations regarding diet and the need for feeding tubes. COGNITIVE IMPAIRMENT Treatments for cognitive dysfunction are largely ineffective. Acetylcholinesterase inhibitors such as donepezil may be considered in patients with memory disturbances. The lowest possible dose should be initiated and titrated slowly.
PATIENT RESOURCE
International Tremor Foundation 7046 West 105th Street Overland Park, KS 66212-1803 Phone: 913-341-3880 Fax: 913-341-1206 E-mail: IntTremFnd@worldnet.att.com http://www.essentialtremor.org/
Huntingtons Disease
Kevin M. Biglan, M.D.
Huntingtons disease (HD) is a progressively disabling and fatal neurodegenerative disorder characterized by the triad of a movement disorder, dementia, and behavioral disturbances. The diagnosis of HD was traditionally based solely on the adult onset of the characteristic clinical illness in the setting of a confirmatory family history. In 1993 the Huntingtons Disease Collaborative Research Group identified the genetic mutation responsible for HD, making precise and accurate genetic diagnosis possible. Unfortunately there are no known effective therapies to slow the progression or delay the onset of HD. Symptomatic treatments have largely focused on ameliorating the motor and psychological dysfunction of individuals affected with HD. However, scientific advances have renewed hope for the development of effective neuroprotective or preventive therapeutic strategies.
292
Huntingtons Disease
consistently effective in improving limb tremors but can lead to improvement in axial, head, and voice tremor as well. SELECTED READING
Deuschl G, Wenzelburger R, Loffler K, et al: Essential tremor and cerebellar dysfunction: clinical and kinematic analysis of intention tremor, Brain 123:1568-1580, 2000. Dogu O, Sevim S, Camdeviren H, et al: Prevalence of essential tremor: door-to-door neurological exams in Mersin Province, Turkey, Neurology 61:1804-1807, 2003. Gulcher JR, Jonsson P, Kong A, et al: Mapping of a familial essential tremor gene, FET1, to chromosome 3q13, Nat Genet 17:84-87, 1997. Louis ED: Clinical practice: essential tremor, N Engl J Med 345: 887-891, 2001. Louis ED: Essential tremor, Lancet Neurol 4:100-110, 2005. Louis ED, Ottman R: How familial is familial tremor? genetic epidemiology of essential tremor, Neurology 46:1200-1205, 1996. Louis ED, Ottman R, Hauser WA: How common is the most common adult movement disorder? estimates of the prevalence of essential tremor throughout the world, Mov Disord 13:5-10, 1998.
Symptomatic Treatments
MOTOR IMPAIRMENT The focus of therapy for motor abnormalities in HD has traditionally been on the control of chorea. However, chorea may not cause serious disability, and antichoreic therapy is beset with adverse effects. In fact, disease progression and pursuant functional decline are associated with a natural reduction of chorea and the emergence of dystonia. Dopaminergic blockade with typical antipsychotics, such as haloperidol, have been the mainstay of treatment for chorea. However, the impact of these medications on swallowing, speech, spontaneous movements, and gait may impair function out of proportion to any improvement in chorea. Therefore, the treatment of chorea should be reserved only for those individuals with severe chorea that interferes with activities of daily living, gait, and balance or is socially isolating. Figure 1 details the treatment approaches to chorea in HD. Amantadine appears to be a well-tolerated medication for treating chorea and is a useful first-line agent for disabling chorea in HD. The presynaptic monoamine depleting agent tetrabenazine, not available in the United States, is an effective agent for chorea management. Its use is limited by the need to import it from Canada and the risk of depression and parkinsonism as side effects. However, if tetrabenazine does become available in the United States, it may ultimately be considered a first- or second-line agent in patients without comorbid depression or parkinsonian features. Depression is not an absolute contraindication for the use of tetrabenazine as long as the depression is treated and closely followed. Atypical antipsychotics may be considered, particularly in individuals with comorbid psychosis, agitation, or irritability. Finally, typical antipsychotics such as haloperidol can be considered in patients with severe chorea where other agents have failed or are poorly tolerated. Some patients with an akinetic-rigid or parkinsonian variant of HD may benefit from dopaminergic therapy. Generally a carbidopa/levodopa preparation started at 25/100 mg daily and increased weekly by 25/100 mg to 25/100 mg three times daily. The dose can ultimately be increased to 300 mg of levodopa three times daily. Unlike in Parkinsons disease, levodopa does not appear to be associated with dyskinesia or worsening chorea in HD. Physical therapy and occupational therapy may be useful in patients with relatively well-preserved cognitive function and gait, balance, and fine motor difficulties. Speech therapists are useful in assessing swallowing function and making recommendations regarding diet and the need for feeding tubes. COGNITIVE IMPAIRMENT Treatments for cognitive dysfunction are largely ineffective. Acetylcholinesterase inhibitors such as donepezil may be considered in patients with memory disturbances. The lowest possible dose should be initiated and titrated slowly.
PATIENT RESOURCE
International Tremor Foundation 7046 West 105th Street Overland Park, KS 66212-1803 Phone: 913-341-3880 Fax: 913-341-1206 E-mail: IntTremFnd@worldnet.att.com http://www.essentialtremor.org/
Huntingtons Disease
Kevin M. Biglan, M.D.
Huntingtons disease (HD) is a progressively disabling and fatal neurodegenerative disorder characterized by the triad of a movement disorder, dementia, and behavioral disturbances. The diagnosis of HD was traditionally based solely on the adult onset of the characteristic clinical illness in the setting of a confirmatory family history. In 1993 the Huntingtons Disease Collaborative Research Group identified the genetic mutation responsible for HD, making precise and accurate genetic diagnosis possible. Unfortunately there are no known effective therapies to slow the progression or delay the onset of HD. Symptomatic treatments have largely focused on ameliorating the motor and psychological dysfunction of individuals affected with HD. However, scientific advances have renewed hope for the development of effective neuroprotective or preventive therapeutic strategies.
Huntingtons Disease
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Movement Disorders
FIGURE 1. Medical management of chorea. No treatment
No
Functionally or socially disabling chorea? Yes Start amantadine 100 mg/day. Increase by 100 mg weekly until 100 mg TID. Edema, confusion and livedo reticularis may occur.
Continue amantadine.
Yes
Chorea controlled? No Comorbid psychosis, irritability, depression or parkinsonian features? Yes No Consider terabenazine 12.5 mg twice a day. Increase by 25 mg/day increments weekly until on a maximum dose of 50 mg three times per day or intolerable side effects. Monitor closely for depression, parkinsonism and somnolence.
Consider quetiapine 25 mg at bedtime. Increase by 25 mg/day weekly until on 100 mg BID or intolerable side effects. Somnolence, weight gain and lightheadedness may occur.
12
Continue current treatment.
Yes
Chorea controlled? No
Consider clozapine 12.5 mg at bedtime. Increase by 12.5 mg/day weekly until on 75 mg daily or intolerable side effects. Somnolence, weight gain and lightheadedness may occur. Weekly complete blood counts due to possibility of agranulocytosis.
Consider haloperidol 0.5 mg twice a day. Double dose weekly until symptoms controlled or intolerable side effects. Monitor for parkinsonism, worsening motor function, falls and tardive dyskinesia
BEHAVIORAL CARE Depression is common in HD, occurring in as many as half of HD patients, and is an important source of morbidity and mortality. The suicide rate is five times more frequent in HD than in the general population and may account for 2% of HD mortality. Selective serotonin reuptake inhibitors (SSRIs) are the treatment of choice for depression in HD. All the available agents appear to be effective; however, if a patient fails to respond, it is often useful to switch agents. Sertraline, starting at 25 mg/day, is useful for depression associated with apathy and somnolence. The dosage should be increased to 50 mg/day after 1 week, and the patient should be followed closely for signs of agitation. Paroxetine, starting at 10 mg as a single night-time dose, may be useful for patients with depression
and insomnia. Mirtazapine is also useful for insomnia associated with depression and may be considered as a first-line treatment in patients with comorbid anxiety. The dose should start at 15 mg at bedtime and may be increased by 15 mg every 4 weeks, depending on efficacy. SSRIs are also useful agents for the treatment of other psychiatric and behavioral disturbances in HD. They should be considered in the initial management of chronic anxiety, obsessive-compulsive symptoms, irritability, and agitation associated with HD. As for depression, these agents should be started at a low dose and titrated slowly. Benzodiazepines are also useful in HD for the treatment of acute anxiety and episodic aggressiveness. Lorazepam, 0.5 mg, given on an as-needed basis, is useful for aggressive episodes and anxiety.
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Huntingtons Disease
Irritability and aggression are common manifestations of the HD personality and are manifested by an inability to control ones temper or a reduced threshold for the development of anger. Patients may overreact to trivial issues and may be verbally and even physically abusive. Underlying psychopathology, such as paranoia, depression, or anxiety, should be sought, and psychiatric evaluation may be useful. SSRIs are the treatment of choice, but if they are ineffective, then valproate may be useful. Extended-release preparations of valproate allowing twice-daily dosing are preferred because they likely enhance compliance. Extended-release valproate should be started at 250 mg twice daily. Liver function tests and valproate levels should be followed, though there is no clear correlation with drug levels and therapeutic response, with many patients reporting improvement at subtherapeutic levels. Atypical antipsychotics, as detailed later, may also be useful. Psychosis may manifest in the form of delusions, paranoia, and even frank hallucinations may occur in 10% to 15% of patients. Atypical antipsychotics are the mainstay of treatment. Quetiapine is started at 25 mg at bedtime and increased every few days in 25-mg increments with twice-daily dosing until symptoms are well controlled. If there is no improvement at dosages of 100 mg twice daily, then psychiatric consultation is advisable. Other atypical antipsychotics are also useful, including olanzapine (Zyprexa), risperidone (Risperdal), and clozapine (Clozaril). Finally, apathy is common in HD. Secondary causes of apathy such as depression and paranoia should be ruled out. Medications that may contribute to apathy such as antipsychotics should be minimized or eliminated.
Study Group (HSG) is an international collaboration of academic medical centers dedicated to advancing the knowledge and treatment of HD. If possible, patients should be referred to HD centers affiliated with the HSG so that they may have access to experimental therapeutics in HD.
Conclusions
Current therapies have largely focused on symptomatic treatments aimed at ameliorating the motor and psychological dysfunction of individuals affected with HD. Although there are currently no effective therapies to slow the progression or delay the onset of HD, scientific advances have renewed hope for the development of effective neuroprotective or preventive therapeutic strategies. The hope of new effective neuroprotective therapies and the opportunity for patients and families to be actively involved in experimental clinical trials of such treatments are essential to the ongoing care of patients with HD. SELECTED READING
Hersch S, Rosas HD: Neuroprotective therapy for Huntingtons disease: new prospects and challenges, Expert Rev Neurother 1:111-118, 2002. Huntingtons Disease Collaborative Research Group: A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntingtons disease chromosomes, Cell 72:971-983, 1993. Huntington Study Group: A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntingtons disease, Neurology 57:397-404, 2001.
PATIENT RESOURCES
Neuroprotection and Experimental Therapeutics

Neuroprotection refers to interventions aimed at favorably influencing the underlying disease process to delay onset or slow progression. A number of neuroprotective trials have been undertaken in individuals with HD with limited success. Recent studies with coenzyme Q10 have suggested a potential disease modifying effect of this compound in HD. Many patients and their families, therefore, inquire about the usefulness of coenzyme Q10. It is important to balance hope with realistic expectations in this population. Certainly coenzyme Q10 at 600 mg daily is well tolerated with minimal side effects, the only down side being cost (@$100 per month) for a potentially ineffective treatment. The issues of cost and lack of clear efficacy of this and other experimental compounds must be discussed, with patients and families ultimately making the decision about whether to initiate this treatment. It is anticipated that in the next few years many new experimental therapies will be tested in clinical trials in patients with HD and presymptomatic patients carrying the HD gene. The opportunity for patients and their families to be involved in clinical trials of experimental compounds is incredibly important. The Huntington
The Huntington Study Group University of Rochester 1351 Mt. Hope Avenue, STE 223 Rochester, NY 14620 http://www.huntington-study-group.org/ Huntingtons Disease Society of America 158 West 29th Street, 7th Floor New York, NY 10001-5300 Phone: 800-345-HDSA Fax: 212-239-3430 http://www.hdsa.org/ Hereditary Disease Foundation 1303 Pico Boulevard Santa Monica, CA 90405 Phone: 310-450-9913 Fax: 310-450-9532 http://www.hdfoundation.org/
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Movement Disorders

Elizabeth OHearn, M.D.
TABLE 1 Ataxia: Differential Diagnosis

A. Inherited 1. Autosomal dominant 2. Autosomal recessive 3. X-linked 4. Mitochondrial B. Acquired 1. Structural/demyelinating 2. Toxic/metabolic 3. Paraneoplastic 4. Infectious 5. Autoimmune C. Idiopathic 1. Multisystem atrophy, cerebellar subtype (MSA-C) 2. Idiopathic cerebellar degeneration
Persons with neurodegenerative disorders that affect the cerebellum often present with a broad-based, unsteady gait. Handwriting may deteriorate because of inaccurate finger movements. Patients may report blurred vision and difficulty reading, and speech may be slurred. These signs constitute ataxia, a word of Greek origin that means a-without or lacking, and taxisorder or straightness, referring to disordered movements. Abnormal cerebellar function produces disordered timing and strength of muscle contraction resulting in movements that are uncoordinated. The cerebellar vermis is essential for walking, and cerebellar hemispheres are required for coordinated limb movement. In most forms of cerebellar degeneration, including that which accompanies aging, atrophy of the vermis precedes loss in lateral parts of the cerebellum. A staggering gait and unexpected falls are typical early signs of cerebellar dysfunction and usually precede upper extremity dysmetria. The cerebellum influences many parts of the brain so that dysfunction of the cerebellum produces abnormalities in many clinical spheres, including cognitive processes. The cerebellum receives input from most of the brain, and it modulates descending projections from several brainstem nuclei (e.g., red nucleus, inferior olive, vestibular, and reticular nuclei). Ascending output from the cerebellum, via the thalamus, exerts a powerful influence on motor cortex and on other cortical regions. It is generally agreed that the cerebellum and basal ganglia differ in function and that cerebellar abnormalities produce distinct signs and symptoms compared to lesions of cerebral cortex or striatum. Sensory ataxia due to loss of proprioception also produces unsteady gait but can be distinguished from cerebellar ataxia by demonstrating loss of position sense. This discussion focuses on inherited ataxias that present in adulthood and are caused by cerebellar degenerative disorders.
genetics have enabled reclassification of familial cerebellar disorders by linkage to genetic abnormalities. When a patient presents with cerebellar dysfunction, it is important to determine whether the neurologic disorder is genetic. Inherited ataxias may be classified, according to patterns of inheritance (Table 2), as disorders that are (1) autosomal dominant (AD); (2) autosomal recessive (AR); or (3) X linked. Mitochondrial disorders with cerebellar degeneration and ataxia (4) are included among genetic ataxias since these syndromes are often due to mutations in mitochondrial or nuclear DNA. Autosomal Dominant Cerebellar Ataxias Currently, 30 AD, progressive, cerebellar degenerative disorders have been described. The Human Genome Organization (http://www.gene.ucl.ac.uk/cgibin/nomenclature/searchgenes.pl) has assigned 26 spinocerebellar ataxia (SCA) numbers to distinct disorders. Four additional AD ataxias have been named differently: dentatorubral-pallidoluysian atrophy (DRPLA), episodic ataxia types 1 (EA1) and 2 (EA2), and fibroblast growth factor 14 (FGF14) ataxia. The responsible gene mutation has been identified in 14 of these 30 AD cerebellar ataxias: SCAs 1, 2, 3, 6, 7, 8, 10, 12, 14, 17, DRPLA, EA1, EA2, and FGF14. Chromosomal linkage has been established in 15 AD ataxias: SCAs 4, 5, 11, 13, 15, 16, and 18 to 26. SCA9 has been assigned to an ataxia that includes ophthalmoplegia and parkinsonian features but for which chromosomal linkage has not been established. SCA26 has been assigned to an ataxia that has not been characterized further.
SCAS 1 to 26. In all SCAs, cerebellar signs are prominent,
12
Diagnostic Approach to Ataxia

In patients with progressive ataxia, establishing a diagnosis may lead to treatment of reversible ataxias and enables provision of prognostic information. Further research on individual ataxias increases the likelihood of identifying pathologic mechanisms and developing disease-specific therapy. Ataxias may be divided into three classes (Table 1): A. inherited; B. acquired (secondary to an identified nongenetic cause); and C. idiopathic (etiology unknown). INHERITED ATAXIAS Ataxias are clinically, genetically, and neuropathologically heterogeneous. Recent advances in molecular
and Purkinje cell degeneration has been found when neuropathologic material has been examined. Although mutations in separate genes are responsible for different SCAs, there is extensive phenotypic overlap among SCAs, probably explained by the shared feature of Purkinje cell loss. Extracerebellar abnormalities, such as retinal lesions, parkinsonian signs, or seizure disorders, accompany cerebellar abnormalities in some SCAs and may help differentiate among inherited ataxias (Table 3).
296
TABLE 2 Inherited Adult-Onset Ataxias

1. Autosomal Dominant Ataxias a. SCAs 1-26 1. Coding region mutation: SCAs 1, 2, 3, 6, 7, 14, 17 2. Noncoding region mutation: SCAs 8, 10, 12 3. Mutation not identified: SCAs 4, 5, 9, 11, 13, 15, 16, and 18-26 b. DRPLA c. Channelopathies: EA1, EA2, SCA6 d. FGF14 ataxia 2. Autosomal Recessive Ataxias a. Friedreichs Ataxia b. Ataxia with vitamin E deficiency c. Wilsons disease d. Other testable AR disorders that may include adult-onset ataxia: abetalipoproteinemia, ataxia with oculomotor ataxia type 1, cerebrotendinous xanthomatosis, hexosaminidase A deficiency, metachromatic leukodystrophy, Niemann-Pick disease type C, progressive myoclonic epilepsies (EPM1, EPM2A, and adult neuronal ceroid-lipofuscinosis or Kufs disease), Refsums disease e. Many other AR disorders with ataxia, usually early onset 3. X-Linked Ataxias a. Fragile X tremor/ataxia syndrome (FXTAS) b. Adrenomyeloneuropathy c. Rare others, usually early onset 4. Mitochondrial Ataxias a. Neuropathy, ataxia, retinitis pigmentosa (NARP) b. Kearns-Sayre syndrome (KSS) c. Myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) d. Myoclonic epilepsy and ragged-red fibers (MERRF) e. Leighs syndrome f. Coenzyme Q10 deficiency
SCA, Spinocerebellar ataxia; DRPLA, dentatorubral-pallidoluysian atrophy; EA, episodic ataxia; FGF, fibroblast growth factor; AR, autosomal recessive.
should be considered in the differential diagnosis of adult-onset AD ataxia.

DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY. In DRPLA, pro-
gressive cerebellar dysfunction may be accompanied by seizures, chorea, myoclonus, or dementia. DRPLA shares with several SCAs and Huntingtons disease the molecular mechanism of expansion of the CAG repeat region in the affected gene, and neuronal intranuclear inclusions containing polyglutamine have been observed at autopsy. DRPLA may be included with the SCAs when considering inherited cerebellar degeneration, especially when there is evidence of neurologic abnormality outside the cerebellum.
CHANNELOPATHIES. Three AD ataxias are due to mutations in genes encoding ion channel proteins: SCA6, EA1, and EA2. In SCA6, the mutation is a CAG expansion in CACNA1A, the gene that encodes a subunit of the P/Q-type voltage-sensitive calcium channel. The number of repeats in affected individuals is small, and it is still debated whether the CAG expansion in SCA6 results in channel malfunction rather than production of toxic polyglutamine. In both EA1 (ataxia with myokymia) and EA2 (without myokymia), transient episodes of vertigo, ataxia, dysarthria, and other signs of cerebellar dysfunction may be elicited by exercise, fatigue, or emotional duress. Neurologic function is normal or notable only for nystagmus between episodes, although slowly progressive cerebellar degeneration may develop. The mutated gene in EA1, KCNA1, encodes a potassium channel protein. EA2 is due to mutations in CACNA1A, the same gene in which different mutations lead to SCA6 or familial hemiplegic migraine. Additional kindreds with episodic ataxia in which the mutations found in EA1 and EA2 are not present have been designated EA3 and EA4. Currently, molecular testing for EA1 and EA2 is available from research laboratories only. FIBROBLAST GROWTH FACTOR 14 ATAXIA. Van Swieten and
In 9 of 10 SCAs in which the responsible gene is identified, the mutation is expansion of a nucleotide repeat region (CAG in SCAs 1, 2, 3, 6, 7, 12, and 17; CTG in SCA8; ATTCT in SCA10). The CAG sequence expansion is located within coding regions of the gene in SCAs 1, 2, 3, 6, 7, and 17. Anticipation occurs in these SCAs so that CAG repeat number correlates with age of onset and disease severity. In all of these except for SCA6 (see later), expression of polyglutamine (encoded by CAG) is likely to be pathogenic. In SCAs 8, 10, and 12 the nucleotide repeat expansion is located in noncoding regions of the gene, and pathogenic mechanisms other than generation of polyglutamine are likely. In SCA14 a missense mutation in the gene encoding protein kinase C (PKC)-gamma is implicated. Sporadic clinical ataxia may also develop de novo owing to change in a nucleotide or pathologic expansion of a nucleotide repeat region that is close to or already increased above normal (also known as a premutation). In addition to the SCAs mentioned earlier, four AD cerebellar degenerative disorders
colleagues (2003) described an AD progressive ataxia, including tremor and dyskinesias, in which the responsible mutation is a nucleotide substitution in the FGF14 gene. Wang and colleagues (2002) have shown that progressive ataxia and paroxysmal dyskinesias develop in mice in whom FGF14 is knocked out. Autosomal Recessive Cerebellar Ataxias Many AR ataxia syndromes have been recognized. Patients with AR ataxia commonly present at birth or during childhood, but adult-onset ataxia occurs in some AR ataxias. Genetic contributions to clinical disorders are often not appreciated so that many patients with an AR ataxia were initially thought to have sporadic or acquired ataxia.
FRIEDREICHS ATAXIA. Friedreichs ataxia (FA) is the most prevalent inherited ataxia and affects about 1 in 50,000 individuals. Patients with FA usually present before 25 years of age with progressive ataxia, reduced or absent reflexes, and reduced proprioception and sensation
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Movement Disorders
TABLE 3 Clinical Signs Suggestive of Specific Inherited Adult-Onset Ataxias

Autosomal Recessive, X-Linked, or Mitochondrial Ataxia AOA1 ANCL, AOA1, NPC, PMEs AOA1, HexA, NPC AOA1, KSS, Leigh, NPC ANCL, PMEs ABL, AMN, AOA1, AVED, FA, Refsums disease HexA, NPC ABL, AVED, NARP, KSS, Leigh ANCL, NPC, PMEs FXTAS
Clinical Sign Cerebellar signs (relatively pure) Choreoathetosis Cognitive impairment Dystonia Dyskinesias Eye movement abnormalities* Myoclonus Paroxysmal ataxia Parkinsonian signs Peripheral neuropathy Psychosis Retinopathy Seizures Tremor, action Tremor, rest
Autosomal Dominant Ataxia SCA5, 6, 11, 14, 15, 16, 19, 22, 26 SCA1, 2, 3, 17; DRPLA SCA1, 2, 3, 10, 12, 13 (MR), 14, 17, 19, 21; DRPLA, FGF14 (many ataxias late in disease) SCA3, 6, 8, 12, 17; DRPLA EA2, FGF14 SCA1, 2, 3, 6, 7, 24; EA2 SCA14, 17, 19, 24; DRPLA EA1, EA2, SCA6 (early) SCA2, 3, 8, 9, 12, 17, 21; DRPLA SCA1, 2, 3, 4, 6, 8, 10, 12, 14, 18, 19, 24, 25; FGF14 SCA7, 17; DRPLA SCA2, 7 SCA7, 10, 17; DRPLA SCA2, 3, 6, 8, 12, 14, 16, 19, 21; DRPLA, FGF14 SCA 21
*May include altered saccade speed, prominent nystagmus, or ophthalmoparesis (does not include mild nystagmus, saccadic dysmetria, and pursuit-signs that are present in many ataxias). Includes postural (e.g., head) or action tremor. ABL, Abetalipoproteinemia; AMN, adrenomyeloneuropathy; ANCL, adult neuronal ceroid lipofuscinosis; AOA1, ataxia with oculomotor apraxia type 1; AVED, ataxia with vitamin E deficiency; DRPLA, dentatorubral-pallidoluysian atrophy; EA, episodic ataxia; FA, Friedreichs ataxia; FGF14, fibroblast growth factor 14 ataxia; FXTAS, fragile X tremor/ataxia syndrome; HexA, hexosaminidase A deficiency; KSS, Kearns-Sayre syndrome; Leigh, Leighs syndrome; MR, mental retardation; NARP, neurogenic muscle weakness, ataxia, retinitis pigmentosa; NPC, Niemann-Pick disease type C; PMEs, progressive myoclonic epilepsies (with ataxia, EPM1, EPM2A, Kufs disease); SCA, spinocerebellar ataxia.
12
of vibration. A hypertrophic cardiomyopathy develops in more than 60%, diabetes in 10%, and sensorineural hearing loss in 10%. Eye movement abnormalities are common, as are secondary scoliosis, pes cavus, or pes equinovarus. Although there is some loss of Purkinje cells and dentate nucleus neurons in FA, the main neuropathology is loss of dorsal root ganglion neurons with degeneration of dorsal columns and spinocerebellar tracts, resulting in sensory ataxia that resembles cerebellar ataxia. FA is due to abnormal expansion of the trinucleotide GAA repeat region in an intron of FRDA, a nuclear gene that encodes the mitochondrial protein frataxin. Mitochondrial dysfunction due to reduced frataxin protein is thought to underlie neuronal loss in FA. Since FA may present in adulthood with variable reflex abnormalities, this diagnosis should be considered in all patients with unexplained adult-onset ataxia. Progressive ataxia due to vitamin E deficiency (AVED), also an AR disorder, is a phenocopy of FA but is less common.
TESTABLE AUTOSOMAL RECESSIVE DISORDERS THAT MAY INCLUDE ADULT-ONSET ATAXIA. Progressive ataxia may occur in some
we pursue other diagnoses, depending on additional clinical features (see Table 3). These testable AR ataxias include abetalipoproteinemia (lipid profile and red blood cell morphology for acanthocytes); ataxia with oculomotor apraxia type 1 or AOA1 (aprataxin gene), cerebrotendinous xanthomatosis (cholestanol level), hexosaminidase A deficiency (hexosaminidase A level), metachromatic leukodystrophy (arylsulfatase A level), and Niemann-Pick disease type C (cholesterol homeostasis in cultured fibroblasts, NPC1 and NPC2 genes); some progressive myoclonic epilepsies (PMEs): Unverricht-Lundborg disease or EPM1 (cystatin B gene), Lafora disease (EPM2A gene), and adult neuronal ceroid-lipofuscinosis (ANCL) or Kufs disease (PPT1, CLN3, CLN4 genes), and Refsums disease (phytanic acid level).
OTHER AUTOSOMAL RECESSIVE DISORDERS WITH ATAXIA. The gene mutations responsible for AOA2, AR spastic ataxia of Charlevoix-Saguenay (ARSCAS), Ataxia-Telangiectasia (A-T), Cayman ataxia, and SCA with axonal neuropathy (SCAN) have been identified, but these ataxias usually present early in life and are not part of our differential for adult-onset ataxia. A-T is a prevalent AR ataxia, but features such as telangiectasias, immunodeficiencies, frequent infections, and increased risk of malignancy help distinguish this ataxia from others.
AR neurodegenerative disorders, and laboratory testing is available for some of these AR ataxias (Table 4). In patients with adult-onset ataxia that is not apparently AD, we start by testing for prevalent (FA) and readily treatable AR ataxias (AVED and Wilsons disease). If serum ceruloplasmin is abnormal, we request a 24-hour urinary copper and an ophthalmologic assessment, including slit-lamp examination, to identify KayserFleischer rings. If these evaluations are unrevealing, then
X-Linked Cerebellar Ataxias

FRAGILE X TREMOR/ATAXIA SYNDROME (FXTAS). Recently, Hagerman and colleagues characterized FXTAS in which
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TABLE 4 Diagnostic Evaluation of Adult-Onset Ataxia

Sequence of Evaluation Neurologic and Medical History Family History Medical Exam Neurologic Exam Ophthalmologic Examination Neuroimaging: MR or CT CT: Chest/Abdomen/Pelvis Lumbar Puncture - if indicated EEG - if indicated (see table 3) Blood Tests Initial Second-Line Heavy Metal Screen: Genetic Ataxias (testable) Autosomal Dominant Ataxias Autosomal Recessive Ataxias Clinical Assessments Age of onset; chronic progressive vs. episodic; other symptoms Is an inherited disorder likely? Liver/spleen, skin, heart, blood abnormalities Cerebellar & non-cerebellar abnormalities (central and peripheral) Eye movement abnormalities; retinal lesions; Kayser-Fleischer rings Brain and cervical spinal cord Is tumor present? Is CSF abnormality suspected? Does the history suggest seizures? CBC, differential, ESR, chemistry panel,CK, Lyme Ab, RPR,TSH,Vitamins B12 and E Paraneoplastic Abs (Hu, Yo, Ri, CV2, MaTa) Anti-gliadin and anti-GAD antibodies Spot urine for mercury Specific Test* SCAs 1, 2, 3, 6, 7, 8, 10, 12, 14, 17, DRPLA Ataxias
Paraneoplastic ataxia Infectious/inflammatory ataxia Ataxias with seizure disorders Acquired causes of ataxia Paraneoplastic ataxia Ataxias associated with autoantibodies Mercury-induced ataxia Specific Diagnosis SCAs 1, 2, 3, 6, 7, 8, 10, 12, 14, 17, DRPLA Friedreich ataxia Ataxia with vitamin E deficiency Wilson disease Abetalipoproteinemia AOA1 Cerebrotendinous Xanthomatosis Hexosaminidase A deficiency Metachromatic Leukodystrophy Niemann-Pick Disease Type C Progressive Myoclonic Epilepsies Refsum disease Fragile X Tremor/Ataxia Syndrome Adrenomyeloneuropathy Mitochondrial disorders with ataxia NARP, KSS, MELAS, MERFF, Leigh CoEnzyme Q10 deficiency ataxia
X-Linked Ataxias Mitochondrial Ataxias
FRDA genetic testing Vitamin E Ceruloplasmin Lipid profile, RBC morphology for acanthocytes Aprataxin genetic testing Cholestanol Hexosaminidase A Arylsulfatase A Fibroblast cholesterol; Niemann-Pick genetic testing EPM1, EPM2A, Kufs disease genetic testing Phytanic acid FMR1 premutation Very long chain fatty acids Serum lactate and pyruvate CSF protein, muscle biopsy for ragged red fibers Specific mitochondrial or nuclear DNA mutations CoEnzyme Q10 levels (from muscle biopsy)
Abbreviations: CSF, cerebrospinal fluid; CBC, complete blood count; ESR, erythrocyte sedimentation rate; CK, creatine kinase; Ab, antibody; RPR, rapid plasma reagin test for syphilis; TSH, thyroid stimulating hormone; FRDA, gene mutated in Friedreich ataxia; FMR1, gene mutated in Fragile X and associated syndromes. See Tables 2 and 3 for additional abbreviations. *Additional AD and AR adult-onset ataxias have been reported. Refer to GeneTests at http://www.geneclinics.org for available clinical and research testing.
late-onset (>50 years), progressive cerebellar ataxia and tremor develop in some male relatives of boys with fragile X syndrome. Patients with FXTAS may also display parkinsonism, autonomic dysfunction, peripheral neuropathy, and mild cognitive impairment. Whereas the normal range of CGG trinucleotide repeats in the probable promoter of the FMR1 gene is 5 to 44, FXTAS develops in some males with 59 to 200 repeats (premutation expansions). Males with more than 200 CGG repeats in FMR1 (a full mutation) develop fragile X syndrome, which includes mental impairment in childhood and dysmorphic features but lacks tremor or progressive ataxia. The reason that a premutation trinucleotide repeat expansion leads to Purkinje cell loss, cerebellar atrophy, and cerebellar signs, whereas a full
mutation in the same gene does not, remains uncertain. Premutation carriers are relatively common in the general population; Jacquemont and associates (2004) reported estimated prevalences of 1 per 259 females and 1 per 813 males. Although the prevalence of FXTAS is unknown, in part because penetrance is variable and age dependent, men older than 50 years of age with progressive ataxia and tremor should be tested for the FMR1 mutation. Mutational analysis of FMR1 is available in many clinical labs (see http://www.geneclinics.org).
ADRENOMYELONEUROPATHY (AMN). Adrenoleukodystrophy (ALD) is an X-linked recessive peroxisomal disorder that affects white matter of the brain and the adrenal cortex. ALD is due to a mutation in the ABCD1 gene that
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results in abnormal accumulation of very long chain fatty acids (VLCFA) in the brain and elevated serum VLCFA. AMN is a phenotypic variant of adrenoleukodystrophy that usually presents in young adulthood with progressive spastic paraparesis and distal sensory loss but may present with cerebellar ataxia. We test serum VLCFA levels in male patients with unexplained adultonset ataxia. Several other rare ataxias are X linked (e.g., cerebellar ataxia with sideroblastic anemia, Pelizaeus-Merzbacher syndrome) but these disorders are usually early onset. Ataxia in Mitochondrial Disorders Cerebellar ataxia may be seen in some mitochondrial encephalopathies and may be genetic or acquired. Genetic mitochondrial disorders are due to mutations (sporadic or inherited) in mitochondrial or nuclear DNA. Acquired mitochondrial disorders result from exogenous factors, such as exposure to drugs, toxins, or infections that lead to mitochondrial dysfunction. Mitochondrial disorders that exhibit ataxia include neuropathy, ataxia, retinitis pigmentosa (NARP); Kearns-Sayre syndrome (KSS); myopathy, encephalopathy, lactic acidosis and strokelike episodes (MELAS), myoclonic epilepsy and ragged-red fibers (MERRF), Leighs syndrome, and coenzyme Q10 (CoQ10) deficiency. Ataxia due to mitochondrial dysfunction may begin at any age, is usually progressive, and is often accompanied by abnormalities in other parts of the nervous system (e.g., seizure disorder, strokelike episode, parkinsonism, retinitis pigmentosa, neuropathy) and involvement of other organs (e.g., myopathy, lactic acidosis, endocrine dysfunction, anemia). If a particular phenotype is recognized, mitochondrial disorders may be diagnosed by testing for specific mutations in mitochondrial or nuclear DNA. In patients with chronic, progressive ataxia plus multiple system involvement, if a particular mitochondrial disorder is not suspected, we check serum lactate and pyruvate levels and consider examination of cerebrospinal fluid (CSF) for elevated protein and a muscle biopsy for evidence of ragged-red fibers. If familial cerebellar ataxia with CoQ10 deficiency is suspected (e.g., progressive ataxia with seizures, cognitive abnormalities, and other findings), CoQ10 levels may be measured in muscle biopsy specimens in the Molecular Neurogenetics Laboratory of Columbia University (see GeneReviews). DiMauro and colleagues reported that ataxia improved, seizures were reduced, and strength increased in some patients with this rare cause of ataxia who received CoQ10 supplementation. CoQ10 is a component of the electron transport chain in mitochondria and may also function as an antioxidant and membrane stabilizer. ACQUIRED ATAXIAS If there is no reason to suspect a genetic etiology, it is important to distinguish among acquired causes of ataxia (see Table 1) so as not to miss a treatable disorder. Acquired ataxias include (1) structural or demyelinating lesions that compromise the cerebellum
or its connections; (2) toxic or metabolic causes; (3) paraneoplastic cerebellar syndromes; (4) infections involving the cerebellum; or (5) autoimmune disorders. Structural or Demyelinating Lesions Structural or demyelination lesions that cause cerebellar dysfunction include posterior fossa tumors, cerebellar strokes or vascular malformations, developmental abnormalities (e.g., Arnold-Chiari malformation), normal-pressure hydrocephalus (NPH), multiple sclerosis (MS), or acute demyelinating encephalomyelopathy (ADEM). The diagnosis of MS should be considered in patients with unexplained sporadic ataxia since MS plaques commonly occur in the cerebellum or in pathways that connect cerebellum to brainstem. A magnetic resonance (MR) imaging is preferred to computed tomography (CT) for detection of focal lesions of the cerebellum because of greater resolution in the posterior fossa. Although distinguishing between ataxia due to NPH versus cerebellar degeneration is not always simple, a gait in which the feet appear to be stuck to the floor, the lack of clear signs of cerebellar dysfunction, the presence of early dementia or urinary incontinence, and ventricular enlargement without marked cerebellar atrophy favor the diagnosis of NPH over cerebellar degeneration. Toxic or Metabolic Causes Many compounds induce Purkinje cell injury (e.g., alcohol, phenytoin, vincristine, 5-fluorouracil). We routinely send a spot urine for a heavy metal screen, looking for exposure to mercury, a known cerebellar toxin. Deficiencies of vitamins (e.g., B1, B12, E) and endocrine abnormalities can cause cerebellar degeneration. Vitamins B1, B12, and E levels and thyroid function are components of our initial laboratory screen in patients with ataxia. Less commonly, parathyroid hormone abnormalities cause ataxia. Paraneoplastic Cerebellar Disorders Paraneoplastic cerebellar disorders (e.g., accompanying lung, breast, ovarian, or other cancers) should be considered in all patients with unexplained ataxia. We search for primary neoplasms with CTs of the chest, abdomen, and pelvis; recommend a mammogram and pelvic examination in women; and test for paraneoplastic antibodies, including anti-Hu, Yo, Ri, CV2, and MaTa. Since neurologic signs may precede evidence of cancer in paraneoplastic disorders, screening for a tumor should be repeated periodically if initial results are negative. Infections Infections primarily affecting the cerebellum may be viral, bacterial, fungal, parasitic (e.g., Lyme and syphilis), or prion (e.g., Creutzfeldt-Jakob disease with a cerebellar focus). Cerebellar lesions on MR imaging, coupled with fever, meningismus, or other supportive signs, may prompt CSF examination and specific laboratory testing.
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Autoimmune Dysfunction Autoimmune dysfunction is the probable mechanism of ataxia following viral infections (e.g., mumps) as well as in ataxia that is part of neurologic dysfunction in systemic lupus erythematosus, neurosarcoidosis, or Sjgrens syndrome. If ataxia is accompanied by a systemic autoimmune disease, we look for cerebellar lesions on MR imaging and examine CSF to detect central nervous system (CNS) inflammation. In addition, several ataxia syndromes have been reported in which autoantibodies are elevated (e.g., antibodies to gliadin, glutamic acid decarboxylase, or gangliosides). There is an increased incidence of antibodies to gliadin and gangliosides in both sporadic and inherited ataxias, suggesting that these antibodies may be secondary to neuronal degeneration. Although a causal link between these antibodies and progressive ataxia is not certain, we test patients for antibodies to gliadin if no other cause is found. If antibodies are present, we recommend a gluten-free diet and refer patients to the movement disorder group at the National Institutes of Health, which studies patients with ataxia and antibodies to gliadin. IDIOPATHIC ATAXIAS When inherited ataxia appears unlikely and an acquired cause is not found, we consider two types of idiopathic cerebellar degeneration: (1) multisystem atrophy (MSA), cerebellar subtype (MSA-C), which is MSA in which cerebellar ataxia is the major motor feature, and (2) idiopathic cerebellar degeneration. MSA-Cerebellar Subtype Evidence of parkinsonism and/or autonomic dysfunction, combined with ataxia, raises the possible diagnosis of MSA. MSA is usually sporadic, although familial disorders have been reported. MSA remains a clinical diagnosis that can be confirmed only by neuropathologic examination. MSA in which ataxia is prominent (MSA-C), previously known as olivopontocerebellar ataxia, represents 20% of all patients with MSA (see Wenning et al., 2003). In tertiary care neurology clinics, Rieff and colleagues estimate that 20% to 30% of patients with ataxia of undetermined etiology eventually meet clinical criteria for the diagnosis of MSA. In similar patient populations, 15% to 20% are found to have a genetic cause of ataxia. Patients who present with isolated cerebellar dysfunction but who later develop parkinsonian signs are given a trial of carbidopa/levodopa (Sinemet), amantadine, or a dopamine agonist. Some of these patients improve mildly, but most do not. Autonomic dysfunction together with progressive ataxia is treated as it is in other neurologic disorders. For symptomatic orthostatic hypotension, we advise placement of blocks under the head of the bed, the use of elastic stockings, and liberalization of dietary sodium. If these measures are insufficient, trials of fludrocortisone (Florinef) are begun. A urologic consultation is obtained for patients with ataxia and bladder dysfunction.
Idiopathic Cerebellar Degeneration In a patient with progressive ataxia with no family history of neurologic disease, negative genetic test results, no apparent acquired etiology, and no evidence of MSA-C, the most likely diagnosis is idiopathic cerebellar degeneration. The number of patients with idiopathic cerebellar degeneration should continue to shrink as more specific causes of ataxia are identified. The neurologic phenotype of patients with ataxia due to different causes, whether inherited, acquired, or idiopathic, overlaps extensively. The high vulnerability of Purkinje cells to degeneration is the likely basis for the phenotypic similarity among ataxias. The uniquely powerful and secure climbing fiber innervation of Purkinje cells may explain the great susceptibility of these cells to excitotoxicity, especially when climbing fiber-mediated glutamatergic drive is coupled with an additional insult, such as that conferred by a genetic mutation. In cerebellar degeneration, gait ataxia commonly appears before limb dysmetria. This sequence may be explained by the preferential loss of Purkinje cells in the vermis of the cerebellum before those in the hemispheres. This regional pattern of PKC loss (vermis before hemispheres) is apparent in most forms of cerebellar degeneration, including that found in aging, and favors an excitotoxic mechanism since the same pattern of neuronal loss is seen in drug-(ibogaine, harmaline, and alcohol) induced PKC degeneration. Whether the vulnerability of PKCs in the vermis is due to intrinsic properties of these cells or to differences in inferior olivary projections to the vermis remains uncertain.
Management of Progressive Cerebellar Degeneration

SYMPTOMATIC THERAPY OF SPASTICITY, TREMOR, AND FATIGUE Increased tone and hyperreflexia in the lower extremities are commonly found in SCA (in patients without peripheral neuropathy). Baclofen, starting with 10 mg daily and increasing weekly by 10 mg daily, may reduce uncomfortable spasticity. However, many patients with ataxia and spasticity find that increased tone in their legs is helpful in maintaining an upright stance. Action tremor is found in some cerebellar disorders (see Table 3) and may respond to propranolol (start with 10 mg daily), primidone (25 mg at bedtime), or clonazepam (0.5 to 1 mg daily) and increase slowly. A trial of Sinemet is warranted in the few patients with ataxia and a parkinsonian rest tremor. Fatigue is a common symptom in patients with ataxia. Since cerebellar dysfunction results in abnormal timing and control of muscle contraction, attempts to make coordinated, smooth movements are effortful and tiring. Discussion of fatigue and the potential advantage of scheduled rest periods and amantadine (100 mg once to three times daily) may be useful. Neurodegeneration is usually accompanied by an increased susceptibility to side effects of CNS-active medications. Although no specific
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antidepressant, anxiolytic, or soporific medication is contraindicated for patients with ataxia, low starting doses and slow escalation are recommended. DISEASE-SPECIFIC TREATMENT OF ATAXIA Pharmacologic treatment has been beneficial in several ataxias. These include deficiencies of vitamin E or CoQ10, in which those compounds are replaced, and EA2, in which episodes of cerebellar dysfunction are significantly reduced by acetazolamide therapy. If ataxia is episodic, then a trial of acetazolamide, starting at 125 mg daily and increasing to as high as 500 mg twice a day, is indicated. Possible side effects include renal calculi, rash, or paresthesias. If episodic ataxia is suspected strongly, we request genetic testing for EA1 and EA2 through R. Baloh, V. Honrubia, and J. Jen at the University of California-Los Angeles Department of Neurology. Other treatable ataxias include cerebrotendinous xanthomatosis (with chenodeoxycholic acid), Refsums disease (dietary restriction of phytanic acid intake), and Wilsons disease (with D-penicillamine). Patients with abetalipoproteinemia and Refsums disease, in addition to those with AVED, may respond to vitamin E. ATTEMPTS TO SLOW ATAXIA PROGRESSION Pharmacologic treatment to arrest or reverse most ataxias is limited, and benefit has been reported only in trials with small numbers of patients. Botez and colleagues and others have reported slowed progression of ataxia, both inherited and noninherited, in small populations of patients treated with amantadine. Since amantadine is safe and may be beneficial, we start patients with most forms of ataxia on amantadine 100 mg daily and slowly increase to 100 mg two or three times a day. We are careful to explain that we do not expect acute improvement in ataxia and note that many patients may require prolonged treatment before a significant benefit is noted. If livedo reticularis develops, amantadine is tapered off. There are reports that serotonergic drugs (Trouillas et al.), gabapentin (Gazulla et al.), or zolpidem (Clauss et al.) might be useful in treating ataxia. We do not have experience with these medications and await larger clinical trials. Antioxidant therapy with vitamin E or CoQ10 has slowed the progression of ataxia in patients who are specifically deficient in those compounds, but trials have not been completed in patients with ataxia of other etiologies. Idebenone, an analog of CoQ10 with antioxidant properties, has produced promising results in small trials of patients with FA. The progression of hypertrophic cardiomyopathy was reduced in some patients with FA who received idebenone, but the course of ataxia was not significantly altered. In patients with FA, trials of riluzole, to modulate glutamate transmission, are ongoing in Europe. Transcranial magnetic stimulation has been reported to improve clinical ataxia scores acutely in some patients, but further study is needed. Promising research in animals with ataxia include energy replacement therapy, inhibition of caspases, modulation of chaperone activity, restoration
of histone acetylation, and administration of small interfering RNA to correct altered gene expression. REFERRALS TO CONSIDER The preservation of comfort, independence, and dignity in patients with progressive cerebellar degeneration may be enhanced through coordination of efforts among patient, family, and health personnel. A primary physician who coordinates health care and manages medical complications, such as aspiration pneumonia, is essential to good general care. All patients with cerebellar degeneration of undetermined etiology should have a (neuro)-ophthalmologic evaluation to identify retinal or corneal lesions, eye movement abnormalities, and for provision of corrective prisms, vestibulo-ocular therapy, and pharmacotherapy. Patients with ataxia are at risk of injury in falls and should be assessed for safety and gait training by physical and occupational therapists. Exercise is beneficial for patients with cerebellar dysfunction, and we encourage patients to devise, with the help of therapists or trainers, an exercise regimen to be performed regularly. Speech and swallowing therapists can help reduce risks of aspiration and improve communication. If a patient develops scoliosis, foot drop, or joint abnormalities, orthopedic consultation is indicated. Cognitive, mood, and personality disorders are not uncommon in patients with cerebellar degeneration. Impaired cognitive skills may include performance of executive functions, working memory, and recall of newly learned information. Psychiatrists and psychologists may provide exercises to enhance these skills. Margolis and others have reported an increased incidence of psychiatric problems, including mood disorders and anxiety, in persons with neurodegenerative disorders primarily affecting the cerebellum. These are treatable psychiatric conditions that should be recognized and treated. Genetic counseling may be helpful in explaining the clinical risk in relatives and the implications of genetic results and in giving advice about genetic testing. Foundations dedicated to ataxia management and research, such as the National Ataxia Foundation and its local chapters, are essential resources for patients and family. We encourage patients with ataxia to stay up to date on research developments and to consider participation in research trials designed to learn more about cerebellar dysfunction and treatment of ataxia. SUGGESTED READING
Albin RL: Dominant ataxias and Friedreich ataxia: an update, Curr Opin Neurol 16:507-514, 2003. Bird TD: Hereditary ataxia overview. GeneReviews and GeneTests http://www.geneclinics.org/ Neuromuscular Diseases Center, Washington University, St. Louis, MO: http://www.neuro.wustl.edu/neuromuscular/ataxia/aindex.html Perlman SL: Spinocerebellar degeneration, Expert Opin Pharmacother 4:1637-1641, 2003. Schols L, Bauer P, Schmidt T, et al: Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis, Lancet Neurol 3:291-304, 2004. Subramony SH: Disorders of the cerebellum, including the degenerative ataxias. In Bradley WG, Daroff RB, Fenichel GM, Jankovic J,
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editors: Neurology in clinical practice, ed 4, Philadelphia, 2004, Butterworth Heinemann, 2169-2187. Taroni F, DiDonato S: Pathways to motor incoordination: the inherited ataxias, Nature Rev Neurosci 5:641-655, 2004.
PATIENT RESOURCES
National Ataxia Foundation 2600 Fernbrook Lane, Suite 119 Minneapolis, MN 55447-4752 Phone: 763-553-0020 Fax: 763-553-0167 E-mail: naf@ataxia.org http://www.ataxia.org/ International Network of Ataxia Friends (INTERNAF) http://www.internaf.org/ We Move (Worldwide Education and Awareness for Movement Disorders) 204 West 84th Street New York, NY 10024 Phone: 800-437-6683 Fax: 212-875-8389 E-mail: wemove@wemove.org http://www.wemove.org/
The Dystonias
H. A. Jinnah, M.D., Ph.D., and Tyler Reimschisel, M.D.
of isolated areas, such as one hand in writers cramp or the periocular muscles in blepharospasm. Segmental dystonia describes cases with involvement of multiple contiguous areas, and multifocal dystonia describes those with involvement of multiple noncontiguous areas. Generalized dystonia describes cases with broad involvement, although specific areas in individual cases are typically more affected than others. Classification by age of onset is also valuable because those with young-onset disease (<30 years) are more likely to have a discoverable inherited condition that often evolves into a generalized form, whereas those with adult-onset disease (>40 years) are more likely to have a relatively static or focal problem without discoverable cause. Dystonia also can be described by temporal aspects, including manner of onset and progression, short-term fluctuations such as diurnal variability or occurrence in discrete attacks, or type and duration of activity that induces dystonia such as writing or walking. Finally, the dystonias may be classified by known or suspected etiology. As shown in Table 2, dystonia has been associated with virtually all known processes that can influence the nervous system, including stroke, space-occupying lesions, toxic/metabolic insults, and inflammatory processes. It is a regular feature of many developmental and degenerative diseases. Dystonia may also occur in the absence of any associated neurologic abnormalities or disease process, in which case it is referred to as primary or idiopathic torsion dystonia.
Dystonia is a neurologic disorder with an extremely broad range of clinical manifestations that may emerge at any age. The basic underlying problem involves overactivity of the primary muscles responsible for voluntary movement, overflow activation of extraneous muscles that are not normally required for a specific movement, and coactivation of muscles that simultaneously antagonize the action of the primary muscles. The net outcome is determined by the severity and distribution of muscles involved. In some cases dystonic movements may manifest merely as transient exaggerations of a normal movement. In other cases dystonic movements take on a quality that is slow, stiff, cramped, twisting, or jerky. In extreme cases dystonia is associated with the development of odd postures that may become progressively bizarre or lead to fixed deformities. Unlike chorea or athetosis, the movements of dystonia tend to be patterned or stereotyped in individual cases.
Diagnosis
CLINICAL EVALUATION Because of the broad range of clinical manifestations and underlying causes, it is difficult to develop universal algorithms for evaluation of all cases of dystonia. The diagnosis relies heavily on a careful clinical evaluation. Important historic features include age at onset,
TABLE 1 Classification Based on Affected Region
Focal dystonia (isolated region) Blepharospasm (periocular muscles only) Oromandibular (jaw, tongue, or perioral) Laryngeal (spasmodic dysphonia) Cervical (torticollis, retrocollis) One limb (writers cramp, foot dystonia) Segmental dystonia (two contiguous regions) Meiges syndrome (blepharospasm + oromandibular dystonia) Cervical dystonia + one arm Multifocal dystonia Hemidystonia (ipsilateral arm and leg) Diffuse (two or more noncontiguous body areas) Generalized (more extensive areas) Both legs, another region, trunk One leg, another region, + trunk
Classification
Classification of the many types of dystonia into specific subgroups is important because of implications for treatment and prognosis. The dystonias can be differentiated by a number of features, including the areas that are affected, the age of onset, temporal aspects, and etiology. The classification by areas affected is shown in Table 1. Focal dystonia describes cases with involvement
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editors: Neurology in clinical practice, ed 4, Philadelphia, 2004, Butterworth Heinemann, 2169-2187. Taroni F, DiDonato S: Pathways to motor incoordination: the inherited ataxias, Nature Rev Neurosci 5:641-655, 2004.
PATIENT RESOURCES
National Ataxia Foundation 2600 Fernbrook Lane, Suite 119 Minneapolis, MN 55447-4752 Phone: 763-553-0020 Fax: 763-553-0167 E-mail: naf@ataxia.org http://www.ataxia.org/ International Network of Ataxia Friends (INTERNAF) http://www.internaf.org/ We Move (Worldwide Education and Awareness for Movement Disorders) 204 West 84th Street New York, NY 10024 Phone: 800-437-6683 Fax: 212-875-8389 E-mail: wemove@wemove.org http://www.wemove.org/
The Dystonias
H. A. Jinnah, M.D., Ph.D., and Tyler Reimschisel, M.D.
of isolated areas, such as one hand in writers cramp or the periocular muscles in blepharospasm. Segmental dystonia describes cases with involvement of multiple contiguous areas, and multifocal dystonia describes those with involvement of multiple noncontiguous areas. Generalized dystonia describes cases with broad involvement, although specific areas in individual cases are typically more affected than others. Classification by age of onset is also valuable because those with young-onset disease (<30 years) are more likely to have a discoverable inherited condition that often evolves into a generalized form, whereas those with adult-onset disease (>40 years) are more likely to have a relatively static or focal problem without discoverable cause. Dystonia also can be described by temporal aspects, including manner of onset and progression, short-term fluctuations such as diurnal variability or occurrence in discrete attacks, or type and duration of activity that induces dystonia such as writing or walking. Finally, the dystonias may be classified by known or suspected etiology. As shown in Table 2, dystonia has been associated with virtually all known processes that can influence the nervous system, including stroke, space-occupying lesions, toxic/metabolic insults, and inflammatory processes. It is a regular feature of many developmental and degenerative diseases. Dystonia may also occur in the absence of any associated neurologic abnormalities or disease process, in which case it is referred to as primary or idiopathic torsion dystonia.
Dystonia is a neurologic disorder with an extremely broad range of clinical manifestations that may emerge at any age. The basic underlying problem involves overactivity of the primary muscles responsible for voluntary movement, overflow activation of extraneous muscles that are not normally required for a specific movement, and coactivation of muscles that simultaneously antagonize the action of the primary muscles. The net outcome is determined by the severity and distribution of muscles involved. In some cases dystonic movements may manifest merely as transient exaggerations of a normal movement. In other cases dystonic movements take on a quality that is slow, stiff, cramped, twisting, or jerky. In extreme cases dystonia is associated with the development of odd postures that may become progressively bizarre or lead to fixed deformities. Unlike chorea or athetosis, the movements of dystonia tend to be patterned or stereotyped in individual cases.
Diagnosis
CLINICAL EVALUATION Because of the broad range of clinical manifestations and underlying causes, it is difficult to develop universal algorithms for evaluation of all cases of dystonia. The diagnosis relies heavily on a careful clinical evaluation. Important historic features include age at onset,
TABLE 1 Classification Based on Affected Region
Focal dystonia (isolated region) Blepharospasm (periocular muscles only) Oromandibular (jaw, tongue, or perioral) Laryngeal (spasmodic dysphonia) Cervical (torticollis, retrocollis) One limb (writers cramp, foot dystonia) Segmental dystonia (two contiguous regions) Meiges syndrome (blepharospasm + oromandibular dystonia) Cervical dystonia + one arm Multifocal dystonia Hemidystonia (ipsilateral arm and leg) Diffuse (two or more noncontiguous body areas) Generalized (more extensive areas) Both legs, another region, trunk One leg, another region, + trunk
Classification
Classification of the many types of dystonia into specific subgroups is important because of implications for treatment and prognosis. The dystonias can be differentiated by a number of features, including the areas that are affected, the age of onset, temporal aspects, and etiology. The classification by areas affected is shown in Table 1. Focal dystonia describes cases with involvement
The Dystonias
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TABLE 2 Classification Based on Etiology

Primary (relatively isolated dystonia) Inherited: early and adult onset, generalized or focal Idiopathic: torticollis, blepharospasm, spasmodic dysphonia, and so forth Dystonia plus syndromes (prominent dystonia with other telltale features) Dystonia/parkinsonism: DOPA-responsive, dopamine agonist responsive, rapid-onset dystonia/myoclonus Secondary (known environmental cause) Perinatal injury: hypoxia/ischemia, kernicterus Infectious/inflammatory: viral, bacterial, fungal, tuberculous, prion related Autoimmune/paraimmune: demyelination, lupus, anticardiolipin, Reyes syndrome, subacute sclerosing panencephalitis Trauma: brain, spinal cord, peripheral nerves Neoplasm: direct effect or paraneoplastic Vascular: ischemic stroke, hemorrhagic stroke, vessel malformations Drugs: dopamine related, SSRI, anticonvulsants, cocaine, MPTP, ergots Toxins: cyanide, manganese, carbon monoxide, carbon disulfide, disulfiram, methanol, 3-nitropropionic acid Other: hypoparathyroidism, central pontine myelinolysis, cervical stenosis, congenital Hereditary/degenerative (recognized syndrome with or without known cause) Parkinsonian: idiopathic Parkinsons disease, corticobasal degeneration, progressive supranuclear palsy, multisystem atrophy Trinucleotide repeat diseases: Huntingtons disease, Machado-Joseph disease and other spinocerebellar ataxias, dentatorubral pallidal luysian atrophy Lysosomal: metachromatic leukodystrophy, GM1 and GM2 gangliosidosis, Niemann-Pick C, Krabbes disease, ceroid lipofuscinosis Amino acidurias: homocystinuria, Hartnups disease Organic acidurias: glutaric aciduria 1, methylmalonic aciduria Mitochondrial: Leighs and Lebers diseases, dystonia/deafness syndrome Metal/mineral metabolism: Wilsons disease, Hallervorden-Spatz disease, Fahrs disease DNA handling: ataxia-telangiectasia, Cockaynes syndrome, xeroderma pigmentosa, Retts syndrome Miscellaneous: Lesch-Nyhan disease, Pelizaeus-Merzbacher disease, neuroacanthocytosis, adult and infantile striatal necrosis
DOPA, Dopamine; SSRI, selective serotonin reuptake inhibitor; MPTP, methylphenyltetrahydropyridine.
COMMON DIAGNOSTIC TESTS A thorough clinical evaluation provides an important guide for selecting among some of the commonly employed tests of neurologic function. Magnetic resonance (MR) imaging of the brain is warranted in virtually all cases, because it can uncover focal abnormalities underlying dystonia in some cases, or it can provide clues toward a developmental or degenerative process. Routine electromyographic (EMG) studies are generally not needed, unless there is suspicion for a neuromuscular cause of abnormal movements that may resemble dystonia, such as stiff person syndrome, tetany, or neuromyotonia. Multielectrode EMG can provide important confirmatory evidence for overflow activation or coactivation of antagonistic muscles when the clinical manifestations do not allow for an unequivocal diagnosis. Electroencephalography (EEG) is not generally needed, unless there is reason to suspect an associated seizure disorder or the dystonia comes in discrete attacks as in the paroxysmal dyskinesias. ADDITIONAL DIAGNOSTIC TESTS A thorough clinical evaluation is even more valuable for guiding a judicious selection of more specific tests, since it is not useful to perform a complete battery of tests covering all potential causes in all cases. When considering the need for further tests, it is helpful to divide patients into two groups based on the age at which dystonia first emerged. For older patients (>40 years), the usefulness of additional testing depends on the type of dystonia. Aside from brain MR imaging, extensive testing is rarely revealing for the primary focal dystonias, such as blepharospasm, cervical dystonia, or writers cramp. Additional testing is also of limited value when the clinical evaluation suggests that dystonia is part of a neurodegenerative syndrome such as corticobasal degeneration or progressive supranuclear palsy. Virtually all inherited developmental disorders may rarely present in adulthood. However, the yield for testing for most of these is very low and generally not necessary, unless the clinical features or family history point in a specific direction. Additional tests are therefore warranted only when the clinical evaluation suggests the dystonia might be related to some other identifiable process. For younger patients (<40 years), additional tests are almost always warranted, especially if the condition is progressive or if there are associated neurologic features that point to a known hereditary cause. Organizing a complete work-up is a formidable task because of the long list of potential diagnostic tests. Rather than performing all the tests, it can be helpful to divide the tests into two groups. The first group of tests is mandatory and should be conducted in all patients without delay. They include tests for all potentially reversible disorders such as Wilson's disease, autoimmune disease, glutaric aciduria, and vitamin E deficiency. Although most of these disorders are quite rare, testing for them is important because dystonia can be prevented or reversed if the diagnosis is made early.
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manner of progression, potential inciting events such as toxin exposures or trauma, and whether other family members are affected. Particularly close attention must be directed toward medications, because there is a long list of agents that can cause both acute dystonic reactions and tardive syndromes with prominent dystonia. The physical examination focuses on the body parts affected and whether or not there are associated findings that might point to a specific syndrome or identifiable cause.
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The second group of tests is much broader and should be considered optional. Although some authorities recommend performing a complete battery of tests covering the additional disorders listed in Table 2, we prefer a more targeted approach that is guided by the results of the clinical evaluation and neuroimaging. For example, disturbances of ocular motility might point to a mitochondrial defect or Niemann-Pick disease. Similarly, abnormalities on MR imaging can point toward a leukodystrophy or Hallervorden-Spatz disease. Because of limited familiarity with most of these rare diseases, consultation with an expert in neurogenetics can facilitate the selection of the most appropriate tests for each case. If there are no associated clinical or neuroimaging features to guide testing, then testing for mutations in the DYT1 gene, the most common of the primary torsion dystonias, is warranted. The decision to proceed with the second group of tests is a matter of personal preference that depends on a number of factors. Further testing is warranted for counseling of other potentially affected family members or carriers and can also be useful for providing information on prognosis and the natural history of the disease. Further testing is also warranted if a definitive diagnosis would provide closure for family members who will otherwise continue for years to seek answers. However, enthusiasm for further testing must be tempered by the large number of potential tests, the risks and discomforts associated with some tests (e.g., biopsy), the recognition that a positive test result will likely point to a disorder without a specific treatment, and the realization that a substantial proportion of cases remain undiagnosed despite exhaustive testing. The decision to proceed with further tests is often a difficult one, especially when a young child is involved. If there is any uncertainty, it can be useful to offer the "test of time" as an alternative, since making a diagnosis will not significantly alter the outcome in the many conditions for which no specific treatments are available. The evolution of symptoms and signs in many patients with early-onset dystonia may make one underlying cause more likely, facilitating a more focused approach to additional testing.
with dystonia, particularly the less common forms, go misdiagnosed for many years or are under the impression that they are suffering from a psychiatric or psychologic ailment. Some become extremely frustrated and frankly depressed. Education allows patients to begin the process of accepting the known realities of the disorder, learning from others, seeking help from local support groups, and keeping up with new trends via online resources. Because patients are often not diagnosed for many years and pursue multiple treatments without benefit, many adopt a fatalistic view that nothing can be done to help. Providing education concerning the many available treatment options helps restore hope and alleviates this fatalistic view. In addition to restoring hope, it is important to provide realistic expectations for the efficacy of each treatment modality and the known risks. The difficult combination of hope with realistic expectations is a key starting ingredient for any satisfactory treatment program. PHYSICAL AND OCCUPATIONAL THERAPY An initial consultation with a physical or occupational therapist can be valuable in many cases to mobilize frozen joints, limit mounting contractures, offer education concerning appropriate exercise programs, and provide assistive devices for those who need them. Although regular treatments by a physical therapist probably do not alter the long-term course of the condition, many patients seem to benefit from return visits when things seem to be going in the wrong direction. MEDICATIONS Successful treatment of dystonia has been reported for an enormous array of medications, but only a few are sufficiently consistent to warrant serious consideration. With a few rare exceptions, none of the medications is dramatically effective, and all have substantial side effects. Despite these caveats, many patients opt to continue one or more to take the edge off the condition. Dopamine-Related Medications
Treatment
GENERAL APPROACH Because of the broad range of clinical manifestations and underlying causes, it is difficult to devise a universal algorithm appropriate for the management of all cases. Most specialists approach treatment in different ways for the many subclasses of dystonia. If a recognized cause is identified, specific treatments may be available to influence the underlying pathogenesis, such as copper-depleting therapies for Wilsons disease. The following sections are a summary of the most common options for symptomatic treatment, which must be tailored to individual needs. COUNSELING The best patient is an educated patient, so treatment in virtually all cases begins with counseling. Many people
All children with dystonia deserve a trial of levodopa therapy, because it can nearly entirely eliminate motor disability in DOPA-responsive dystonia. Though such cases classically present with diurnal fluctuations in disease severity, all children with dystonia should be treated because relatively fixed or progressive presentations also occur. All adults with limb dystonia similarly deserve a trial of levodopa, because focal limb dystonia can be the presenting manifestation of Parkinsons disease. Start with one tablet of carbidopa/levodopa 25/100 daily and increase by one tablet every 3 to 5 days. Most children with DOPA-responsive dystonia respond to very low doses, but some require higher doses. An adequate trial for adults requires 1200 mg of levodopa daily (20 mg/kg in children) for at least 1 month. Paradoxically, dopamine receptor antagonists have also been reported to be effective in the treatment of some forms of dystonia. However, they can also provoke
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tardive movement disorder syndromes. The most common is tardive dyskinesia, but a syndrome with predominantly axial dystonia known as tardive dystonia may also occur. These developments may then unnecessarily complicate the clinical picture, so dopamine antagonists cannot be enthusiastically endorsed for most cases. Trihexyphenidyl and Related Anticholinergics Trihexyphenidyl has proven efficacy in many types of dystonia, although the benefits may not be dramatic and side effects are often limiting. Treatment begins with 1 mg daily and is increased by 1 mg every 3 to 5 days over a period of 1 month to a total dose of 2 mg three times a day. It may then be increased by 2-mg increments every week until side effects emerge or a dose of 30 mg three times a day is reached. It is worth noting that benefits may not occur until reaching 60 to 100 mg daily, well above the usual recommended doses. Young patients tolerate these extreme doses surprisingly well, although older patients do not. Patients should be warned about common side effects such as cognitive impairment, sedation, blurry vision, dry mouth, constipation, exacerbation of narrow-angle glaucoma, and heat intolerance. Clonazepam and Related Benzodiazepines Clonazepam also can be helpful for a variety of the dystonias, but again the benefits are often not dramatic, and there are concerning side effects. Start with a dose of 0.5 mg daily and increase by 0.5 mg every 3 to 5 days to a maximum dose of 2 mg three times a day. Patients should continue on the minimal doses required for benefits. They should be warned about side effects of cognitive impairment, sedation, impaired coordination, and negative interactions with alcohol. The potential for physical and psychologic dependence must be discussed explicitly, as well as the potential dangers of sudden discontinuation. Baclofen Another commonly used drug with some efficacy in several types of dystonia is baclofen. Start at 5 mg daily and increase by 5 mg every 3 to 5 days to a maximum dose of 30 mg four times a day. Warn patients about potential cognitive impairment, sedation, gastrointestinal upset, and impaired coordination. Abrupt discontinuation should also be discouraged, particularly at high doses. BOTULINUM TOXINS Local injections of botulinum toxins are extraordinarily effective for many dystonias and other disorders associated with excessive muscle activity. This treatment modality is most commonly considered for the treatment of focal and segmental dystonias, because of the technical difficulties associated with delivering the medication to patients with more widespread involvement. Two preparations are currently available: Botox and Myobloc.
The details of their use are not further addressed here, because there are excellent chapters in this volume, several books devoted to their use, and instructional seminars yearly. Although botulinum toxins are more commonly used in the treatment of the focal and segmental dystonias, they can also be extremely valuable in generalized dystonia, where they are often underutilized. The goal of treatment is not to treat all involved muscles but rather to target those areas that cause the most discomfort. For example, it is not unusual for cervical dystonia to be the most prominent and disabling element for some patients with generalized dystonia. Treatment of the cervical dystonia with botulinum toxin alleviates a primary source for discomfort and reduces the risk for acquired myelopathy. SURGICAL PROCEDURES A number of surgical procedures have been developed for specific types of dystonia. The surgical procedures are usually reserved for those cases with severely disabling or discomforting dystonia where less invasive therapies, such as oral medications and injection of botulinum toxins, have proven unsatisfactory. Intrathecal Baclofen Some patients experience remarkable improvements with continuous delivery of baclofen into the cerebrospinal fluid via a chronically implanted pump. The most significant improvements have been reported for patients with dystonia and spasticity of the legs, such as those with cerebral palsy. However, improvements are not limited to this population. This approach for the treatment of dystonia is probably underutilized, largely as a consequence of uncertainties regarding the best candidates, the limited numbers of centers with adequate experience with the technique, and the small but definite risks. Nevertheless, it is worth considering when other options have provided inadequate responses. Selective Denervation for Cervical Dystonia The use of botulinum toxins and oral medications provide the first line of therapy for most patients with cervical dystonia, but destruction of nerves innervating select cervical muscles offers a useful alternative for patients who do not respond to these modalities. This procedure probably also is underutilized as a consequence of the limited numbers of centers with adequate experience and the known side effects and risks. However, it can again be valuable for selected patients where the less invasive approaches have proved unworkable. Functional Neurosurgery Focused lesions of specific structures of the brain have also been employed as a treatment for dystonia. More recently, the lesion approach has been replaced by deep brain stimulation. Two consistent phenomena have been observed among the centers offering deep brain
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Tourettes Syndrome WE MOVE 204 West 84th Street New York NY, 10024 http://www.wemove.org/ National Spasmodic Torticollis Association 9920 Talbert Avenue Fountain Valley CA, 92708 http://www.torticollis.org/
stimulation for dystonia. First, improvements are often delayed by months after the procedure. Second, there is marked individual variability in responses. Some cases respond dramatically, whereas others show no effect. Some of the variability is related to the site selected for stimulation, with the pallidum and thalamus emerging as good targets. Perhaps a more important source of variability is the type of dystonia. In general the primary torsion dystonias seem to respond better than dystonias secondary to a known insult, though some benefits have been reported for most types. The Activa stimulator is approved under the U.S. Food and Drug Administration Humanitarian Device Exemption for use in primary torsion dystonias by centers with approval by an Institutional Review Board. The procedure is not widely used because of limited experience selecting the best responding cases, the need for intraoperative electrophysiologic measurements to guide precise placement of the stimulator, the risks of surgery, and the need for ongoing management of the stimulator. However, it can be the only effective means of managing severe dystonia in selected cases. ALTERNATIVE MEDICINE Because of the limitations of traditional medical and surgical therapies, more than half of dystonia patients admit to seeking nontraditional remedies such as massage, acupuncture, chiropractic manipulations, herbal and dietary supplements, biofeedback, and others. Discouraging such trials does nothing for the physician-patient relationship, unless the approach is known to be counterproductive or dangerous. Instead, it is more useful to view such trials with an open mind. At the same time, it is important to explicitly inform patients that these alternatives are only rarely covered by medical insurance. Patients must be reminded regularly to critically re-evaluate whether the costs outweigh any benefits.
Tourettes Syndrome
Diagnosis of T ic Disorders
Tics are quite common and often benign in the general population. Despite this, they may cause significant concern, leading to unnecessary emergency department visits and specialist referrals. Tics can in some cases interfere with social relationships and occupational function. Tic phenomenology is stereotypic movements and vocalizations occurring throughout the day in bouts, increasing during periods of stress, excitement, or relaxation and decreasing or disappearing during purposeful movements of the involved muscle groups. Examples include blinking, head jerking, sniffing, and grunting. In some cases, particularly in older children and adults, stereotyped movements may be more complex, such as words, complex movements of several muscle groups, and socially inappropriate or dangerous gestures or behaviors. Young children with tics often have no awareness that the tics are occurring. Older children can often describe an urge to perform a tic, an ability to suppress tics at the cost of rising inner tension, and sensory abnormalities in the body location of the tic. Tics can generally be distinguished clinically from stereotypies, nervous habits, fidgeting, myoclonus, and chorea. Electroencephalograms are unnecessary, and neuroimaging is usually not helpful when the neurologic examination is otherwise normal. I do not routinely check for streptococcal antibodies or perform any other laboratory tests. Tourettes syndrome is a childhood-onset neuropsychiatric disorder characterized by greater than 1 year of motor and vocal tics. Transient tic disorder is diagnosed when symptoms occur for less than 1 year. Some individuals may have only motor or, less commonly, only vocal tics. Many families are affected with an autosomal dominant inheritance pattern, with male relatives more prominently affected by tics and females more prominently affected with obsessions and compulsions. Most patients with Tourettes syndrome who present to physicians also have symptoms of other psychiatric or developmental disorders such as obsessive-compulsive disorder (OCD), generalized anxiety disorder, attention deficit hyperactivity disorder (ADHD), pervasive disorder
Summary
Dystonia is a neurologic disorder with a broad range of clinical manifestations and underlying causes. There are many options for treatment of the dystonias. In some cases, the treatments are dramatically effective and almost curative. In others, improvements are more modest. Virtually all patients with dystonia can enjoy some improvement in their quality of life if treatments are tailored to individual needs. SUGGESTED READING
Fahn S, Hallett M, Delong MR: Dystonia, Adv Neurol 94:4, 2004.
PATIENT RESOURCES
Dystonia Medical Research Foundation 1 East Wacker Drive, Suite 2430 Chicago IL, 60601 http://www.dystonia-foundation.org/
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Tourettes Syndrome WE MOVE 204 West 84th Street New York NY, 10024 http://www.wemove.org/ National Spasmodic Torticollis Association 9920 Talbert Avenue Fountain Valley CA, 92708 http://www.torticollis.org/
stimulation for dystonia. First, improvements are often delayed by months after the procedure. Second, there is marked individual variability in responses. Some cases respond dramatically, whereas others show no effect. Some of the variability is related to the site selected for stimulation, with the pallidum and thalamus emerging as good targets. Perhaps a more important source of variability is the type of dystonia. In general the primary torsion dystonias seem to respond better than dystonias secondary to a known insult, though some benefits have been reported for most types. The Activa stimulator is approved under the U.S. Food and Drug Administration Humanitarian Device Exemption for use in primary torsion dystonias by centers with approval by an Institutional Review Board. The procedure is not widely used because of limited experience selecting the best responding cases, the need for intraoperative electrophysiologic measurements to guide precise placement of the stimulator, the risks of surgery, and the need for ongoing management of the stimulator. However, it can be the only effective means of managing severe dystonia in selected cases. ALTERNATIVE MEDICINE Because of the limitations of traditional medical and surgical therapies, more than half of dystonia patients admit to seeking nontraditional remedies such as massage, acupuncture, chiropractic manipulations, herbal and dietary supplements, biofeedback, and others. Discouraging such trials does nothing for the physician-patient relationship, unless the approach is known to be counterproductive or dangerous. Instead, it is more useful to view such trials with an open mind. At the same time, it is important to explicitly inform patients that these alternatives are only rarely covered by medical insurance. Patients must be reminded regularly to critically re-evaluate whether the costs outweigh any benefits.
Tourettes Syndrome
Diagnosis of T ic Disorders
Tics are quite common and often benign in the general population. Despite this, they may cause significant concern, leading to unnecessary emergency department visits and specialist referrals. Tics can in some cases interfere with social relationships and occupational function. Tic phenomenology is stereotypic movements and vocalizations occurring throughout the day in bouts, increasing during periods of stress, excitement, or relaxation and decreasing or disappearing during purposeful movements of the involved muscle groups. Examples include blinking, head jerking, sniffing, and grunting. In some cases, particularly in older children and adults, stereotyped movements may be more complex, such as words, complex movements of several muscle groups, and socially inappropriate or dangerous gestures or behaviors. Young children with tics often have no awareness that the tics are occurring. Older children can often describe an urge to perform a tic, an ability to suppress tics at the cost of rising inner tension, and sensory abnormalities in the body location of the tic. Tics can generally be distinguished clinically from stereotypies, nervous habits, fidgeting, myoclonus, and chorea. Electroencephalograms are unnecessary, and neuroimaging is usually not helpful when the neurologic examination is otherwise normal. I do not routinely check for streptococcal antibodies or perform any other laboratory tests. Tourettes syndrome is a childhood-onset neuropsychiatric disorder characterized by greater than 1 year of motor and vocal tics. Transient tic disorder is diagnosed when symptoms occur for less than 1 year. Some individuals may have only motor or, less commonly, only vocal tics. Many families are affected with an autosomal dominant inheritance pattern, with male relatives more prominently affected by tics and females more prominently affected with obsessions and compulsions. Most patients with Tourettes syndrome who present to physicians also have symptoms of other psychiatric or developmental disorders such as obsessive-compulsive disorder (OCD), generalized anxiety disorder, attention deficit hyperactivity disorder (ADHD), pervasive disorder
Summary
Dystonia is a neurologic disorder with a broad range of clinical manifestations and underlying causes. There are many options for treatment of the dystonias. In some cases, the treatments are dramatically effective and almost curative. In others, improvements are more modest. Virtually all patients with dystonia can enjoy some improvement in their quality of life if treatments are tailored to individual needs. SUGGESTED READING
Fahn S, Hallett M, Delong MR: Dystonia, Adv Neurol 94:4, 2004.
PATIENT RESOURCES
Dystonia Medical Research Foundation 1 East Wacker Drive, Suite 2430 Chicago IL, 60601 http://www.dystonia-foundation.org/
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of development, and learning disabilities. Given this pattern of comorbidity and the higher prevalence of tics in children in special education, it is reasonable to consider tics as a clinical marker of possible broader brain dysfunction. A common clinical presentation involves excessive impulsivity and hyperactivity in early childhood, tics in early elementary school that escalate and peak in the middle school years and wane somewhat thereafter in most cases, and obsessiveness or anxiety.
inform teachers and coaches. In most cases, being direct and calm reduces bullying or social stigmatization. I encourage all patients with at least moderate symptoms to avail themselves of the many wonderful services of the Tourette Syndrome Association, and I hand out educational information and website addresses. Education and reassurance may reduce the perceived need for medication.
Management of Tourettes Syndrome

The rule in movement disorders that symptomsuppressing medication should be reserved for impairing symptoms applies in Tourettes syndrome. Tics often occur as brief, benign behaviors requiring no direct medical intervention. It is essential to be clear why tic suppression is desired and to inform patients that in most cases medical suppression will be partial. There are three main indications for tic-suppressing medication: (1) pain, (2) functional impairment, and (3) social impairment. Given the high prevalence of anxiety in individuals with tics and their family members, successful management requires educating the patient and family and building a trusting relationship. Clinicians seeing children with tics should keep in mind that one or both parents may have OCD or an anxiety disorder, making tics and associated symptoms exceptionally stressful. I begin new evaluations by acquainting myself with the patients activities and interests. I return to these topics at follow-up visits prior to asking about current symptom severity because decisions about treatment need to occur in the context of the impact on the patients life. I find that most patients older than 7 years of age have awareness of at least some of their tics and can give a reasonable history. I inventory the tics in terms of body location, asking the patient to imitate them if necessary. I ask whether the patient feels he or she can hold in the tics, even for a few seconds, and whether an urge to do the tic is present. I ask whether the tic just happens or whether it feels voluntary (often the answer is between voluntary and involuntary). I ask the age of onset. To place the tic severity in an objective context, I assess the number, frequency, and intensity of tics. To determine whether medical treatment may be indicated, I ask about pain, functional interference, and whether tics interfere with relationships or favorite activities. Most patients acknowledge that they can perform daily tasks and activities without direct interference from tics, and in fact that they tend not to tic when they are engaged in focused activity. For example, eye tics usually do not interfere with ball playing. I assess social impairment by inquiring what the patient does when asked by a peer about their tics. I encourage all patients with noticeable symptoms to be direct and to acknowledge that they have Tourettes syndrome if that is the case. I encourage parents to
Principles of Medical Treatment of Tourettes Syndrome in Children

1. Rank the tics, ADHD, OCD, anxiety, learning problems, and behavior problems in order of perceived severity. For many children with Tourettes syndrome, the tics are not the most impairing problem. 2. Consider nonpharmacologic and pharmacologic treatment for each problem, starting with the most concerning symptom. 3. Assess tic-related social impairment realistically. Frequent tics in children younger than 10 years of age often have few or no consequences. Frequent tics in an adolescent may have serious emotional consequences. Educating the teacher, coaches, and classmates can reduce social impairment. 4. Remind families that tics often diminish spontaneously, and long-term reductions in tics may occur in late teens, irrespective of treatment. 5. If the child reads below grade level or has other learning problems, encourage formal assessment through the school or a psychologist. Children with Tourettes syndrome may qualify for modified educational methods. 6. If ADHD is the most concerning problem, consider treating with clonidine, guanfacine, atomoxetine, or methylphenidate. Many children with tics and ADHD do not experience impairing tic exacerbations on stimulants and may have tic improvement. If symptoms of OCD, anxiety, or pervasive disorder of development are present, ticcing or compulsions may escalate on stimulants. If a patient has done well for months to years on stimulants for ADHD prior to an exacerbation of tics, it is not always necessary to discontinue stimulants. 7. If behavior problems are the chief complaint, or if a first-degree family member has a bipolar or psychotic disorder, refer to a psychologist and a psychiatrist. Some parents mistakenly conclude the child has no control over goal-directed, socially inappropriate behavior because the child has no control over tics. In families where parents abdicate their authority and responsibility for discipline, medications will be of little use. Families of children with rage attacks need substantial support and parent training. 8. If the familys anxiety is pathologic, refer to a psychologist. Anxiety is often a family affair. A hovering, anxious parent makes the tics worse. 9. If OCD or generalized anxiety disorder is present, treatment with a selective serotonin reuptake
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10.
11.
12. 13.
inhibitor may be beneficial and may secondarily reduce tics. Do not begin treatment with two central nervous system drugs simultaneously. Start one, wait 2 to 4 weeks, then reassess all symptoms before starting the second medication. Monitor both benefit and side effects at regular intervals. Monitor children on neuroleptics and atypical antipsychotics for weight gain and extrapyramidal side effects. Maintain stable dosing during the school year; consider tapering medications in the summer. Because tics often wane in the mid- to late teens, consider weaning patients completely off tic-suppressing medication at this time.
sometimes to unrealistic appraisals of the impact of the Tourettes syndrome diagnosis. Conversely, some patients have wonderful resilience and are personally and occupationally successful, despite frequent tics. Adult patients with chronic, moderate or severe tics may experience chronic pain. Exercise and stretching regimens, as well as good sleep hygiene, are important. I encourage most adults to discontinue D2-receptor blocking agents, if possible, due to risk of tardive dyskinesia, weight gain, and adverse effects on mood and cognition. Some adults are alert and experience reduced tics on daily benzodiazepines, without development of tolerance and increasing dose requirements.
Principles of Medical Treatment of Tourettes Syndrome in Adults

Principles 1 to 3, 6, and 9 to 11 in the previous section apply to the medical treatment of adult Tourettes syndrome. I find the prevalence of depression, anxiety, and OCD to be higher in adult patients, leading
Medications in Tourettes Syndrome

1. First-line therapy for tics is the alpha2-agonist clonidine (Catapres); also use guanfacine (Tenex), which may be less sedating. Clonidine and guanfacine may help ADHD in patients with tics. 2. Second-line therapy is not well established. Many experts recommend D2-receptor blocking agents as
TABLE 1 Medications for Tourettes Syndrome

Medication Alpha2-Adrenergic Agonists Clonidine (Catapres) 0.1 mg Dosing Considerations
Catapres patch, TTS-1, TTS-2, TTS-3
Guanfacine (Tenex) 1 mg Alternatives Baclofen (Lioresal) 10 mg Clonazepam (Klonopin) 0.5 mg Pergolide (Permax) 0.05 mg
Begin 0.05 mg qhs for 3 days; increase by 0.05 mg q 3-7 days up to max 0.1 mg tid or qid Main side effects: sedation, lightheadedness Discontinue gradually, by 0.05 mg q 3 days Continuous-release patch, changed weekly May reduce peak sedation Main side effects: rash, skin irritation Not recommended to patients with eczema or chronic dry skin Begin 0.5 mg qhs for 3 days, then increase by 0.5 mg q 3 days to max 2 mg bid May be less sedating than clonidine Begin 10 mg qhs for 3 days, then increase by 10 mg q 3 days to max 30 mg tid Discontinue gradually Begin 0.5 mg qhs, increasing as needed to 1-2 mg bid or tid Begin 0.05 mg qhs for 3 days, then increase by 0.05 mg q 3 days to max 0.15 mg tid Main side effect: nausea
Dopamine2-Receptor Blocking Agents Pimozide (Orap) 2 mg Begin 1 mg qhs; increase q 3-5 days to max 4 mg, divided into 1 or 2 times per day Baseline and periodic ECGs recommended (prolonged QTc) Watch for drug interactions Fluphenizine (Prolixin) 1 mg Begin 0.5 mg qhs; increase q 3-5 days to max 4 mg, divided into 1 or 2 times per day Risperidone (Risperdal) 1 mg Begin 0.5 mg qhs; increase q 3-5 days to max 4 mg per day, divided into 1 or 2 times per day Weight gain is major problem Ziprasidone (Geodon) 20 mg Begin 20 mg qhs; increase weekly to max 80 mg, divided into 1 or 2 times per day Check ECGI select this when patients or first-degree family members are overweight or obese because weight gain appears to be less Main side effect: sedation
ECG, Electrocardiogram.
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second-line treatment. Given the weight gain and adverse mood and cognitive effects of dopamine blocking agents, I often try other medications next, such as pergolide, baclofen, desipramine, and clonazepam. 3. Typical neuroleptic medications or atypical antipsychotics should be reserved for more seriously impairing or self-injurious symptoms. They can be highly effective in some individuals. Advise of risks of cognitive blunting, sedation, depression, anxiety/panic, akathisia, dystonia, tardive dyskinesia, weight gain, and QT prolongation. General practitioners may consider subspecialty consultation. 4. Treatment of ADHD in patients with tics includes stimulants, which may be effective in many cases, but when initiating them, I advise of the possibility of worsening tics. I usually start long-acting methylphenidate at 0.5 mg/kg/day and generally do not exceed 1 mg/kg/day in children with tics. When referred patients on higher doses than this, I reduce the dose and reassess (Table 1).
SUGGESTED READING
Leckman JF, Cohen DJ, editors: Tourettes syndrome: tics, obsessions, compulsions, New York, 1999, John Wiley & Sons. Singer HS: Current issues in Tourette syndrome, Mov Disord 15:1051-1063, 2000. Tourette Syndrome Study Group: Treatment of ADHD in children with tics, Neurology 58:527-536, 2002.
PATIENT RESOURCES
Tourette Syndrome Association, Inc. Phone: 800-237-0717 http://www.tsa-usa.org/ Children Who Have ADD (ChADD) Phone: 800-233-4050 http://www.chadd.org/ Other helpful sites: http://www.planettic.com/ http://www.tourettesyndrome.net/ http://www.wemove.org/ OC Foundation, Inc. http://www.ocfoundation.org/
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SECTION 13
Degenerative Disease
Alzheimers Disease
Rachelle Smith Doody, M.D., Ph.D.
AD is diagnosed by first establishing the expected clinical features of memory loss and at least one other impaired domain,* and there is usually some impact on functioning. Second, the clinician must rule out any systemic or structural brain disorders that could be causing the symptoms. The diagnostic process sometimes identifies another feature or concern that does not cause the dementia alone but contributes to the symptoms and needs to be treated (e.g., depression, metabolic disturbance, vitamin deficiency, cerebrovascular disease).
Alzheimers disease (AD) is an age-related, chronic, neurodegenerative disease that is treatable, but for which there is no curative therapy. It begins with subtle recent memory loss, sometimes affecting nonverbal memory or verbal memory disproportionately. Those with verbal memory problems are more easily recognized. As the disease progresses, problems with orientation, language, visuospatial skills, praxis, and executive function (judgment and problem solving) will arise, although it may take several years to develop all of these features. Once a patient has both impaired recent memory and one of these other domains of impairment, he or she meets the threshold for diagnosing AD. Various behavioral features may arise over the course of the disease, from subtle personality changes to depression, sleep disturbance, agitation, and psychosis. If the patient lives long enough after diagnosis, significant functional loss will also develop. AD is associated with reduced survival when it is diagnosed at younger ages, but may not impact survival when diagnosed late in the lifespan. Most clinicians and researchers recognize a prodromal state that may precede the development of AD, commonly referred to as mild cognitive impairment (MCI). Although definitions vary, this category most often refers to individuals with demonstrable memory difficulties but no second domain of dysfunction (e.g., no disorientation) and no functional impairment. Individuals with this amnestic form of MCI are at greater risk for developing AD in subsequent years. In clinical practice, MCI is sometimes mistakenly designated in cases that actually have mild AD because the clinician has not sought out subtle impairment in all of the nonmemory domains. The distinction is important since there are no U.S. Food and Drug Administrationapproved therapies for MCI, whereas even patients with very mild AD may benefit from medications and other interventions.
Initiating Therapy
Several factors must be taken into account before initiating therapy. First, what is the most prominent feature (e.g., memory loss, psychosis, self-neglect)? Second, what is the treatment history, if any? It is not uncommon to see AD patients who have reportedly failed a previous therapy or reacted adversely to it, or stopped the therapy because they misunderstood the expected results. Finally, who will administer the therapy? This latter issue must be addressed openly before any drugs are started. If necessary, home health or other formal services may need to be put in place. Patients vary in their willingness to accept help with medications, but if they are told that this is the policy for all patients with their diagnosis, most will eventually accept the intervention. If the patient is particularly resistant or suffers from severe anosognosia (lack of awareness of illness), these arrangements might have to be made with other interested parties, such as family members, who can try to introduce them gradually and without too much discussion. Assuming that cognitive symptoms and/or functional loss are the most prominent features, therapy begins with a cholinesterase inhibitor or memantine (Table 1). An American Academy of Neurology Practice Parameter on the Management of Dementia, based on an evidencebased review, indicates that cholinesterase inhibitors
*According to the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimers Disease and Related Disorders Association or National Institutes of Health criteria, as well as Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria.
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TABLE 1 Antidementia Drugs

Drug Donepezil Starting Dose 5 mg qd Minimum Effective Dose 5 mg qd Maintenance Dose 5-10 mg qd Adverse Events GI: nausea, vomiting, diarrhea Dizziness Vivid dreams if given at bedtime GI: nausea, vomiting, diarrhea Dizziness Weight loss GI: nausea, vomiting, diarrhea Dizziness Weight loss Confusion, anxiety, or sedation during titration Comment 20 mg qd (or 10 mg bid) often used off-label Best given as morning dose 4.5 mg bid is an option Must retitrate if therapy is interrupted
Rivastigmine
1.5 mg bid
3 mg bid
3-6 mg bid
Galantamine
4 mg bid
8 mg bid
8-12 mg bid
Memantine
5 mg qd
5 mg bid
10 mg bid
Titration from 5 mg qd to 5 mg bid to 5 mg/10 mg to 10 mg bid
GI, Gastrointestinal.
are the standard of care for mild to moderate cases (usually defined in clinical trials with Mini-Mental Status Examination scores from 10 to 24). The parameter was written before trials of cholinesterase inhibitors for moderate to severe AD or trials of memantine were completed (Mini-Mental Status Examination scores 3 to 17 in these moderate to severe AD studies). The recommendations in this chapter are one view of how the clinician might incorporate the newer information. There are several principles to consider with respect to choice of initial therapy. First, patients must be escalated to a therapeutic dose, and for cholinesterase inhibitors the trials data suggest that the benefits to patients are best with higher doses. Therefore, if a patient starts on a therapy but cannot tolerate a therapeutic dose, the agent should be discontinued and replaced by another agent. Second, the wealth of the clinical data for mild to moderate stages concerns cholinesterase inhibitors, whereas the wealth of the data for moderate to severe stages concerns memantine. So if the patient is newly diagnosed, but already at a more severe stage, the clinician may start with memantine, whereas mild to moderate stages at the initial diagnosis might start with a cholinesterase inhibitor. There are good data from at least one study suggesting that it may be desirable to eventually treat most patients, especially those in moderate or severe stages, with both memantine and a cholinesterase inhibitor. The data are still being collected regarding combination therapy for milder cases. When disturbed behavior is the prominent feature, this should be treated first as discussed in the following section, with appropriate addition of a cholinesterase inhibitor or memantine after the behavioral problem is controlled. The clinician should keep in mind that all of these agents have been shown to suppress or improve disruptive behaviors in AD patients, so if the severity is low to moderate, these specific antidementia treatments may resolve the behavioral problem without the need
for a second drug. As in most aspects of medicine, it is best to initiate only one treatment at a time.
Behavioral and Psychosocial Interventions

Depending on the specific phenomenology under discussion, the prevalence rates for behavioral problems in AD vary widely, from about 20% to about 80%. Apathy, the most common problem, is not always considered in studies reporting on disturbed behavior, and there is no specific treatment identified for this complaint. As mentioned earlier, cholinesterase inhibitors and memantine favorably influence behavior in many AD patients. This section discusses the management of behavioral problems for which the other agents alone have not been effective, or for behavioral problems that are the initial focus of treatment, before the antidementia drugs are added. Most abnormal behaviors benefit from both pharmacologic and nonpharmacologic treatments. SLEEP DISTURBANCE The most common cause of sleep disturbance in AD patients is poor sleep hygiene. Many patients lose their sense of time and timing, so that they do not realize that bedtime has come, or they are disoriented enough that they think the night has passed and get up after only a short time in bed. Even more disruptive, many patients are understimulated during the day and spend their time alternating between naps and wakefulness and they continue this pattern through the night. So the treatment of sleep disturbance begins with collecting information about the daily sleep patterns over the past week or two and instituting a normal routine for the patient that consists of a regular bedtime and avoidance of daytime naps.
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It is not desirable to treat sleep disturbance in AD with a daily sleeping pill (hypnotic agent) since the agent will lose potency over time and most produce an abnormal and nonrestful sleep. Short-term use of a hypnotic might be indicated if the sleep disturbance is associated with an acute condition (illness in the patient, temporary change of caregiver or location), and intermediate-acting agents are preferred with the least possible accumulation potential and central nervous system side effects (e.g., zolpidem or lorazepam). These should not be used for more than a couple of weeks without a drug holiday. If the sleep disturbance is related to sundowning (a daily pattern of confusion with anxiety and other behavioral changes as the day progresses), a sedating atypical antidepressant (e.g., trazodone [Desyrel] or mirtazapine) may be helpful. DEPRESSION The relationship between depression and AD is complex. First-time depression occurring in late middle age or in an elderly person and accompanied by cognitive impairment may remit when treated with antidepressants, but it seems to be associated with a higher risk for developing AD later on. Patients who present this way should be monitored, at least annually, for cognitive decline. On the other hand, the typical scales used to diagnose depression contain many questions that AD patients endorse positively, which can lead to a diagnosis of depression in someone who actually has AD and is not depressed. If the patient and informant deny dysphoria, or if the patient who receives one or more adequate antidepressant trials continues to lose functional ability, dementia should be strongly suspected. Patients with newly diagnosed or established AD may present with mixed AD and depression, so that both AD and depression require treatment. Often the depression is made worse by a mismatch between the patients abilities and current activities, such as when a patient is understimulated or underengaged or still trying to carry out a demanding role despite cognitive difficulties that make this impossible or stressful. Adjustments to this balance can resolve depression without the use of medications. An understimulated patient might engage in volunteer work or day center programs (depending on the degree of dementia), and a patient in too demanding a situation can retire or renegotiate family responsibilities. Formal counseling can be invaluable in these situations. For pharmacologic treatment of depression in AD patients, the American Academy of Neurology Practice Parameter recommends using a selective serotonin reuptake inhibitor (SSRI) since this class of antidepressants is better tolerated in older patients and seems to be better tolerated by those with dementia. Agents in this class include paroxetine, sertraline, citalopram, escitalopram, and fluoxetine. They should be dosed initially at the lowest dose and gradually escalated as needed. ANXIETY Everyone experiences anxiety, so it is to be expected that AD patients will as well. The best approach is reassurance
and distraction, with a predictable routine set up for the day and adequate support provided to the patient. Very anxious caregivers sometimes induce severe or chronic anxiety in the patient inadvertently. This situation should be considered and pointed out if it occurs. For short-term treatment of anxiety related to a life event (e.g., loss of a caregiver) or recurrent anxiety related to a specific and unavoidable trigger (e.g., fear of dental procedures), a low-dose anxiolytic might be called for, such as lorazepam 0.5 to 2 mg orally once or twice a day, either as a standing dose for less than a month or as an as-needed dose. If compulsive behaviors or panic attacks are involved, the SSRI class of antidepressants may be helpful (see the earlier discussion on depression for prescribing principles). AGITATION Agitation needs to be distinguished from anxiety by history. It is a more severe emotional state that results in verbal or physical aggressiveness in some patients and psychomotor signs (e.g., pacing) in others. It is essential to rule out pain, fear, or an unmet need (e.g., social isolation) before attributing agitation to AD. Pacing does not usually respond to medications, but it causes great energy expenditure, and patients may need nutritional supplements to maintain good health. In AD patients, agitation may be triggered by the circumstances, often in a recurrent manner, or it may be untriggered. History is critical for determining if there is one or more trigger, such as a particular resident in the same facility, a particular caregiver, or a particular activity that always brings about the agitation. If the trigger is avoidable, simple alteration of this environmental issue will reduce or eliminate the agitation. If the trigger cannot be avoided (e.g., bathing), if the agitation is untriggered, or if it involves severe verbal aggression or any physical aggression, medications should be considered. The most effective agents are the atypical antipsychotics, discussed in the following section. Sometimes the use of an antiepileptic drug, such as valproic acid or gabapentin, is effective, either alone or in combination with an antipsychotic drug that may have reduced the symptoms but did not achieve a complete effect. PSYCHOSIS Hallucinations (usually visual) and delusions are the most common psychotic features seen in AD patients. Sometimes hallucinations are mild and are even recognized by the patient as not real; these do not need to be treated. Sometimes delusions are circumscribed (e.g., believing that ones parents are still alive, despite being reminded to the contrary) and infrequent, and these do not need to be treated. If the psychotic symptom is distressing to the patient, particularly if it is frequent, use of an antipsychotic drug should be considered. The American Academy of Neurology Practice Parameter suggests that the so-called atypical antipsychotics such as quetiapine, olanzapine, and risperidone are effective and probably better tolerated
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with fewer side effects in dementia patients. Such patients cannot tolerate the high doses of these agents used to treat young and middle-aged schizophrenia patients. Suggested guidelines for use are quetiapine 25 mg daily titrated as high as 100 mg three times a day; olanzapine 2.5 to 10 mg daily given as a single dose or twice a day; and risperidone 0.5 to 2 mg daily given as a single dose or twice a day. INCONTINENCE Even in AD patients, much incontinence is avoidable. Incontinence is not a common finding in mild stages, so other causes should always be sought. Patients who have difficulty with problem solving, move slowly, are apraxic, or are severely demented are prone to incontinence. The American Academy of Neurology Practice Parameter recommends a scheduled voiding routine (e.g., take the patient to the bathroom every 2 hours while awake), which can avert daytime incontinence throughout the course of the disease in many patients. Nocturnal incontinence should be managed with appropriate bedding and undergarments at night, and this should be initiated after three or more episodes of nocturnal incontinence if there is no urinary tract infection. The clinician may have to ask to learn that this problem is present. ELDER ABUSE OR NEGLECT Abuse and neglect can occur in any settingat home or in an institutionand in members of any socioeconomic class. Volatile or angry caregivers should be asked if they ever lose their temper with the patient. Patients should be questioned directly if abuse is suspected. Neglect may be due to ignorance or to preexisting problems in the relationship between the patient and caregiver. The evidence of neglect (e.g., unwashed hair, soiled clothing) should be gently pointed out and discussed with the caregiver. If it is immediately corrected, it may not require further action. Repeated evidence of neglect or any evidence of abuse should be reported to adult protective services. Patients living alone may neglect themselves, and these cases should also be reported.
concurrent medical and behavioral problems, and to advise the patient and family appropriately at times of transition such as retirement, moving, instituting care, and so forth. Patients treated continuously seem to decline at a slower rate over time. In the course of management, cholinesterase inhibitors can be increased and memantine can be added to cholinesterase inhibitors, or vice versa, if there are signs of progression. Although we do not have data from controlled studies lasting longer than 1 year, many clinicians believe that antidementia drugs continue to affect the patients outcome, even after several years of treatment. There are no clear-cut rules for stopping these agents, and precipitous declines do occur in some patients when they are stopped, even in severe cases. In the course of long-term management, appropriate referrals can also be suggested as needed. Early on, this might take the form of a referral for counseling or referral to an early-stage support group for the patient and a caregiver support group for the caregiver. Over time, the clinician might need to suggest or authorize the caregiver to institute some respite assistance, either informally using family and friends or formally, using paid providers or centers. In some, but not all cases, long-term care should be considered when the at-home support system cannot meet the patients needs. Although we cannot arrest or cure AD, we can help patients and their families to deal with the condition. Most AD patients will die from other conditions that account for the majority of deaths in older age groups (heart disease, stroke, cancer) and not as a consequence of their AD. Persistent therapy helps achieve the best outcomes, because it helps patients to maintain their functional abilities. SUGGESTED READING
Alzheimers Disease Research Forum: http://www.alzforum.org/ Doody RS, Stevens JC, Beck C, et al: (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology, Neurology 56:1154-1166, 2001. Knopman DS, DeKosky ST, Cummings JL, et al: Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology, Neurology 56:1143-1153, 2001.
PATIENT RESOURCES
Alzheimers Association 225 North Michigan Avenue, Suite 1700 Chicago, IL 60601 Phone: 800-272-3900 http://www.alz.org Alzheimers Disease Education and Referral Center P.O. Box 8250 Silver Spring, MD 20907 Phone: 800-438-4380 http://www.alzheimers.org/ Eldercare Locator Administration on Aging 330 Independence Avenue, S.W. Washington, D.C. 20201 Phone: 800-677-1116 http://www.eldercare.gov/ Madison Institute of Medicine, Inc. http://www.alzheimers.factsforhealth.org/ Johnson: Current Therapy in Neurologic Disease (7/E)
Long-Term Goals in the Management of Alzheimers Disease

The preceding discussion indicates that patients should receive a diagnosis and then be started on treatment for cognitive loss, functional decline, and/or behavioral problems. They should then be monitored in each of these realms for change. The frequency of monitoring will increase during periods when symptoms are changing or when medications are being adjusted but should not occur less frequently than yearly in stable patients. The goal is to maintain the patient at the same level for as long as possible, to identify and avert or treat
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Jee-Hyang Jeong, M.D., and Bruce L. Miller, M.D.
diagnosis but also increase the difficulty of using traditional symptomatic therapies. For example, some of the symptomatic therapies used to control agitation, psychosis, compulsions, or disinhibition compound the motor deficits present in many patients exacerbating underlying deficits in swallowing or gait. Conversely, the medications that improve movement in FTLD patients often exacerbate the behavioral syndromes.
Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease that affects the frontal and anterior temporal regions, basal ganglia, and sometimes motor neurons. It is the third most common degenerative dementia following Alzheimers disease and dementia with Lewy bodies in prevalence. FTLD typically affects individuals between the ages of 45 and 70 years, and its prevalence approaches that of Alzheimers disease before the age of 60. Pick first described patients with selective frontal or temporal lobe atrophy in 1892, yet diagnostic accuracy for the disorder (now called FTLD) still remains flawed due to the lack of recognition of this disorder in both the lay public and medical community. This lack of recognition continues to inhibit the development of effective therapies for FTLD. Indeed, research into treatments for FTLD remains in its infancy. Currently most treatments for FTLD remain symptomatic, with disease-modifying therapies still in the development stage. There are genetic and sporadic cases of FTLD. Both intron and exon mutations in the tau gene on chromosome 17 are associated with an autosomal dominant form of FTLD. More recently, a mutation in the valosin gene on chromosome 9 has been described in a family with autosomal dominantly inherited frontotemporal dementia (FTD), bone disease, and inclusion body myopathy. Familial amyotrophic lateral sclerosis (ALS) with FTLD has been linked to chromosome 9, and there are still other families linked to chromosomes 17 (near tau) and 3 in whom genetic mutations have not yet been uncovered. Most FTLD cases are sporadic with only a small minority associated with genetic mutations. Management issues, mostly related to whether or not genetic testing should be performed, are more complicated in genetic cases. Even though differentiation of FTLD from Alzheimers disease (AD) is usually straightforward, many FTLD patients are misdiagnosed with AD during life and still others are diagnosed as suffering from primary psychiatric conditions. In contrast to AD where memory loss is usually the first symptom, FTLD begins as a neurobehavioral or language disorder. Corticobasal degeneration, progressive supranuclear palsy, and ALS also merge clinically and pathologically with FTLD. For example, nearly 80% of FTLD patients show basal ganglia and brainstem degeneration by the time of death, and ALS arises in up to 15% of patients with FTLD. Conversely, up to one third of patients who begin with ALS develop clinical features suggestive of FTLD. The psychiatric and motor symptoms are the most treatable component of FTLD, whereas treatment of the cognitive syndrome remains elusive. The mixed behavioral and motor syndromes that are routinely seen in FTLD patients not only confound
Clinical Subtypes and Treatment Considerations

The Neary research criteria divide FTLD into three clinical subtypes: (1) FTD, (2) progressive nonfluent aphasia (PNFA), and (3) semantic dementia (SD). All three FTLD subtypes are associated with distinctive clinical problems, all of which require different treatment approaches. FTD is characterized by insidious onset and gradual progression with early decline in social conduct, emotional blunting, loss of insight, and apathy. Frontal executive deficits are nearly universal in FTD by the time of presentation. Both the behavioral syndrome and the executive deficits are severely debilitating and difficult to treat. In contrast, PNFA is a nonfluent aphasia syndrome with relative sparing of behavior and executive function in the initial phases. With PNFA treatment strategies usually focus on speech and language deficits of these patients. SD is a progressive temporal lobe syndrome characterized by anomia, loss of semantic knowledge, emotional blunting, and impairment in the recognition of facial emotions. Treatment for SD patients often centers around language and behavior. The neuropsychiatric profile for patients with FTLD varies between the three clinical subtypes, although overeating, repetitive compulsive behaviors, apathy, agitation, and disinhibition develop in most of these patients as the disease progresses. Overeating is common, and patients tend to gorge. In combination with the swallowing deficits due to parkinsonism or ALS, the gorging on food can be life threatening. Similarly, compulsive pacing can lead to wander off from home, sometimes with disastrous results. This spectrum of psychiatric symptoms usually requires medical management, either within the home or at chronic care facilities. With all clinical subtypes of FTLD the coassociation of progressive movement disorders including progressive supranuclear palsy, corticobasal degeneration, and motor neuron disease leads to specific treatment issues. Patients who develop parkinsonian or motor neuron features have greatly shortened survivals and in FTLD with ALS the average patient lives less than 2 years from the time of diagnosis. Because parkinsonism and ALS severely shorten survival, treatment plans often need to consider when to withdraw medications and hospice care. Unlike AD, where troubling behaviors often emerge in the middle and late stages of the illness, behavioral disturbances in FTLD are seen in the early stages of the disease and often attenuate as the dementia worsens. Psychiatric disorders, often atypical by virtue of their late-life onset or their clinical features, are common
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in FTLD. Atypical depressive episodes are seen in many patients, and it is common to see apathy mistaken for depression in FTLD. Insight is impaired, and many FTLD patients with depressive features deny sadness. Compulsions and repetitive or stereotypic behaviors are seen in FTLD, but formal obsessive-compulsive disease is less common. Unexplained anxiety, irritability, or euphoria are common. Frank psychosis with delusions or hallucinations is uncommon, but blunted affect, bizarre behaviors, and altered social pragmatics can lead to the diagnosis of schizophrenia or late-life psychosis. FTLD often disrupts the family infrastructure due to infidelities, bad financial decisions, or disinhibited behaviors. The caregiver burden associated with FTLD is extremely high and exceeds that seen with other dementias including AD. The troubling behaviors including disinhibition, blunting of personality, bizarre ritualistic behaviors, and indifference to concerns of others are particularly hard for families to cope with. Further exacerbating the caregiver burden, many patients have been misdiagnosed as suffering from a primary psychiatric patient prior to reaching the clinic. Much of the burden associated with FTLD is anatomically driven. With all of the FTLD subtypes, bilateral frontotemporal atrophy eventually emerges, but the initial presentation is often asymmetric with either right or left, frontal or temporal dysfunction. Those who present with predominantly rightsided atrophy exhibit more severe and a wider range of behavioral symptoms than those with predominantly left-sided disease. The blunt and remote affect that is often found in patients with right anterior temporal lobe dysfunction leads to dramatic social decline and can resemble psychotic disorder.
most prominent finding being neuronal loss and gliosis. This has been called dementia lacking distinctive histology or frontal lobe dementia of the non-Alzheimer type. Some suggest that this type of FTLD is due to abnormal expression of tau (tauless tauopathy), although as with ubiquitin inclusions the underlying mechanism for this FTLD subtype is unknown. FTLD cases with ubiquitin pathology are more likely to progress rapidly than are tau cases, due largely to the coassociation with ALS. All three subtypes are associated with frontotemporal atrophy, neuronal loss, and microvacuolation of the superficial cortical areas.
Treatment
In the field of FTLD development of pharmacologic therapies has lagged far behind what has occurred with AD. There have been no completed human trials studies designed to either improve or slow down the cognitive deficits associated with FTLD. Sadly, even with regard to symptomatic therapies there is a paucity of placebocontrolled studies for FTLD. Animal models where tau is overexpressed or where human mutations are placed into transgenic mice are helping investigators to explore the potential utility of new compounds for the treatment of FTLD. Currently realistic goals for treatment include symptomatic management of behavioral symptoms with pharmacologic and nonpharmacologic approaches and maintenance of quality of life for the patient and family. First we review medication and nonpharmacologic approaches to the symptomatic relief of cognitive and behavioral symptoms. Also, we describe new pharmacologic approaches to FTLD. COGNITIVE APPROACHES There is little evidence to either support or refute the concept that FTLD is caused by oxidative brain damage. Based on modest, albeit controversial, success with vitamin E at a dosage of 1000 IU twice daily in slowing the progression of AD, some clinicians will treat FTLD patients with this compound. Similarly, other antioxidants like alpha-lipoic acid or vitamin C have been tried in an anecdotal fashion. Similarly, B vitamins and folic acid are often tried by families desperately hoping to find a treatment. The evidence to support the use of antioxidants and other vitamins is scant. Acetylcholinesterase compounds have shown efficacy for the symptomatic treatment of AD. However, there have been no published placebo-controlled treatment trials for FTLD with this class of medications. The paucity of studies with cholinesterase inhibitors is in part based on the lack of evidence for a cholinergic deficit associated with FTD or any of the other FTLD subtypes. Indeed, earlier studies suggest that the cell counts in the nucleus basalis of Meynert are relatively normal in FTD. Additionally, anecdotal experience with the acetylcholinesterase inhibitors reports worsening of depression, agitation, irritability, and disinhibition associated with cholinesterase inhibition. Therefore, we
Pathologic Issues
There are three major neuropathologic subgroups associated with FTLD: one group with tau aggregation, a second subtype with ubiquitin inclusions, and a third with bland pathology and no inclusions. The tau inclusions can take the shape of classic Pick bodies, which are well-circumscribed silver-staining neuronal inclusions, or they can be less well circumscribed (neuronal achromasia) with no silver staining (Picklike bodies). These tau inclusions can be seen in familial cases with and without tau mutations and also in sporadic cases. There is strong overlap between this pathologic subtype with corticobasal ganglionic degeneration and progressive supranuclear palsy where tau inclusions are found. Ubiquitin inclusions represent the second major type of pathology in FTLD. They are most commonly seen in medial temporal structures such as the dentate gyrus but are also found in motor neurons in the brainstem and spinal cord. The ubiquitin inclusion FTLD subtype is strongly associated with ALS, although there are FTLD patients who never manifest motor neuron symptoms despite the presence of ubiquitin inclusions at pathology. Some call this the FTD-MND syndrome. Finally, there are cases where no inclusions are present. The pathology in these cases is bland with the
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do not recommend these compounds for either the cognitive or behavioral disorder associated with FTLD. In the next year several studies into the efficacy of cholinesterase inhibitors for the progressive aphasia (PA) subtypes of FTLD are likely to be completed. As with the cholinergic story, evidence for glutamate toxicity in the pathogenesis of FTLD is lacking. There is a profound loss of glutamatergic neurons in frontal cortex in FTLD, but there are no data to suggest that the mechanism for this loss is via excessive excitotoxic activity at the level of NMDA receptors. Despite the absence of a strong scientific rationale for NMDA blockers, the recent successes with these compounds in slowing progression of AD have stimulated an interest in their use for FTLD. Several treatment studies with the new NMDA receptor blocker, memantine, are underway. Whether or not this compound will either have symptomatic benefits or slow the progression of any of the FTLD subtypes remains unknown. MANAGEMENT OF BEHAVIORAL SYMPTOMS: DIETARY CHANGES, COMPULSIONS, SEXUAL BEHAVIOR Despite the absence of cognitive therapies for FTD, the debilitating behavioral symptoms that accompany this illness are amenable to treatment. Neuropathologic studies suggest that FTD is associated with large decreases in serotonin concentration in the brainstem and temporal and frontal lobes. Some suggest that some of the symptoms commonly seen are secondary to a serotonergic defect. In particular, the hyperorality, carbohydrate craving, compulsions, repetitive or impulsive behaviors, irritability, agitation, and depression that accompany FTD appear linked to low brain serotonin. Therefore, the first approach to most of the behavioral syndromes in FTD should include consideration of the selective serotonin reuptake inhibitors (SSRIs). There are several studies to date using SSRIs for treatment of the behavioral symptoms in FTD. In one open-label study with paroxetine, fluoxetine, and sertraline, and in another placebo-controlled study with trazodone, there was marked improvement in disinhibition, carbohydrate craving, and compulsive behaviors. Treatment with SSRIs in FTD is generally well tolerated, and they are currently the treatment of choice for many behaviors seen in FTLD spectrum disorders. Side effects that can limit use include sedation, diarrhea, and occasionally repetitive movements. These medications should not be used ubiquitously in FTLD; rather, they should be prescribed to target specific symptoms. There are few hard data to guide the choice of antidepressants. In patients with profound apathy, agents with dopaminergic activity such as bupropion or compounds with mixed activity such as venlafaxine are preferable to the pure SSRIs. Conversely, if sedation is a target of therapy, an SSRI is usually the drug of choice. It is important to start antidepressants at a low dosage and slowly titrate upward, targeting specific symptoms or behaviors. Encouraging realistic expectations with the family is important. In patients in whom
efficacy diminishes over time, the clinician should encourage increasing the dosage. Sometimes the behavioral syndromes associated with FTLD can endanger the patient or family and the community. Some patients insist on leaving the household to wander, whereas in others, theft, reckless driving, and even assault require urgent intervention. In these circumstances (assuming that SSRIs have proved ineffective), the clinician needs to consider more potent compounds. Because the traditional antipsychotics can exacerbate parkinsonism, atypical antipsychotics are usually the treatment of choice for disabling behavioral syndromes. The compounds most commonly used include risperidone, olanzapine, or quetiapine. Low doses are usually effective, but even low doses of the atypical antipsychotics can precipitate parkinsonism or swallowing difficulties. Anticonvulsants such as sodium valproate and carbamazepine have also been tried for modulating agitation and aggression in FTLD. However, there are no formal studies on the anticonvulsants, and these compounds remain second-line considerations for the treatment of these symptoms. Benzodiazepines often worsen behavior in dementia by exacerbating confusion. However, there are occasional patients with FTD where benzodiazepines are helpful. The use of stimulants in FTLD syndromes usually converts apathetic syndromes to agitated delirium, and these compounds should be avoided. Table 1 lists the medications that are commonly used to treat behavioral symptoms of FTLD.
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TABLE 1 Medications Frequently Used for the Treatment of Behavioral Problems in FTD
Drugs: Generic Name (Trade Name) Initial Dose, mg Usual Daily Dose, mg
Selective Serotonin Reuptake Inhibitors Paroxetine (Paxil) 10 Sertraline (Zoloft) 25 Trazodone (Desyrel) 25 Fluoxetine (Prozac) 10 Nefazodone (Serzone) 50 Citalopram (Celexa) 10 Venlafaxine (Effexor) 25 Atypical Antipsychotics Olanzapine (Zyprexa) Quetiapine (Seroquel) Risperidone (Risperdal) Anticonvulsants Valproate (Depakote) Carbamazepine (Tegretol) Beta Blocker Propranolol
FTD, Frontotemporal dementia.
10-40 50-200 25-250 10-40 200-600 10-40 75-300 5-20 25-400 2-6 250-1000 200-800 10-100
2.5 12.5 0.5 125 bid 100 bid 10 bid
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Nonpharmacologic Treatment
BEHAVIORAL MANAGEMENT Families often develop sophisticated and effective management strategies for patients with FTLD. Finding the proper outlet is important, and daily exercise often alleviates problems related to wandering or agitation. Similarly, avoiding naps in the daytime can sometimes prevent nocturnal wandering. Realistic compromises related to diet, exercise, and sexual relations need to be explored with the family. Special attention to the home environment is important, and locking the refrigerator is sometimes necessary to avoid gorging while keeping doors locked may be necessary to protect the patient from wandering away from home. Childproofing the house can help the patient who is prone toward putting objects into his or her mouth. Caregiver support groups often allow family members to explore jointly effective approaches for difficult behaviors. There is little formal research or rehabilitative approaches in FTLD, but some groups are beginning to explore the value of speech or language therapy. Similarly, behavioral modification approaches are under study. Many FTLD patients have cognitive potentials that should be encouraged. In particular, PA and SD patients sometimes have untapped visual or musical abilities that can be facilitated. Table 2 summarizes the major treatment options for FTLD. CAREGIVER STRATEGIES The behavioral symptoms that caregivers face day in and day out are exhausting, and accepting that the burden has to be shared can be hard for many family members. At least 10% of caregivers suffer serious
illnesses that they attribute to the process of caregiving. One of the major responsibilities of the neurologist is to encourage the caregiver to find time away from the patient. Sometimes daytime companions are remarkably helpful and can take the patient on walks or out shopping while the primary caregiver gets time to rest or accomplish work. There are no clear answers for how to manage the individual. Remaining calm and firm is often effective. In this disease, the patient loses the intellectual and emotional rapport as an adult partner and caregivers often need to assume the role of a parent. It is important to plan ahead and to confront decisions that may have to be made regarding subsequent treatment of infections or methods of feeding should patients become unable to swallow. FTD affects judgment, and caregivers should protect patients from situations where judgment is important. If patients continue to work, they should be guided into roles that do not entail financial decisions. Other problems such as sexual impropriety or aggression toward others are often encountered, with patients unaware that they have transgressed social boundaries. Patients with FTD should not be allowed to drive because of numerous reported incidents including hit-and-run accidents, running traffic lights, and even driving too slowly. Often, it is also unwise to leave to FTD patients childrens care due to potential risks of abandonment.
Management of FTD/MND
Although there is no cure for FTD, FTD/MND bears its importance by early death of the patient due to involvement with the respiratory system. So it is important to assess muscle strength, swallowing ability, and balance with gait to optimize functional abilities throughout the
TABLE 2 Clinical Characteristics of Frontotemporal Degeneration Subtypes

Clinical Type
Characteristic Frontotemporal Dementia Progressive Nonfluent Aphasia Semantic Dementia
Primary anatomy involved Dominant feature
Bilateral orbitofrontal and dorsolateral frontal involvement Frontal executive dysfunction with attention difficulties Early decline in social conduct, emotional blunting, loss of insight, and apathy Hyperorality, carbohydrate craving Behavior management by SSRI and possible trial of memantine
Mostly left frontal or frontotemporal involvement Expressive language disturbance with stuttering Relatively spared in early stage but typical behavioral symptom emerges as disease progresses Speech therapy
Behavioral symptoms
Mostly bilateral temporal lobe with asymmetric left anterior temporal involvement Fluent but empty speech due to loss of semantics Prosopagnosia, associative agnosia with progression Compulsion with emotional blunting Impaired emotional recognition Language therapy Treatment for emotional blunting and compulsion with SSRI
Treatment focus
SSRI, Selective serotonin reuptake inhibitor.
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disease course, once diagnosis of FTD/MND has been made. The patients total weight and breathing capacity (forced vital capacity) should be monitored closely by a swallowing clinician for malnutrition associated with dysphagia. Educating the patient and family about the prognosis before the decision of feeding tube placement is important. Pulmonary function should be measured throughout the course of the disease, and a team approach with an MND neurologist and pulmonary clinician in the management of the patient is important.
Future Treatment Direction: Animal Models

The great advances made in the molecular and genetic characterization of AD in the last 2 decades have lagged behind in FTLD. Discovery of tau mutations as a causative factor for some cases of FTD has facilitated animal research into these conditions. Animal models for FTLD include overexpressed tau and transgenic mice expressing the human tau mutations V337M and P301L. These animal models have showed an increased exploratory behavior, impairment in cued and context fear conditioning, but no significant impairment in the Morris water maze test paralleling with the clinical characteristics of FTD. Treatment studies have started with these transgenic mice and are likely to facilitate better therapies for FTLD and related conditions. SUGGESTED READING
Dickson D, Bergeron C, Hauw JJ, et al: Neurodegeneration: the molecular pathology of dementia and movement disorders, Los Angeles, 2003, ISN Neuropath Press. Foster NL, Wilhelmsen KC, Sima AAF, et al: Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference, Ann Neurol 41:706-715, 1997. Neary D, Snowden JS, Gustafson L, et al: Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria, Neurology 51:1546-1552, 1998. Pasquier F, Fukui T, Sarazin M, et al: Laboratory investigations and treatment in frontotemporal dementia, Ann Neurol 54(Suppl 5):S32-S35, 2003. Perry R, Miller BL: Treatment of frontotemporal dementia, Neurology 56(Suppl 4):S46-S51, 2001.
Prion disease (PrD) occurs as a sporadic, genetic, or acquired disease. It results from the neuronal accumulation of a misfolded isoform of a normal brain protein, known as the prion protein (PrP). The normal cellular form of the protein, designated PrPC, is a glycoprotein with unknown function, whereas the pathogenic isoform is designated PrPSc (which relates to a PrD of sheep called scrapie). Once PrPSc is present in the brain, it replicates by an autocatalytic mechanism, whereby PrPSc binds to endogenous PrPC and converts it to PrPSc. The disease is not spread by typical modes of transmission, and the infectious agent is highly resistant to standard disinfection techniques. PrD can occur at almost any age and may present with almost any neurologic or psychiatric feature. The most common presentation is a rapidly progressive dementia, associated with ataxia and myoclonus, known as Creutzfeldt-Jakob disease (CJD); however, at least four other less common subtypes exist, including Gerstmann-Strussler-Scheinker disease (GSS), fatal insomnia (FI), new-variant (v) CJD, and kuru. The overwhelming majority of cases (85%) occur as a spontaneous disease, with or without a genetic predisposition. Roughly 15% are due to one of more than 25 known germline autosomal dominant mutations of the PrP gene (PRNP). A polymorphic site at codon 129 of PRNP can encode either methionine or valine. Approximately 90% of CJD patients are homozygous for either Met or Val (MM129 or VV129), compared with only 50% of nonaffected individuals, suggesting homozygosity is a risk for PrD. It is noteworthy that 100% of cases of vCJD are homozygous MM129. The acquired forms of PrD result from the introduction of prions through prion-contaminated biologicals (growth hormone, gonadotrophic hormone), transplantation of prion-infected tissues (dura mater grafts, corneal transplants), the use of improperly sterilized surgical or neurodiagnostic tools and, as evidenced most recently by the emergence of new variant CJD, by introduction of prions into the food chain. CREUTZFELDT-JAKOB DISEASE CJD is the most common PrD. Age at onset is between 60 and 70 years for sporadic (s) CJD, and younger than 50 for familial (f) CJD, although exceptions occur. The core diagnostic features of CJD include the triad of progressive dementia, ataxia, and myoclonus, although the symptoms at onset may be quite varied. Confusion and memory disturbance are the most common presenting features (70%), with a smaller percentage (15% to 20%) presenting with ataxia. Pyramidal and extrapyramidal features are also common. Myoclonus occurs in more than 70% of patients, especially in midto late stages of disease. Startle myoclonus is often easily elicited following a noise or other stimulus. The typical course of sCJD is less than 6 months and fCJD may extend from one to several years. At end stage, the patient typically displays akinetic mutism. Diffuse vacuolation (spongiform change) of the neuropil in association with gliosis is the typical pathologic picture.
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The Prion Diseases

Definitions and Descriptions

The prion diseases (PrDs), or transmissible spongiform encephalopathies, are progressive neurodegenerative diseases with transmissible properties. They are rare disorders, affecting only one person per million per year.
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disease course, once diagnosis of FTD/MND has been made. The patients total weight and breathing capacity (forced vital capacity) should be monitored closely by a swallowing clinician for malnutrition associated with dysphagia. Educating the patient and family about the prognosis before the decision of feeding tube placement is important. Pulmonary function should be measured throughout the course of the disease, and a team approach with an MND neurologist and pulmonary clinician in the management of the patient is important.
Future Treatment Direction: Animal Models

The great advances made in the molecular and genetic characterization of AD in the last 2 decades have lagged behind in FTLD. Discovery of tau mutations as a causative factor for some cases of FTD has facilitated animal research into these conditions. Animal models for FTLD include overexpressed tau and transgenic mice expressing the human tau mutations V337M and P301L. These animal models have showed an increased exploratory behavior, impairment in cued and context fear conditioning, but no significant impairment in the Morris water maze test paralleling with the clinical characteristics of FTD. Treatment studies have started with these transgenic mice and are likely to facilitate better therapies for FTLD and related conditions. SUGGESTED READING
Dickson D, Bergeron C, Hauw JJ, et al: Neurodegeneration: the molecular pathology of dementia and movement disorders, Los Angeles, 2003, ISN Neuropath Press. Foster NL, Wilhelmsen KC, Sima AAF, et al: Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference, Ann Neurol 41:706-715, 1997. Neary D, Snowden JS, Gustafson L, et al: Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria, Neurology 51:1546-1552, 1998. Pasquier F, Fukui T, Sarazin M, et al: Laboratory investigations and treatment in frontotemporal dementia, Ann Neurol 54(Suppl 5):S32-S35, 2003. Perry R, Miller BL: Treatment of frontotemporal dementia, Neurology 56(Suppl 4):S46-S51, 2001.
Prion disease (PrD) occurs as a sporadic, genetic, or acquired disease. It results from the neuronal accumulation of a misfolded isoform of a normal brain protein, known as the prion protein (PrP). The normal cellular form of the protein, designated PrPC, is a glycoprotein with unknown function, whereas the pathogenic isoform is designated PrPSc (which relates to a PrD of sheep called scrapie). Once PrPSc is present in the brain, it replicates by an autocatalytic mechanism, whereby PrPSc binds to endogenous PrPC and converts it to PrPSc. The disease is not spread by typical modes of transmission, and the infectious agent is highly resistant to standard disinfection techniques. PrD can occur at almost any age and may present with almost any neurologic or psychiatric feature. The most common presentation is a rapidly progressive dementia, associated with ataxia and myoclonus, known as Creutzfeldt-Jakob disease (CJD); however, at least four other less common subtypes exist, including Gerstmann-Strussler-Scheinker disease (GSS), fatal insomnia (FI), new-variant (v) CJD, and kuru. The overwhelming majority of cases (85%) occur as a spontaneous disease, with or without a genetic predisposition. Roughly 15% are due to one of more than 25 known germline autosomal dominant mutations of the PrP gene (PRNP). A polymorphic site at codon 129 of PRNP can encode either methionine or valine. Approximately 90% of CJD patients are homozygous for either Met or Val (MM129 or VV129), compared with only 50% of nonaffected individuals, suggesting homozygosity is a risk for PrD. It is noteworthy that 100% of cases of vCJD are homozygous MM129. The acquired forms of PrD result from the introduction of prions through prion-contaminated biologicals (growth hormone, gonadotrophic hormone), transplantation of prion-infected tissues (dura mater grafts, corneal transplants), the use of improperly sterilized surgical or neurodiagnostic tools and, as evidenced most recently by the emergence of new variant CJD, by introduction of prions into the food chain. CREUTZFELDT-JAKOB DISEASE CJD is the most common PrD. Age at onset is between 60 and 70 years for sporadic (s) CJD, and younger than 50 for familial (f) CJD, although exceptions occur. The core diagnostic features of CJD include the triad of progressive dementia, ataxia, and myoclonus, although the symptoms at onset may be quite varied. Confusion and memory disturbance are the most common presenting features (70%), with a smaller percentage (15% to 20%) presenting with ataxia. Pyramidal and extrapyramidal features are also common. Myoclonus occurs in more than 70% of patients, especially in midto late stages of disease. Startle myoclonus is often easily elicited following a noise or other stimulus. The typical course of sCJD is less than 6 months and fCJD may extend from one to several years. At end stage, the patient typically displays akinetic mutism. Diffuse vacuolation (spongiform change) of the neuropil in association with gliosis is the typical pathologic picture.
13
The Prion Diseases

Definitions and Descriptions

The prion diseases (PrDs), or transmissible spongiform encephalopathies, are progressive neurodegenerative diseases with transmissible properties. They are rare disorders, affecting only one person per million per year.
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GERSTMANN-STRUSSLER-SCHEINKER SYNDROME GSS is a familial PrD, always associated with a mutation of the PRNP gene. Symptoms of truncal and appendicular ataxia in addition to pyramidal and/or extrapyramidal signs typically begin before 55 years of age. Dementia occurs late in the disease. The duration of disease is from 2 to 7 years. Pathology shows amyloid plaques deposited primarily within the cerebellum. FATAL INSOMNIA The onset of this disease includes weeks to months of intractable insomnia, followed by dysfunction of the autonomic nervous system (sweating, lacrimation, respiratory or blood pressure dysregulation). Ataxia follows, along with the delayed onset of dementia. Age at onset is 40s to 50s, and duration of disease is 1 to 2 years. FI is both familial (f FI) and sporadic (sFI). The pathologic profile includes mild to no spongiform change, prominent neuronal dropout, and astrocytic gliosis localized primarily to the thalamus and inferior olivary nucleus. VARIANT CJD vCJD is a disease that is due to ingestion of beef or beef products contaminated with bovine spongiform encephalopathy (BSE). It occurs in teens and young adults, begins with behavioral disturbances such as depression or apathy, and often has an associated pain syndrome. The pathologic diagnosis is confirmed by the presence of large PrP-amyloid deposits circumscribed by extensive vacuolation, also called florid plaques.
dementia; at least two of the following features: myoclonus, visual or cerebellar disturbance, pyramidal/ extrapyramidal signs, akinetic mutism and either periodic sharp wave complexes (PSWCs) on electroencephalogram (EEG) and/or positive 14-3-3 cerebrospinal fluid (CSF); and less than 2 years duration. A possible CJD diagnosis is made by the presence of the features of probable CJD, but the EEG is not available or it is atypical. The WHO criteria for probable vCJD includes documentation of a progressive neuropsychiatric disorder for more than 6 months and four of the five features (early psychiatric symptoms, persistent painful sensory symptoms, ataxia, myoclonus or chorea dystonia, dementia), a nonperiodic EEG, and a magnetic resonance (MR) imaging study showing high signal in pulvinar. A typical work-up for PrD is described in the following sections.
HISTORY AND PHYSICAL EXAMINATION. A rapidly progressive dementia in association with myoclonus is highly suggestive of sCJD, whereas the onset of insomnia in midlife followed by autonomic disturbances and ataxia is highly characteristic of either sFI or f FI. The onset of ataxia and/or dysarthria, seen with GSS, and in 15% to 20% of sCJD cases, is less likely to be considered a PrD on initial encounter, especially since the dementia may be minimal at the time of presentation. The slower rate of progression of fCJD may also be difficult to recognize initially and may be confused with Alzheimers disease. A detailed family history is imperative. Country of birth and travel history should be obtained and include time spent in the United Kingdom from 1985 to 1996. A history of exposure to growth hormone, gonadotrophic hormone, dura mater grafts, or neurosurgical procedures is generally unhelpful unless the source can be identified and tested. LABORATORY ASSESSMENT. Standard blood work for dementia should be performed, including complete blood count with differential, electrolytes, calcium, vitamin B12, folate, and thyroid-stimulating hormone. To this, add antithyroglobulin and antithyroperoxidase antibodies to rule out Hashimotos encephalopathy, a common masquerader of CJD and one that is treatable with steroids. These antibodies are typically elevated at a titer of greater than 1:5000 in true Hashimotos encephalopathy. This disease may cause progressive encephalopathy, seizures, and an abnormal EEG. At least a month of therapy on high dose prednisone (40 mg/day) may be necessary to see an improvement. To complete the blood work for evaluation of PrD, the following should be considered: a heavy metal screen, a panel of paraneoplastic-associated antibodies (e.g., limbic encephalitis [anti-Ri antibodies]) and cerebellar syndrome (anti-Yo antibodies), among others; a vasculitis panel (C-reactive protein and/or erythrocyte sedimentation rate are initially sent, and if positive, antinuclear antibody, double-stranded DNA, anti-ribonucleoprotein, anti-Smith, SS-A, and SS-B should be sent) especially in younger patients (<55 years of age), in whom there is a greater likelihood of the first episode of vasculitis or connective tissue disease. Although the absence of strokes on MR imaging may
Diagnostic Evaluation of the Patient with Prion Disease

The diagnosis of PrD may be difficult for a variety of reasons, the most notable of which is the range of phenotypes with which it may present. Because sCJD is typically rapidly progressive, it is usually considered in the context of more acute neurologic processes, such as toxic-metabolic, infectious, or inflammatory conditions, including viral, bacterial, and parasiticrelated encephalopathies/encephalitides, central nervous system or systemic vasculitides, heavy metal poisoning (especially bismuth ingestion), autoimmune diseases such as Hashimotos thyroiditis with related encephalopathy, and paraneoplastic syndromes. On the other hand, the familial forms of PrD are generally more protracted and may be mistaken for one of the more common neurodegenerative diseases, such as Alzheimers disease, dementia with Lewy bodies, frontotemporal dementia, Huntingtons disease, spinocerebellar ataxia, or progressive supranuclear palsy, among others. A definite diagnosis of any of the PrDs requires neuropathologic confirmation. Based on criteria set forth by the World Health Organization (WHO), the diagnosis of probable CJD includes a progressive
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argue against vasculitis, this is sometimes difficult to assess, necessitating a cerebral angiogram. Copper and ceruloplasmin should also be sent, especially in younger individuals, to rule out Wilsons disease. If there is a history of chronic diarrhea in association with dementia, ophthalmoplegia, and myoclonus, testing for Whipples disease (small bowel biopsy, polymerase chain reaction for Tropheryma whippelii) should be considered. Genetic testing for mutations of PRNP is available on a research basis from a handful of laboratories and may be useful for patients with protracted symptoms and a suspicious family history.
NEUROIMAGING. MR imaging of the brain should be
the EEG shows intermittent bursts of periodic or pseudoperiodic discharges, the EEG may be repeated every other day to see the evolution to sustained PSWCs. These may then disappear with disease progression.
BRAIN BIOPSY. This is reserved only for patients in whom
a treatable diagnosis is clearly in question. We rarely perform a biopsy in these patients but will consider it for younger patients with atypical presentations and for a higher likelihood of finding another disease, such as vasculitis.
BIOSAFETY PRECAUTIONS. A common question with PrD relates to how the patient should be managed in the hospital. Although blood appears to have a theoretical potential for transmission, the chances of transmission through accidental exposure are very low. Nonetheless, precautions for handling blood and body fluids should be in place and the nursing staff should be made aware of this, as should phlebotomy and other ancillary staff. Because of the low risk of transmission in this setting, an isolation room is not required. However, a private room facilitates the handling of soiled bedding and needle disposal. All staff involved in any potential invasive diagnostic testing (i.e., interventional radiology or surgical teams) need to be notified of the potential diagnosis of PrD. Any surgical procedure should use disposal instruments, and the operating room suite needs to undergo a specific preparative and postoperative clean-up procedure. PHARMACOLOGIC MANAGEMENT. Although a variety of drugs, such as amphotericin B, pentosan polysulfate, congo red, quinacrine, and chlorpromazine, have shown promise in the test tube or in cultured cells infected with prions, none have shown any significant benefit in an animal model of PrD. Regardless, clinical trials have begun to test quinacrine (1gm loading dose, followed by 100 mg three times a day) in patients. Results are not yet in at the time of writing . Other symptoms such as myoclonus can be treated with clonazepam (Klonopin) (0.5 to 5 mg orally three times a day), and if seizures are present, either higher doses of clonazepam or diphenylhydantoin (4 to 6 mg/kg/day orally in divided doses once to three times a day) can be administered. At the end of the work-up of an inpatient, a course of empiric steroids (1 gm/day in divided doses) is often administered as a final check that an undetected inflammatory process has not been overlooked.
performed on all patients with a question of PrD. Mild to moderate generalized atrophy may be seen in some patients, but this is not a consistent finding. Recent evidence, and our clinical experience, suggests that hyperintensity of the basal ganglia on diffusion-weighted MR imaging (DWI) is observed in the majority of patients with sCJD, and in many fCJD cases. The utility of this in GSS and FI have not yet been studied. In vCJD hyperintensity of the pulvinar of the thalamus is characteristically observed by proton-weighted MR imaging, although DWI also appears to demonstrate this finding. A reduction in uptake of radiolabeled glucose in the thalamus by positron emission tomography scan is highly characteristic of FI.
LUMBAR PUNCTURE. CSF examination must be performed
13
in all patients suspected to have PrD, to rule out fungal, viral, and bacterial infection. If the history is poorly established and the patient presents abruptly to the hospital in an encephalopathic state, prophylaxis for herpes encephalitis should be considered (acyclovir, 10 mg/kg intravenously every 8 hours for 10 days), while results of the lumbar puncture are pending. The CSF typically does not show an immunologic response in patients with PrD, although a minor elevation in protein of about 10% or so is common. The 14-3-3 protein can be detected in CSF of patients with PrD to variable degrees. The test raises the level of diagnostic confidence if positive but does not rule out PrD if negative, because it has been shown in some hands, including our own, to be negative in as many as 40% or more of autopsy-proven CJD cases. Repeat testing in some negative cases may reveal a positive result, as the disease progresses.
EEG. The characteristic feature is the presence of PSWCs,
which are triphasic, or sharp wave bursts that occur every 0.5 to 2 seconds. PSWCs are typically generalized discharges but may initially be unilateral then spread bilaterally. They are detected in approximately 70% of sCJD cases, and they are much less common in fCJD, and generally absent in GSS, FI, and vCJD, where a slow wave pattern is more typical. Thus, as with the 14-3-3 protein, a positive study helps, and a negative study does not rule out PrD. Also, as with the 14-3-3 test, repeated studies may improve the likelihood of their detection. We typically repeat the EEG every few weeks, if suspicion is high. If the patient is in the hospital and
SUGGESTED READING
Mastrianni JA: Prion diseases, Clin Neurosci Res 3:469-480, 2004.
PATIENT RESOURCES
Centers for Disease Control and Prevention website for information on prion diseases: http://www.cdc.gov/ncidod/diseases/cjd/cjd.htm The CJD Foundation (a public interest group) http://www.cjdfoundation.org/ The CJD Voice (a support group for families) http://www.cjdvoice.org/
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Nicholas J. Maragakis, M.D. and Richard M. Kimball MSN, MPH, RN
IMAGING Extensive neuroimaging studies are usually not necessary in ALS. Targeted magnetic resonance (MR) imaging of regions in which clinical and examination findings suggest dysfunction are usually sufficient. For patients with bulbar signs and symptoms, an MR imaging study of the brain with contrast is sufficient. For patients with limb weakness and hyperreflexia, MR imaging of the cervical spine is warranted to exclude cervical stenosis (see Table 2). LABORATORY STUDIES There is no single laboratory-based study that identifies ALS patients. Laboratory studies may play a role in excluding other neurologic diseases that may present with similar features to ALS (Table 3). Because Lyme disease is endemic to the Eastern coast of the United States, Lyme disease testing from the blood is often obtained. Lyme disease can mimic a number of features of ALS and should be checked primarily because it is a treatable disorder. We only order Lyme testing from the blood using an enzymelinked immunosorbent assay method, and if the results are equivocal, then a Western blot is performed. Although the question of chronic Lyme disease mimicking ALS is often raised, we do not treat for Lyme disease in the absence of a confirmation based on clinical and serologic studies. We also routinely check for vitamin B12 levels, thyroid function studies, and rapid plasma reagin with fluorescent treponemal antibody absorption. Although vitamin B12 deficiency, thyroid disease, and neurosyphilis can have some features of ALS, we evaluate for these disorders primarily because they are also treatable. The creatine kinase (CK) level can be elevated in some patients with ALS and is more often elevated in the spinal form of the disease. An elevated CK level is not, however, predictive of outcome and therefore is only helpful as an adjunct to clinical evaluation of the patient. Other studies such as lumbar puncture, Anti-GM1 antibodies (multifocal motor neuropathy), antiacetylcholine receptor antibodies (myasthenia gravis), and serum lead levels may be helpful in specific situations if the suspicion for other disorders is raised based on the patients history and clinical findings but are not part of our routine evaluations (see Table 3). GENETIC ANALYSES
Epidemiology
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder in developed countries. Epidemiologic data suggest that the disorder has an incidence of 3:100,000 with a slight male prevalence. ALS may present in either a spinal or bulbar form. The diagnosis may be difficult to render when symptoms first occur because the disorder is insidious and there is no uniform pattern of signs and symptoms at the time of presentation. Because there is no known cure for the disorder and it is almost uniformly fatal, many health care professionals may be uncomfortable in both making the diagnosis and providing follow-up management.
Making the Diagnosis

CLINICAL FEATURES Two primary forms of the disease are recognized: bulbar and spinal onset. Bulbar-onset disease may present with dysarthria, dysphagia, or shortness of breath with sparing of extraocular movements. Spinal-onset disease usually presents with asymmetric distal weakness often as foot drop or grip weakness. The absence of sensory complaints or pain is usually the case. Prominent sensory complaints should prompt either a search for another cause of weakness (brachial neuritis) or a second disease in addition to ALS, such as diabetic neuropathy. Prominent autonomic dysfunction is generally not a feature. It has been increasingly recognized that dementia, particularly frontotemporal dementia, may coexist with the development of disease. Although there are specific Word Federation of Neurology criteria for the diagnosis of ALS, these are primarily used for research purposes and entry of patients into clinical trials. Practically, the diagnosis can be made with the observation of upper motor neuron dysfunction, lower motor neuron dysfunction, and progression of weakness over a period of months (Table 1). ELECTROPHYSIOLOGY Electromyography (EMG) and nerve conduction studies (NCSs) remain a cornerstone in providing a diagnosis and excluding other disorders. Additionally, EMG often may reveal denervation in muscles that are not clinically affected at the time of examination. EMG/ NCS are part of every new diagnosis, and if symptoms and signs suggest ALS but EMG/NCS are inconclusive, we often repeat the study after a period of 6 months (Table 2).
Approximately 10% of all ALS is inherited. Of those cases that are familial, approximately 20% carry a mutation in the superoxide dismutase gene (SOD1). This gene is therefore present in approximately 1% to 2% of all ALS patients. Patients and their family members often inquire whether they should be tested for the SOD1 gene mutation. We typically advocate SOD1 gene testing when there is a family history of the disease. An important consideration is that even in familial cases, a negative
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TABLE 1 Diagnostic Features of Amyotrophic Lateral Sclerosis (ALS)

Symptoms Dysarthria Dysphagia Dyspnea Limb weakness Emotional lability Prominent muscle cramping Signs Symptoms and Signs Inconsistent with ALS Diagnosis Visual loss Diplopia Pain as a prominent symptom Autonomic dysfunction Numbness and tingling in the extremities Sphincter dysfunction
Lower motor neuron signs Weaknessoften asymmetric and distal Atrophyoften asymmetric Fasciculations Hypotonia in atrophic muscles Upper motor neuron signs Hyperreflexia Extensor plantar response Spasticity
SOD1 gene test does not mean that the patients children will not inherit the disease. It only effectively excludes familial ALS associated with the SOD1 gene mutation. There are other mutations as yet unrecognized. While the SOD1 test is commercially available, careful explanation of the implications of gene testing should be considered. For this reason we recommend genetic counseling before SOD1 gene testing.
Discussing the Diagnosis of ALS with the Patient

One of the complaints that patients have is my doctor told me that I have Lou Gehrigs disease, that there is no cure, and to get my affairs in order. Whether real or perceived, one of the critical issues in discussing the
diagnosis with the patient is allowing time to discuss the diagnosis, present an initial approach to management, and answer questions. For most patient encounters where a previous diagnosis has not been made, we usually reserve the new patient visit for taking the history, performing the examination, and reviewing imaging studies. Then decisions can be made about other studies that may be necessary, such as neurometrics, more imaging, laboratory studies, and so forth. Following the completion of those studies, we typically set up an additional visit for discussing the diagnosis, management, prognosis, and clinical trials.
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Management Overview
OVERALL PHILOSOPHY It is important to consider the overall condition of the ALS patient in terms of physical progression of the disease, but it is equally important to consider the psychologic, environmental, economic, and social conditions of the patient. This is vital in our increasingly demanding, expensive, and litigious society. Patients will lose their voice, ability to move, ability to swallow, and eventually their ability to breathe independently. Thus, they will need extraordinary support from their health care providers and families. The diagnosis of ALS should therefore be seen only as the start of a close relationship between the patient and the health care providers (Figure 1). PHARMACOTHERAPY Usually, one of the first questions patients ask of their health care providers is whether there are any medications to cure the disease or at least slow its progression. We approach this subject with both realism and optimism. The only U.S. Food and Drug Administrationapproved drug currently for use in treating ALS is riluzole (Rilutek). Although its effect on survival was shown to be modest (3 months), it currently stands as the cornerstone for ALS pharmacotherapy. Although many health care providers dismiss its effect as trivial,
TABLE 2 Electrophysiologic and Imaging Studies in the Diagnosis of ALS

Study Electrophysiology EMG Comments
NCS
Finding of acute and chronic denervation in at least three regions (cranial, cervical, thoracic, and lumbosacral) is indicative of the disease Helpful in assessing sensory neuropathy and evaluating for motor neuropathies (multifocal motor neuropathy) Use for patients with prominent bulbar symptoms and signs Helpful in patients whose symptoms spare the bulbar region Evaluate for radiculopathy (often a diagnostic consideration in foot drop)
Imaging MRI of the brain MRI of the cervical spine MRI of the lumbosacral spine
ALS, Amyotrophic lateral sclerosis; EMG, electromyography; NCS, nerve conduction study; MRI, magnetic resonance imaging.
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TABLE 3 Diagnostic Laboratory Studies for ALS Versus Other Neurologic Disorders
Laboratory Studies Creatine kinase Lyme serology Thyroid function study Vitamin B12 RPR, FTA Anti-GM1 antibodies Antiacetylcholine receptor antibodies Lumbar puncture Disease to Exclude ALS (may be elevated in spinal form), inflammatory myopathies, myositis Lyme disease Graves disease, hypothyroidism Pernicious anemia, malabsorption Neurosyphilis Multifocal motor neuropathy Myasthenia gravis Infectious etiologies (CSF pleocytosis), demyelinating disease (high CSF protein), and infiltrating meningitides (abnormal cells in CSF) Inherited form of ALS
SOD1 gene testing
ALS, Amyotrophic lateral sclerosis; RPR, rapid plasma reagin; FTA, fluorescent treponemal antibody absorption; CSF, cerebrospinal fluid.
not recognized when a patient is more sedentary. Passive range of motion exercises are of particular importance in avoiding contractures and/or joint injuries, which can result in pain and further immobility. Another important aspect of physical therapy includes maintaining ambulation. ALS patients often experience foot drop. Foot drop, even if subtle, can significantly increase the risk of falling. Therefore, a careful assessment of fall-risk is vital during ALS visits. Foot drop can be ameliorated with the use of ankle-foot orthoses. Gait assessments are also available to maintain safety and independence for as long as possible in ALS patients. Depending on the region of onset and the severity of the disability, canes, walkers, and wheelchairs are appropriate for maintaining quality of life and safety. Often vanity results in patients not wanting to use assist devices. Therefore, frank discussions with patients should occur at the time of diagnosis and subsequent visits to assess need, availability, and usefulness of appropriate durable medical equipment. Many local Muscular Dystrophy Association and ALS Association chapters provide loan closets for use of equipment commonly needed for ALS patients. OCCUPATIONAL THERAPY A significant part in the management of ALS is the maintenance of activities of daily living (ADLs) for these patients with progressive weakness. Patients and family members are witness to the unrelenting reduction in a patients capability to perform ADLs. Occupational therapy provides adaptive equipment including large-handled utensils for eating, Velcro fasteners for dressing, reaching devices, and bathroom equipment. Our recommendations include a home visit to identify activities in which the patient will require assistance. These include transfer from bed to chair, chair to toilet, and bathing. In addition, assessing bedding arrangements is important. This is necessary to reduce the risks for an immobile patient as well as to address the risks for skin breakdown and breathing problems. Hospital beds should be considered for ALS patients. Important aspects of a hospital bed include the ability to protect the patient from falls, to raise and lower for easier transfers and to ease orthopnea, and protect the patient from pressure sores and possible infections and other sequelae of skin breakdown. Wheelchair accessibility within the home is also assessed so that ramps or other devices, which will allow increased accessibility, can be installed. Home adaptation or moving should be discussed with ALS patients and their caregivers. Adaptations with the use of elevators or lifts is a possibility but should be weighed against cost, caregiver burden, and financial means. We recommend the early introduction of these issues to the patient so that problems can be identified and modifications made before the patient finds them a necessity. Continuing assessment with the use of the ALS functional rating scale or other ADL rating scales will be vital for referring patients to an occupational therapist for specific issues.
we believe that its use is warranted as the basis for the addition of other potential candidate drugs. Furthermore, it is generally well tolerated. An important consideration, however, is that it is expensive. We also generally suggest vitamins E and C for their antioxidant properties. They are inexpensive, well tolerated, and widely available. A host of drugs and nutritional supplements have been studied first in ALS mouse models and then in human clinical trials. These studies have been based on a number of theories about ALS pathogenesis, but currently drugs acting on the glutamatergic system, neuroinflammatory modulators, and growth factors are receiving significant scientific attention. No presentation of ALS pharmacotherapy is complete without a discussion about the opportunities for enrollment into clinical trials. A current list of clinical trials in ALS is found in Table 4. As the disease progresses, patients may develop a number of symptoms that can be effectively managed with medications. Table 5 provides a sampling of some of the common medications we use in treating various symptoms of the disease. PHYSICAL THERAPY Patients often question whether exercise is beneficial in helping preserve muscle strength throughout the disease. To date, no prospective studies have established whether exercise has a beneficial effect in ALS management. The improvement in the psychologic well-being of patients, however, may make exercise an appropriate treatment that could contribute to quality of life. Our recommendations are for exercise that does not fatigue the patient but provides enjoyment. Furthermore, one must be aware that patients who were previously enjoying some form of exercise may be at risk for injuries such as fractures because of subtle weakness
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1st clinic visit
Initial history and physical examination (Table 1)
Pertinent laboratory studies (Table 3)
Electrophysiologic studies (EMG/nerve conduction study) (Table 2)
Imaging studies (MRI brain and/or spinal cord) (Table 2)
Baseline pulmonary function test
Follow-up clinic visit
Discussion of ALS diagnosis
Initiate pharmacotherapy for ALS treatment (Riluzole 50mg po bid)
Discussion of ALS clinical trials (Table 4)
Symptomatic treatment (Table 5)
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Assess psychologic issues (depression and anxiety)
Physical and occupational therapy
Speech evaluation
Nutrition and swallowing assessment (PEG placement if indicated)
Respiratory management (initiate BiPAP if FVC<50% hypercapnea, or respiratory symptoms)
Reassess at 3 month intervals End of life issues (homecare, hospice)
FIGURE 1. Algorithm for the approach and treatment for amyotrophic lateral sclerosis (ALS). PEG, Percutaneous endoscopic gastrostomy; BiPAP, bilevel positive airway pressure; FVC, forced vital capacity; EMG, electromyogram.
SPEECH THERAPY Speech pathologists play an important role in the evaluation of dysarthria and dysphagia. Anticipating the needs of patients prior to the evolution of profound dysarthria is important in maintaining a patients independence.
Assistive communication devices (ACDs) such as communication boards with voice synthesizers are of use particularly in patients with bulbar-onset ALS who maintain good limb strength but are unable to communicate effectively in the disease course. Many of these devices are portable and can be carried easily
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TABLE 4 Current Amyotrophic Lateral Sclerosis Clinical Trials

Drug Celecoxib (Celebrex) Minocycline Myotrophin (Cephalon) The Vesthighfrequency chest wall oscillation TCH 346 (Novartis) AVP-923-Neurodex Coenzyme Q10 Ceftriaxone Sodium phenylbutyrate Mechanism of Action/Indication Inhibits cyclooxygenase 2, which may result in reduced glutamate release and reduced free radical formation Antibiotic, inhibits microglial activation Insulin-like growth factor 1, trophic factor Loosen and clear pulmonary secretions from the airway Prevents degeneration of neurons from programmed cell death Treatment of pseudobulbar affect Energy metabolism, antioxidant Antibiotic, promotes glutamate transporter protein synthesis Regulates DNA transcription, effective in models of neurodegeneration
Studies have demonstrated the beneficial effects of supplemental nutrition in maintenance of muscle mass and prolongation of survival in ALS patients. PEG tube placement is usually the current choice for nutritional supplementation. It has advantages over nasogastric tube placement including comfort and cosmetic concerns. RESPIRATORY MANAGEMENT Because pulmonary issues become important in ALS management, attention should be given to signs and symptoms of respiratory involvement. Indeed, most deaths are due to pulmonary complications resulting from respiratory muscle weakness. For this reason we recommend prevention strategies such as immunizations against bacterial pneumonia and influenza as well as dietary changes to prevent aspiration of food as noted earlier. When a patient complains of dyspnea, orthopnea, new-onset morning headaches, or other respiratory-related issues, formal pulmonary testing is suggested. This should include upright and supine forced vital capacities (FVC), maximal inspiratory and expiratory pressures (MIP and MEP, respectively), and arterial blood gases. Current therapies for respiratory insufficiency includes the use of intermittent bilevel positive airway pressure (BiPAP), suction machines, airway clearance systems, and cough assist devices. BiPAP is generally implemented in patients with 50% or less FVC or other respiratory measures. BiPAP is a noninvasive ventilator modality shown to reduce the work of breathing and improve not only gas exchange, but also exercise tolerance, sleep quality, and overall quality of life. The use of BiPAP in ALS was found to substantially prolong survival in ALS patients. Some patients may be interested in the use of a long-term ventilator. A discussion of tracheostomy and the requirements for care should be initiated with these patients early in the disease course. The ability to handle secretions can also affect patient comfort. The accumulation of secretions can lead to coughing, choking, and potentially aspiration pneumonia. To ameliorate the production of secretions, anticholinergics such as glycopyrrolate (Robinul) can be used during the day. Other drugs with anticholinergic side effects such as tricyclic antidepressants (TCAs) can have the benefit of drying up secretions as well. Administration of TCAs is particularly effective at night because the effect is long-lasting and daytime drowsiness can be avoided. For these reasons, patients with ALS should be assessed by a pulmonologist who can assist with these issues. DEPRESSION AND ANXIETY Patients should be questioned about their emotional response to the disease. Depressive symptoms such as depressed mood, sleep disturbances, loss of appetite, and sexual interest may be clues to depression and should be treated. Conversely, some patients have episodic anxiety manifesting as dyspnea or chest pain. We address these issues routinely because many
in a handbag. These might include software programs for laptop computer to dedicated personal digital assistant (PDA)-style communication devices to devices that use head and eye movement for communication. The particular device should be considered in light of the present and future needs of the patient. Patients need to be educated early on the usefulness of ACDs and reassessed at regular intervals to determine timely intervention. TTY (text telephone), internet-based text messaging and e-mail have become popular with anarthric ALS patients and caregivers to keep in touch with one another and with health care professionals. NUTRITION As the disease progresses, patients lose muscle mass secondary to denervation atrophy. In addition, bulbar involvement results in speech and swallowing difficulties. Patients are unable to adequately maintain caloric needs leading to malnutrition due to increased caloric need from lost muscle mass and increased effort to maintain normal activities. The presence of malnutrition is an independent prognostic factor for worsened survival. Strategies to increase caloric intake and maintain hydration include educating on high-caloric foods, using softer foods, avoiding stress and distractions at mealtimes to avoid choking, and using thickening agents for liquids to aid in swallowing. These substitute methods will be effective only as long as the patient has some coordinated innervation of the bulbar muscles. Open discussions of artificial nutrition options including percutaneous endoscopic gastrostomy (PEG) or other enteral feeding tubes should be started early in the disease process, especially in patients with bulbar-onset disease.
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TABLE 5 Commonly Used Medications in Managing Amyotrophic Lateral Sclerosis (ALS)

Medication: Generic Name (Trade Name) Riluzole (Rilutek) Baclofen (Lioresal) Tizanidine (Zanaflex) Glycopyrrolate (Robinul) Amitryptyline (Elavil) Scopolamine patch Sertraline (Zoloft) Lorazepam (Ativan) Zolpidem (Ambien) Quinine Common Side Effects Elevated liver transaminases LFTs should be assessed once/mo for first 3 mo Drowsiness, dizziness, nausea Drowsiness, dizziness Constipation, mydriasis, blurred vision, urinary retention Constipation, mydriasis, blurred vision, urinary retention Drowsiness, blurred vision, dizziness Nausea, insomnia, headache Drowsiness, dizziness, ataxia Headache, myalgias Thrombocytopenia, arrhythmias
Treatment Prolongs life in ALS Reduces spasticity Reduces spasticity, muscle cramps Reduces oral secretions (sialorrhea) Reduces sialorrhea, antidepressant Reduces sialorrhea Depression and anxiety Anxiety, insomnia Insomnia Muscle cramps
Class Antiglutamatergic Muscle relaxant Muscle relaxant Anticholinergic Tricyclic antidepressant Anticholinergic SSRI Anxiolytic, benzodiazepine Anxiolytic, nonbenzodiazepine Antimalarial
Dose 50 mg PO bid Start at 10 mg PO qd and titrate upward to tid as tolerated 4 mg PO qd then titrate upward to tid as tolerated (max 36 mg/day) 1-2 mg PO tid Start 10 mg PO qhs then titrate to symptoms (max 150 mg/day) Place 1.5 mg patch behind ear q 3 days 50-200 mg PO qd 1-2 mg PO q 6-8 hr 5-10 mg PO qhs 650 mg PO qhs
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LFT, Liver function test; SSRI, selective serotonin reuptake inhibitor; ALS, amyotrophic lateral sclerosis.
patients are reluctant to seek help for these symptoms, ascribing them as a natural response to the disease.
Frequently Asked Questions by Patients and Their Families

How long do I have to live?
Because the presentation and progression of ALS is so heterogeneous, we avoid making specific predictions about survival, particularly after seeing the patient for an initial visit. Patients more often than not perceive specifics as death sentences. We know that ALS patient survival ranges from 2 to 5 years, but it is also warranted to relay that some patients live well beyond that time frame and that hope is important. One of the most important aspects of ALS care is scheduled patient visits at least on a 3-month basis or more frequently if new symptoms appear more rapidly. These scheduled visits allow for frequent assessments and anticipation of the needs of the patient in the coming months.
be discouraged. We do point out to patients, however, that there is little scientific evidence to support the use of many of these compounds in ALS and that there is little regulatory control as to how they are made. It is important to relay to patients that these supplements can be harmful as well as potentially helpful.
What is the promise of stem cell transplantation and gene therapy in ALS?
Stem cell and gene therapies represent bold and unconventional approaches to the treatment of a number of different diseases, including ALS. For this reason alone they are potentially exciting and have demonstrated some efficacy in mouse models of ALS. We emphasize, however, that these are not mainstream alternatives to conventional pharmacotherapy and their application in human ALS patients will require time.
If I enter a clinical trial, is there a chance I might get the placebo?

Because ALS is a devastating disease, the lay community often misinterprets the initiation of a clinical trial as proof that a drug will work. Patients may then seek to obtain study drugs outside the trial since its better that I am guaranteed the drug than have the chance of getting a placebo. Some trials are open label for compassionate use but the most effective, and standard,
What are your thoughts on the use of dietary supplements for treating ALS?
Because there is no known cure for ALS, we believe that the use of supplements should not necessarily
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method for establishing efficacy is with a double-blinded control trial. Furthermore, we relay to the patient that all drugs have side effects and in theory the study drug could actually cause an increase in morbidity and paradoxically speed disease progression. We also emphasize that many trials enroll two patients on study drug for every one on placebo. When these issues are explained in plain terms, most patients feel appreciative that these questions are addressed and that they can make an informed decision about entry into clinical trials.

Stephanie K. Daniels, Ph.D., and Anne L. Foundas, M.D.
Conclusions
ALS is not an uncommon disease, and it has devastating consequences not only to patients but their caregivers. ALS, likely other neurodegenerative diseases, probably arises from a number of predisposing factors such as genetic mutations and possibly toxic mechanisms. These may trigger cascades of cellular events, including glutamate neurotoxicity, free radical formation, and aberrant protein synthesis. Although the only drug currently approved for use in ALS is riluzole, a number of other drugs with different mechanisms of action are either being studied in human clinical trials or are being tested in animal models of the disease. Until satisfactory progress is made in effectively treating the disease, a number of measures including maintaining adequate nutrition and pulmonary function have been shown to improve disease outcome. These, combined with aiding patients in quality-of-life issues such that can be administered by a multidisciplinary group of health care providers can lead to meaningful gains for the patients who currently suffer with ALS. PATIENT RESOURCES
ALS Association National Office 27001 Agoura Road, Suite 150 Calabasas Hills, CA 91301 Phone: 818-880-9007 http://www.alsa.org/ Muscular Dystrophy AssociationUSA National Headquarters 3300 E. Sunrise Drive Tucson, AZ 85718 Phone: 800-572-1717 http://www.mdausa.org/ Project ALS 511 Avenue of the Americas, PMB #341 New York, NY 10011 Phone: 800-603-0270 http://www.projectals.org/ Robert Packard Center for ALS Research at Johns Hopkins University 600 N. Wolfe Street, Meyer 6-109 Baltimore, MD 21287-5953 http://www.alscenter.org/
Dysphagia is defined as a disorder of swallowing and can be associated with a variety of neurologic conditions, both developmental and acquired. Dysphagia is common in the clinical setting of acute stroke and can be a major source of disability impacting diet, nutrition, hydration, and pulmonary status. Other common conditions associated with dysphagia include Alzheimers disease, vascular and frontotemporal dementia, Parkinsons disease, and motor neuron disease, especially in the advanced stages. This chapter focuses on the diagnosis and treatment of acquired disorders of swallowing (dysphagia) in the clinical setting of the acute stroke patient. Dysarthria is discussed in relation to dysphagia. Dysarthria is a disorder of speech resulting from disturbances in muscular control affecting respiration, articulation, phonation, resonance, or prosody. Dysarthria is a common associated clinical deficit found in individuals with dysphagia. While specific efficacious treatments for dysarthria are limited, various therapy approaches targeting the affected components of speech are available. Before the diagnosis and treatment of dysphagia are discussed, a brief review of the neural substrates of swallowing and the different stages of swallowing are presented.
Anatomy and Stages of Swallowing

Swallowing is mediated by a number of central brainstem, cortical, and subcortical brain regions and by peripheral sensory receptors and motor effectors. The most critical central anatomic site is located in the medulla and is called the medullary swallowing center. When this brainstem region is lesioned in acute stroke patients, dysphagia inevitably results and is usually severe and protracted. Sensory cranial nerve nuclei involved with swallowing are located in the brainstem and include the mesencephalic, chief sensory nucleus, and nucleus of the spinal tract of the trigeminal nerve (cranial nerve [CN] V), and the nucleus solitarius (vagal nerve [CN X], glossopharyneal nerve [CN IX], and facial nerve [CN VII]). The motor nuclei that contain the motor neurons that innervate the muscles that mediate swallowing include the motor nucleus of CN V, the facial motor nucleus (CN VII), the nucleus ambiguous (spinal accessory nerve [CN IX, X, XI]), and the hypoglossal nucleus (CN XII). These brainstem sensory nerves project centrally to subcortical and then to cortical sensory representations that in turn feed forward to motor representations at
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method for establishing efficacy is with a double-blinded control trial. Furthermore, we relay to the patient that all drugs have side effects and in theory the study drug could actually cause an increase in morbidity and paradoxically speed disease progression. We also emphasize that many trials enroll two patients on study drug for every one on placebo. When these issues are explained in plain terms, most patients feel appreciative that these questions are addressed and that they can make an informed decision about entry into clinical trials.

Stephanie K. Daniels, Ph.D., and Anne L. Foundas, M.D.
Conclusions
ALS is not an uncommon disease, and it has devastating consequences not only to patients but their caregivers. ALS, likely other neurodegenerative diseases, probably arises from a number of predisposing factors such as genetic mutations and possibly toxic mechanisms. These may trigger cascades of cellular events, including glutamate neurotoxicity, free radical formation, and aberrant protein synthesis. Although the only drug currently approved for use in ALS is riluzole, a number of other drugs with different mechanisms of action are either being studied in human clinical trials or are being tested in animal models of the disease. Until satisfactory progress is made in effectively treating the disease, a number of measures including maintaining adequate nutrition and pulmonary function have been shown to improve disease outcome. These, combined with aiding patients in quality-of-life issues such that can be administered by a multidisciplinary group of health care providers can lead to meaningful gains for the patients who currently suffer with ALS. PATIENT RESOURCES
ALS Association National Office 27001 Agoura Road, Suite 150 Calabasas Hills, CA 91301 Phone: 818-880-9007 http://www.alsa.org/ Muscular Dystrophy AssociationUSA National Headquarters 3300 E. Sunrise Drive Tucson, AZ 85718 Phone: 800-572-1717 http://www.mdausa.org/ Project ALS 511 Avenue of the Americas, PMB #341 New York, NY 10011 Phone: 800-603-0270 http://www.projectals.org/ Robert Packard Center for ALS Research at Johns Hopkins University 600 N. Wolfe Street, Meyer 6-109 Baltimore, MD 21287-5953 http://www.alscenter.org/
Dysphagia is defined as a disorder of swallowing and can be associated with a variety of neurologic conditions, both developmental and acquired. Dysphagia is common in the clinical setting of acute stroke and can be a major source of disability impacting diet, nutrition, hydration, and pulmonary status. Other common conditions associated with dysphagia include Alzheimers disease, vascular and frontotemporal dementia, Parkinsons disease, and motor neuron disease, especially in the advanced stages. This chapter focuses on the diagnosis and treatment of acquired disorders of swallowing (dysphagia) in the clinical setting of the acute stroke patient. Dysarthria is discussed in relation to dysphagia. Dysarthria is a disorder of speech resulting from disturbances in muscular control affecting respiration, articulation, phonation, resonance, or prosody. Dysarthria is a common associated clinical deficit found in individuals with dysphagia. While specific efficacious treatments for dysarthria are limited, various therapy approaches targeting the affected components of speech are available. Before the diagnosis and treatment of dysphagia are discussed, a brief review of the neural substrates of swallowing and the different stages of swallowing are presented.
Anatomy and Stages of Swallowing

Swallowing is mediated by a number of central brainstem, cortical, and subcortical brain regions and by peripheral sensory receptors and motor effectors. The most critical central anatomic site is located in the medulla and is called the medullary swallowing center. When this brainstem region is lesioned in acute stroke patients, dysphagia inevitably results and is usually severe and protracted. Sensory cranial nerve nuclei involved with swallowing are located in the brainstem and include the mesencephalic, chief sensory nucleus, and nucleus of the spinal tract of the trigeminal nerve (cranial nerve [CN] V), and the nucleus solitarius (vagal nerve [CN X], glossopharyneal nerve [CN IX], and facial nerve [CN VII]). The motor nuclei that contain the motor neurons that innervate the muscles that mediate swallowing include the motor nucleus of CN V, the facial motor nucleus (CN VII), the nucleus ambiguous (spinal accessory nerve [CN IX, X, XI]), and the hypoglossal nucleus (CN XII). These brainstem sensory nerves project centrally to subcortical and then to cortical sensory representations that in turn feed forward to motor representations at
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the cortical level. These cortical motor representations, located in premotor and primary motor brain regions, send projections back to brainstem regions to activate oromotor, pharyngeal, laryngeal, and esophageal structures that mediate swallowing. Swallowing consists of three distinct phases: the oral phase, the pharyngeal phase, and the esophageal phase. The oral phase of swallowing is the first phase and is initiated when a bolus of food or liquid enters the oral cavity and ends when the bolus is propelled toward the pharynx. This stage of swallowing is under volitional control and includes tongue movements and sensory receptors in the oral cavity. The pharyngeal stage of swallowing begins when the bolus reaches the ramus of the mandible and continues until the bolus enters the esophagus. Stages of coordinated responses include the closing of the nasopharynx and glottis, shortening of the pharynx, and elevation of the larynx. The bolus is propelled into the pharynx toward the upper esophageal sphincter. The esophageal stage is primarily under involuntary control and begins when the bolus enters the esophagus and continues until the bolus enters the stomach via the lower esophageal sphincter.
include dysphonia, dysarthria, abnormal gag reflex, abnormal volitional cough, voice change after swallow, and cough after swallow. The presence of two or more of these six clinical features is highly predictive of patients at risk of aspiration. Clinical bedside examinations, including an oromotor and bedside swallowing test, can be used to determine which clinical features are present in acute and subacute stroke patients. This simple yet valid screening for dysphagia in acute stroke patients can easily be used by speech pathologists. Given that aspiration and the ensuing complications can increase the length of hospitalization and delay the initiation of rehabilitation, it is imperative that patients with a risk of aspiration be identified within the first days of admission so that proper management, such as diet alteration, and rehabilitation strategies can be implemented early in the clinical course. A clinical decision-making f lowchart (Figure 2) for dysphagia management in the acute stroke population has been instituted at the Veterans Affairs Medical Center in New Orleans. With early identification and intervention, the development of aspiration pneumonia can be reduced in acute stroke patients, consequently decreasing length of hospitalization and expediting rehabilitation efforts. OROMOTOR EXAMINATION A comprehensive assessment of oral musculature symmetry, strength, agility, and sensation should be completed in any patient with a suspected swallowing problem (see Figure 1). This examination includes a detailed examination of cranial nerves and sensory and motor systems. Additional features of the oromotor examination include measurements of isolated movements and continual speech and nonspeech movements of the mandible, lips, tongue, velum, and larynx. Light touch of the face, production of a volitional cough, and the gag reflex are examined. Dysphonia is defined as a change in voice quality and can be characterized as wet, strained, breathy, or nonspecific hoarseness. Assessment for dysarthria includes the evaluation of articulatory precision and agility, fluency, resonance, and intelligibility. BEDSIDE SWALLOWING EXAMINATION The bedside swallowing assessment consists of administration of liquid, semisolid, and solid consistencies at varying calibrated volumes with assessment of oral transition, oral retention, initiation of laryngeal elevation, laryngeal excursion, voice quality after swallow, and spontaneous cough. Assessments should be initiated with a 5 mL liquid bolus and progressed to 10 and 20 mL volumes. The evaluation for liquids should be terminated if the patient coughs or has alterations in vocal quality immediately following or within 1 minute after swallowing. Semisolid and solid volumes should be initiated at volumes of 1 tsp and progressed to continuous ingestion. Administration of a consistency should be terminated if a patient demonstrates either a cough or changes in voice quality after the swallow.
Clinical Examination and Clinical Predictors

STROKE AND DYSPHAGIA Dysphagia occurs in about two thirds of acute stroke patients with estimates, that up to 38% of these poststroke patients may aspirate. Many of these stroke patients develop aspiration pneumonia, which often increases the length of hospitalization and delays rehabilitation efforts designed to improve stroke outcome. Clinical features evident during the first few days poststroke may identify stroke patients at risk for the development of aspiration pneumonia, thus facilitating early intervention to prevent this complication. We have identified six clinical predictors that, when any two are present, seem to be predictive of dysphagia and are associated with an increased risk of aspiration. CLINICAL EXAMINATION Speech pathology should complete a clinical swallowing assessment on all acute stroke patients with the goals being the development of a management program and the identification of patients who warrant instrumental swallowing examination. The clinical examination involves (1) obtaining a complete case history on the swallowing and feeding; (2) screening cognitive factors that might influence oral intake; (3) examining oral and laryngeal functioning; and (4) evaluating swallowing at bedside. Details of this examination are discussed in more detail in the following sections, and an example of a clinical swallowing assessment is presented in Figure 1. Based on a detailed clinical examination, our research group has identified six clinical features in patients at risk for dysphagia. These clinical features
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Clinical Swallowing Examination

MANDIBLE (Cranial Nerve V - Trigeminal) Symmetry on Extension____________________ LIPS (Cranial Nerve VII Facial) Symmetry: Rest_____________ Retraction____________ Protrusion______________ Strength_______________________________ Nonspeech Coordination: Repetitive Movement___________ Alternating Movement__________ Speech Coordination: Repetitive (/p, w/)____________ Alternating (/p-w/)__________________ TONGUE (Cranial Nerve XII - Hypoglossal) Symmetry: Rest____________ Elevation YES/NO Protrusion____________ Lateralization____________ Lateralization YES/NO Fasciculations YES/NO Strength____________________________
Strength_______________________________ Nonspeech Coordination: Repetitive Movement________ Alternating Movement_____________ Speech Coordination: Repetitive (/t, k/)__________ Alternating Movement (/t-k/)_____________ Alternating Movement (/p^ t^ k^/)___________________________________________________ Multisyllabic Word Repetition (tip top, baseball player, caterpillar, emphasize)________________ _____________________________________________________________________________ Conversation: (speech, voice, coordination characteristics)______________________________ Laryngeal Function: Isolated Movement (/i-i-i/ on one breath)____________________________ Alternating Movement (/u-i/)_______________________________________________________ Buccofacial Apraxia: "Blow out a candle"_________ "Lick an ice cream cone"_______________ "Lick milk off your top lip"_______ "Sip thru a straw"_________ "Kiss a baby"_______________ VELUM (Cranial Nerves IX - Glossopharyngeal, X - Vagal, XI Spinal Accessory) Symmetry: Rest_______________ Elevation________________ Coordination: Repetitive Movement (/a/)_____________________________________________ Appearance of Hard Palate_______________________________________________________ Dentition______________________________________________________________________ REFLEXES (Cranial Nerves IX - Glossopharyngeal, X - Vagal, XI Spinal Accessory) Gag (Abnormal: YES/NO)________________________________________________________ Swallow (Cough: YES/NO)________________________________________________________ (Voice Change: YES/NO)_________________________________________________________ ADDITIONAL INFORMATION c/o Facial Numbness or Tingling: YES/NO Light Touch_________________________________ Dysphonia: YES/NO (mild, moderate, severe) ________________________________________ Dysarthria: YES/NO (mild, moderate, severe)_________________________________________ Breath Support_________________________________________________________________ Resonance____________________________________________________________________ Volitional Cough (Abnormal: YES/NO)_______________________________________________
FIGURE 1. Clinical swallowing examination form.
VIDEOFLUOROSCOPIC SWALLOW STUDIES Videofluoroscopic swallow studies (VFSSs) are considered the gold standard for the accurate assessment of oropharyngeal dysphagia, particularly with reference to silent aspiration. However, in some instances this radiographic procedure may not be readily available and it may not always be cost effective. Consequently, our research team developed and validated the clinical swallow examination that can be used as a part of an algorithm to determine the need for the VFSS in
acute stroke patients (see earlier discussion and Figure 1). Although this clinical assessment may also apply to other clinical populations, we have not directly studied the utility of this critical pathway in other neurologic disorders commonly associated with disorders of swallowing like advanced Alzheimers disease, Parkinsons disease, and motor neuron disease (amyotrophic lateral sclerosis, primary lateral sclerosis). VFSS samples are typically recorded using a videocassette recorder. A counter timer may be coupled to
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Six clinical predictors Abnormal cough Abnormal gag Dysarthria Dysphonia Voice change after swallow Cough after swallow
Acute stroke patient swallow assessment
Clinical examination Water swallow study
Dysphagia is common poststroke and can significantly increase morbidity and mortality in poststroke patients. Early screening, instrumental evaluation, and aggressive rehabilitation based on results of the instrumental study can facilitate medical, physiologic, and functional outcomes in these patients. Acknowledgments
No clinical predictors or only 1 present
Two or more clinical predictors present
This work was supported, in part, by grants from the South Central Veterans Affairs Health Care Network Pilot Project Grant and the Department of Veterans Affairs Rehabilitation Research and Development Career Development Grant (B3019V). SUGGESTED READING
Daniels SK: Optimal patterns of care for dysphagic stroke patients, Semin Speech Language 21:323-332, 2000. Daniels SK, Brailey K, Priestly DH, et al: Aspiration in acute stroke patients, Arch Phys Med Rehabil 79:14-19, 1998. Daniels SK, McAdam CP, Brailey K, Foundas AL: Clinical assessment of swallowing and prediction of dysphagia severity, Am J SpeechLanguage Pathol 6:17-24, 1997. Logemann JA: Evaluation and treatment of swallowing, ed 2, Austin, TX, 1998, Pro-Ed. Miller AJ: (1999). The neuroscience principles of swallowing and dysphagia, San Diego, 1999, Singular.
VSS not indicated Follow clinically No significant aspiration risk
VSS indicatedrequest study Initiate therapy as needed Increased risk of aspiration
FIGURE 2. Algorithm for swallowing examination. VSS, Video swallowing study.
the videocassette recorder to imprint digital time in hundredths of a second on each video frame and enables the clinician to obtain precise temporal measurements. A video recording of the oral cavity (anterior to the lips) and the pharynx (inferior to the upper esophageal sphincter) is obtained in the lateral plane as the patient swallows, in duplicate, liquid barium at volumes of 3, 5, 10, and 20 mL and 1 tsp of barium paste. Swallowing of masticated bolus should be examined with 1/2 of a barium-coated cookie. If possible, sequential swallowing should also be evaluated because this is the normal mode of liquid ingestion. The VFSS is initiated with a 3 mL volume and advanced accordingly, unless the patient exhibits significant aspiration that cannot be eliminated with therapeutic intervention. In these cases the study is discontinued.
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Treatment
Rehabilitation of dysfunction; prevention of aspiration, dehydration, and malnutrition; and reestablishment of oral intake are the treatment goals for stroke patients with dysphagia. Recommendations concerning mode of nutritional intake and the specific type swallowing therapy to employ should be based on the physiologic findings of the instrumental examination. Specific compensatory treatments such as posture changes and modification of bolus characteristics are attempted during the VFSS to determine their effectiveness. Benefits of compensatory treatment are immediate but not permanent, whereas rehabilitative therapy aims to change swallowing physiology over time, resulting in permanent improvement in swallowing. Selected treatments should have research-based evidence of their effectiveness. Recovery of swallowing in acute stroke patients may be rapid, warranting reassessment within a few weeks of the initial swallowing evaluation.
Idiopathic intracranial hypertension (IIH) is a common neurologic problem occurring primarily in obese women of childbearing age. The cause is unknown, and it has been associated with many conditions (Table 1). The major symptoms are headache, brief visual obscurations in one or both eyes, and horizontal double vision. Less common symptoms include pain in the neck, shoulders, back, legs, arms, and pulsatile tinnitus. Consciousness is never altered. Spinal fluid pressure is elevated, protein is normal or low (frequently < 20 mg/dL). Glucose and cell counts are normal. The spinal fluid pressure is almost invariably greater than 200 mm H2O. If cerebrospinal fluid (CSF) pressure is not elevated at the first lumbar puncture, a repeat tap should be done to establish that the pressure is truly increased. Troughs of normal CSF pressure in patients with IIH are seen occasionally. Papilledema is usually bilateral, but occasionally it may be unilateral. Furthermore, a condition known as IIH without papilledema occurs where the presenting finding is only chronic daily headache. Visual loss is the only serious, potentially permanent complication of IIH; papilledema may cause
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Six clinical predictors Abnormal cough Abnormal gag Dysarthria Dysphonia Voice change after swallow Cough after swallow
Acute stroke patient swallow assessment
Clinical examination Water swallow study
Dysphagia is common poststroke and can significantly increase morbidity and mortality in poststroke patients. Early screening, instrumental evaluation, and aggressive rehabilitation based on results of the instrumental study can facilitate medical, physiologic, and functional outcomes in these patients. Acknowledgments
No clinical predictors or only 1 present
Two or more clinical predictors present
This work was supported, in part, by grants from the South Central Veterans Affairs Health Care Network Pilot Project Grant and the Department of Veterans Affairs Rehabilitation Research and Development Career Development Grant (B3019V). SUGGESTED READING
Daniels SK: Optimal patterns of care for dysphagic stroke patients, Semin Speech Language 21:323-332, 2000. Daniels SK, Brailey K, Priestly DH, et al: Aspiration in acute stroke patients, Arch Phys Med Rehabil 79:14-19, 1998. Daniels SK, McAdam CP, Brailey K, Foundas AL: Clinical assessment of swallowing and prediction of dysphagia severity, Am J SpeechLanguage Pathol 6:17-24, 1997. Logemann JA: Evaluation and treatment of swallowing, ed 2, Austin, TX, 1998, Pro-Ed. Miller AJ: (1999). The neuroscience principles of swallowing and dysphagia, San Diego, 1999, Singular.
VSS not indicated Follow clinically No significant aspiration risk
VSS indicatedrequest study Initiate therapy as needed Increased risk of aspiration
FIGURE 2. Algorithm for swallowing examination. VSS, Video swallowing study.
the videocassette recorder to imprint digital time in hundredths of a second on each video frame and enables the clinician to obtain precise temporal measurements. A video recording of the oral cavity (anterior to the lips) and the pharynx (inferior to the upper esophageal sphincter) is obtained in the lateral plane as the patient swallows, in duplicate, liquid barium at volumes of 3, 5, 10, and 20 mL and 1 tsp of barium paste. Swallowing of masticated bolus should be examined with 1/2 of a barium-coated cookie. If possible, sequential swallowing should also be evaluated because this is the normal mode of liquid ingestion. The VFSS is initiated with a 3 mL volume and advanced accordingly, unless the patient exhibits significant aspiration that cannot be eliminated with therapeutic intervention. In these cases the study is discontinued.
13

Treatment
Rehabilitation of dysfunction; prevention of aspiration, dehydration, and malnutrition; and reestablishment of oral intake are the treatment goals for stroke patients with dysphagia. Recommendations concerning mode of nutritional intake and the specific type swallowing therapy to employ should be based on the physiologic findings of the instrumental examination. Specific compensatory treatments such as posture changes and modification of bolus characteristics are attempted during the VFSS to determine their effectiveness. Benefits of compensatory treatment are immediate but not permanent, whereas rehabilitative therapy aims to change swallowing physiology over time, resulting in permanent improvement in swallowing. Selected treatments should have research-based evidence of their effectiveness. Recovery of swallowing in acute stroke patients may be rapid, warranting reassessment within a few weeks of the initial swallowing evaluation.
Idiopathic intracranial hypertension (IIH) is a common neurologic problem occurring primarily in obese women of childbearing age. The cause is unknown, and it has been associated with many conditions (Table 1). The major symptoms are headache, brief visual obscurations in one or both eyes, and horizontal double vision. Less common symptoms include pain in the neck, shoulders, back, legs, arms, and pulsatile tinnitus. Consciousness is never altered. Spinal fluid pressure is elevated, protein is normal or low (frequently < 20 mg/dL). Glucose and cell counts are normal. The spinal fluid pressure is almost invariably greater than 200 mm H2O. If cerebrospinal fluid (CSF) pressure is not elevated at the first lumbar puncture, a repeat tap should be done to establish that the pressure is truly increased. Troughs of normal CSF pressure in patients with IIH are seen occasionally. Papilledema is usually bilateral, but occasionally it may be unilateral. Furthermore, a condition known as IIH without papilledema occurs where the presenting finding is only chronic daily headache. Visual loss is the only serious, potentially permanent complication of IIH; papilledema may cause
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TABLE 1 Patients with Intracranial Hypertension of Known Causes

Condition Associated with Intracranial Hypertension Vitamin A intoxication Comments Liver lovers headache and patients taking large daily quantities of vitamin A or retinoic acid congeners Due to hypercoaguable state; post-traumatic in the puerperium Unilateral or bilateral Occasional cases of newly treated hypothyroidism in children may be seen
The typical overweight patient with IIH can present a problem because of MR imaging weight limitations and claustrophobia. In such patients CT scan with contrasted venography can be better because of absent claustrophobia with its use.
Laboratory Studies
Most of the reputed associations listed with IIH occur with no greater frequency in patients with pseudotumor than in age- and sex-matched controls. Extensive laboratory studies are not helpful in most patients. The most important studies to perform include serum calcium to rule out hypoparathyroidism, antinuclear antibody, venereal disease research laboratory test, and fluorescent treponemal antibody. Further endocrine studies are useful only if there is serious reason to believe the patient is cushingoid, addisonian, or suffering from hypoparathyroidism. A lumbar puncture is crucial and must be performed on any patient suspected of having IIH. Not only does one need an elevated opening pressure (>200 mm H2O) to make the diagnosis, but the CSF must be studied to exclude tumor, hemorrhage, inflammation, or infection.
Thrombosis of the sagittal or lateral cerebral sinuses Radical neck dissection Treated cases of deprivation dwarfism Hypoparathyroidism Guillain-Barr syndrome and elevated CSF protein Pickwickian syndrome and sleep apnea Systemic lupus erythematosus Tetracycline, doxycycline, or lithium
Vision Assessment
Visual loss is the only proven serious complication of IIH. Proper assessment of visual function using modern kinetic or static perimetry, visual acuity testing, and fundus photography should be undertaken. The need for repeated accurate observations of best corrected visual acuity, careful perimetric examination, and examination for relative afferent pupil defects cannot be overstressed (Marcus Gunn pupil). Perimetry by the standard kinetic Goldmann technique using an Armaly-Drance testing strategy detects visual defects when about 30% of the fibers are lost.
TABLE 2 Conditions Mistaken for IIH
Combination of anomalously elevated optic disks (pseudopapilledema) and headache Unrecognized brain tumors (rare when MR imaging and MR venography are done) Glioma Gliomatosis cerebri Metastatic tumors, especially pelvic tumors, breast and lung cancer to venous sinuses Meningeal carcinomatosis Spinal cord or peripheral nerve (cauda equina) tumors with high protein in the CSF Arteriovenous malformation with high intracranial venous sinus pressure Infectious diseases Viral encephalitis CNS syphilis with optic papillitis Sarcoidosis of the meninges
IIH, Idiopathic intracranial hypertension; CSF, cerebrospinal fluid; CNS, central nervous system.
serious blinding visual loss in 10% to 25% of patients. Thus, the alternative name benign intracranial hypertension is a misnomer. The first problem in management of these patients is to clearly establish that they have IIH and not some other condition. Since IIH is overwhelmingly a problem of obese women of childbearing age, one should be especially careful when making this diagnosis in men, women who are not obese, children, and older patients (>50 years of age). Children can have IIH. The incidence of 1:100,000 is the same as in adults, but the sex incidence is equal. IIH precipitated by antibiotic use (tetracyclines, doxycyclines, and nalidixic acid) and steroid withdrawal is seen more commonly in children than in adults. Probably the most common reason for a mistaken diagnosis of IIH is the patient who has headaches and pseudopapilledema. Table 2 includes the important conditions mistaken for pseudotumor cerebri.
Diagnostic Imaging
Magnetic resonance (MR) imaging has supplanted most earlier studies of IIH. The MR scan shows normal or small ventricles, and an empty sella occurs in about 70% of patients. The occasional sagittal sinus or lateral sinus thrombosis may not be detected on MR imaging alone and MR venography or computed tomographic (CT) venography can be used if this is suspected.
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Static perimetry is an even more sensitive method and has become the visual field examination of choice. Tangent screen measurement of the blind spot size is inadequate and may lull the examiner into complacency, since serious peripheral field loss, a harbinger of rapid visual field collapse, may not be detected on a tangent screen. Examination for a relative afferent pupil defect (RAPD) may reveal asymmetries in pupil function, suggesting visual loss that is frequently unrecognized by the patient. RAPD is objective evidence of loss of visual field and is proportional to the amount of field lost. Visual acuity should be measured in good light at 20 feet with best eyeglass correction or using a pinhole. Anything less than 20/20 is evidence of visual loss unless the patient is known to have a lazy amblyopic eye. Hand-held Snellen visual acuity testing is second best and in patients who are presbyopic, glasses must be used. Visual evoked potentials (VEP) unfortunately give little information about impending visual loss in IIH. VEP confirms that central vision (visual acuity) is usually the last scrap of vision to be lost in association with papilledema similar to what occurs in glaucoma. When central vision is affected, VEP latencies become prolonged. Do not fall into the trap of making decisions regarding treatment using VEP. It is not helpful and may lull one into a sense of security. Fundus photographs provide objective evidence of disk swelling improvement or deterioration. With fundus photography abundantly available, it is possible to have photographs done that permit the clinician to accurately and objectively assess the efficacy of any particular treatment regimen. Memory of disk swelling serves everyone poorly when trying to recollect fundus appearances, and most drawings are too crude to be useful. The sudden appearance of multiple nerve fiber layer infarcts, hemorrhages, or new optociliary collateral veins may be a forerunner of visual deterioration and should be documented.
Treatment
Once the preliminary radiologic, laboratory, CSF, and visual studies have been done, the treatment used depends on the patients symptoms, the severity of visual loss, and the presence of other underlying conditions such as glaucoma, systemic hypertension, episodic hypotension, renal failure, pregnancy, or other medical conditions. Characteristic treatment settings include those in the following discussion. The patient with chronic headaches and no papilledema needs headache management only. The asymptomatic patient who has no visual loss, in whom the condition was incidentally discovered, needs no treatment and should be followed at 1- to 3-month intervals with ophthalmologic studies to look for evidence of visual loss. If visual loss occurs, treat with acetazolamide or furosemide; if it progresses, consider surgery early. When the patient has only headache and visual loss is trivial or nil, he or she can be treated simply with standard headache medications. Paradoxically, although headaches are frequently relieved with
lumbar puncture, long-term intracranial pressure (ICP) monitoring in patients with IIH has shown no clear, unambiguous correlation between the height of CSF pressure and the severity of headaches. Severe, persistent headache frequently responds to spinal tap. Severe chronic headache as a major symptom of IIH on rare occasion may require a lumboperitoneal (LP) shunt or ventriculoperitoneal shunt. I have had to resort to shunt infrequently and urge the vigorous use of prophylactic migraine medication in an attempt to control headache before ever considering shunts. If headaches are postural after LP, and remit when recumbent, consider a blood patch, since patients with IIH may also develop post-lumbar puncture headaches. The patient with serious loss visual field or loss of visual acuity should not undergo multiple trials of different medications before surgery is contemplated. Optic nerve sheath fenestration (ONSF) or a shunting procedure should be done early rather than late if the patient reports visual loss as a major complaint, especially if visual fields are constricted. Surgery may not always prevent visual loss from progressing, especially when the visual loss is severe at presentation, is rapidly progressive, or has been present for many days or weeks. Careful documentation of visual acuity, visual fields, and photographic appearance of the fundus is crucial, since patients with serious visual loss may actually believe that the treatment caused or worsened the problem. Rapidly progressive visual loss with IIH is seen only occasionally, but the patient may present with serious visual loss and lose vision to the point of total blindness within a few days. These patients are frequently men, usually black, and have high blood pressure. None of them qualifies for a diagnosis of hypertensive encephalopathy, but the management of their high blood pressure and their increased ICP poses a serious treatment challenge. To date, all the patients that I have seen with constellation of severe hypertension, IIH, and rapid visual failure have despite LP shunt optic nerve sheath fenestration and multiple medications, developed severe irreversible visual loss. Attempts to regulate systemic blood pressure should be cautious: A rapid drop in the same time blood pressure may well decrease blood flow at the optic disk and precipitate ischemic infarction. The pregnant IIH patient with persistent headache is probably best treated with repeat lumbar punctures or prophylactically with beta blockers. Opioid analgesics can be used for individual headaches. These methods are safe during pregnancy and should provide headache relief. If headache is incapacitating, bed rest and, as a last resort, LP shunt could be considered. If visual loss ensues while the patient is pregnant, ONSF is the safest way to preserve vision. Pregnancy is not a contraindication to any treatment. IIH is not an indication for therapeutic abortion. There is no need for anesthesia to be modified or for cesarean section to be performed. Routine vaginal delivery is safe. Renal disease is a common IIH concomitant condition. If the patient has renal disease and requires hemodialysis, recurrent drops in blood pressure with volume shifts
13
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are common. Hypotension is poorly tolerated by a swollen optic disk and may result in compound visual loss due to chronic papilledema and to ischemic disk infarction. Visual loss due to hypotensive spells can be prevented with ONSF.
DIGITALIS Digitalis can be used to reduce CSF production through Na/K-ATPase inhibition. The dose is 0.25 mg per day of Digoxin. Although it has not been used in large numbers of patients, it is occasionally effective where diuretics are not. If one feels compelled to use it with diuretics, special attention must be paid to serum potassium levels. Frequent lumbar punctures are advocated by some, but I have had the most success when the objective of spinal tap therapy was headache relief. Repeated lumbar taps frequently are difficult and painful in obese patients and reduce patient compliance. Furthermore, CSF is regenerated at a rate of 20 mL/hr. Occasional patients develop post-lumbar puncture headaches. It is likely that patients who improve with frequent spinal taps do so because of the leak of CSF from the multiple fenestrations in the lumbar theca. These holes may act like an LP shunt.
Specific Treatment Modalities

Diet is recommended for all obese patients with IIH. For the otherwise asymptomatic obese patient, diet may be the only therapeutic recommendation. Diet should be recommended with encouragement and not with threats of blindness. If the patient is sent for dietary instruction, avoid obese dietitiansthey give a double message. Use of commercial weight reduction programs is also helpful. As little as 6% weight loss frequently eliminates papilledema; however, it may return if the patient regains the lost weight. Diuretics have been used for years. The most commonly used diuretic is acetazolamide, a carbonic anhydrase inhibitor, 1000 to 2000 mg daily (up to 4000 mg) in the 500 mg sequel form (two times per day). Diuretics are capable of reducing headache frequency and severity and decreasing transient visual obscurations, but to date none of the diuretics has ever been subjected to a randomized, prospective trial of therapy. Side effects of acetazolamide are numbness and tingling of the hands and feet and circumoral numbness. Rarely, patients taking acetazolamide develop renal stones. They all develop a mild metabolic acidosis, which is never serious, and the serum bicarbonate of 16 to 18 mEq/L is objective evidence of compliance. In addition to the somatosensory symptoms, these patients complain that carbonated beverages taste metallic. Patients may rarely become anorectic or depressed. It is unusual for these symptoms to cause a patient to stop taking the medication. Potassium wasting occurs and may require potassium chloride replacement. Furosemide is a chloride reuptake inhibitor and mild carbonic anhydrase inhibitor that may be used in 40- to 160-mg doses divided to a twice daily dose of 20 to 80 mg. The problem of potassium wasting is even greater here but can be controlled. The diuresis may present a practical problem (e.g., an office assistant lost her job because the furosemide caused her to go to the bathroom too frequently), and timing of doses at 7 or 8 AM and 4 to 5 PM will prevent nocturia. These drugs may be used for many months to more than a year. Oral corticosteroids are commonly used and are initially effective, but when given for 2 to 6 weeks and discontinued (a regimen commonly advocated), recurrence of papilledema is the rule. The temptation to prolong the corticosteroid administration takes the patient into 6- to 12-month bouts of chronic steroid use with all of the attendant complications. I avoid the use of steroids altogether. Their administration adds new problems to patient management, and results are ordinarily no better than using acetazolamide or furosemide. Hair loss, further weight gain, abdominal striae, and acne further detract from the patients already low self-esteem.
Surgery
Surgery is considered when the patient is losing vision or has severe, unremitting headaches, unresponsive to medical management. The use of surgery to relieve headache is self-explanatory. However, before surgery is recommended for headache alone, every effort should be made to relieve the headache with standard prophylactic medications such as beta blockers, calcium channel blockers, and tricyclic antidepressants. An LP shunt is effective in relieving headaches but is fraught with problems. An LP shunt is not a recommended technique for relief of CSF pressure in any patient who will subsequently require abdominal surgery (e.g., renal transplantation). The frequency with which LP shunts require revision and their propensity to fail make them treacherous at best. Failure of an LP shunt may precipitate rapid visual failure. Patients with LP shunt require careful long-term follow-up since shunt failure, even many years after placement, may result in abrupt return of papilledema. Acquired Chiari malformation, acquired cervical syrinx, lumbar root irritation, and infections are common complications. ONSF, usually performed by an ophthalmic plastic surgeon, is an effective way of preserving or restoring vision but is not as reliable for the relief of headache. By making a hole in the bulbous anterior dural sheath of the optic nerve, the nerve sheath collapses around the nerve. The sheath no longer fills with CSF under pressure, and development of axoplasmic stasis and papilledema is prevented. The earlier the procedure is performed, and the less severe the visual field loss, the greater the likelihood of success. Severe visual loss frequently fails to respond to ONSF. When a patient loses visual acuity, develops a visual field defect, or has enlargement of a preexisting visual field abnormality, surgery should be undertaken immediatelyearly rather than late. Surgical intervention usually reverses or arrests visual loss. A small percentage of patients, usually those with the worse visual fields, have a poor response to ONSF.
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Bariatric surgery is an answer to massive obesity and works in the long run, but it should not be used in an attempt to rescue failing vision. It is fraught with many complications, and although it is not as gruesome a procedure when done laparoscopically, there are risks. It is not a panacea and should be reserved for those with gigantic body mass index. All surgical procedures reduce CSF pressure and, except for bariatric surgery, are suitable for visual rescue when visual field loss progresses even after maximum medical therapy. Ventriculoperitoneal shunt has gained some popularity since LP shunt has many complications. Image-guided insertion of the ventricular cannula into a normal or small ventricle almost eliminates the risk of placement trauma to the brain and visual pathways. We will hear more about this procedure in the future because it will probably replace LP shunt. Some visual loss is a feature of about one half of all patients with IIH, although serious visual loss is seen in only about 10% to 25%. Most patients have a symptomatic course that lasts 6 to 12 months once the condition is discovered. Recurrence occurs in about 10% of patients and may occur from months to many years later. Spinal fluid pressure remains elevated in 75% to 80% of patients with IIH, even when papilledema is no longer present. Late progression of visual loss without papilledema is unusual and may be evidence of some other ocular disease progress such as glaucoma. Patients with IIH optimally be followed at least once a year after papilledema is gone to be sure that it has not reappeared.
and describes newer approaches to treatment using adjustable shunts.
Diagnosis
The diagnosis of NPH begins either with the clinical presentation or neuroimaging that reveals enlarged ventricles, or both (Figure 1). The classic NPH triad is well known, but the entire triad does not need to be present to consider NPH. On the other hand, most experts in NPH agree that gait impairment ought to be present, and if the gait is entirely normal, then other diagnoses ought to be considered first. Similarly, neuroimaging (either computed tomography [CT] or magnetic resonance [MR] imaging) ought to show ventriculomegaly, meaning that the ventricles are larger than expected for the patients age. This determination is not always easy to make because the ventricles enlarge with age. Periventricular hyperintensity on T2-weighted imaging is common in the elderly population and does not reliably point toward or away from the diagnosis of NPH. In most circumstances, the combination of the clinical presentation and the neuroimaging puts the patient in the category of could be NPH. An important aspect of NPH diagnosis is the differential diagnosis of gait impairment, urinary urgency and incontinence, and dementia, which are among
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NPH symptoms
Ventriculomegaly on neuroimaging
No: unlikely to be NPH

Michael A. Williams, M.D., and Daniele Rigamonti, M.D.
Exclude other treatable conditions
Large volume LP Continuous CSF drainage via spinal catheter
No improvement: consider spinal catheter No improvement: unlikely to be NPH No improvement: adjust shunt setting and reassess in 3 months. If no improvement at lowest setting, evaluate shunt function.
Normal pressure hydrocephalus (NPH) is a syndrome of gait impairment, urinary urgency and incontinence, and dementia that is treatable by surgical diversion of cerebrospinal fluid (CSF) either by a shunt for communicating hydrocephalus or by endoscopic third ventriculostomy for obstructive hydrocephalus. NPH was first described 40 years ago by neurosurgeon Solomon Hakim. Since then, it has enjoyed status as one of the few reversible forms of dementia. However, a persistent challenge for neurologists and neurosurgeons has not necessarily been the treatment but rather the diagnosis. This chapter includes a brief overview of diagnostics approaches used in the United States and Europe
Patient improves: refer to neurosurgeon for shunt surgery
Patient improves: consider shunt adjustment to achieve better response
FIGURE 1. Algorithm for management of normal pressure hydrocephalus (NPH). LP, Lumbar puncture; CSF, cerebrospinal fluid.
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Bariatric surgery is an answer to massive obesity and works in the long run, but it should not be used in an attempt to rescue failing vision. It is fraught with many complications, and although it is not as gruesome a procedure when done laparoscopically, there are risks. It is not a panacea and should be reserved for those with gigantic body mass index. All surgical procedures reduce CSF pressure and, except for bariatric surgery, are suitable for visual rescue when visual field loss progresses even after maximum medical therapy. Ventriculoperitoneal shunt has gained some popularity since LP shunt has many complications. Image-guided insertion of the ventricular cannula into a normal or small ventricle almost eliminates the risk of placement trauma to the brain and visual pathways. We will hear more about this procedure in the future because it will probably replace LP shunt. Some visual loss is a feature of about one half of all patients with IIH, although serious visual loss is seen in only about 10% to 25%. Most patients have a symptomatic course that lasts 6 to 12 months once the condition is discovered. Recurrence occurs in about 10% of patients and may occur from months to many years later. Spinal fluid pressure remains elevated in 75% to 80% of patients with IIH, even when papilledema is no longer present. Late progression of visual loss without papilledema is unusual and may be evidence of some other ocular disease progress such as glaucoma. Patients with IIH optimally be followed at least once a year after papilledema is gone to be sure that it has not reappeared.
and describes newer approaches to treatment using adjustable shunts.
Diagnosis
The diagnosis of NPH begins either with the clinical presentation or neuroimaging that reveals enlarged ventricles, or both (Figure 1). The classic NPH triad is well known, but the entire triad does not need to be present to consider NPH. On the other hand, most experts in NPH agree that gait impairment ought to be present, and if the gait is entirely normal, then other diagnoses ought to be considered first. Similarly, neuroimaging (either computed tomography [CT] or magnetic resonance [MR] imaging) ought to show ventriculomegaly, meaning that the ventricles are larger than expected for the patients age. This determination is not always easy to make because the ventricles enlarge with age. Periventricular hyperintensity on T2-weighted imaging is common in the elderly population and does not reliably point toward or away from the diagnosis of NPH. In most circumstances, the combination of the clinical presentation and the neuroimaging puts the patient in the category of could be NPH. An important aspect of NPH diagnosis is the differential diagnosis of gait impairment, urinary urgency and incontinence, and dementia, which are among
13
NPH symptoms
Ventriculomegaly on neuroimaging
No: unlikely to be NPH

Michael A. Williams, M.D., and Daniele Rigamonti, M.D.
Exclude other treatable conditions
Large volume LP Continuous CSF drainage via spinal catheter
No improvement: consider spinal catheter No improvement: unlikely to be NPH No improvement: adjust shunt setting and reassess in 3 months. If no improvement at lowest setting, evaluate shunt function.
Normal pressure hydrocephalus (NPH) is a syndrome of gait impairment, urinary urgency and incontinence, and dementia that is treatable by surgical diversion of cerebrospinal fluid (CSF) either by a shunt for communicating hydrocephalus or by endoscopic third ventriculostomy for obstructive hydrocephalus. NPH was first described 40 years ago by neurosurgeon Solomon Hakim. Since then, it has enjoyed status as one of the few reversible forms of dementia. However, a persistent challenge for neurologists and neurosurgeons has not necessarily been the treatment but rather the diagnosis. This chapter includes a brief overview of diagnostics approaches used in the United States and Europe
Patient improves: refer to neurosurgeon for shunt surgery
Patient improves: consider shunt adjustment to achieve better response
FIGURE 1. Algorithm for management of normal pressure hydrocephalus (NPH). LP, Lumbar puncture; CSF, cerebrospinal fluid.
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the most common problems of the elderly population. Common conditions that affect gait include peripheral neuropathy; cervical or lumbar stenosis and myelopathy; parkinsonism; and arthritis of the hips, knees, or ankles, to name a few. Urinary incontinence may reflect prostate disease for men or stress incontinence for women. Dementia can be caused by Alzheimer disease, frontotemporal dementia, vascular dementia, or parkinsonism, among others. In practice, the most common mimicking syndrome is vascular dementia because it tends to affect the periventricular areas of the brain that are also affected by NPH. The decision for shunt surgery should be based on more than the clinical presentation and neuroimaging. Ideally, the decision-making goal is to recommend shunt surgery for patients who are highly likely to respond to a shunt and to recommend against shunt surgery for patients who are unlikely to respond to a shunt. Thus, a diagnostic test that demonstrates whether CSF removal will reverse the patients symptoms is advisable before shunt surgery. In other words, it is important to demonstrate the benefit of CSF diversion before surgery so that the expected benefits and the risks of the surgical intervention can be compared and discussed with patients and their families. In the United States, the two most common approaches are (1) to assess the clinical response to a large volume lumbar puncture (LP), meaning 40 to 50 mL of CSF removed via an 18- or 20-gauge spinal needle, and the patients response (especially gait) is examined over the next 4 to 6 hours; and (2) to assess the clinical response to continuous CSF drainage performed by insertion of a temporary spinal catheter for controlled drainage at a rate of 10 mL/hr for 48 to 72 hours, which entails hospitalization and also requires nursing staff who are trained and comfortable managing external CSF drainage. Continuous CSF drainage via spinal catheter is currently performed on a regular basis at only a few centers in the United States. Generally speaking, if there is a definite response to the large-volume LP, then shunt surgery can be recommended. The test is specific, but it is not sensitive. Thus, if there is no response to the large-volume LP, it is possible either that the patient does not have NPH or the patient needs more CSF removal for a longer period before the response is evident. The advantage of continuous CSF drainage is that the test is both sensitive and specific. Patients who respond to this test have a high likelihood of responding to shunt surgery, and those who do not respond to continuous CSF drainage have a low likelihood of responding to shunt surgery, and recommendations can be made accordingly. Spinal catheter insertion carries about a 2% risk of infection (meningitis), and patients should be advised of this in advance. In Europe, the more common approach to diagnosis is to assess CSF outflow resistance by infusion of artificial CSF while making measurements of the CSF pressure response. This test method is well established and has been studied prospectively in the Dutch NPH study and shown to have good predictive value. The test is detailed
and rather complicated to perform, and few centers in the United States use it.
Treatment
Once the decision for shunt surgery has been made, the patient is referred to a neurosurgeon. We have found that there is a significant advantage to having neurologists and neurosurgeons work together to care for patients throughout their entire experience of diagnosis and treatment of NPH. There are at least three main considerations in selecting the shunt: (1) the site of the proximal catheter (i.e., lumbar vs. ventricular); (2) the site of the distal catheter (i.e., peritoneal, atrial, or pleural); and (3) the selection of single-setting versus adjustable valves. We usually recommend a ventricular proximal catheter because the design of most valves makes it easier to investigate shunt problems in this configuration. A few patients strongly prefer not to have the shunt catheter passed through the brain, and in such cases, we use a lumboperitoneal shunt. The distal catheter site depends on the surgeons assessment of the patients anatomy and surgical history. For example, previous abdominal surgical procedures sometimes render the peritoneal cavity less suitable for CSF absorption. In regard to the valve selection, our view is that an important advance in the treatment of NPH has been the introduction of adjustable shunts. These shunts (now made by several different manufacturers) can be adjusted transcutaneously in the outpatient setting by use of a magnetic device. In essence, a magnetic field applied directly over the shunt is used to adjust the tension on a spring-and-ball valve mechanism. The lower the resistance in the mechanism, the more easily CSF will flow. Our experience has been that after the insertion of the shunt, most patients require one or two adjustments to lower the valve resistance and permit more CSF drainage. Without the adjustable shunt mechanism, the only way to change the resistance of the valve is to remove it and replace it with another one surgically. We make adjustments no more frequently than every 2 to 3 months, because it takes time for the patient to respond to the new setting. Similarly, if there is CT or MR imaging evidence of CSF overdrainage (e.g., subdural hygroma), the valve resistance can be increased to reduce CSF flow, which can reduce the size of the hygromas. Patients with adjustable shunts may have MR scans performed, but because the adjustable shunts have a magnetic mechanism, we presume that exposure to the magnetic field of the MR scanner will alter the shunt setting. Our practice is to have the patients come to the clinic within a few days of the MR scan to have the valve reset to its most recent setting. The most common problem of any and all shunts is that they are nothing more than tiny plumbing systems, and as such, they can become obstructed. Generally this is clinically manifested when a patient has initially responded to the shunt and then later develops the
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original NPH symptoms, although sometimes to a lesser degree. Radionuclide shunt patency imaging (injection of a tracer into the shunt reservoir) can demonstrate whether flow through the shunt is blocked or slowed.
Michio Hirano, M.D.
Recovery
Patients with NPH can experience improvement in all symptoms after shunt surgery, including gait impairment, urinary urgency and incontinence, and dementia. The ultimate extent of their recovery is determined by the comorbid conditions and by the degree of irreversible cerebral injury from the NPH itself. For example, patients with both NPH and bladder or prostate disease may not achieve as much improvement in urinary urgency or incontinence as hoped for, or patients with arthritis affecting the legs or lumbosacral spine may not have as much improvement in gait as desired. In such circumstances, the symptoms that lag in response may deserve further evaluation for other treatable causes. Because none of the diagnostic tests available has 100% sensitivity or specificity, there are patients who will not have improvement of any of their symptoms after shunt surgery. In these cases, before we conclude the patient does not have NPH, we will determine whether the shunt is functioning as expected (e.g., radionuclide shunt patency study) and revise the shunt if it is not functioning properly. In the uncommon instances in which the shunt is functioning and the patient has not improved, then we can conclude that either the patient does not have NPH or that the comorbid conditions are severe enough that treatment of the NPH cannot overcome the symptoms. SUGGESTED READING
Boon AJ, Tans JT, Delwel EJ, et al: Dutch normal-pressure hydrocephalus study: prediction of outcome after shunting by resistance to outflow of cerebrospinal fluid, J Neurosurg 87:687-693, 1997. Drake JM, Sainte-Rose C: The shunt book, Boston, 1995, Blackwell Science. Duinkerke A, Williams MA, Rigamonti D, Hillis AE: Cognitive recovery in idiopathic normal pressure hydrocephalus. Cogn Behav Neurol 17:179-184, 2004. Williams MA, Razumovsky AY, Hanley DF: Comparison of Pcsf monitoring and controlled CSF drainage diagnose normal pressure hydrocephalus, Acta Neurochir Suppl 71:328-330, 1998.
Mitochondrial encephalomyopathies encompass clinically diverse disorders that are grouped together because they are due to defects in the respiratory chain (oxidative phosphorylation [OXPHOS]). OXPHOS is the final common biochemical pathway of mitochondrial energy metabolism that allows the conversion of fatty acids, carbohydrates, and amino acids to H2O and CO2. OXPHOS can be impaired by genetic and environmental factors, such as medications, leading to nervous system and muscle disorders.
Mitochondrial Biochemistry and Genetics

OXPHOS requires a coordinated transfer of electrons through four multi-subunit enzymes (complexes I to IV) that generate a proton gradient across the inner mitochondrial membrane. The electrochemical gradient is used by complex V to produce adenosine triphosphate (ATP). Four OXPHOS enzymes (complexes I, III to V) contain subunits encoded in both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA), whereas subunits of complex II are encoded in nDNA only. The dual genetic origins of OXPHOS enzymes account for several unusual characteristics of mitochondrial encephalomyopathies. mtDNA is a small (16.6 kilobase [kb]) doublestranded circular molecule that encodes only 37 genes: 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs), and 13 polypeptides that are subunits of the OXPHOS enzymes. In contrast to nDNA, which comprises paired autosomal and sex chromosomes in each cell, mtDNA is present in hundreds to thousands of copies per cell. Alterations of mtDNA may be present in some of the molecules (heteroplasmy) or in all (homoplasmy). Most mtDNA mutations are heteroplasmic. When the proportion of an mtDNA mutation exceeds a critical level, OXPHOS is compromised (threshold effect). The proportion of an mtDNA mutation can vary from organ to organ (tissue distribution). Because brain and skeletal muscle have high-energy requirements, mitochondrial disorders commonly manifest as encephalomyopathies. The tissue distribution of mtDNA mutations is determined by the dispersion of the genomes during mitosis (mitotic segregation). The mitochondrial genome is inherited through mothers (maternal inheritance). Therefore, mtDNA mutations are passed from mothers to all of their children, but only daughters and not sons are able to transmit the mutations to their children. Curiously, single deletions of mtDNA occur sporadically and are rarely maternally transmitted. 13
PATIENT RESOURCE
The Hydrocephalus Association http://www.hydroassoc.org/
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original NPH symptoms, although sometimes to a lesser degree. Radionuclide shunt patency imaging (injection of a tracer into the shunt reservoir) can demonstrate whether flow through the shunt is blocked or slowed.
Michio Hirano, M.D.
Recovery
Patients with NPH can experience improvement in all symptoms after shunt surgery, including gait impairment, urinary urgency and incontinence, and dementia. The ultimate extent of their recovery is determined by the comorbid conditions and by the degree of irreversible cerebral injury from the NPH itself. For example, patients with both NPH and bladder or prostate disease may not achieve as much improvement in urinary urgency or incontinence as hoped for, or patients with arthritis affecting the legs or lumbosacral spine may not have as much improvement in gait as desired. In such circumstances, the symptoms that lag in response may deserve further evaluation for other treatable causes. Because none of the diagnostic tests available has 100% sensitivity or specificity, there are patients who will not have improvement of any of their symptoms after shunt surgery. In these cases, before we conclude the patient does not have NPH, we will determine whether the shunt is functioning as expected (e.g., radionuclide shunt patency study) and revise the shunt if it is not functioning properly. In the uncommon instances in which the shunt is functioning and the patient has not improved, then we can conclude that either the patient does not have NPH or that the comorbid conditions are severe enough that treatment of the NPH cannot overcome the symptoms. SUGGESTED READING
Boon AJ, Tans JT, Delwel EJ, et al: Dutch normal-pressure hydrocephalus study: prediction of outcome after shunting by resistance to outflow of cerebrospinal fluid, J Neurosurg 87:687-693, 1997. Drake JM, Sainte-Rose C: The shunt book, Boston, 1995, Blackwell Science. Duinkerke A, Williams MA, Rigamonti D, Hillis AE: Cognitive recovery in idiopathic normal pressure hydrocephalus. Cogn Behav Neurol 17:179-184, 2004. Williams MA, Razumovsky AY, Hanley DF: Comparison of Pcsf monitoring and controlled CSF drainage diagnose normal pressure hydrocephalus, Acta Neurochir Suppl 71:328-330, 1998.
Mitochondrial encephalomyopathies encompass clinically diverse disorders that are grouped together because they are due to defects in the respiratory chain (oxidative phosphorylation [OXPHOS]). OXPHOS is the final common biochemical pathway of mitochondrial energy metabolism that allows the conversion of fatty acids, carbohydrates, and amino acids to H2O and CO2. OXPHOS can be impaired by genetic and environmental factors, such as medications, leading to nervous system and muscle disorders.
Mitochondrial Biochemistry and Genetics

OXPHOS requires a coordinated transfer of electrons through four multi-subunit enzymes (complexes I to IV) that generate a proton gradient across the inner mitochondrial membrane. The electrochemical gradient is used by complex V to produce adenosine triphosphate (ATP). Four OXPHOS enzymes (complexes I, III to V) contain subunits encoded in both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA), whereas subunits of complex II are encoded in nDNA only. The dual genetic origins of OXPHOS enzymes account for several unusual characteristics of mitochondrial encephalomyopathies. mtDNA is a small (16.6 kilobase [kb]) doublestranded circular molecule that encodes only 37 genes: 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs), and 13 polypeptides that are subunits of the OXPHOS enzymes. In contrast to nDNA, which comprises paired autosomal and sex chromosomes in each cell, mtDNA is present in hundreds to thousands of copies per cell. Alterations of mtDNA may be present in some of the molecules (heteroplasmy) or in all (homoplasmy). Most mtDNA mutations are heteroplasmic. When the proportion of an mtDNA mutation exceeds a critical level, OXPHOS is compromised (threshold effect). The proportion of an mtDNA mutation can vary from organ to organ (tissue distribution). Because brain and skeletal muscle have high-energy requirements, mitochondrial disorders commonly manifest as encephalomyopathies. The tissue distribution of mtDNA mutations is determined by the dispersion of the genomes during mitosis (mitotic segregation). The mitochondrial genome is inherited through mothers (maternal inheritance). Therefore, mtDNA mutations are passed from mothers to all of their children, but only daughters and not sons are able to transmit the mutations to their children. Curiously, single deletions of mtDNA occur sporadically and are rarely maternally transmitted. 13
PATIENT RESOURCE
The Hydrocephalus Association http://www.hydroassoc.org/
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Mitochondrial Diseases (Table 1)

DISORDERS CAUSED BY MITOCHONDRIAL DNA MUTATIONS More than 150 point mutations of mtDNA have been reported in patients with diverse clinical presentations. About 60% of the mutations have been identified in tRNA genes and therefore impair mitochondrial protein synthesis. The most prominent phenotypes are mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS) and myoclonus epilepsy with ragged-red fibers (MERRF). Both disorders are maternally inherited and are associated with lactic acidosis and abnormal mitochondrial proliferation that manifest as ragged-red fibers (RRFs) in skeletal muscle
stained with the modified Gomori trichrome technique. Clinically, MELAS is characterized by stroke-like episodes that are atypical because they usually affect young people (typically < 40 years of age) and generally affect cortex and subjacent white matter and therefore do not conform to the distributions of large cerebral arteries. In contrast, MERRF is clinically defined by myoclonus epilepsy and often manifests ataxia. Approximately 80% of MELAS patients have an A3243G mutation in the tRNALeu(UUR) gene, whereas about 80% of MERRF patients have an A8344G mutation in the tRNALys gene. In contrast with tRNA defects, many mtDNA mutations in polypeptide-coding genes often do not show RRFs as exemplified by patients with Leber hereditary optic neuropathy, a maternally inherited
TABLE 1 Clinical Definitions of Mitochondrial Encephalomyopathies

Disorders Disorders due to MtDNA Mutations Kearns-Sayre syndrome Characteristics 1. Onset < 20 yr of age 2. Ophthalmoparesis 3. Pigmentary retinopathy Plus, at least one of the following: CSF protein > 100 mg/dL, cardiac conduction block, ataxia 1. Stroke at a young age (typically < 40 yr of age) 2. Encephalopathy (seizures, dementia, or both) 3. Ragged-red fibers, lactic acidosis at rest, or both 1. Myoclonus, or myoclonic epilepsy 2. Cerebellar syndrome 3. Ragged-red fibers 1. Neurogenic weakness 2. Cerebellar syndrome 3. Pigmentary retinopathy Painless subacute optic neuropathy Maternal inheritance, but typically affects young men Onset typically in infancy or childhood, but can occur in adulthood; typically < 6 mo of age in a previously normal infant Developmental arrest or regression, hypotonia, feeding difficulty, respiratory abnormalities, vision loss, oculomotor palsies, and nystagmus Brain MR imaging reveals symmetric lesions of the basal ganglia and midline brainstem Ptosis and PEO generally typically beginning in young adulthood Multiple deletions of mtDNA Myopathic form Hepatopathy 1. 2. 3. 4. 5. 6. Ophthalmoparesis, ptosis, or both Peripheral neuropathy Gastrointestinal dysmotility Cachexia Leukoencephalopathy on brain imaging Mitochondrial myopathy Myopathic form: myoglobinuria, encephalopathy (seizures or mental retardation), RRF in muscle biopsy Cerebellar form: cerebellar ataxia with prominent cerebellar atrophy in brain MR imaging scans Infantile encephalomyopathy with visceral organ involvement
Mitochondrial encephalopathy, lactic acidosis and strokelike episodes (MELAS) syndrome Myoclonus epilepsy ragged-red fibers (MERRF) syndrome Neuropathy, ataxia, retinitis pigmentosa syndrome
Leber hereditary optic neuropathy Disorders due to Nuclear DNA Mutations Leighs syndrome
Autosomal dominant or recessive progressive external ophthalmoplegia (asPEO) mtDNA depletion syndromes Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)
Coenzyme Q10 deficiency
RRF, Ragged-red fiber; mtDNA, mitochondrial DNA; CSF, cerebrospinal fluid.
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disorder that causes subacute loss of central or cecocentral vision usually in one eye followed within days to months by loss of vision in the second eye. LHON commonly manifests in young men. Three mtDNA point mutations in genes encoding subunits of respiratory chain complex I account for more than 90% of patients with LHON. In most LHON patients, the mtDNA mutations are homoplasmic. Two other disorders caused by mutations in a polypeptide-coding gene is neuropathy, ataxia, and retinitis pigmentosa (NARP) and maternally inherited Leighs syndrome (MILS); both are due to mutations in subunit 6 of complex V (ATPase 6). When the levels of mutation are 70% to 90%, patients develop NARP, but when greater than 90%, infants develop MILS, a devastating necrotizing encephalopathy that affects deep gray matter structures including basal ganglia and periaqueductal neurons. In contrast to LHON, NARP, and MILS, which are maternally inherited disorders of the nervous system without RRFs, sporadic patients have presented with pure myopathies manifesting as exercise intolerance, sometimes associated with recurrent myoglobinuria. The patients have had lactic acidosis, RRFs, or both, and most have had mtDNA mutations in the gene encoding cytochrome b, a component of complex III. An mtDNA point mutation in an rRNA gene causes maternally inherited aminoglycoside-induced deafness and nonsyndromic deafness. In addition to point mutations, large-scale mtDNA rearrangements (single deletions, duplications, or both) have been identified in patients with progressive external ophthalmoplegia (PEO) or Kearns-Sayre syndrome (KSS), a multisystem disorder characterized by PEO, ptosis, pigmentary retinopathy, cardiac conduction block, elevated cerebrospinal fluid (CSF) protein, and cerebellar ataxia. Some individuals with mtDNA rearrangements have developed Pearsons syndrome manifesting as sideroblastic anemia and pancreatic exocrine insufficiency. All three disorders are typically sporadic and can be caused by identical mutations that differ in tissue distribution and heteroplasmy as exemplified by infants who initially have high proportions of an mtDNA deletion in bone marrow and pancreas causing Pearsons syndrome. Individuals who survive the severe anemia develop PEO or KSS as the proportion of the mtDNA mutation decreases in replicating hematopoietic and pancreas cells and increases in postmitotic muscle cells. In fact, most patients with PEO or KSS have no detectable mtDNA deletions in blood. DISORDERS CAUSED BY NUCLEAR DNA MUTATIONS Only 13 subunits of OXPHOS enzymes are encoded by mtDNA, whereas more than 70 are encoded by nDNA. Consequently, disorders of respiratory chain enzymes can be inherited in mendelian or sex-linked patterns and most commonly present as Leighs syndrome. Mutations in nuclear encoded subunits of complex I or II cause autosomal recessive Leighs syndrome. In contrast, mutations in ancillary proteins required for the assembly of complex III, IV, or V cause Leighs syndrome
as well as other disorders affecting brain, skeletal muscle, heart, liver, and kidney. A subset of autosomal mitochondrial disorders are caused by primary mutations in nDNA that adversely affect the integrity of the mtDNA and lead to depletion, multiple deletions, and multiple point mutations of mtDNA. Among these disorders is mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) a multisystem autosomal recessive disease. MNGIE is caused by mutations in thymidine phosphorylase, an enzyme that is required for nucleoside homeostasis. Defects of thymidine phosphorylase lead to accumulation of nucleosides that are hypothesized to unbalance nucleotide pools to cause aberrant mtDNA replication. Additional defects of mitochondrial nucleoside/nucleotide metabolism have been identified in patients with mtDNA depletion syndrome, which generally presents in infancy with variable combinations of myopathy, hepatopathy, and encephalopathy. Furthermore, autosomal dominant or recessive progressive external ophthalmoplegia with multiple deletions of mtDNA is caused by mutation in the mtDNA polymerase, twinkle (a putative mtDNA helicase), and skeletal and heart musclespecific adenine nucleotide translocator 1. DRUG-INDUCED MITOCHONDRIAL DISORDERS Depletion of mtDNA can also be caused by nucleoside analogs such as zidovudine (AZT), zalcitabine (ddCyd), and didanosine (ddI), which are used frequently to treat human immunodeficiency virus infection. Zidovudine has been associated with a myopathy characterized by RRF and mtDNA depletion. The condition resolves after discontinuing the drug.
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Therapy
SYMPTOMATIC TREATMENT Therapies for mitochondrial encephalomyopathies primarily focus on ameliorating clinical manifestation rather than therapies to correct the underlying biochemical and genetic defects.
CENTRAL NERVOUS SYSTEM. Seizures should be treated
aggressively in mitochondrial encephalopathy patients because they may aggravate the underlying metabolic abnormalities. Conventional anticonvulsant drugs are usually effective. Although valproic acid is often used to treat myoclonus epilepsy, it should be administered with caution and with L-carnitine because valproate inhibits carnitine uptake. Zonisamide is often effective for myoclonus epilepsy due to mitochondrial encephalomyopathies. Acute strokes in MELAS may have associated edema that can be severe; therefore, high-dose steroids may be beneficial, although they may provoke diabetes mellitus.
EYE. In patients with ptosis that is cosmetically unacceptable or obscures vision, slings connecting
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the tarsal plate of the upper eyelid to the frontalis muscle are often beneficial and may be less likely to cause exposure keratitis than would blepharoplasty. Cataracts may require surgery.
EAR, NOSE, AND THROAT. Sensorineural hearing loss is one of the most common symptoms in mitochondrial encephalomyopathies. Hearing aids are helpful. In MELAS patients with severe cochlear dysfunction, cochlear implants have been successful. Dysphagia due to palatal muscle weakness is a common symptom and can be ameliorated by dietary modification. Swallow studies can be useful to assess patients risks of aspiration. HEMATOLOGIC SYSTEM. In Pearsons syndrome, sideroblastic anemia may respond to blood transfusions. Although the anemia often resolves, children often develop PEO or KSS later in life. ENDOCRINE SYSTEM. Diabetes mellitus, which may be insulin dependent, should be treated. Hypothyroidism is often a manifestation of mitochondrial encephalomyopathies and responds to thyroid hormone. Hypoparathyroidism is sometimes present in patients with KSS. Growth hormone deficiency sometimes contributes to the short stature of patients; however, replacement therapy is controversial because it may detrimentally increase metabolic demand in tissues with compromised energy metabolism. HEART. In KSS patients with cardiac conduction blocks,
blood, CSF, or both. Treatment of elevated lactate with bicarbonate has only transient buffering effects and may exacerbate cerebral symptoms. A more specific and longer lasting therapy for lactic acidosis is dichloracetate (DCA), which inhibits phosphorylation of pyruvate dehydrogenase complex, thus maintaining the enzyme in the active dephosphorylated state. The efficacy of DCA for mitochondrial encephalomyopathies is being tested in clinical trials. The drug is not commercially available and can cause peripheral neuropathy and hepatopathy.
ADMINISTRATION OF ALTERNATE ELECTRON ACCEPTORS. As an attempt to bypass the OXPHOS block, patients with complex III deficiencies have been given high doses of alternative electron acceptorsmenadiol diphosphate, precursor of vitamin K3 (40 mg daily) and vitamin C (4 gm daily). These compounds have redox potentials that are predicted to fit the gap produced by complex III deficiency; unfortunately, the documented improvement in one patient was only transient. ADMINISTRATION OF METABOLITES AND COFACTORS. It is com-
insertion of a pacemaker can be life saving. In patients with severe cardiomyopathies in isolation or with relatively mild multisystem disorders, cardiac transplantation has been successfully performed.
GASTROINTESTINAL SYSTEM. Infants with Leighs syndrome often develop severe feeding problems before neurologic symptoms become apparent. Gastroesophageal reflux and recurrent vomiting are common symptoms and may be relieved by drugs or surgical intervention (gastric fundoplication). Severe gastrointestinal dysmotility is a clinical hallmark of MNGIE and is sometimes associated with MELAS. Gastrostomy or parenteral nutrition can be beneficial in patients with severe gastrointestinal dysmotility. Exocrine pancreas dysfunction, a feature of Pearsons syndrome, responds to enzyme replacement. KIDNEY. Renal tubular acidosis and Fanconis syndrome require therapies to restore electrolyte balance. Patients with myopathies and recurrent myoglobinuria require aggressive hydration to prevent renal damage or dialysis during periods of severe muscle breakdown. MYOPATHY. Mitochondrial encephalomyopathy patients
mon practice to recommend vitamins and cofactors, usually as a cocktail, to patients with mitochondrial encephalomyopathies (Table 2). Nevertheless, the rationale for most of these compounds is based on the hypothetical argument that they are normal components of the respiratory chain and, if given as supplements, may enhance OXPHOS. For example, riboflavin (vitamin B2) is a precursor for cofactors required by complexes I and II. Riboflavin and nicotinamide treatment of a MELAS patient (with the A3243G mtDNA mutation) was associated with less frequent episodes of encephalopathy. The administration of micronutrients is better justified for vitamins and cofactors that have been demonstrated to be deficient in mitochondrial encephalomyopathy patients. In KSS patients, folate concentrations have been lower than normal in blood and CSF; therefore, administration of folic acid or folinic acid is rational. Similarly, free carnitine in blood of mitochondrial
TABLE 2 Vitamins and Cofactors for Mitochondrial Encephalomyopathies

Agents Vitamins Thiamin (vitamin B1) Riboflavin (vitamin B2) Menadione (vitamin K3) Antioxidants Vitamin C Vitamin E Coenzyme Q10 Alpha lipoic acid Idebenone Other
L -Carnitine
Dosage
50-200 mg daily 50-600 mg daily 5-80 mg daily 100-4000 mg daily 200-1200 I.U. daily 150-3000 mg daily Up to 400 mg tid 45-360 mg tid Up to 1000 mg tid 1-10 mg daily
are often deconditioned; therefore, moderate exercise can improve muscle function. SPECIFIC APPROACHES TO TREATMENT
REMOVAL OF NOXIOUS METABOLITES. Respiratory chain defects
cause accumulations of lactate, pyruvate, and alanine in
Folate
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encephalomyopathy patients is often lower than normal, but esterified carnitine tends to be increased. This shift may be due to reduced fatty acid metabolism through beta oxidation, which feeds electrons into coenzyme Q10 (CoQ10) in the respiratory chain. Therefore, restoration of normal free-carnitine levels may be achieved by oral supplementation of L-carnitine (1000 mg three times daily). Carnitine is usually taken with CoQ10 (50 to 200 mg three times daily), to improve respiratory chain functions and to function as an antioxidant to scavenge reactive oxygen species (ROS). Patients with primary deficiencies of carnitine or CoQ10 often respond dramatically to supplementation therapy. Primary carnitine deficiency is an autosomal recessive disorder of plasma membrane carnitine transport and typically presents in infancy as a progressive cardiomyopathy. With carnitine supplementation, this cardiomyopathy resolves within a few months. Primary CoQ10 deficiency is apparently autosomal recessive and probably due to diverse genetic causes. There are three major forms: (1) myopathy with recurrent myoglobinuria, RRFs and encephalopathy manifesting as seizures, ataxia, or mental retardation; (2) ataxia with cerebellar atrophy and often associated neuropathy, pyramidal tract signs, seizures, or mental retardation; and (3) encephalomyopathy with visceral organ involvement. All three forms improve with CoQ10 supplementation.
ADMINISTRATION OF ANTIOXIDANTS. Defects of OXPHOS, particularly deficiencies of complex I or III, can cause increased production of toxic ROS that damage lipids, DNA, and proteins. CoQ10, idenbenone (a synthetic quinone compound similar to CoQ10), alpha lipoic acid, and vitamins C and E have been administered as antioxidants to prevent ROS-mediated damage. Anecdotal reports have suggested beneficial effects of antioxidants in mitochondrial encephalomyopathies; however, doubleblind, randomized, placebo-controlled trials have not proved the efficacy of these compounds in patients.
sampling of amniocytes or chorionic villi may not be predictive of the mutation load in the fetus. Second, the heteroplasmy of the mutation may shift in the fetus during pregnancy or postnatally due to mitotic segregation. In particular, levels of tRNA mutations are particularly variable in patients with MELAS. Nevertheless, for homoplasmic mtDNA mutations, prenatal testing is feasible. In addition, ATPase 6 mutations that cause NARP and MILS show less tissue and age-related variations in heteroplasmy; therefore, prenatal identification of very high levels of these mutations would predict that the infant will be severely affected. In fact, prenatal testing has been successfully performed in one pregnancy and the high level of the ATPase 6 mutation identified through amniocentesis was confirmed in the fetus. Theoretically, pronuclear transfer could be used to reduce or eliminate the mutant mtDNA in oocytes from women with pathogenic mutations. In this procedure, nuclei from oocytes containing mtDNA mutations are extracted and placed into enucleated donor oocytes with normal mtDNA. Thus, the oocyte would contain presumably normal nDNA of the mother without her mutant mtDNA. Acknowledgments Dr. Hiranos work is supported by NIH grants (P01NS11766 and R01HD37529) and by a Muscular Dystrophy Association grant. SUGGESTED READING
DiMauro S, Schon EA: Mitochondrial respiratory chain diseases, N Engl J Med 348:2656-2668, 2003. Hirano M: Mitochondrial disorders due to mutations in the nuclear genome. In Rosenberg RN, Prusiner SB, DiMauro S, et al, editors: The molecular and genetic basis of neurologic and psychiatric disease, ed 3, Boston, 2003, Butterworth-Heinemann, 197-204. Schon EA, DiMauro S: Medicinal and genetic approaches to the treatment of mitochondrial disease, Curr Med Chem 10:25232533, 2003.
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Genetic Counseling
Prenatal testing is feasible for autosomal mitochondrial encephalomyopathies with known genetic causes. Of course, it is not possible to perform prenatal testing for autosomal recessive conditions before an affected individual is born; however, subsequent fetuses can be screened. In contrast, prenatal testing for mtDNA-based mitochondrial disorders has pitfalls. Because most pathogenic mtDNA mutations are heteroplasmic and therefore may show variations in levels from tissue-to-tissue,
PATIENT RESOURCES
Muscular Dystrophy AssociationUSA National Headquarters 3300 E. Sunrise Drive Tucson, AZ 85718 Phone: 800-572-1717 http://www.mdausa.org/ United Mitochondrial Disease Foundation 8085 Saltsburg Road, Suite 201 Pittsburgh, PA 15239 Phone: 412-793-8077 Fax: 412-793-6477 http://www.umdf.org/
SECTION 14
Toxins and Deficiency Diseases

John C. M. Brust, M.D.
Ethanol taken with other drugs, including barbiturates, benzodiazepines, other sedatives, antidepressants, neuroleptics, and opioids, can produce additive or even synergistic intoxication. Ethanol intoxication can mask the presence of meningitis, head trauma, hepatic encephalopathy, WernickeKorsakoff disease, and other disorders that commonly affect alcoholics.
Ethanol Intoxication
By blocking glutamatergic neurotransmission and facilitating gamma aminobutyric acid (GABA)-ergic neurotransmission, ethanol is a central nervous system depressant; hyperactivity and euphoria associated with intoxication reflect cerebral disinhibition, and severe intoxication can cause coma, apnea, and death. Signs of intoxication are greater when blood ethanol concentrations are rising than when they are falling, and heavy drinkers tend to be tolerant to ethanol; the correlations shown in Table 1 represent broad generalizations. These considerations mean that sedatives should be avoided in intoxicated patients who are hyperactive or even violent, for sedation can progress rapidly to coma (Table 2). For patients who are stuporous or comatose, treatment is similar to that of other depressant drugs. Hypoventilation requires intubation and artificial ventilation in an intensive care unit. Hypoglycemia is often present, and if the serum glucose level is unknown, 50% glucose is given. Thiamine and multivitamins are given to all patients. Blood pressure and cardiac status are monitored, and hypovolemia and acid-base or electrolyte imbalances are corrected. Ethanols rapid gastric absorption makes gastric lavage impractical unless other drugs have been ingested. Stimulants such as amphetamine or caffeine can precipitate seizures or cardiac arrhythmia. Ethanol is metabolized at a rate that lowers blood ethanol concentrations by only 10 to 25 mg/dL per hour, and so intoxication can last many hours. For patients with extremely high ethanol levels, apnea, or marked acidosis, hemodialysis should be considered.
Ethanol Withdrawal
Chronic ethanol use is associated with both psychic dependence (addiction) and physical dependence, the latter producing symptoms and signs that emerge within hours or a few days of abstinence. Early symptoms (within 48 hours of withdrawal) include tremor (coarse, distal, rapid, and worse with movement), hallucinosis (visual, auditory, or both, with variable insight), and seizures (generalized tonic-clonic, usually single or in a brief cluster and without focal signature, although sometimes progressing to status epilepticus). Without treatment a minority of patients with early withdrawal symptoms will progress to delirium tremens, consisting of not only tremor and hallucinations but also delirium (extreme inattentiveness and unawareness of the environment, often with agitation and fluctuating levels of alertness) and autonomic overactivity. (Seizures are not a feature of delirium tremens, and their presence mandates a search for an additional diagnosis such as meningitis.) Delirium tremens tends to begin and end abruptly, lasting hours or a few days. A fatal outcome is not unusual, most often attributable to sepsis, liver failure, or other ethanol-related disorder but sometimes occurring without warning. Ethanol withdrawal is most appropriately treated with pharmacologic agents that have cross-tolerance with ethanoli.e., benzodiazepines or barbiturates (Table 3). (Ethanol itself is inappropriate; parenterally it has a low margin of safety, and it is directly neurotoxic.) Early mild symptomstremor, anxietyrespond to longacting benzodiazepines, taken orally and tapered over several days. More severe symptoms require parenteral 343
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TABLE 1 Correlation of Symptoms with Blood Ethanol Concentration

Blood Ethanol Concentration, mg/dL 50-150
TABLE 3 Treatment of Ethanol Withdrawal

Prevention or Reduction of Early Mild Symptoms Chlordiazepoxide 25-100 mg or diazepam 5-20 mg PO q8 hr for the first day, tapering over 3-6 days Thiamine 100 mg and multivitamins For More Severe Symptoms, Including Delirium Tremens Diazepam 10 mg IV or lorazepam 2 mg IV or IM, repeated q 5-15 min until calming and normalization of vital signs. Maintenance doses q 1-4 hr prn If refractory to benzodiazepines, phenobarbital 260 mg IV repeated in 30 min prn If refractory to phenobarbital, pentobarbital 3-5 mg/kg IV, with endotracheal intubation and repeated doses to produce general anesthesia Careful attention to fluid and electrolyte balance; several liters of saline per day, or even pressors, may be needed Cooling blanket or alcohol sponges for high fever Prevent or correct hypoglycemia Administer thiamine and multivitamins Consider coexisting illness, e.g., liver failure, pancreatitis, sepsis, meningitis, or subdural hematoma
From Brust JCM: Neurological aspects of substance abuse, ed 2, Woburn, MA, 2004, Butterworth Heinemann.
Symptoms Euphoria or dysphoria, shyness or expansiveness, friendliness or argumentativeness Impaired concentration, judgment, and sexual inhibitions Slurred speech and ataxic gait, diplopia, nausea, tachycardia, drowsiness, or labile mood with sudden bursts of anger or antisocial acts Stupor alternating with combativeness or incoherent speech, heavy breathing, vomiting Coma Respiratory paralysis, death
150-250
300 400 500
benzodiazepine administration, and lorazepam, which, unlike diazepam, can be given either intramuscularly or intravenously, and which has a more prolonged anticonvulsant action, is the drug of choice. Neuroleptics are not used for hallucinations: they are not cross-tolerant with ethanol; they lower seizure threshold; they cause hypotension, dystonia, and liver damage; and they impair thermoregulation. (An exception might be a patient whose only symptoms are hallucinations, especially when accompanied by delusions, or whose hallucinations have outlasted other withdrawal symptoms.) Phenytoin is
TABLE 2 Treatment of Acute Ethanol Intoxication

For Obstreperous or Violent Patients Isolation, calming environment, reassuranceavoid sedatives Close observation For Stuporous or Comatose Patients If hypoventilation, artificial respiration in an intensive care unit If serum glucose in doubt, 50% glucose IV Thiamine, 100 mg, and multivitamins, IM or IV Careful monitoring of blood pressure; correction of hypovolemia or acid-base imbalance Consider hemodialysis if patient severely acidotic, deeply comatose, or apneic Avoid emetics or gastric lavage Avoid analeptics Do not forget other possible causes of coma in an alcoholic, as well as concomitant drug use
ineffective in preventing ethanol withdrawal seizures, which are unlikely to occur (or recur) with benzodiazepine treatment. Status epilepticus, on the other hand, is treated in standard fashion. Hypomagnesemia, often present during early withdrawal, is treated with magnesium sulfate. Hypokalemia and hypocalcemia, also often present, may not respond to replacement until hypomagnesemia is corrected. In contrast to early withdrawal, delirium tremens cannot be abruptly reversed by any agent, including sedatives cross-tolerant with ethanol. Treatment of delirium tremens is an emergency sometimes requiring huge doses of parenteral sedatives. Patients should be prone or in lateral decubitus position and restrained as needed. In some patients symptoms are refractory to benzodiazepines, requiring a switch to barbiturates. Respiratory depression must be anticipated, and hepatic encephalopathy can be precipitated, resulting in coma that outlasts delirium tremens by days. During delirium tremens fluid loss can be severe, requiring replacement of several liters per day. Hyponatremia is especially likely if liver failure is present, and its overcorrection can cause central pontine myelinolysis. Hypokalemia can cause cardiac arrhythmia. Very high fever may require a cooling blanket or even parenteral cooling. As with ethanol intoxication, all patients treated for ethanol withdrawal should receive thiamine and multivitamins, and the possible coexistence of other ethanolrelated illnesses such as hypoglycemia, liver failure, pancreatitis, sepsis, meningitis, or subdural hematoma should be a constant consideration.
Wernickes Disease and Korsakoffs Psychosis
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Wernickes Disease and Korsakoffs Psychosis

Robert Laureno, M.D., and Sara E. Benjamin, M.D.
Wernickes disease is the brain disorder due to thiamine deficiency. Its characteristic clinical manifestations are abnormalities of mentation, eye movement, and ambulation. The mental derangement is an acute or subacute state of apathy and confusion, one component of which is impaired memory. When there is clearing of global confusion but there is persistence of a dementia, which disproportionately affects memory, the mental condition is known as Korsakoffs psychosis or Korsakoffs amnesic state. (Hence Raymond Adams, Maurice Victor, and their collaborators have used the encompassing term Wernicke-Korsakoff syndrome.) The typical oculomotor features of Wernickes disease are nystagmus, abducens palsy, and/or gaze palsy. Occasionally there may be internuclear ophthalmoplegia or even total ophthalmoplegia. The third feature of Wernickes disease is ataxia of gait. In a given patient, one or another of these manifestations may be mild or severe, and one or another may dominate the clinical picture. In advanced Wernickes disease, orthostatic hypotension, hypothermia, and stupor or coma may occur. Commonly associated with Wernickes disease is nutritional peripheral polyneuropathy. Thiamine plays an essential coenzyme role in intermediary carbohydrate metabolism. Wernickes disease occurs when thiamine stores are insufficient to support the metabolism of carbohydrates. On neuropathologic examination there is symmetric damage to the neuropil in affected brain regions, typically the periaqueductal gray matter, the walls (medial aspect of each thalamus) and floor (mamillary bodies) of the third ventricle, the floor of the fourth ventricle (tegmentum), and the midline cerebellum. There can be neuronal loss and/or petechial hemorrhage depending on the severity and acuteness of the disease.
after treatment with thiamine; horizontal nystagmus can decrease in hours or days. When Wernickes disease is severe, acute lesions can be detected on magnetic resonance (MR) imaging scans (increased signal in the symmetrically affected territories, especially the medial thalamic regions). However, the MR scan is not a sensitive test for this disease. We have not used testing for red blood cell transketolase, which, when decreased, supports the diagnosis of Wernickes disease. Blood thiamine levels are not useful. When treating a patient for possible Wernickes disease, one must be cautious to exclude other cerebral, cerebellar, and brainstem disorders that can mimic aspects of this disease. Furthermore, the unequivocal presence of Wernickes encephalopathy does not exclude coexisting neurologic disease. The alcoholic is vulnerable to so many central nervous system disorders that the clinician must be vigilant in this regard. Brain imaging, like examination of cerebrospinal fluid, is typically more useful in documenting or excluding other neurologic disorders than in proving the diagnosis of Wernickes disease.
Treatment
Treatment of Wernickes disease is a medical emergency. When thiamine deficiency is prolonged, the encephalopathy can evolve into Korsakoffs psychosis. That amnestic state is often irreversible. Following the method of Victor and colleagues, we prescribe thiamine 50 mg intravenously and 50 mg intramuscularly; multivitamins are simultaneously given by vein. On subsequent days, parenteral thiamine, 100 mg, is given, and multivitamins are continued. (A parenteral route is used because absorption of orally administered thiamine is reduced in alcoholic patients.) After the patient has been able to consume a balanced diet for several days, thiamine supplementation may be discontinued. Prescription of oral multivitamins should be continued indefinitely. The physician should provide thiamine not only when the diagnosis of Wernickes disease is clear but also whenever the diagnosis of Wernickes disease is a possibility. In our experience, an occasional patient may have symptoms without signs (i.e., incipient or smoldering Wernickes disease). When a patient is malnourished or is at risk for being malnourished, a complaint of imbalance or dizziness should raise concern. Such symptoms in a patient who has undergone gastric surgery for obesity, for example, should prompt inquiry as to whether the patient has been taking the appropriate supplementary B vitamins. Any encephalopathy in a setting that predisposes to Wernickes disease should prompt treatment with thiamine, even in the absence of neuro-ophthalmic stigmata. Furthermore, thiamine should be provided to any overtly malnourished or chronically alcoholic patient who will be receiving a carbohydrate load, such as a dextrose and water infusion. For example, when an alcoholic patient has had a seizure and is about to receive dextrose by vein for possible hypoglycemia or dextrose in saline as a routine intravenous infusion, thiamine
14
Diagnosis
The physician must consider the diagnosis of Wernickes disease as soon as possible, when any of its neurologic features is present and especially when a constellation of characteristic findings occurs in a typical setting, such as alcoholism or other states of potential hypovitaminosis. These include malabsorption, dietary faddism, gastric surgery for obesity, chronic dialysis without vitamin supplementation, and persistent vomiting (e.g., hyperemesis gravidarum). The diagnosis can be strengthened by documentation of neuro-ophthalmic improvement
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and multivitamins should be given simultaneously. Otherwise the administered sugar could precipitate Wernickes disease. Thiamine is a very safe medication. Nevertheless, the physician must remember that the patient may develop an allergic reaction to any pharmaceutical. Fortunately, thiamine so rarely causes anaphylaxis that the vitamin should be prescribed without hesitation, whenever Wernickes disease is a possible diagnosis.

George A. Ricaurte, M.D., Ph.D., and Una D. McCann, M.D.
Outcome of Therapy
Early Wernickes disease, manifest by mild abducens palsy and nystagmus, is exquisitely sensitive to thiamine treatment. Typically such cases are totally reversible. Moderately advanced cases are highly treatable. In these patients, recovery from gait ataxia may be incomplete. In patients with Korsakoffs psychosis, 80% are left with a permanent amnesic syndrome despite thiamine administration. The amnesia leaves these patients alert, sociable, and fluent but totally disabled due to their inability to learn and remember. Such patients require chronic institutionalization or the supervision of a responsible person. One of us remembers a patient who was married to her long-term boyfriend in a hospital solarium so that she could go home with a legal guardian. The economic and social costs of drug abuse are enormous. In the most recent comprehensive analysis conducted by the Office of National Drug Control, the total costs associated with complications of illicit drug use in the United States were $160.7 billion annually. Included within this number are the medical costs associated with the treatment of overdose and withdrawal from a variety of drugs of abuse. The purpose of this chapter is to provide a practical guide for the recognition and management of overdose and withdrawal from a variety of commonly abused illicit drugs. Drug classes to be discussed include opiates, stimulants, benzodiazepines, dissociative anesthetics, and gamma-hydroxybutyrate (GHB) and its analogs.
General Principles Conclusions

The following are principles concerning Wernickes disease: Any neurologic syndrome that raises the possibility that Wernickes disease is present necessitates immediate treatment with thiamine. Physicians must be knowledgeable of the settings in which Wernickes disease occurs, so that mild symptoms or mild signs will prompt them to consider the diagnosis and to administer thiamine promptly. Expeditious therapy can prevent the development of a chronic amnesic syndrome. Being aware that a carbohydrate load can precipitate Wernickes disease, the physician should provide thiamine simultaneously with any infusion of a dextrose solution to a malnourished patient. In summary, whenever the thought occurs that a patient could have or could be at risk for Wernickes disease, it is time to prescribe thiamine. SUGGESTED READING
Victor M, Adams RD, Collins GH: The Wernicke-Korsakoff syndrome, Philadelphia, 1989, FA Davis. Victor M, Ropper AH: Adams and Victors principles of neurology, New York, 2001, McGraw-Hill.
When an otherwise healthy patient presents with altered mental status, suspicion for illicit drug intoxication should be high. Remember, patients may not be willing or able to provide an accurate history of drugs consumed, and even when they do, the possibility of drug impurities or contaminants must be considered. Also, bear in mind that polydrug use is quite common and that more than one drug toxicity may require attention. With this in mind, vital signs should be determined and monitored regularly, in an effort to detect emerging hyperthermia, malignant hypertension, or reduced cardiac output. Blood oxygenation levels should be established and monitored, since sudden desaturation requiring intubation is not uncommon. An electrocardiogram should be obtained. All such patients should have urine and drug toxicology screens, with an extra blood sample collected in case additional toxicology testing is needed to rule out drugs that are not typically detected by routine clinical toxicology testing. Fluid electrolyte status should be determined promptly by physical examination, routine chemical panels, along with a urinalysis (including osmolality, electrolytes and creatine kinase concentrations). A complete blood count should be obtained. Administration of glucose, thiamine, and naloxone, at usual doses, should occur. If there is a history or suspicion of recent oral drug ingestion, use of activated charcoal to promote emesis should be considered, recognizing that a number of drugs are absorbed very rapidly (see later). A head computed tomographic or magnetic resonance imaging scan should be obtained. If there is any suspicion for an infectious process, a lumbar puncture should be performed.
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and multivitamins should be given simultaneously. Otherwise the administered sugar could precipitate Wernickes disease. Thiamine is a very safe medication. Nevertheless, the physician must remember that the patient may develop an allergic reaction to any pharmaceutical. Fortunately, thiamine so rarely causes anaphylaxis that the vitamin should be prescribed without hesitation, whenever Wernickes disease is a possible diagnosis.

George A. Ricaurte, M.D., Ph.D., and Una D. McCann, M.D.
Outcome of Therapy
Early Wernickes disease, manifest by mild abducens palsy and nystagmus, is exquisitely sensitive to thiamine treatment. Typically such cases are totally reversible. Moderately advanced cases are highly treatable. In these patients, recovery from gait ataxia may be incomplete. In patients with Korsakoffs psychosis, 80% are left with a permanent amnesic syndrome despite thiamine administration. The amnesia leaves these patients alert, sociable, and fluent but totally disabled due to their inability to learn and remember. Such patients require chronic institutionalization or the supervision of a responsible person. One of us remembers a patient who was married to her long-term boyfriend in a hospital solarium so that she could go home with a legal guardian. The economic and social costs of drug abuse are enormous. In the most recent comprehensive analysis conducted by the Office of National Drug Control, the total costs associated with complications of illicit drug use in the United States were $160.7 billion annually. Included within this number are the medical costs associated with the treatment of overdose and withdrawal from a variety of drugs of abuse. The purpose of this chapter is to provide a practical guide for the recognition and management of overdose and withdrawal from a variety of commonly abused illicit drugs. Drug classes to be discussed include opiates, stimulants, benzodiazepines, dissociative anesthetics, and gamma-hydroxybutyrate (GHB) and its analogs.
General Principles Conclusions

The following are principles concerning Wernickes disease: Any neurologic syndrome that raises the possibility that Wernickes disease is present necessitates immediate treatment with thiamine. Physicians must be knowledgeable of the settings in which Wernickes disease occurs, so that mild symptoms or mild signs will prompt them to consider the diagnosis and to administer thiamine promptly. Expeditious therapy can prevent the development of a chronic amnesic syndrome. Being aware that a carbohydrate load can precipitate Wernickes disease, the physician should provide thiamine simultaneously with any infusion of a dextrose solution to a malnourished patient. In summary, whenever the thought occurs that a patient could have or could be at risk for Wernickes disease, it is time to prescribe thiamine. SUGGESTED READING
Victor M, Adams RD, Collins GH: The Wernicke-Korsakoff syndrome, Philadelphia, 1989, FA Davis. Victor M, Ropper AH: Adams and Victors principles of neurology, New York, 2001, McGraw-Hill.
When an otherwise healthy patient presents with altered mental status, suspicion for illicit drug intoxication should be high. Remember, patients may not be willing or able to provide an accurate history of drugs consumed, and even when they do, the possibility of drug impurities or contaminants must be considered. Also, bear in mind that polydrug use is quite common and that more than one drug toxicity may require attention. With this in mind, vital signs should be determined and monitored regularly, in an effort to detect emerging hyperthermia, malignant hypertension, or reduced cardiac output. Blood oxygenation levels should be established and monitored, since sudden desaturation requiring intubation is not uncommon. An electrocardiogram should be obtained. All such patients should have urine and drug toxicology screens, with an extra blood sample collected in case additional toxicology testing is needed to rule out drugs that are not typically detected by routine clinical toxicology testing. Fluid electrolyte status should be determined promptly by physical examination, routine chemical panels, along with a urinalysis (including osmolality, electrolytes and creatine kinase concentrations). A complete blood count should be obtained. Administration of glucose, thiamine, and naloxone, at usual doses, should occur. If there is a history or suspicion of recent oral drug ingestion, use of activated charcoal to promote emesis should be considered, recognizing that a number of drugs are absorbed very rapidly (see later). A head computed tomographic or magnetic resonance imaging scan should be obtained. If there is any suspicion for an infectious process, a lumbar puncture should be performed.
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After completion of these common, basic steps, the clinical picture may be useful in narrowing down the list of potential drugs involved. However, since polydrug use is the rule rather than the exception, the clinician should always be vigilant for emerging toxicities during the course of treatment.
Opiates
Several opiate analgesic drugs are subject to misuse. They include heroin (by far the most common), oxycodone (Oxycontin), fentanyl (Sublimaze), propoxyphene (Darvon), hydrocodone (Vicodin), hydromorphone (Dilaudid), meperidine (Demerol), codeine, and 3-methylfentanyl (China white). Although these various opiate drugs differ in potency, efficacy, and duration of action, excessive doses of any opiate drug result in stupor and/or coma, respiratory depression, and pupillary constriction (pinpoint pupils). Although prominent pupillary constriction is a helpful clue to opiate intoxication, its absence should not exclude the diagnosis, since extreme hypoxia secondary to respiratory depression can cause mydriasis. Also, some opiates (e.g., meperidine) can induce mydriasis. Opiate overdose is a medical emergency. Respiratory depression is typically the most pressing concern. Thus, an airway should be immediately established, and manual or mechanical ventilation should be initiated. If possible, a head imaging study should be performed to exclude other potential causes of obtundation. To reverse respiratory depression and other hallmarks of suspected opiate overdose, the narcotic antagonist naloxone (Narcan) should be administered intravenously (IV) (or intramuscularly [IM], if IV access is a problem, as it can be in opiate addicts) at an initial dose of 0.4 mg (either IV or IM). Signs of effective opiate antagonism (arousal, deeper and more rapid respirations, increased pupil size) should be evident within 60 to 90 seconds of naloxone administration. If the effects of naloxone are in question, additional doses of 0.4 mg should be administered. Recall that the duration of action and potency of various opiate drugs vary; thus, some opiate addicts may require larger naloxone doses. Up to 10 to 20 mg of naloxone can be given without significant side effects. Indeed, the only significant side effect of naloxone is precipitation of acute withdrawal, but this occurs only in the opiate-dependent individual and generally subsides within 1 to 2 hours. Signs of withdrawal include restlessness, abdominal cramping, diarrhea, and hypothermia with goose bumps (cold turkey). Also, bear in mind that naloxones plasma half-life is relatively short (1 hour after IV administration), and that repeated dosing is necessary within 45 to 70 minutes of the initial dose. Depending on the opiate involved in the overdose, repeated naloxone administration may be needed for more than 24 hours. When prolonged opiate antagonism is needed, continuous IV infusion of naloxone is in order, starting at an infusion rate of 0.2 to 0.4 mg/hr. The dose can be increased as needed. Nalmefene (Revex) is a longer acting opioid antagonist that is also available.
Pulmonary edema is another serious, but less common, complication of opiate overdose. It is generally not of cardiac origin and is therefore designated as noncardiogenic pulmonary edema (NCPE). NCPE should be suspected when the chest radiograph shows interstitial edema without cardiomegaly. The pathophysiology of NCPE is unclear. NCPE does not respond to naloxone or diuretics and carries a significant mortality rate. Thus, it should be treated aggressively with the oversight of a pulmonary specialist and knowledge of central venous and left ventricular end-diastolic pressures. Other complications of opiate overdose include seizures (probably secondary to hypoxia), rhabdomyolysis (usually due to pressure necrosis), and infection (often secondary to phlebitis and/or unsterile drug paraphernalia). Treatment of these complications should be directed at the primary etiology (e.g., reversing hypoxia in the case of convulsions), then at the complication itself (e.g., vigorous hydration to prevent myoglobinuric renal failure in the setting of rhabdomyolysis). Although acute complications of opiate intoxication most often are seen in the emergency department, other sequelae of opiate abuse such as risks associated with parenteral drug administration (human immunodeficiency virus, hepatitis B and C) may come to a clinicians attention in a hospital ward, and still others may present during routine office visits (e.g., opioid dependence). The diagnosis of opioid dependence rests on the presence of a combination of cognitive, behavioral, and physiologic symptoms reflecting impaired control over drug use and continued use despite adverse consequences. There are several pharmacologic approaches to the treatment of opioid dependence. One involves therapy with opiate agonist drugs that have a longer duration of action than heroin and can be taken orally. The drug most often used for this purpose is methadone, a full opioid agonist. It is given orally in daily doses ranging from 20 up to 100 mg (doses < 40 mg/day are insufficient for most addicts). Another orally active drug gaining increasing use in the treatment of opioid dependence is buprenorphine (Sobutex), a partial opioid agonist. It is given sublingually at an initial dose of 4 mg and can be gradually increased up to 32 mg daily. A product combining buprenorphine with naloxone (Suboxone) is also available. This combination product takes advantage of the fact that naloxone has poor sublingual bioavailability and, if taken IV, will precipitate withdrawal. Thus, the combination product is designed to minimize IV abuse of buprenorphine. Sobutex sublingual tablets are available in various buprenorphine/naloxone combinations (8/2, 16/4, 32/8 mg). In addition to agonist drugs, opiate antagonists have been tried in the treatment of opiate dependence. Because opiate antagonists can precipitate acute withdrawal in the opiate-dependent individual, use of narcotic antagonists should be limited to opiate-free subjects seeking to prevent relapse. The principal agent tested for this purpose has been naltrexone (Trexan), a pure narcotic antagonist chemically related to naloxone but longer lasting. Naltrexone is well absorbed after oral
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administration, not addictive, and extremely effective in blocking the reinforcing effects of a wide range of opiate agonists. Yet another approach calls for cessation of opiate use ("detoxification"). Detoxification calls for the gradual reduction of opiate dose, with the ultimate goal of complete abstinence. This is often accomplished within the confines of residential treatment programs, which can last days to several months. Various strategies have been employed, with variable success, to facilitate complete cessation of opiate use. One has employed gradually decreasing doses of agonist drugs such as methadone and buprenorphine. Another has involved the use of clonidine (Catapres), 0.2 mg given orally every 4 to 6 hours, to suppress symptoms of opiate withdrawal. The dose of clonidine can be increased up to 1.2 mg/day, given in divided doses. Yet another approach involves the use of naltrexone in combination with clonidine. A series of rapid and ultrarapid detoxification procedures are evolving.
Stimulants
Stimulants, including amphetamine and its analogs and cocaine, are among the most frequently abused drugs. As a group, their effects are mediated by activation of the sympathetic nervous system and, therefore, they share a number of acute pharmacologic and toxic effects. There are also differences among the stimulant drugs, based on differences in typical use patterns, routes of administration and settings in which the drugs are used, and distinct pharmacologic features of the drugs themselves. Three of the more commonly abused stimulants methamphetamine, methylenedioxymethamphetamine (MDMA), and cocaineare discussed here. METHAMPHETAMINE The bulk of recreationally used methamphetamine is manufactured from ephedrine or pseudoephedrine in clandestine laboratories and is available in powder, crystalline, or liquid forms. Abusers typically first take methamphetamine by the oral or intranasal route and, with time and increased tolerance, may use it IV or by smoking the crystalline form. As with other amphetamines, methamphetamines acute pharmacologic effects are mediated by release of dopamine and norepinephrine from catecholaminergic axon terminals, as well as blockade of reuptake inactivation, leading to a variety of desired and less desired effects. The psychological and physiologic effects of methamphetamine evolve over the hours following use and can be separated into early and late effects. Drug effects are related to plasma drug concentrations and are influenced by the route of drug administration, with IV administration leading to peak concentrations within seconds, smoking leading to peak plasma concentrations within minutes, and oral administration leading to peak plasma concentrations approximately 3 hours following use.
Early psychological effects of methamphetamine are euphoria, excitement, hypomania, and at higher doses, hallucinations, delusions, psychosis, anxiety, and paranoia. Early physiologic effects of methamphetamine include hypertension, tachycardia, anorexia, increased temperature, mydriasis, tics, and/or stereotypic movements. High doses can lead to hyperthermia, hypertensive crises, seizures, cardiac arrhythmias, cardiac arrest, cardiovascular collapse, and stroke. Overall, effects of drug last 6 to 12 hours, with some residual effects still evident 12 hours after ingestion. Some methamphetamine abusers engage in a binge pattern of use (a methamphetamine run), characterized by repeated, regular dosing of methamphetamine over several days during which time users will refrain from eating and sleeping until they run out of the drug or are too exhausted to continue use. Treatment of acute methamphetamine toxicity is largely supportive and tailored to the signs and symptoms of the individual patient. An electrocardiogram should be obtained to rule out arrhythmia, and blood pressure should be monitored regularly for signs of an emerging hypertensive crisis. Similarly, temperature should be closely monitored for development of malignant hyperthermia. The first line of treatment for agitation, anxiety, and other psychiatric symptoms are the benzodiazepines. If psychosis and agitation persists, judicious use of antipsychotics can be employed, but with the recognition that side effects of these medications could complicate the clinical picture and may lower the seizure threshold. Blood pressure can be lowered by use of nitrates or calcium channel blockers, using doses that would be appropriate for other forms of idiopathic acute hypertension. When core temperatures exceed 39C, ice baths, cooling blankets, and fans should be used in an effort to lower temperature. After methamphetamine use is stopped abruptly, several withdrawal symptoms can occur, including severe depression, sometimes with psychotic features, anxiety, paranoia, lethargy, irritability, and aggression. Psychotic symptoms have been reported in some instances to persist for months or years after methamphetamine use has stopped. There are several reports indicating that methamphetamine users develop a persistent loss of dopamine axonal markers, suggesting that methamphetamine is neurotoxic toward brain dopamine neurons in humans, as it is known to be in animals. A number of reports suggest that methamphetamine use is associated with chronic cognitive impairment, which can interfere with treatments aimed at maintenance of methamphetamine abstinence. There are no pharmacologic treatments for methamphetamine dependence. Selective serotonin uptake inhibitors are often used to treat the depressive symptoms associated with acute abstinence and withdrawal, which can persist for months. There are no data regarding the optimum duration of antidepressant treatment for methamphetamine-related depressive symptoms. Following recovery from methamphetamines acute toxic effects and withdrawal, treatment is similar to that employed for stimulant use and dependence in general and is focused on cessation of drug use and maintenance
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of abstinence. To this end, a multipronged approach is employed using a variety of cognitive, behavioral, and psychological methods that are most intensely applied immediately after detoxification but maintained for months to years. The three areas that are emphasized initially are (1) helping an individual develop a sufficiently high motivation for becoming abstinent, (2) the development of strategies for avoiding use, and (3) education regarding techniques to recognize and resist triggers for reinitiating old use patterns (i.e., response prevention). METHYLENEDIOXYMETHAMPHETAMINE MDMA (ecstasy) is a ring-substituted amphetamine analog that has widespread use in the setting of clubs and all-night dance parties, sometimes referred to as raves. In this setting, MDMA is often taken repeatedly during the night, in an effort to prolong its desired effects. Although structurally related to amphetamine and methamphetamine, it also has structural similarities with mescaline and, as a consequence, has some subjective effects that are more commonly associated with psychedelic compounds. In addition to leading to stimulation of the central nervous system (CNS) and peripheral nervous system, MDMA is a potent releaser of serotonin and thus has indirect actions at a variety of serotonin receptors. Within 15 to 20 minutes following ingestion (MDMA is typically taken orally), a constellation of clinical and psychological effects occur, including euphoria, a sense of closeness to others, pressured speech, mydriasis, tachycardia, increased blood pressure, hyperthermia, hyperreflexia, decreased hunger and thirst, nystagmus, and bruxism. As with methamphetamine, acute adverse effects of MDMA are, for the most part, exaggerations of its pharmacologic actions. Less severe adverse effects include anxiety, agitation, confusion, tremulousness, insomnia, nausea, and palpitations. More serious adverse effects include potentially fatal malignant hypertension, severe hyperthermia, cardiac arrhythmias, myocardial infarction, severe strokes (both ischemic and hemorrhagic), cerebral edema, and seizures. As with methamphetamine, treatment for these syndromes is largely supportive, using the same measures that would be employed for the idiopathic forms of these same syndromes. Less well understood adverse effects of MDMA that have been reported are the development of a syndrome of inappropriate antidiuretic hormone (SIADH) secretion, marked elevation in serum creatine kinase in the absence of muscle injury, and persistent neuropsychiatric complications. MDMA-related hyperthermia has received particular attention, in part because it is hypothesized to occur more frequently with MDMA than with other stimulants (e.g., methamphetamine) because of the setting and use patterns of MDMA. In particular, since MDMA is typically used in crowded, hot settings and while individuals are engaging in vigorous activity, it is hypothesized that a combination of heat, activity, and dehydration increases the likelihood for MDMA-related
hyperthermic reactions. Left untreated, MDMAinduced malignant hyperthermia can rapidly develop into a cluster of serious complications, including disseminated intravascular coagulation, rhabdomyolysis, renal failure, and, ultimately, death. The current view is that treatment of MDMA (and methamphetamine)induced hyperthermia should use an approach similar to that used for other types of drug-induced malignant hyperthermia. If there is suspicion or documentation of recent MDMA ingestion, use of activated charcoal and/or gastric lavage should be employed. Benzodiazepines should be administered to reduce agitation and associated physical exertion. As was noted with methamphetamine, antipsychotic use should be minimized, since their effects could complicate the clinical picture and since high-dose benzodiazepines are usually sufficiently effective. As soon as development of hyperthermia is suspected, clinicians should make aggressive efforts in reducing core body temperature by use of fans, cooling blankets, or ice baths and nonsteroidal anti-inflammatory agent (to inhibit prostaglandin-induced temperature increases). If the syndrome has progressed to a more advanced stage, the patient should be pharmacologically immobilized and intubated, if necessary (to reduce muscular thermogenesis). Given the potential of SIADH, fluid and electrolyte status should be closely monitored, and aggressive IV hydration should be used to maintain central blood pressure and to promote drug excretion. Although urine acidification can increase urinary excretion of amphetamines, it is not recommended, since some MDMA users also have myoglobinuria, and acidification of the urine could lead to the precipitation of myoglobin in the kidneys, which could lead to renal failure. As was noted for methamphetamine, there is growing evidence that MDMA use can lead to long-term deficits in cognitive function. Further, it appears that some MDMA users develop lasting deficits in brain serotonin axons and axon terminals, similar to that which is known to occur in MDMA-treated monkeys. It is not clear whether MDMA-induced cognitive deficits or MDMA-related psychiatric syndromes (mood, anxiety, and psychotic syndromes) are related to MDMA- induced serotonin neurotoxicity or to other factors that have not been identified. Unlike methamphetamine users, MDMA users do not typically develop uncontrollable cravings for drug that necessitate intensive cognitive behavioral treatment strategies, and MDMA users often successfully abstain from further MDMA use without engaging in formal drug abuse treatment programs. There have been no controlled studies regarding the optimal treatment for MDMA-induced psychiatric syndromes. COCAINE Despite efforts to curb cocaine use in the United States, it continues to be among the most popular drugs of abuse. Cocaine is available in a variety of different forms, including cocaine hydrochloride powder, which can be inhaled or dissolved in water for IV injection;
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freebase cocaine, which can be smoked by mixing it with tobacco or heating it in special pipes; and crack cocaine, a crystalline form of cocaine that is smoked. As with methamphetamine, the route of administration by which cocaine is taken significantly influences the time course of its physiologic and psychological effects. Smoked cocaine reaches the CNS within 8 to 10 seconds and produces a sudden and intense euphoria. IV cocaine takes approximately 15 seconds to reach the CNS vasculature and also leads to a rapid onset of the desired psychological effects. Intranasal cocaine requires minutes to reach the brain and, because it causes local vasoconstriction, has protracted absorption and a longer duration of action. Cocaine, like the amphetamines, is a catecholamine and serotonin reuptake inhibitor and therefore stimulates the CNS and the peripheral sympathetic systems, in addition to the serotonin system. It is also a local anesthetic, so it impairs the conduction of nerve impulses via blockade of neuronal sodium channels. Following cocaine ingestion (or injection), psychological effects include excitation, euphoria, hypomania, and a sense of power. Acute physiologic effects include vasoconstriction, increased heart rate, and increased blood pressure. Overdose of cocaine can lead to agitation, delirium, psychosis, seizures, hypertension, hyperpyrexia, cardiac arrhythmia, myocardial infarction, and stroke. As with the amphetamines, cocaine toxicity can lead to fatal malignant hyperthermia with multiorgan failure involving the brain, heart, lungs, kidneys, liver, and muscular system. Cocaine-related vascular problems can be related to excessive blood pressure with rupture of vessels and hemorrhage or to vasospasm and tissue necrosis. More rarely, cocaine-related vasculitis has been reported (as with amphetamines). A first line of therapy in an agitated patient with cocaine-related agitation and/or seizures is to administer benzodiazepines. This is sometimes effective in reducing blood pressure and temperature as well. If hypertension persists, use of calcium channel blockers or nitrates should be employed. Use of beta blockers should be avoided since unopposed alpha-adrenergic activity could increase coronary artery spasm and peripheral vasoconstriction. As with the amphetamines, hyperthermia should be treated using ice baths, cooling blankets, and fans. Metabolic acidosis should be corrected using sodium bicarbonate. Continued use of cocaine can also lead to a number of serious medical conditions. For example, cardiac conditions associated with chronic cocaine use include direct cardiac endothelial injury. Individuals who chronically use cocaine intranasally can perforate their nasal septa, secondary to vasoconstriction of the mucous membrane, leading to tissue necrosis. A variety of pulmonary conditions have also been described in chronic cocaine users, including hypersensitivity pneumonitis and pulmonary granulomas. There are no effective pharmacotherapies for the treatment of cocaine addiction. The most effective longterm treatment strategies are those described earlier for methamphetamine. Cocaine, like methamphetamine, when stopped abruptly, is typically associated with
intense cocaine cravings that are extremely difficult to resist without formal intervention using cognitive behavioral methods aimed at increasing the motivation to maintain abstinence, development of strategies for resisting the impulse to reinitiate use, and the recognition of situations that are likely to trigger resumption of cocaine use.
Benzodiazepines
The abuse liability of benzodiazepines is a subject of debate. However, of the various benzodiazepines, flunitrazepam (Rohypnol) is currently the subject of considerable attention because of its propensity to be misused to facilitate sexual assault (date rape drug). Like other benzodiazepines, flunitrazepam is an agonist of the gamma-aminobutyric acid (GABA)-A receptor complex that produces muscle relaxant, anxiolytic, sedative, anticonvulsant, and amnestic effects. Street names for flunitrazepam tablets include roffies and forget pill. Adverse effects of flunitrazepam and other benzodiazepines are dose related and include impaired psychomotor behavior, ataxia, confusion, somnolence, and amnesia. Respiratory depression can also occur. However, this is much more likely when benzodiazepines are used or abused in combination with other CNS depressants, such as opiates, or GHB and its various analogs. Indeed, overdose fatalities with flunitrazepam and other benzodiazepines are exceedingly rare unless other CNS active drugs are involved. Occasionally, benzodiazepines can produce paradoxical reactions consisting of excitement, stimulation, and hyperactivity. In addition to supportive care, treatment of confirmed flunitrazepam (or other benzodiazepine) overdose calls for administration of the selective, competitive benzodiazepine receptor antagonist flumazenil (Romazicon). Repeated IV bolus injections of 0.1 to 0.3 mg over 15 to 30 seconds, up to a cumulative dose of 2 to 3 mg, are well tolerated. Reversal of stupor or coma secondary to pure benzodiazepine overdose by flumazenil is rapid (45 to 60 seconds). An IV infusion of flumazenil at a rate of 0.3 to 0.5 mg per hour can also be given to prevent patients from relapsing into coma. When using flumazenil, remember that it can precipitate withdrawal in the benzodiazepine-dependent individual. Effects can be minimized by slowly decreasing the dose of flumazenil. Physical dependence in the context of chronic benzodiazepine use is well documented and is associated with a potentially severe withdrawal syndrome. Treatment of benzodiazepine withdrawal, should it occur, involves replacement with long-acting benzodiazepine (e.g., diazepam, clonazepam), followed by gradual taper.
Phencyclidine and Other Dissociative Anesthetics

Phencyclidine (PCP), ketamine, and dextromethorphan are all noncompetitive antagonists at brain N-methylD-aspartate (NMDA) receptor sites. They are often
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referred to as dissociative anesthetics because PCP and ketamine were initially developed as general anesthetic agents. However, they were soon discovered to be associated with postanesthetic emergence reactions during which patients appear awake but have altered sensory input. In addition to blocking the effects of excitatory amino acids (e.g., glutamate), PCP and ketamine produce mild to moderate sympathomimetic effects. Acute pharmacologic effects of PCP and related drugs include tachycardia, increased blood pressure, and altered mental status. Tachycardia is the most common finding on physical examination. Intoxication results in hyperexcitability, severe agitation, psychosis, and respiratory and cardiovascular depression. Rhabdomyolysis can occur and is believed to be secondary to pronounced motor agitation. Management of PCP and ketamine intoxication is primarily supportive. In cases of severe agitation or anxiety, one or several doses of a benzodiazepine or a high-potency antipsychotic can be used. Since high doses of ketamine can induce vomiting, aspiration precautions should be taken in the stuporous patient. Rhabdomyolysis should be treated with liberal hydration with a close eye on renal function and electrolytes. The pharmacologic effects of ketamine are short lived (<1 hour); by contrast, PCP intoxication can last for many hours. Neither physical dependence nor a withdrawal syndrome has been reported after abuse of PCP and related NMDA antagonist drugs.
Postintubation sedation with a short-acting benzodiazepine should be used because it is not uncommon for patients to emerge suddenly from the sedative effects of GHB and become agitated and combative. Respiratory and CNS depression secondary to GHB typically resolve in 2 to 6 hours. In chronic users of high doses of GHB and its analogs, tolerance and physical dependence can develop, and a withdrawal syndrome has been identified on abrupt drug discontinuation. The syndrome closely resembles delirium tremens in the alcoholic patient. As such, it is characterized by tremulousness, anxiety, tachycardia, diaphoresis, and insomnia. Withdrawal can last 3 to 12 days and can progress to profound disorientation and prolonged psychosis. In the management of GHB withdrawal, large doses of a benzodiazepine may be necessary. This should be followed by a benzodiazepine taper, as in the management of alcohol withdrawal. In cases refractory to benzodiazepines, a barbiturate can be used. Use of a newer antipsychotic agent for severe psychosis is also reasonable. On discharge from the emergency department, it is important to alert patients to the possible emergence of a withdrawal syndrome.
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Conclusion
A number of popular drugs of abuse can lead to acute, sometimes life-threatening toxic syndromes. Several of the more common toxic syndromes and presentations have been reviewed here. After implementing a series of common strategies for the assessment, diagnosis, and treatment of drug toxicity, drug-specific treatment strategies should be employed, being vigilant for the possibility of polysubstance use and consequent drugdrug interactions or emerging drug toxicities. Acknowledgments We thank Peter Rosenblatt and Mary Bush for their assistance in preparing the manuscript. Supported by U.S.P.H.S. Grants DA5707, DA13790, DA09487, DA00206, and DA10217. SUGGESTED READING
Opiates Fudala PJ, Woody GW: Recent advances in the treatment of opiate addiction, Curr Psychiatry Rep 6:339-346, 2004. Sterrett C, Brownfield J, Korn CS, et al: Patterns of presentation in heroin overdose resulting in pulmonary edema, Am J Emerg Med 21:32-34, 2003. Methamphetamine Rawson RA, Gonzales R, Brethen P: Treatment of methamphetamine use disorders: an update. J Subst Abuse Treat 23:145-150, 2002. Simon SL, Dacey J, Glynn S, et al: The effect of relapse on cognition in abstinent methamphetamine abusers, J Subst Abuse Treat 27:59-66, 2004. MDMA Abraham H, McCann U, Ricaurte G: Psychedelic drugs. In Davis K, Charney D, Coyle J, Nemeroff C, editors: Neuropsychopharmacologya fifth generation of progress, Philadelphia, 2002, Lippincott Williams & Wilkins, 1545-1556.
GHB and Its Analogs

GHB (liquid ecstasy) is a drug that has become increasingly popular in recent years. Gammabutyrolactone (GBL) and 1,4- butanediol (BD) are GHB precursors that are metabolically converted to GHB once ingested. They are marketed as health supplements under various brand names. GHB, GBL, and BD are used for their sedative euphorigenic effects and are often used chronically for their putative anabolic effects. They are also used at parties. Effects of GHB occur within minutes and typically last 1 to 4 hours. Chemically, GHB and its precursors are analogs of the inhibitory neurotransmitter GABA; they are also found endogenously in the CNS, in trace amounts. Adverse effects are invariably secondary to overdose. Signs and symptoms of overdose include drowsiness, disorientation, confusion, bradycardia, and hypotension. The most serious concern is respiratory depression that may progress to respiratory arrest, coma, and, sometimes, death. Complications of GHB and related drugs are more likely to occur when they are ingested along with other CNS-depressant drugs such as alcohol. Unfortunately, GHB and its analogs are not detected by routine drug screens, so the patient history is crucial. Treatment of GHB overdose is primarily symptomatic and supportive. Gastric lavage is not useful because GHB is rapidly absorbed from the gastrointestinal tract. Endotracheal intubation is indicated to protect the airway and, if necessary, to provide ventilatory support.
352
Henry JA, Jeffreys KJ, Dawling S: Toxicity and deaths from 3,4-methylenedioxy-methamphetamine (ecstasy), Lancet 340: 384-387, 1992. Kalant H: The pharmacology and toxicology of ecstasy (MDMA) and related drugs, Can Med Assoc J 165:917-928, 2001. Cocaine Ricaurte GA, McCann UD: Neuropathology of cocaine abuse, Curr Opin Psychiatry 12: 277-280, 1999. Shanti CM, Lucas CE: Cocaine and the critical care challenge, Crit Care Med 31:1851-1859, 2003. Flunitrazepam and Other Benzodiazepines Lader M: Anxiolytic drugs: dependence, addiction and abuse, Eur Neuropsychopharmacol 4:85-91, 1994. Simmons MM, Cupp MJ: Use and abuse of flunitrazepam, Ann Pharmacother 32:117-119, 1998. PCP and Dissociative Anesthetics Green SM, Li J: Ketamine in adults: what emergency physicians need to know about patient selection and emergence reactions, Acad Emerg Med 7:278-281, 2000. Jansen KL: A review of the nonmedical use of ketamine: use, users and consequences, J Psychoactive Drugs 32:419-433, 2000. Milhorn HT: Diagnosis and management of phencyclidine intoxication, Am Fam Physician 43:1293-302, 1991. GHB and Its Analogs Mason PE, Kerns WP: Gamma-hydroxybutyric acid (GHB) intoxication, Acad Emerg Med 9:730-739, 2002. Miotto K, Darakjian J, Basch J, et al: Gamma-hydroxybutyric acid: patterns of use, effects, and withdrawal, Am J Addict 10:232-241, 2001. Nicholson KL, Balster RL: GHB: a new and novel drug of abuse, Drug Alcohol Depend 63:1-22, 2001.

Morri E. Markowitz, M.D.
Lead has been mined for millennia, and knowledge of its potential for toxicity has been extant for nearly as long. An elegant and accurate early description of clinical lead poisoning caused by occupational lead exposure was recorded by a Greek physician, Nikander, approximately 2200 years ago. Treatment was also suggested by Nikander: remove the patient from further exposure. This remains a mainstay of therapy to the present. Children are the group most likely to become lead poisoned in the United States. Within that category, age is a determinant of prevalence: children 1 to 5 years of age are most likely to have elevated blood lead concentrations. The blood lead level (BLL) is the gold standard for determining health risks from lead. Currently, a level higher than 10 g/dL in whole blood is considered to be of concern, as defined by the Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics. However, this level was established based on clinical studies performed prior to 1991. Subsequent studies and data reanalyses of older investigations indicate that lead is a neurotoxicant at levels below this threshold. Thus, the BLL considered
elevated is likely to be revised downward, possibly to 5 g/dL within the next few years. Lead is a component of dozens of compounds that have been incorporated into hundreds of commercial products. Most children in the United States become lead poisoned after ingestion of lead-containing household paint or the dust derived from that paint. Although it is a widely disseminated source of exposure to children (and adults) living in older housing, new sources of lead are identified continuously. Recent (in 2003 and 2004) examples include imported Mexican-produced candies that used lead-contaminated chili powder, a deodorant powder produced in the Dominican Republic, and toy rings with lead enamel imported from China available in vending machines for 25 cents. Thus lead exposure can be anticipated (old paint) but is also insidious. The metabolism of lead differs in children and adults. After absorption, lead is distributed to all tissues; excretion is primarily through the kidney. Seventy percent of retained lead is found in the skeleton of children compared to more than 90% in adults. Once in bone, the half-life of lead is measured in years, in contrast to a halflife of weeks in blood. Under circumstances of increased bone turnover, this skeletal lead can be released at an accelerated rate that can cause renewed toxicity. Examples of this include prolonged immobilization (> 1 week of nonweight-bearing), hyperthyroidism, and pregnancy and lactation. Biochemically, lead toxicity may occur in any cell or tissue. Lead competes with essential metals such as calcium, zinc, and iron for cell entry and protein binding. When protein bound, lead alters enzyme function either to induce inappropriate activity or else to inhibit function. The result is deficits in metabolic pathway products and excesses of substrates. Both result in cellular dysfunction. For example, neurotransmitter release is in part a calcium-dependent process. Likewise, neuroreceptor availability is a zinc-dependent process. Both are perturbed by lead resulting in altered interneuronal cell communications. The clinical correlates of blood lead begin at a level of about 20 g/dL. As mentioned, subclinical effects on cognitive function and other negative correlates with stature and hearing occur without a clear BLL threshold, using our current units for the measurement of blood lead in micrograms per deciliter. Most children with elevated blood lead concentrations are found to have levels in the 10- to 20-g/dL range. Thus, most cases of lead poisoning are subclinical. Table 1 summarizes the clinical and subclinical correlates of BLLs in children and adults. Treatment is guided by the BLL. Lead-poisoned children are identified by screening programs where highrisk children are tested regardless of symptoms or the certain identification of sources of exposure. The CDC has set guidelines for identifying high-risk groups. In states such as New York where old housing is common, universal blood lead testing of all children at ages 1 and 2 years is mandated. If individual practitioners recognize specific children at risk at other ages, screening should be performed then as well. For example, if a 5-year-old child with developmental delay or hyperactivity and pica behavior is being assessed, obtaining a blood sample for lead analysis would be appropriate.
352
Henry JA, Jeffreys KJ, Dawling S: Toxicity and deaths from 3,4-methylenedioxy-methamphetamine (ecstasy), Lancet 340: 384-387, 1992. Kalant H: The pharmacology and toxicology of ecstasy (MDMA) and related drugs, Can Med Assoc J 165:917-928, 2001. Cocaine Ricaurte GA, McCann UD: Neuropathology of cocaine abuse, Curr Opin Psychiatry 12: 277-280, 1999. Shanti CM, Lucas CE: Cocaine and the critical care challenge, Crit Care Med 31:1851-1859, 2003. Flunitrazepam and Other Benzodiazepines Lader M: Anxiolytic drugs: dependence, addiction and abuse, Eur Neuropsychopharmacol 4:85-91, 1994. Simmons MM, Cupp MJ: Use and abuse of flunitrazepam, Ann Pharmacother 32:117-119, 1998. PCP and Dissociative Anesthetics Green SM, Li J: Ketamine in adults: what emergency physicians need to know about patient selection and emergence reactions, Acad Emerg Med 7:278-281, 2000. Jansen KL: A review of the nonmedical use of ketamine: use, users and consequences, J Psychoactive Drugs 32:419-433, 2000. Milhorn HT: Diagnosis and management of phencyclidine intoxication, Am Fam Physician 43:1293-302, 1991. GHB and Its Analogs Mason PE, Kerns WP: Gamma-hydroxybutyric acid (GHB) intoxication, Acad Emerg Med 9:730-739, 2002. Miotto K, Darakjian J, Basch J, et al: Gamma-hydroxybutyric acid: patterns of use, effects, and withdrawal, Am J Addict 10:232-241, 2001. Nicholson KL, Balster RL: GHB: a new and novel drug of abuse, Drug Alcohol Depend 63:1-22, 2001.

Morri E. Markowitz, M.D.
Lead has been mined for millennia, and knowledge of its potential for toxicity has been extant for nearly as long. An elegant and accurate early description of clinical lead poisoning caused by occupational lead exposure was recorded by a Greek physician, Nikander, approximately 2200 years ago. Treatment was also suggested by Nikander: remove the patient from further exposure. This remains a mainstay of therapy to the present. Children are the group most likely to become lead poisoned in the United States. Within that category, age is a determinant of prevalence: children 1 to 5 years of age are most likely to have elevated blood lead concentrations. The blood lead level (BLL) is the gold standard for determining health risks from lead. Currently, a level higher than 10 g/dL in whole blood is considered to be of concern, as defined by the Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics. However, this level was established based on clinical studies performed prior to 1991. Subsequent studies and data reanalyses of older investigations indicate that lead is a neurotoxicant at levels below this threshold. Thus, the BLL considered
elevated is likely to be revised downward, possibly to 5 g/dL within the next few years. Lead is a component of dozens of compounds that have been incorporated into hundreds of commercial products. Most children in the United States become lead poisoned after ingestion of lead-containing household paint or the dust derived from that paint. Although it is a widely disseminated source of exposure to children (and adults) living in older housing, new sources of lead are identified continuously. Recent (in 2003 and 2004) examples include imported Mexican-produced candies that used lead-contaminated chili powder, a deodorant powder produced in the Dominican Republic, and toy rings with lead enamel imported from China available in vending machines for 25 cents. Thus lead exposure can be anticipated (old paint) but is also insidious. The metabolism of lead differs in children and adults. After absorption, lead is distributed to all tissues; excretion is primarily through the kidney. Seventy percent of retained lead is found in the skeleton of children compared to more than 90% in adults. Once in bone, the half-life of lead is measured in years, in contrast to a halflife of weeks in blood. Under circumstances of increased bone turnover, this skeletal lead can be released at an accelerated rate that can cause renewed toxicity. Examples of this include prolonged immobilization (> 1 week of nonweight-bearing), hyperthyroidism, and pregnancy and lactation. Biochemically, lead toxicity may occur in any cell or tissue. Lead competes with essential metals such as calcium, zinc, and iron for cell entry and protein binding. When protein bound, lead alters enzyme function either to induce inappropriate activity or else to inhibit function. The result is deficits in metabolic pathway products and excesses of substrates. Both result in cellular dysfunction. For example, neurotransmitter release is in part a calcium-dependent process. Likewise, neuroreceptor availability is a zinc-dependent process. Both are perturbed by lead resulting in altered interneuronal cell communications. The clinical correlates of blood lead begin at a level of about 20 g/dL. As mentioned, subclinical effects on cognitive function and other negative correlates with stature and hearing occur without a clear BLL threshold, using our current units for the measurement of blood lead in micrograms per deciliter. Most children with elevated blood lead concentrations are found to have levels in the 10- to 20-g/dL range. Thus, most cases of lead poisoning are subclinical. Table 1 summarizes the clinical and subclinical correlates of BLLs in children and adults. Treatment is guided by the BLL. Lead-poisoned children are identified by screening programs where highrisk children are tested regardless of symptoms or the certain identification of sources of exposure. The CDC has set guidelines for identifying high-risk groups. In states such as New York where old housing is common, universal blood lead testing of all children at ages 1 and 2 years is mandated. If individual practitioners recognize specific children at risk at other ages, screening should be performed then as well. For example, if a 5-year-old child with developmental delay or hyperactivity and pica behavior is being assessed, obtaining a blood sample for lead analysis would be appropriate.
353
TABLE 1 Clinical and Subclinical Correlates of Blood Lead Levels

Blood Lead Level, g/dL 70 50 (chronic exposure in adults) >20 (in children) >0 (in children) Correlate Death (rare < 100 g/dL) Encephalopathy (seizures) Kidney failure (gouty nephropathy) Hypertension (headaches) Peripheral neuropathy (wrist drop) Anemia (pallor, weakness) Gastrointestinal complaints (abdominal pain, nausea, vomiting, constipation) Hyperactivity; diminished IQ, hearing, and stature
TABLE 2 Treatment Components

Blood Lead Level, g/dL >0 < 10 10-45 Treatment None, or as for 10-45 g/dL Identify and eliminate exposure; reduce non-food-related hand-to-mouth activity; dietary counseling to ensure adequate, but not extra, calcium and iron intake for age, unless correcting prior nutritional deficiencies Chelation: 45-70 g/dL1 drug 70 g/dL2 drugs
45
Four components of therapy include (1) identification of the source of lead exposure and separation of the child from that source; (2) behavior modification, when age appropriate, to eliminate non-nutritive hand-tomouth activity; (3) nutritional counseling to optimize essential metal intake (calcium and iron at recommended dietary intakes for age) and to correct deficits; and (4) chelation therapy for the limited number of children with BLLs higher than 45 g/dL (Table 2). The first three components are appropriate for anyone at risk from lead poisoning and are not BLL dependent.
Chelation therapy is currently not advised for children with lower levels because there are no data to support its efficacy at levels below 45 g/dL either in terms of altering the long-term trend in BLLs or in causing a sustained improvement in biochemical or cognitive outcomes. For children with high blood concentrations between 45 and 70 g/dL, chelation prevents further increases to more threatening levels. For children with very high BLLs (>70 g/dL), chelation can be life saving and improves symptoms. Four drugs are available in the United States for chelation (Table 3). Of these, two can only be used parenterally and two are administered orally. Additional agents are in use abroad. First-line therapy for children
14
TABLE 3 Chelating Agents

Drug CaNa2EDTA (versenate, edetate) Dose 1000-1500 mg/m2/day for 5 days Comments Route: IV, continuous or divided dose q 6 hr (with each dose over at least 1 hr); can also be given IM when mixed 1:1 by volume with procaine 1%; use higher dose for encephalopathic patients Toxicity: proteinuria, pyuria, rising BUN/creatinineall rare; hypercalcemia if too rapid an infusion; tissue inflammation if infusion infiltrates Monitor urinalysis daily, especially for high dose; keep specific gravity < 1.015 Route: PO, divided q 8 hr for 5 days, then q 12 hr for remaining 14 days Toxicity: GI distress, rashes, elevated LFTs, depressed WBCsall uncommon and reversible Monitor pretreatment, day 6, then weekly Calculation for children should be based on body surface area, not weight Route: only IM, divided q 4 hr; dose and duration depend on severity of intoxication; always given in combination with CaNa2EDTA; first dose precedes CaNa2EDTA administration by 4 hr Toxicity: GI distress, altered mentation; elevated LFTs, hemolysis if G6PD deficiency; no concomitant iron Rx Monitor LFTs; rule out G6PD deficiency Route: PO, divided q 12 hr on an empty stomach Toxicity: rashes, fever, blood dyscrasias, elevated LFTs, proteinuria, allergic cross-reactivity with penicillin Monitor urinalysis, CBC, liver and renal function tests Fever possible with/without rash after 2nd wk of treatment
DMSA (succimer [Chemet])
1050 mg/m2/day for 5 days, followed by 700 mg/m2/day for 14 days 300-450 mg/m2/day for 3-5 days
BAL (dimercaprol, British antilewisite)
D-Penicillamine
(Cuprimine)
Initial dose: 10 mg/kg/day, increase over 2 wk to 25-40 mg/kg/day for 12-20 wk
BUN, Blood urea nitrogen; GI, gastrointestinal; LFT, liver function test; WBC, white blood cell count; G6PD, glucose-6-phosphate dehydrogenase; CBC, complete blood count.
354
TABLE 4 Recommended Drugs for Various Blood Lead Levels

Blood Lead Level, g/dL 100 Recommended Drug BAL and CaNa2EDTA Comments Use high doses; may decrease BAL dose after 3 days if asymptomatic Use CaNa2EDTA at 1000 mg/m2/day Use BAL at 300 mg/m2/day Use CaNa2EDTA at 1000 mg/m2/day
SUGGESTED READING
American Academy of Pediatrics, Committee on Environmental Health: Screening for elevated blood lead levels, Pediatrics 101:1072-1078, 1998. CDC: Preventing lead poisoning in young children: A statement by the Centers for Disease Control, Atlanta, 1991, CDC. CDC: Screening young children for lead poisoning: guidance for state and local public health officials, Centers for Disease Control and Prevention, Bethesda, MD, November 1997, U.S. Department of Health and Human Services, Public Health Service, 92-95. Treatment Guidelines for lead exposure in children. American Academy of Pediatrics Committee on Drugs 1993-1994, Pediatrics 96:155-160, 1995.
70 <100
45 < 70 < 45
DMSA and CaNa2EDTA or BAL and CaNa2EDTA DMSA or CaNa2EDTA None

Elijah W. Stommel, M.D., Ph.D., and Michael R. Watters, M.D.
See Table 3 for alternative drug names.
with BLLs less than 100 g/dL includes dimercaptosuccinic acid (DMSA) and calcium disodium versenate (CaNa2EDTA) (Table 4). Either drug can be used alone for children with levels between 45 and 70 g/dL, and both are used together for those with BLLs 70 to 100 g/dL. British antilewisite (BAL) can be substituted for DMSA at levels greater than 70 g/dL if DMSA is not tolerated. It should be substituted for DMSA for encephalopathic patients. Few centers use penicillamine. BLLs fall precipitously with chelation but rebound within days to weeks after completion of a round of therapy, as release from bone stores occurs. For children with levels higher than 70 g/dL, repeated courses of chelation therapy are needed to maintain BLLs lower than 45 g/dL. Allow intervals of at least 3 days between courses, if possible, to reduce the chance of treatment-related toxicities. Other aspects of care for encephalopathic patients with increased intracranial pressure from lead toxicity are nonspecific, such as fluid restriction and anticonvulsants for seizure control. Since most children requiring chelation are asymptomatic, follow-up of BLLs is essential. Trough BLLs should be obtained after 5 days of chelation (day 6). The subsequent timing for repeat testing depends on the pretreatment level. If initially higher than 100 g/dL, then one can expect a rebound post-treatment level to surpass 45 g/dL within days to a few weeks. If the BLL is initially 45 to 70 g/dL, repeat samples should be obtained 2 to 4 weeks post-treatment and monthly thereafter until levels remain below 25 g/dL. With repeated courses of chelation, concern about essential trace element depletion has been raised. Further nutritional counseling and the use of supplements may be of benefit, but there are no controlled trials. Follow serum zinc and copper levels and ferritin to guide treatment.
Biological neurotoxins abound in nature. Humans may be affected by environmental exposure, ingestion, or envenomation. Gastrointestinal manifestations are common and may result in electrolyte disturbances and volume depletion. Supportive therapy includes maintenance of electrolytes and preservation of cerebral and renal perfusion. Pain control is important for envenomations. Judicious use of antivenins and maintenance of cardiopulmonary function may be life saving. For some biological toxins, specific medications may be indicated (Table 1).
Ingested Marine Toxins

Toxic-producing marine microorganisms include marine algae, bacteria, dinoflagellates, and diatoms. Harmful algal blooms are one of the most economically significant and scientifically complex coastal issues facing our nation today. Virtually every coastal state has reported major toxic blooms, which can cause human illness and death, alter marine habitats, and adversely impact marine and recreational industries. Their neurotoxins may be harmless to many fish and shellfish but result in toxicity when ingested by marine mammals or humans. Ingestion typically results in gastrointestinal disturbances of emesis and diarrhea, followed by sensorimotor disturbances. CIGUATERA Ciguatera results from the ingestion of toxin-laden tropical reef fish, with most of the symptoms attributable to ciguatoxin, although other toxins may coexist to
354
TABLE 4 Recommended Drugs for Various Blood Lead Levels

Blood Lead Level, g/dL 100 Recommended Drug BAL and CaNa2EDTA Comments Use high doses; may decrease BAL dose after 3 days if asymptomatic Use CaNa2EDTA at 1000 mg/m2/day Use BAL at 300 mg/m2/day Use CaNa2EDTA at 1000 mg/m2/day
SUGGESTED READING
American Academy of Pediatrics, Committee on Environmental Health: Screening for elevated blood lead levels, Pediatrics 101:1072-1078, 1998. CDC: Preventing lead poisoning in young children: A statement by the Centers for Disease Control, Atlanta, 1991, CDC. CDC: Screening young children for lead poisoning: guidance for state and local public health officials, Centers for Disease Control and Prevention, Bethesda, MD, November 1997, U.S. Department of Health and Human Services, Public Health Service, 92-95. Treatment Guidelines for lead exposure in children. American Academy of Pediatrics Committee on Drugs 1993-1994, Pediatrics 96:155-160, 1995.
70 <100
45 < 70 < 45
DMSA and CaNa2EDTA or BAL and CaNa2EDTA DMSA or CaNa2EDTA None

Elijah W. Stommel, M.D., Ph.D., and Michael R. Watters, M.D.
See Table 3 for alternative drug names.
with BLLs less than 100 g/dL includes dimercaptosuccinic acid (DMSA) and calcium disodium versenate (CaNa2EDTA) (Table 4). Either drug can be used alone for children with levels between 45 and 70 g/dL, and both are used together for those with BLLs 70 to 100 g/dL. British antilewisite (BAL) can be substituted for DMSA at levels greater than 70 g/dL if DMSA is not tolerated. It should be substituted for DMSA for encephalopathic patients. Few centers use penicillamine. BLLs fall precipitously with chelation but rebound within days to weeks after completion of a round of therapy, as release from bone stores occurs. For children with levels higher than 70 g/dL, repeated courses of chelation therapy are needed to maintain BLLs lower than 45 g/dL. Allow intervals of at least 3 days between courses, if possible, to reduce the chance of treatment-related toxicities. Other aspects of care for encephalopathic patients with increased intracranial pressure from lead toxicity are nonspecific, such as fluid restriction and anticonvulsants for seizure control. Since most children requiring chelation are asymptomatic, follow-up of BLLs is essential. Trough BLLs should be obtained after 5 days of chelation (day 6). The subsequent timing for repeat testing depends on the pretreatment level. If initially higher than 100 g/dL, then one can expect a rebound post-treatment level to surpass 45 g/dL within days to a few weeks. If the BLL is initially 45 to 70 g/dL, repeat samples should be obtained 2 to 4 weeks post-treatment and monthly thereafter until levels remain below 25 g/dL. With repeated courses of chelation, concern about essential trace element depletion has been raised. Further nutritional counseling and the use of supplements may be of benefit, but there are no controlled trials. Follow serum zinc and copper levels and ferritin to guide treatment.
Biological neurotoxins abound in nature. Humans may be affected by environmental exposure, ingestion, or envenomation. Gastrointestinal manifestations are common and may result in electrolyte disturbances and volume depletion. Supportive therapy includes maintenance of electrolytes and preservation of cerebral and renal perfusion. Pain control is important for envenomations. Judicious use of antivenins and maintenance of cardiopulmonary function may be life saving. For some biological toxins, specific medications may be indicated (Table 1).
Ingested Marine Toxins

Toxic-producing marine microorganisms include marine algae, bacteria, dinoflagellates, and diatoms. Harmful algal blooms are one of the most economically significant and scientifically complex coastal issues facing our nation today. Virtually every coastal state has reported major toxic blooms, which can cause human illness and death, alter marine habitats, and adversely impact marine and recreational industries. Their neurotoxins may be harmless to many fish and shellfish but result in toxicity when ingested by marine mammals or humans. Ingestion typically results in gastrointestinal disturbances of emesis and diarrhea, followed by sensorimotor disturbances. CIGUATERA Ciguatera results from the ingestion of toxin-laden tropical reef fish, with most of the symptoms attributable to ciguatoxin, although other toxins may coexist to
355
TABLE 1 Standard Treatments for Marine and Biological Toxins

Serious Drug Side Effects Dehydration, hypotension, electrolyte imbalance Agitation, confusion, hallucinations, Stevens-Johnson syndrome Confusion, agitation, seizures Constipation, pancreatitis Serum sickness, anaphylaxis Serum sickness, anaphylaxis Serum sickness, anaphylaxis Serum sickness, anaphylaxis Serum sickness, anaphylaxis Hypersalivation, dyspnea, seizures
Indication Ciguatera Tetrodotoxin Scombroid
Drug/treatment Mannitol Pulmonary resuscitation Cimetidine
Dose 1 gm/kg of a 20% solution 300 mg
Route IV IV
Diphenhydramine
10-50 mg 9 gm qid for 2 wk See package insert See package insert See package insert See package insert See package insert 0.5-2 mg; may repeat q 10-30 min prn
PO/IV/IM PO IV/IM IV/IM IV/IM IV/IM IV/IM IM or slow IV (not > 1 mg/min IV) IV
Pfiesteria
Jellyfish
Cholestyramine Topical vinegar/hot water immersion 45-50C, 113-120F Antivenin (Chironex) Antivenin where available Heat therapy Pulmonary resuscitation Pulmonary resuscitation, hemodialysis with myotoxicity Coral snake antivenin Crotalidae antivenin Sea snake antivenin Physostigmine
Venomous fish Cone snails Snake bites Eastern coral snake Viper bite Sea snake Datura species Mushroom poisoning Amanita phalloides Gyromitrin
14
Liver transplant Pyridoxine
25 mg/kg over 15-30 min; may be repeated prn to a total dose of 15-20 gm/day 1-2 mg initially; repeat prn q 20-30 min 2-10 mg 2-5 mg See package insert Adults: 500-800 mg IV of 10% solution (5-8 mL) Infants and children: 60-100 mg/kg (0.6-1 mL/kg)
Peripheral neuropathy, neuronopathy, seizures, headache Cardiac arrhythmias, respiratory depression Neuroleptic malignant syndrome, cardiac arrhythmias Sedation Serum sickness, anaphylaxis Hypotension, cardiac arrest, confusion, cardiac arrhythmias, atrioventricular block
Muscarin Psilocybin
Atropine Haloperidol (Haldol) Diazepam
IV/IM IM/IV IV/PO IV/IM IV
Black widow spider
Latrotoxin antivenin Calcium gluconate
Tick paralysis
Remove tick
356
cause cardiovascular instability or contractile muscular responses. Ciguatoxin opens sodium channels, especially at the nodes of Ranvier, to result in nodal swelling and interference with salutatory conduction. Experimentally, such nodal swelling may be reversed with mannitol. Clinical series have shown that parenteral mannitol (1 gm/kg of a 20% solution), if given within the first few hours, may result in dramatic improvement. However, mannitol has been shown in a double-blinded study to be no better than normal saline if treatment is delayed by a mean of 6.5 hours after the onset of ciguateric symptoms. Symptoms may persist chronically or transiently flair after ingestion of fish, fishmeal-fed poultry, serotonin-rich diets, or alcohol, necessitating avoidance of these foods. SHELLFISH TOXINS Shellfish toxins include those associated with dinoflagellate blooms that may discolor the ocean water (red tides) and result in massive fish fills from saxitoxin (paralytic shellfish toxin) or brevetoxins (neurotoxic shellfish poison), as well as diatom blooms of domoic acid (amnestic shellfish toxin). The emesis associated with brevetoxin ingestion helps purge some of the toxins from the patient and may contribute to its rather mild symptomatology. Neurologic symptoms from saxitoxin are not consistently preceded by gastrointestinal symptoms, and the patient may present only with an acute syndrome of sensory disturbances with significant bulbar and limb paralysis. Gastric lavage and the administration of activated charcoal in saxitoxin are therefore important in the initial management of saxitoxin ingestion if diagnosed early. Because an acid pH may enhance the effects of saxitoxin, correction of respiratory acidosis with appropriate ventilatory support and serum alkalization may be helpful. Investigators at the National Oceanographic and Atmospheric Administration have shown that cholestyramine may reduce the toxic effects of brevetoxin in mice, but its usefulness has yet to be established in human ingestion of brevetoxins (although useful in Pfiesteria toxicity) (see later). Domoic acid, a glutamate agonist structurally similar to kainic acid, may produce a severe amnestic syndrome with temporal lobe seizures. The onset of symptoms is typically more than 24 hours after ingestion of toxic shellfish, and induced emesis with gastric lavage is therefore of little value once central nervous system (CNS) manifestations occur. As with other shellfish toxins, no specific antidote exists, although based on the pharmacology of domoic acid, the use of benzodiazapines or theoretically glutamate antagonists such as valproic acid or kynurenic acid might be helpful in suppressing the excitotoxic effects. Supportive care is essential with attention to stabilizing cardiopulmonary status and control of seizures when present. TETRODOTOXIN Tetrodotoxin is produced by marine bacteria and may be found in some (but not all) pufferfish as well as the California newt; frogs of the genus Atelopus; the
blue-ringed octopus; and some species of starfish, parrotfish, angelfish, gastropod mollusks and xanthid crabs. An initial feeling of lightness or floating is generally followed by gastrointestinal distress. These symptoms are followed by increasing paralysis with loss of limb and brainstem reflexes and respiratory compromise. Gastric lavage and activated charcoal are often helpful if given early in the course of the poisoning. No antidote exists, and treatment is supportive, with attention to cardiopulmonary support. SCOMBROID Scombroid poisoning is the most common seafood poisoning in the United States related to the improper storage of fish, mostly large pelagic fish of the Scombridae family. Enteric bacteria (Escherichia coli, Proteus morganii, Proteus vulgaris) act on the flesh of the fish to produce elevated histamine levels through the breakdown of histidine. Scombroid-laced fish is sometimes described as tasting peppery, which is thought to be related to elevated histamine levels. Nausea, headache, and a burning sensation of mouth and oropharynx are common neurologic symptoms. Exposures often mimick an allergic reaction due to urticarial rash and pruritus. Scombroid exposure responds to charcoal, along with aggressive symptomatic care with histamine blockers. The H2 blocker cimetidine, 300 mg intravenously (IV), has been shown to be effective in scombroid poisoning. The addition of the H1 blocker diphenhydramine 50 mg IM is recommended to minimize the vascular effects of histamine. Corticosteroids are occasionally needed. Scombroid exposures are self-limited and hence long-term therapy is usually unnecessary.
Aerosolized Marine Toxins

Brevetoxins within red tides may be aerosolized by rough seas or breaking waves. Although no specific pharmacologic therapy is recommended for ingested brevetoxins, medications for bronchospasm may be needed following aerosolized exposures. Recreational water activities amidst dead fish in brackish estuaries of the eastern United States may aerosolize the toxin of Pfiesteria. Ventilation defects in laboratories have also resulted in aerosolization of Pfiesteria toxin. Such exposures may result in conjunctival irritation, rhinorrhea, wheezing, and coughingsymptoms that may be treated symptomatically. Handling of affected fish (typically with ulcerative skin lesions) may also result in exposure to Pfiesteria. For the more severe neurobehavioral and cognitive symptoms of Pfiesteria, cholestyramine may be useful. Cholestyramine (9 gm orally four times a day for 2 weeks) has been shown to reduce Pfiesteria-associated symptoms and to hasten visual contrast sensitivity recovery time. Chlorinated bleach kills Pfiesteria in laboratory practice, and skin exposed to ulcerative dead or dying fish may be rinsed liberally with bleach (diluted with 10 parts water).
357
Contact Marine Toxins

Prevention of envenomation by jellyfish, venomous fish, and cone snails is extremely important when entering the marine environment. Awareness of the habitat, attention to swarming patterns and sightings, and usage of protective footwear and clothing may further decrease the risk of envenomation. The venoms of jellyfish and venomous fish contain large proteins that typically produce severe and immediate pain. These toxins are thermosensitive and may be degraded by heat. Class I studies have established the efficacy of heat therapy for envenomations by jellyfish and Class III support for venomous fish envenomations. Affected areas are characteristically very painful, and a contact urticarial rash with hemorrhagic features further identifies sites of envenomation from jellyfish nematocysts. Provided vital signs are stable, affected body parts may be immersed in hot water (45 to 50C [113 to 120F]), which may result in almost immediate relief of pain. Immersion of an unaffected limb can monitor against excessively hot water and reduce the risk of scalding. For jellyfish stings, topical vinegar may prevent undischarged nematocysts from activating and hence limit envenomation until heat therapy is available. The spines from venomous fish may require surgical dbridement, wound irrigation, and removal of any retained fragments. Local anesthetic agents (e.g., 1% lidocaine without epinephrine) may also be helpful in pain control. Antivenins are manufactured in Australia for the Australian box jellyfish (Chironex) and the deadly stonefish. Stonefish antivenins may also be given for severe systemic reactions to scorpion fish envenomations. Mortality from major envenomations by large Chironex may exceed 15%, with death over the initial 10 minutes, which does not allow sufficient time for test dosing for serum sickness reactions. Antivenins for weeverfish and scorpionfish are manufactured in Croatia. Antivenins should be used according to package insert. Cone snail venoms contain thousands of toxic neuropeptides, with marked specificity for receptors. Conus peptides can discriminate between closely related cellular targets. Both presynaptic and postsynaptic actions result in an effective blockade of neuromuscular junction transmission, with resulting rapid muscular paralysis with respiratory insufficiency. Most envenomations occur while handling the cone snail. Pulmonary resuscitation may be critical until mechanical ventilation is available. Survivors may experience intense local pain at the site of envenomation, which may benefit from injections of local anesthetic agents.
hemolytic toxins, and myotoxins. Immobilization of the envenomation site, inactivity, and hydration are important supportive measures. The Florida Antivenin Bank makes antivenins available for emergency use through the Miami-Dade Fire Rescue Venom Response Unit (305-596-8576). Both polyvalent Crotalidae antivenins and eastern coral snake monovalent antivenins are manufactured within the United States by Wyeth-Ayerst. Antivenins for Elapidae species are manufactured in South America and India. Sea snake monovalent antivenins are manufactured in Australia. Structural similarities between the venoms of land and sea snakes enable the substitution of land snake antivenin for sea snake antivenin if the latter is not available. Generally the IV route is preferred for antivenin administration. Intramuscular administration may be used, but the antivenin should be injected into a large muscle mass. The antivenin is most effective when given within 4 hours after an envenomation. The possibility of anaphylaxis needs to be considered with all antivenins, and hence the urgency of the medication needs to be weighed against the need for skin testing. In 1998, CroTab, a sheep-derived Crotalidae polyclonal antibody, was developed. Sheep-derived polyclonal antibodies are known to produce a reduced allergic response in humans. This proprietary process purifies the final product by separating the antibody fragments and discarding those known to produce allergic responses and other side effects. Antivenin premedication with steroids and diphenhydramine should be considered. Hemodialysis may be needed to prevent renal failure associated with myotoxins. Skin testing for serum sickness reactions should be in accordance with package insert for the antivenin utilized.
14
Plant Toxins: Datura and Toxic Mushrooms

Belladonna alkaloids include hyoscine, hyoscyamine, atropine, and scopolamine. These anticholinergic plant toxins are found in Datura species, to include Angels trumpet (Datura candida) and Jimsonweed (Datura stramonium), and toxicity results after consumption of herbal tea made from these plants or after ingestion of seeds, leaves, or flower nectar. Anticholinergic signs and delirium are common. Supportive measures may include activated charcoal, bladder cauterization for urinary retention, and upper gastrointestinal gentle suction for ileus. Benzodiazepines can be used as necessary for agitation. Physostigmine (adult dose 1 to 2 mg over 5 minutes) may be needed for uncontrollable hyperthermia, supraventricular tachycardia with hemodynamic instability, therapy-resistant seizures, extreme delirium, or coma. Toxic mushrooms include Amanita phalloides, gyromitrin, muscarin, and psilocybin species. Correct diagnosis often depends on an intact specimen for prompt identification by a qualified mycologist. Mortality with Amanita varies from 30% to 90%, which in part is due to hepatic encephalopathy. Liver toxicity from gyromitrin is less pronounced, and death is exceedingly rare.
Snake Envenomations
In general, the apparatus for envenomation in sea snakes is less effective than that found among land snakes, but the toxins are much more potent. Most bites by sea snakes do not result in envenomation, particularly if a wetsuit is worn. Snake toxins include neurotoxins,
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With all toxic mushroom ingestions, gastrointestinal decontamination, when appropriate, and supportive care are necessary. With gyromitrin it is relevant to give high-dose pyridoxine (25 mg/kg IV, repeated according to clinical status) in cases of severe CNS toxicity. If pyridoxine fails to cure seizures, a benzodiazepine such as diazepam should be given. Acetylcysteine and folinic acid have also been discussed for gyromitrin poisoning on a theoretical basis, but their usefulness remains unclear. No controlled clinical trials are available to support the utilization of pharmacologic agents for hepatic toxicity, although liver transplantation can be life saving for those with acute liver failure secondary to Amanita. Treatment with charcoal hemoperfusion may be helpful but probably is ineffective. Forced diuresis with sodium bicarbonate may also be helpful, eliminating 60% to 80% of the total urinary amanitin in the first 2 hours. Although there are no controlled clinical trials, a few anecdotal studies provide the basis for regimens recommended to treat Amanita poisoning, including the use of IV penicillin G (or silibinin when available) and thioctic acid (or alpha-lipoic acid). Muscarin poisoning produces parasympathetic hyperactivity and can be treated symptomatically with atropine. Psychotic symptoms or agitation associated with psilocybin can be treated symptomatically with neuroleptics or benzodiazepines.
Tick Paralysis
Toxins are contained in the tick saliva. Typically the patient has an acute ascending paralysis over days with no sensory symptoms. The toxins have been shown to block axonal sodium channels and also inhibit the release of acetylcholine at presynaptic motor nerve terminals causing total neuromuscular blockade. The tick species responsible for most cases of human tick paralysis in the United States and Canada are Dermacenter andersonii (the Rocky Mountain wood tick), and Dermacenter variabilis (the American dog tick). Tick paralysis can be confused for a number of disorders but usually is mistaken for Guillain-Barr syndrome. Detection and removal of the tick usually results in rapid improvement (hours to 1 or 2 days) in the patients condition. A careful search for the tick with a fine-tooth comb can be helpful. Antiserum is generally not recommended nor necessary. SUGGESTED READING
Felz MW, Smith CD, Swift TR: A six-year-old girl with tick paralysis, N Engl J Med 342:90-94, 2000. Karlson-Stiber C, Persson H: Cytotoxic fungi: an overview, Toxicon 42:339-449, 2003. Oberndorfer S, Grisold W, Hinterholzer G, Rosner M: Coma with focal neurological signs caused by Datura stramonium intoxication in a young man, J Neurol Neurosurg Psychiatry 73:458-459, 2002. OMalley GF, Dart RC, Kuffner EF: Successful treatment of latrodectism with antivenin after 90 hours, N Engl J Med 340:65, 1999. Scott S, Thomas C: Poisonous plants of paradise, Honolulu, 2000, University of Hawaii Press. Spencer PS, Schaumburg HH, Ludolph AC: Experimental and clinical neurotoxicology, 2 ed, New York, 2000, Oxford University Press. Stommel EW, Watters MR: Marine neurotoxins: ingestible toxins, Curr Treat Options Neurol 6:105-114, 2004. Watters MR, Stommel EW: Marine toxins: envenomations and contact toxins, Curr Treat Options Neurol 6:115-123, 2004.
Black Widow Spider Envenomation

Black widow spiders (Latrodectus) contain latrotoxins that stimulate neuronal calcium channels to result in excessive exocytosis of synaptic vesicles, leading to serious neuromuscular, neurosecretory, and cardiovascular effects. Death is rare but may occur in young children or elderly hypertensive individuals. Latrotoxins do not cross the blood-brain barrier, and symptoms derive from somatic and autonomic peripheral nervous system cholinergic and neuromuscular junction actions. A specific antivenin neutralizes the venom of all Latrodectus species and should be administered according to package insert. Symptomatic treatment includes the use of analgesics, muscle relaxants, and IV calcium gluconate.
PATIENT RESOURCES
Centers for Disease Control and Prevention (Marine Toxins) http://www.cdc.gov/ncidod/dbmd/diseaseinfo/marinetoxins_g.htm Toxins of Biological Origin (The EH&S Biosafety Office) http://www.ehs.ufl.edu/Bio/toxin.htm/ Venomous Reptiles on the Net http://www.venomousreptiles.org/
SECTION 15
Peripheral Nerve Disease

Richard K. Olney, M.D.
endotracheal intubation when force vital capacity has fallen below 15 mL/kg of body weight. Occasionally, monitoring may be performed initially in a standard inpatient room for ambulatory patients with normal forced vital capacity and maximum inspiratory force who present after 2 weeks of neuropathic symptoms. SUPPORTIVE CARE The most critical aspect of supportive care is respiratory support, since intubation is required in approximately 30% of patients. Ventilator-dependent patients remain in the ICU. Tracheostomy is performed electively in the majority who remain ventilator dependent for more than 2 weeks. Although labile blood pressure is common, another life-threatening complication of GBS that is rare but difficult to treat is cardiovascular collapse. Increases in intravenous fluid volume may be adequate for minor episodes of hypotension. The choice of IVIg over PE helps expand intravascular volume in patients with hypotension. In rare cases, denervation of arteriolar musculature may cause cardiovascular collapse that may not respond to pressor agents, particularly in a predictable manner, due to denervation hypersensitivity. Nutritional maintenance is an important aspect of care. For patients without dysphagia, a regular diet is adequate. Occasionally pureed foods may be adequate for patients with mild dysphagia; however, this is often just an interim solution for a day or two. As soon as dysphagia from bulbar weakness raises concern for aspiration, I have a nasogastric or nasojejunal tube placed to maintain adequate caloric and micronutrient intake. If bulbar function is not likely to recover over the initial 2 weeks, I then recommend replacement of this nasoenteral tube with a percutaneous endoscopic gastrostomy. I initiate a physical therapy referral on admission. Initially this treatment focuses on ensuring that each joint receives a full range of motion several times a day. This usually consists of passive range of motion for all joints for which strength is less than 3 of 5 MRC. Also, gentle active range of motion is encouraged for those joints for which surrounding strength is 3 or better. I recommend aggressive active physical therapy only after the nadir of weakness has passed and improvement begins. 359
Diagnosis
Guillain-Barr syndrome (GBS) is an acute inflammatory polyradiculoneuropathy. Although the onset is often heralded by tingling in the hands or feet, GBS is characterized by symmetric weakness and loss of tendon reflexes that progress over several days to 4 weeks, with approximately half of cases reaching maximal weakness within 2 weeks. Sensory impairment is usually minimal but infrequently prominent. The diagnosis is usually confirmed by elevated cerebrospinal fluid protein that is not associated with a pleocytosis and often by characteristic nerve conduction abnormalities.
Treatment
Patients with GBS require close monitoring, supportive care, and, if deficits are becoming significant, treatment with intravenous immunoglobulins (IVIgs) or plasma exchange (PE). MONITORING PROGRESSION I admit all patients who are suspected to have GBS for diagnostic evaluation and close observation. Since approximately 30% of patients with GBS require ventilatory support, close observation is performed in the intensive care unit (ICU) or a step-down unit, so that forced vital capacity and maximal inspiratory pressure can be measured every 4 hours. Intubation is safest when performed electively prior to respiratory arrest. Arterial blood gases are not too helpful in recognizing the timing for endotracheal intubation, because neither oxygen concentration falls nor carbon dioxide concentration rises until respiratory arrest is eminent. Respiratory failure is recognized most sensitively by monitoring maximum inspiratory pressure and forced vital capacity. I recommend elective
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Other supportive measures are those typical for most ICU patients. Measures to help prevent deep vein thrombosis and pressure sores are started on admission for those who are not ambulatory. Development of pulmonary embolism and hospital acquired infection are other life-threatening conditions that may be prevented or treated. INTRAVENOUS IMMUNOGLOBULINS OR PLASMA EXCHANGE I treat patients with GBS who are unable to walk without assistance within 4 weeks of neuropathic symptom onset with either IVIg or PE. Clinical trials support greater benefit when treatment is initiated within 2 weeks of neuropathic symptom onset, especially for IVIg; however, approximately half of patients with GBS do not reach their nadir until after 2 weeks, so I prescribe treatment for patients between 2 and 4 weeks after onset, if progression is continuing over the most recent few days. I also start treatment for those patients who I think are likely to become unable to walk without assistance. These latter patients are generally patients who present within the first 2 weeks after onset of neuropathic symptoms and in whom the combination of current motor deficits and time to reach this level suggests to me from my experience that loss of ambulation is probable over the next few days. This decision may be made at admission or after 1 or 2 days of observation in the hospital. IVIg and PE are equally effective, and the combination of both has not been shown to be more effective than either alone. I prescribe whichever treatment can be started more quickly, unless there is a known contraindication to one modality. The usage of prednisone or methylprednisolone has not been shown to be of benefit in GBS, so these drugs are not used. Unless there is a shortage or recall, IVIg treatment can almost always be started more quickly, often within a few hours of admission. The primary contraindication to IVIg therapy is immunoglobulin A (IgA) deficiency; if the patient with GBS has a personal history of recurrent respiratory infections or autoimmune disease or a family history of IgA deficiency, IgA levels are measured before administration of IVIg. In such patients, PE may often be started more rapidly than IVIg in our medical center, depending on the time and day of admission. The total dosage of IVIg is 2 gm/kg over 2 to 5 days. I prescribe 0.4 gm/kg/day for 5 consecutive days, since this is the dosage schedule that has been studied most thoroughly in clinical trials. In young patients who have low risk for thrombotic events, I do not object to more rapid administration, at 1 gm/kg/day for 2 days. However, I advise against this more rapid administration schedule in patients who are older than 60 years of age; who have a personal history of angina pectoris, myocardial infarction, transient ischemic attack, or ischemic stroke; or who have a family history of these vascular events at ages younger than 60 years. PE may be started more rapidly than IVIg in occasional patients, if IVIg is not available or there is a specific clinical concern of IgA deficiency. The most
common contraindication to PE is hypotension or labile blood pressure. In GBS patients who have tachycardia or episodes of blood pressures lower than 100/50 mm Hg, I strongly prefer IVIg therapy. PE is more invasive and requires insertion of a double-lumen catheter (such as a Quinton), which often causes a 6- to 12- hour delay in initiating treatment. The usual volume of PE is 1 to 1.5 blood volumes (40 to 60 ml/kg of body weight). Four to six PEs are performed typically on an alternateday schedule, using albumin as replacement. I always prefer a full course of six exchanges. If concern for infection from the central catheter requires its removal after four or five exchanges have been completed, I do not have another central line reinserted. Occasionally patients need to be retreated with IVIg or PE. These are patients who have started to improve during the initial course of treatment with IVIg or PE and then start to become weaker again 1 to 2 weeks later. Repeated treatment with the original modality is usually chosen; however, if the initial treatment was PE and the reason for not using IVIg initially has been resolved (e.g., IgA level has been tested and is now known to be normal), the use of IVIg is less invasive and often easier. OTHER TREATMENTS Pain is not unusual during the acute progressive phase of weakness. Cramping pain is sometimes relieved adequately with quinine sulfate 300 mg every 12 hours. I do not hesitate to prescribe narcotic analgesics to those whose pain is not adequately palliated by quinine. SUGGESTED READING
Hughes RA, Wijdicks EF, Barohn R, et al: Practice parameter: immunotherapy for Guillain-Barr syndrome. Report of the Quality Standards Subcommittee of the American Academy of Neurology, Neurology 61:736-740, 2003. Kieseier BC, Hartung HP: Therapeutic strategies in the GuillainBarr syndrome, Semin Neurol 23:159-168, 2003. Sheikh KA, Griffin JW: Variants of the Guillain Barr syndrome: progress toward fulfilling Kochs postulates, Ann Neurol 49: 694-696, 2001.
PATIENT RESOURCES
Guillain-Barr Syndrome Foundation International http://www.guillain-barre.com/ At this site, much useful information is available to patients and family members. Especially for ventilator-dependent patients, a visit from a former GBS patient can be arranged and is usually quite helpful.
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Carol Lee Koski, M.D.
Immune or inflammatory mechanisms are implicated in a number of chronic disorders affecting the peripheral nerves and sensory ganglia. One of the more commonly recognized is idiopathic chronic inflammatory demyelinating polyneuropathy (CIDP). CIDP is distinguished from more subacute neuropathies by its clinical course that may progress steadily or in a stepwise fashion over a period of more than 8 weeks. Its relatively symmetric motor and sensory involvement of extremities is associated with a loss of deep tendon reflexes. A recurrent variety also exists in which monophasic episodes in individual patients may be separated by months to years. A predominantly sensory form can occur resulting in sensory ataxia; however, 70% of patients develop motor signs within 2 to 3 years. A primary axonal form is also proposed, although its diagnosis is one of exclusion. CIDP is clinically distinct from a variety of other chronic acquired demyelinating polyneuropathies including multifocal motor neuropathy, multifocal motor sensory neuropathy (Lewis-Sumner syndrome), and selected paraprotein-associated polyneuropathies. One of the critical issues facing the practicing neurologist is early recognition and treatment of CIDP patients when they are more likely to respond and in some cases go into remission. Unfortunately there is no definitive diagnostic test. The diagnosis instead is based on the clinical history and neurologic examination and
is supported by electrodiagnostic studies, cerebrospinal fluid (CSF) findings, blood studies to exclude other disorders, and, infrequently, nerve biopsy. Particularly early patients may have predominantly sensory paresthesias prior to the onset of motor weakness. However, even then nerve conduction studies can show features of peripheral nerve demyelination with partial motor conduction block at other than compression points, temporal dispersion of compound action potentials, prolonged distal and F wave latencies, and reduced conduction velocities that involve at least two and frequently more nerves as the course extends over time. CSF frequently shows increased protein and normal cell counts. Nerve biopsy is usually not required but should be considered in cases where the diagnosis is in question, for example, with pure sensory syndromes or where other etiologies such as vasculitis are suspected. In CIDP the biopsy shows inflammatory infiltrates, macrophage-mediated demyelination, remyelination, and onion bulb formation. Although the pathophysiology underlying CIDP is not well understood, up to 80% of CIDP patients respond to one or more therapeutic regimens that have been tested in open-label or randomized, controlled trials. An individual patients clinical response to immunomodulatory therapy can confirm a hypothesis of endoneurial inflammation. As an initial measure, patients can be treated with corticosteroids, plasma exchange, or intravenous immunoglobulin (IVIg) (Figure 1). The results from a single randomized, controlled trial of 28 patients provided limited evidence that oral prednisone (1 mg/kg body weight), given in decreasing doses over 9 months, induced a small but significant improvement in patients with CIDP as determined by graded muscle strength, neurologic disability, and some attributes of nerve conduction.
15
CIDP
Pulse methylprednisilone 1g i.v. x 5 dys/mo
IVIg 2g/Kg
Plasma exchange 5 times, qod
Prednisone 60100 mg po/day 36 mo Taper monthly by 510 mg/day No relapse Relapse
Pulse methylprednisilone 1g i.v. x 5 dys/mo
IVIg 1 g/Kg every 46wks 36 mo Extend interval between infusions
Pulse cyclophosphamide 1 g/m2 every mox3 Relapse Repeat 23 pulses Relapse Immunophilin No relapse Monitor
No relapse Continue infusions every 34mo
Relapse
Taper to qod
Add cyclophosphamide, azathioprine, mycophenolate mofetil or immunophilin
FIGURE 1. Algorithm for the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP). IVIg, Intravenous immunoglobulin. Johnson: Current Therapy in Neurologic Disease (7/E)
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A Cochrane review of corticosteroid use for this disorder concluded that the trial results provided relatively weak support for the extensive anecdotal use of corticosteroids. Although treatment with corticosteroids is relatively inexpensive, a wide range of psychiatric and metabolic consequences is associated with its chronic use. These include irritability, depression, psychosis, hyperglycemia, osteoporosis, ischemic necrosis of the head of the femur, hypertension, gastric ulcers, and weight gain. These side effects contribute to morbidity as well as to an economic burden that increases as duration of treatment and dosage increase. Other approaches to corticosteroid therapy, such as alternate-day therapy or pulsed doses of intravenous methylprednisolone given as 1 gm/day over 5 days each month, can be used to limit side effects, but over time, in my own experience, side effects still develop. Randomized, controlled trials have also demonstrated that both plasma exchange and IVIg induce a rapid but temporal improvement in the neurologic disability score, nerve conduction attributes, and grip strength within 2 to 6 weeks in 56% to 100% of patients. With plasma exchange, an initial course consists of five exchanges performed on alternate days. Clinical improvement is lost within 7 to 14 days if plasma exchange is discontinued. Under the supervision of an experienced plasmapheresis team the procedure is usually well tolerated, but complications can include cardiac arrhythmia from electrolyte imbalance, citrate-induced hypocalcemia, hemolytic anemia, infection and thrombosis at the site of venous access, allergic reactions leading to anaphylaxis and activation of coagulation, complement and fibrinolytic cascades, as well as aggregation of platelets. Hypotension during plasma exchange is aggravated by the concomitant administration of angiotensinconverting enzyme inhibitors. During the course of plasma therapy, patients are anticoagulated due to the loss of platelets and clotting factors removed with plasma. In the absence of liver dysfunction, clotting factors in the circulation return to normal within 24 hours. Use of this procedure is limited by the need for chronic central venous access, which can be associated with sepsis most commonly due to Staphylococcus. As a consequence of all these issues, plasma exchange may be used in the initial management of patients to establish immunoresponsiveness, or in the short term during institution of another regimen. Most patients ultimately require other measures for long-term maintenance. The efficacy of IVIg appears to be similar to that of plasma exchange. Because of the ease of IVIg administration through a peripheral line and ability to give the drug in the outpatient setting, it is frequently my initial treatment of choice. In many patients a beginning response can be documented with improved motor function within 3 to 5 days of infusion. Continued improvement can occur over 3 to 6 weeks prior to relapse of symptoms, but the response can be frequently maintained with 1 gm/kg body weight given on a monthly basis. IVIg is usually well tolerated particularly in initial courses of IVIg, and preparations available are thought to be safe since no incidence of human immunodeficiency virus, hepatitis B, or prion
disease transmission was reported. Side effects can occur in a limited number of patients, some of which are more severe than others. The more common of these reflect infusion rate and can include headache, myalgias, fever, chills, tachycardia, and hypertension. They can be limited by slowing the infusion rate or by premedication with aspirin, acetaminophen, methylprednisolone, or diphenhydramine. Other more serious adverse events, occurring in approximately 0.04% of patients, are delayed and reflect both product and patient factors. These delayed effects include renal tubular necrosis, thromboembolic events, aseptic meningitis, anaphylaxis, and hemolysis. A macular-papular rash of the forehead, forearms, and chest may occur in the first 2 weeks following administration. Occasionally, the rash may be leukocytoclastic. The development of thromboembolic events with IVIg treatment is multifactorial, reflecting the osmolality of the IVIg product as well as a prior history of atherosclerotic or cardiovascular disease in individual recipients. If IVIg is given to patients with a potential risk for thromboembolic events, the infusion concentrations should be limited to 5% and lyophilized products reconstituted with water when possible to further reduce the hyperosmolarity. Patients should be on platelet inhibitors such as aspirin and under some circumstances, such as with a history of deep vein thrombosis, subcutaneous enoxaparin or heparin. The incidence of renal failure is more frequently associated with hyperosmolar sucrose-stabilized products but has occurred using most of the products on the market. One of the best predictors of this adverse event is preexisting renal compromise in patients. IVIg should be avoided in patients with clearly documented renal disease and used cautiously in patients with a creatinine of 1.5. In a significant proportion of patients, CIDP is not self-limiting and, if untreated, can lead to serious disability and wheelchair dependence. Disease can smolder for years and may have to be treated over a prolonged period. Maintenance of all of the regimens thus far discussed may have serious consequences, both medical and economic. Although inexpensive, corticosteroids frequently have to be maintained at high levels for at least 3 months and then gradually withdrawn each month by 5 to 10 mg/day. It is usual for patients to be on the drug for at least 1 year. Even patients with good clinical responses to higher doses can relapse as the drug is lowered or in trying to switch to an alternateday regimen. Side effects associated with corticosteroids such as depression, weight gain, osteoporosis, and glucose intolerance have significant long-term medical consequences with reduced quality of life. In younger patients in whom IVIg is well tolerated, I prefer to maintain them on IVIg rather than expose them to prolonged use of drugs such as corticosteroids or other potentially teratogenic drugs that might cause sterility. CIDP frequently can be controlled on doses of 1 gm/kg each month that with time can be given at longer intervals provided the patient does not relapse. In older patients with comorbid disease, chronic IVIg use over the last 5 years has led to a doubling of thromboembolic sequelae. In these particular patients who are older and are nonreproductive, immunosuppressive drugs such as
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cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil, azathioprine, and interferon (IFN)-1 and IFN- can be used to limit steroid and immunoglobulin use and may be indicated because of progression or poor response to alternate therapies. One anecdotal series of patients were treated with the cytotoxic drug, cyclophosphamide, which was given as a pulsed dose of 1 gm/m2 each month for 3 to 6 months. Prior to the therapy patients were hydrated orally with 2 L of water and received antiemetic drugs, including 20 mg of intravenous dexamethasone and 10 mg of intravenous metoclopramide. Total white blood cell and lymphocyte counts were monitored weekly to measure myelosuppression and effectiveness of the dose given. Monthly treatments were discontinued after the patients showed sustained improvement over at least 2 months without relapses between pulses. More than 80% of patients had a remission in response to this protocol when they were treated within the first 2 years of disease. Thirty percent of these patients relapsed and required retreatment in 6 to 36 months. Retreatment was followed by long-term remission. Treatment with cyclophosphamide seriously worsened the condition of two patients who had the disease for 10 years or longer. This paradoxical response was noted previously with other regimens in patients with long-established disease and suggests a disturbance of a regulatory immune mechanism that limits disease progression. Although cyclophosphamide may be indicated in some patients because of progression and poor response to alternate therapies, in other patients the potential consequences of sterility, teratogenicity, and myelosuppression limit its use. In a limited number of patients I have successfully used mycophenolate mofetil, 1 gm orally twice a day, to discontinue IVIg use. This drug, which is like azathioprine but unlike cyclophosphamide, is not cytotoxic for dividing cells. Therefore to maintain the response the drug had to be given on a more chronic basis. With stable control of disease, gradual drug withdrawal must be carefully monitored for relapse. In this chapter my comments are limited to management of idiopathic CIDP. Other immune-mediated endoneurial neuropathies may not respond to therapy in the same manner. For example, corticosteroid and plasma exchange may be poor choices for multifocal motor neuropathy because of reduced efficacy and increased morbidity. In CIDP randomized and controlled trials support the use of corticosteroids, plasma exchange, and IVIg, whereas anecdotal experience suggests that cytotoxic and myelosuppressive drugs contribute to remission. Selection of a therapeutic regimen should take into consideration not only drug efficacy but also the age, reproductive status, and comorbid disease in a given patient as well as the likely chronicity of the disease process. Comorbid disease in patients can prevent the use of a particular therapy. Corticosteroids may be contraindicated in patients with diabetes mellitus or osteoporosis. A history of allergy, antibodies to IgA, or renal disease may prevent the use of IVIg. Poor venous access, cardiovascular instability, and availability of the technology may limit the use of plasma exchange. Antimetabolites, alkylating agents,
and immunophilins all have known teratogenic effects that may be cumulative over an extended period of use and associated with increased sterility and lymphoproliferative disease in future years. In addition, patients with preexisting hepatic, hematopoietic, or renal disease may not tolerate individual drugs. Most CIDP patients, if treated early and aggressively, respond well to therapy with preservation of endoneurial function. SUGGESTED READING
Dyck PJ, Litchy WJ, Kratz KM, et al: A plasma exchange versus immune globulin infusion trial in chronic inflammatory demyelinating polyradiculoneuropathy, Ann Neurol 36:838-845, 1994. Dyck PJ, OBrien PC, Oviatt KF, et al: Prednisone improves chronic inflammatory demyelinating polyradiculoneuropathy more than no treatment, Ann Neurol 11:136-141, 1982. Good JL, Chehrenama M, Mayer RF, Koski CL: Pulse cyclophosphamide therapy in chronic inflammatory demyelinating polyneuropathy, Neurology 51:1735-1738, 1998. Hahn AF, Bolton CF, Pillay N, et al: Plasma-exchange therapy in chronic inflammatory demyelinating polyneuropathy: a double-blind, sham-controlled, crossover study, Brain 119(pt 4): 1055-1066, 1996. Hahn AF, Bolton CF, Zochodne D, Feasby TE: Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy: a double-blind, placebo-controlled, crossover study. Brain 119(pt 4):1067-1077, 1996. Hughes R, Bensa S, Willison H, et al: Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy, Ann Neurol 50:195-201, 2001. Mehndiratta MM, Hughes RA: Corticosteroids for chronic inflammatory demyelinating polyradiculoneuropathy, Cochrane Database Syst Rev 1:CD002062, 2002. Mendell JR, Barohn RJ, Freimer ML, et al: Randomized controlled trial of IVIg in untreated chronic inflammatory demyelinating polyradiculoneuropathy, Neurology 56:445-449, 2001.
15
Painful Neuropathy
Beth Murinson, M.D., Ph.D.
The term painful neuropathy is broadly used to describe disorders arising from disease of the peripheral nerves and resulting in pain. In the narrowest sense painful neuropathy can be used to mean the pain syndrome associated with distal symmetrical peripheral neuropathy (DSPN) or small-fiber neuropathy. For this chapter, the broad range of possibilities is important because it is often the case that patients referred for evaluation and treatment of painful neuropathy have something other than DSPN. The neurologist must be prepared to recognize these alternatives and direct the treatment plan accordingly. Although these alternative diagnoses are considered here, they are covered in detail in other chapters of this book, and the latter part of this chapter is directed toward the evaluation and treatment of patients with small-fiber neuropathy.
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cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil, azathioprine, and interferon (IFN)-1 and IFN- can be used to limit steroid and immunoglobulin use and may be indicated because of progression or poor response to alternate therapies. One anecdotal series of patients were treated with the cytotoxic drug, cyclophosphamide, which was given as a pulsed dose of 1 gm/m2 each month for 3 to 6 months. Prior to the therapy patients were hydrated orally with 2 L of water and received antiemetic drugs, including 20 mg of intravenous dexamethasone and 10 mg of intravenous metoclopramide. Total white blood cell and lymphocyte counts were monitored weekly to measure myelosuppression and effectiveness of the dose given. Monthly treatments were discontinued after the patients showed sustained improvement over at least 2 months without relapses between pulses. More than 80% of patients had a remission in response to this protocol when they were treated within the first 2 years of disease. Thirty percent of these patients relapsed and required retreatment in 6 to 36 months. Retreatment was followed by long-term remission. Treatment with cyclophosphamide seriously worsened the condition of two patients who had the disease for 10 years or longer. This paradoxical response was noted previously with other regimens in patients with long-established disease and suggests a disturbance of a regulatory immune mechanism that limits disease progression. Although cyclophosphamide may be indicated in some patients because of progression and poor response to alternate therapies, in other patients the potential consequences of sterility, teratogenicity, and myelosuppression limit its use. In a limited number of patients I have successfully used mycophenolate mofetil, 1 gm orally twice a day, to discontinue IVIg use. This drug, which is like azathioprine but unlike cyclophosphamide, is not cytotoxic for dividing cells. Therefore to maintain the response the drug had to be given on a more chronic basis. With stable control of disease, gradual drug withdrawal must be carefully monitored for relapse. In this chapter my comments are limited to management of idiopathic CIDP. Other immune-mediated endoneurial neuropathies may not respond to therapy in the same manner. For example, corticosteroid and plasma exchange may be poor choices for multifocal motor neuropathy because of reduced efficacy and increased morbidity. In CIDP randomized and controlled trials support the use of corticosteroids, plasma exchange, and IVIg, whereas anecdotal experience suggests that cytotoxic and myelosuppressive drugs contribute to remission. Selection of a therapeutic regimen should take into consideration not only drug efficacy but also the age, reproductive status, and comorbid disease in a given patient as well as the likely chronicity of the disease process. Comorbid disease in patients can prevent the use of a particular therapy. Corticosteroids may be contraindicated in patients with diabetes mellitus or osteoporosis. A history of allergy, antibodies to IgA, or renal disease may prevent the use of IVIg. Poor venous access, cardiovascular instability, and availability of the technology may limit the use of plasma exchange. Antimetabolites, alkylating agents,
and immunophilins all have known teratogenic effects that may be cumulative over an extended period of use and associated with increased sterility and lymphoproliferative disease in future years. In addition, patients with preexisting hepatic, hematopoietic, or renal disease may not tolerate individual drugs. Most CIDP patients, if treated early and aggressively, respond well to therapy with preservation of endoneurial function. SUGGESTED READING
Dyck PJ, Litchy WJ, Kratz KM, et al: A plasma exchange versus immune globulin infusion trial in chronic inflammatory demyelinating polyradiculoneuropathy, Ann Neurol 36:838-845, 1994. Dyck PJ, OBrien PC, Oviatt KF, et al: Prednisone improves chronic inflammatory demyelinating polyradiculoneuropathy more than no treatment, Ann Neurol 11:136-141, 1982. Good JL, Chehrenama M, Mayer RF, Koski CL: Pulse cyclophosphamide therapy in chronic inflammatory demyelinating polyneuropathy, Neurology 51:1735-1738, 1998. Hahn AF, Bolton CF, Pillay N, et al: Plasma-exchange therapy in chronic inflammatory demyelinating polyneuropathy: a double-blind, sham-controlled, crossover study, Brain 119(pt 4): 1055-1066, 1996. Hahn AF, Bolton CF, Zochodne D, Feasby TE: Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy: a double-blind, placebo-controlled, crossover study. Brain 119(pt 4):1067-1077, 1996. Hughes R, Bensa S, Willison H, et al: Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy, Ann Neurol 50:195-201, 2001. Mehndiratta MM, Hughes RA: Corticosteroids for chronic inflammatory demyelinating polyradiculoneuropathy, Cochrane Database Syst Rev 1:CD002062, 2002. Mendell JR, Barohn RJ, Freimer ML, et al: Randomized controlled trial of IVIg in untreated chronic inflammatory demyelinating polyradiculoneuropathy, Neurology 56:445-449, 2001.
15
Painful Neuropathy
Beth Murinson, M.D., Ph.D.
The term painful neuropathy is broadly used to describe disorders arising from disease of the peripheral nerves and resulting in pain. In the narrowest sense painful neuropathy can be used to mean the pain syndrome associated with distal symmetrical peripheral neuropathy (DSPN) or small-fiber neuropathy. For this chapter, the broad range of possibilities is important because it is often the case that patients referred for evaluation and treatment of painful neuropathy have something other than DSPN. The neurologist must be prepared to recognize these alternatives and direct the treatment plan accordingly. Although these alternative diagnoses are considered here, they are covered in detail in other chapters of this book, and the latter part of this chapter is directed toward the evaluation and treatment of patients with small-fiber neuropathy.
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The impact of painful neuropathy on society is underappreciated. There are reliable estimates that 8% of the population older than 55 years of age has peripheral neuropathy, and it has been reported that 5% of Medicare beneficiaries have peripheral neuropathy as a primary diagnosis. The medical costs are measured in the tens of billions of dollars. The suffering associated with painful neuropathy can range from minor to profound and is compounded by the fact that neuropathy may present without visible signs to validate the patients pain experience. This can lead to a sense of social isolation or feeling of craziness that the compassionate physician must endeavor to dispel. Support groups and education are useful antidotes to this comorbidity. The symptoms of peripheral neuropathy can be extremely disruptive to a patients lifestyle, preventing normal sleep and leading to decreased activity because he or she often finds that normal walking results in subsequent pain exacerbations. It is essential for the neurologist to remember that, when severe, the pain associated with neuropathic disease exceeds the pain of childbirth, renal colic, and amputation. Multimodal treatment is often needed. The causes of painful neuropathy are multiple. Grouping these into categories will improve the rapid generation of a differential diagnosis in the clinical setting. A list of possible causes of peripheral neuropathy organized by category is shown in Table 1.
TABLE 1 Possible Causes of Peripheral Neuropathy

Focal Metabolic Diabetes: diabetic amyotrophy Infectious/immune mediated Varicella Brachial plexitis CMV plexitis (end-stage AIDS) Rheumatoid Lupus Vasculitis: mononeuritis multiplex Lyme sarcoid Physical injury Repetitive injury/entrapment Traumatic nerve injury Iatrogenic nerve injury Nerve impingement/radiculopathy Neoplastic infiltration Other Radiation Plexography Trigemiral neuralgia Diffuse Metabolic Prediabetic Diabetes Renal Infectious/immune mediated AIDP HIV Sjgrens syndrome Rheumatoid Paraneoplastic Toxic/nutritional deficiency Arsenic Dideoxynucleosides (antiretrovirals) Pyridoxine Thalidomide Malnutrition: vitamin B deficiency Anorexia/bulimia Postgastrectomy Alcoholism cis-platinum/paclitaxel/visca alkaloids Other Amyloid Fabrys disease Idiopathic Erythromelalgia Heritable forms
CMV, Cytomegalovirus; AIDS, acquired immunodeficiency syndrome; AIDP, acute inflammatory demyelinating polyneuropathy; HIV, human immunodeficiency virus.
Evaluation
Evaluation of peripheral neuropathy begins with a detailed history and thorough neurologic examination. Recognizing that patients referred for peripheral neuropathy may have pain arising from central causes (e.g., Dejerine-Roussy syndrome and myelopathy) is important. Reflexes are especially valuable in distinguishing central and peripheral processes. Central causes of pain often produce an upper motor neuron pattern of increased reflexes, increased tone, and a central pattern of sensory loss (e.g., hemianesthesia). Test the hypothesis that the pain is consistent with established patterns of peripheral innervation. Occasionally patients with disease of non-neurologic origin may be referred with a diagnosis of peripheral neuropathy; the differential diagnosis can include peripheral vascular disease, venous stasis, and cellulitis. Finally because many patients with painful neuropathy are older adults, there may be unrelated coexistent neurologic deficits. Attentive history taking and a careful review of records can clarify complex examination findings. HISTORY It is important to characterize patients sensory complaints as carefully as possible. It is often the case that unpleasant sensory phenomena are described with a single word: pain. The neurologist should recognize that small-fiber neuropathy is typically a burning pain in the feet that is moderately severe, gradually increasing, not relieved by regular analgesia, often associated
with a loss of sensation, and worst at night, as well as noting that important variants include sporadic shocklike pains in the legs, a feeling of having socks bunched under the toes, and the painful sensation of walking directly on the bones of the feet. In evaluating the patient with pain, each form of pain experienced by the patient should be characterized with respect to character, location, intensity, timing, associated symptoms, factors that worsen the pain, and interventions that relieve the pain. It is useful to develop a standardized system for reviewing pain complaints similar to following a routine pattern when
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conducting the basic neurologic examination. To better resist the inclination to disregard pain complaints, it is important to have a rational structure for evaluating these symptoms. One benefit of carefully assessing pain complaints is that patients immediately perceive that this physician cares about them in a way that others have not. EXAMINATION Based on the history, a differential diagnosis should be formed. The examination then specifically targets the elements of this differential, seeking physical evidence to support or refute the potential diagnoses. It is absolutely crucial to examine the regions identified as painful. This begins with observation for erythema or other discoloration, alterations of shape, evidence of muscle atrophy, asymmetry, and bony abnormalities. Next is palpation for thermal differences, edema, absence of normal pulsations, areas of focal tenderness, and induration. This is followed by manual testing judging muscle strength, sensory function, coordination, reflexes, and gait assessment. Following the examination, the differential diagnosis may remain broad, but it should then be possible to rank-order the potential diagnoses from most to least likely. Figure 1 illustrates the process of creating a basic differential diagnosis for a patient referred for peripheral neuropathy. This thought process must be undertaken for each patient, and various features will be highlighted depending on the nuances of the presentation and examination. The large-fiber neuropathies are typically characterized by painless sensory loss and are therefore not explicitly included in Figure 1. Detailed testing of sharp sensation is valuable in evaluating painful neuropathy. Begin proximally in each limb with a disposable sharp object. Ask if the object feels subjectively sharp in the proximal limb and note the response. Advance the sharp tip rapidly down the limb at approximately 5 cm intervals so that the entire limb is tested in 3-6 seconds. This approach takes advantage of temporal summation that is characteristic of C-fibers and in the presence of small fiber dysfunction this strategy will often elicit pronounced hyperalgesia. Testing with a cold tuning fork is less informative as this is mediated principally by thin myelinated fibers. Warm testing may preferentially activate C-fibers but it is difficult to reproducibly generate a mild warm stimulus in the exam room setting. LABORATORY STUDIES Laboratory evaluation of these patients begins with a complete blood count (CBC) and basic chemistry panel. Important metabolic causes of neuropathy may be identified at this stage, including uncontrolled diabetes. Nerve conduction studies and electromyogram are appropriate for the evaluation of most syndromes in the differential diagnosis of peripheral neuropathy. Varicella eruption (shingles) is an important exception to this rule. Skin biopsy stained for the pan-axonal marker PGP 9.5 is very helpful in confirming the clinical
impression of small-fiber neuropathy, and it can be extremely reassuring to patients to have an objective laboratory measure of their disease. Based on the elements in the differential diagnosis, a variety of diagnostic modalities should be considered. The evaluation may proceed with imaging to look for structural causes (myelopathy, radiculopathy), evaluation of cerebrospinal fluid (Guillain-Barr syndrome, CIDP, paraneoplastic) or other laboratory studies. For cases in which the history, examination, and nerve conduction studies are most consistent with small-fiber neuropathy or DSPN, the following work-up is recommended: erythrocyte sedimentation rate, serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) with immunofixation, thyroid studies, liver function tests, connective tissue studies (antinuclear antibodies, Rh, SS-A), vitamin B12 level, 2-hour glucose tolerance test, urinalysis, infectious serology (rapid plasma reagin, Lyme disease, human immunodeficiency virus [HIV], hepatitis C, cryoglobulins), a lipid profile, paraneoplastic testing such as Hu, and a heavy metal screen of the urine. Tests that should be considered depending on the level of suspicion include a bone survey to follow-up the SPEP/UPEP, lumbosacral magnetic resonance (MR) imaging, genetic testing, angiotensin-converting enzyme level, and a chest radiograph. Nerve biopsy should be performed when there is a clinical rationale to support this invasive procedure. The reasons to perform nerve biopsy include a suspicion of vasculitis, amyloid, leprosy, or sarcoid.
15
Treatment
Addressing the reversible causes of peripheral neuropathy is critical but need not delay symptomatic treatment. Neither should symptomatic control delay the effort to find and treat a reversible cause. For those patients found to have diabetes, they should be referred to a comprehensive diabetes care program. Dietary counseling and diabetes education are essential for maintaining the tight blood sugar control that is known to effectively combat diabetic small-fiber neuropathy. Identification of an M protein often necessitates referral to a hematologist. A skeletal survey, when appropriate, should be ordered at the time of referral to provide the hematologist with important information. Some of the reversible causes may require surgical intervention or referral for nerve blockade (see Figure 1). Some painful neuropathies arise from infectious or inflammatory causes, and treatment of the underlying processes is described elsewhere. Treatment of Fabrys disease is changing, and treatment of amyloid has become more aggressive, depending on type. Begin with monotherapy using a first-line agent. There are several excellent first-line therapies available for painful neuropathy (Table 2). None of these is a panacea, and all are symptomatic. At present there is no therapy available that will reverse the course of idiopathic small-fiber neuropathy. The symptomatic treatment of painful neuropathy depends heavily on individual patient characteristics.
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Patient complains of pain, paresthesias or numbness
Distal
Initially and most prominently in the toes
Forefoot
Heel
Proximal continues below
Symmetrical
Asymmetrical
See proximal Mortons neuroma
DSPN: Distal Symmetrical Poly-Neuropathy
Tarsal tunnel syndrome
Proximal
Symmetrical
Asymmetrical
Distal numbness?
Pain radiating to spine?
Acute?
Named nerve distribution? e.g. sural, occipit. lat. fem. cutane. Vasculitis
Dermatomal distribution?
Myotomal, sclerotomal or viscerotomal distribution?
Advanced peripheral neuropathy
Spondylosis
GBS
Varicella
Neuropathic pain Key: Current therapy is symptomatic and described in this chapter.
Radiculopathy
Referred pain syndrome: look for cause
Often requires immunomodulating therapy, symptom control is described in this chapter. Assessment for interventional management appropriate, symptom control in this chapter.
FIGURE 1. Common causes of referral for painful neuropathy: principal features. GBS, Guillain-Barr syndrome.
The term neuromodulating agents is used to characterize drugs initially described as members of other drug classes. This includes anticonvulsants, antiarrhythmics, and antidepressants (see later). The use of these drugs often necessitates substantial patient education, and despite being counseled by the physician, patients may be disconcerted by the questions of friends, family, and well-meaning pharmacists. A written reminder may be useful in forestalling additional questions and delays in compliance. Gabapentin, originally developed as an anticonvulsant, has proved tremendously useful in the treatment
of neuropathic pain. Although a small percentage of patients experience a paradoxical worsening of pain with gabapentin, necessitating discontinuation, for most patients it is a well-tolerated and effective therapy. Available in 100- and 300-mg strengths, gabapentin can be given as a standing daily dose, most often beginning with a single dose at bedtime and tapering up for efficacy. Many patients find that gabapentin is effective as a prn medication and may choose to time their dosing schedule to meet their particular pain demands. Some patients whose work requires sophisticated cognitive functioning find that higher doses of gabapentin are
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TABLE 2
Drugs Used to Treat Painful Neuropathy

Drug: Generic Name (Trade Name) Gabapentin (Neurontin) Most Common Side Effects Somnolence, dizziness, ataxia, paradoxical pain Skin reaction Serious Side Effects Leukopenia, StevensJohnson syndrome Large doses: potential for cardiac effects Respiratory depression Respiratory depression Respiratory depression Seizures Typical Cost, $/Month 130 (900 mg/day)
Class Neuromodulators
Initial Dose 300 mg qhs (may use 100 mg in elderly) 5% patch
Monitoring
Lidocaine
40
Opiates
Oxycodone (Oxycontin, Percodan, Percocet) Fentanyl (Duragesic) Hydrocodone (Hycodan, Lortab, Vicodin) Tramadol (Ultram)
5 mg q 6 hr
25 g/hr change q 72 h 5 mg q 6 hr
Mixed-action central analgesic
50 mg q 12 hr
Tricyclic antidepressants (neuromodulators)
Desipramine (Norpramin)
25 mg
Physical dependence and tolerance* Physical dependence and tolerance* Physical dependence and tolerance* Some abuse potential, use caution in opiatetreated patients Pretreatment ECG if age > 40 yr CBC, weight, ECG if age > 40 yr Pretreatment ECG if age > 40 yr
Sedation, constipation, nausea Somnolence, constipation, pruritus Sedation, constipation, nausea GI side effects
30
120
Variable 20-300 80-150
15
Dry mouth, tachycardia, orthostasis Constipation, confusion, dry mouth, urinary retention Sedation, forgetfulness, dry mouth, dental caries
Nortriptyline (Pamelor)
25 mg
Amitriptyline (Elavil)
10 mg
Dysrhythmias, blood dyscrasias, SSRI interaction Dysrhythmias, Blood dyscrasias, SSRI interaction Dysrhythmias, Blood dyscrasias, SSRI interaction
16-70
15-200
15-200
*Opiates should be used with caution in patients with a history of substance abuse; tolerance may necessitate rotation. Coadministration of SSRIs and tricyclic antidepressants results in marked increases in serum tricyclic antidepressant levels and risk for cardiac arrhythmia. GI, Gastrointestinal; ECG, electrocardiogram; SSRI, selective serotonin reuptake inhibitor; CBC, complete blood count.
disorienting and impair mental function. The decision then needs to be made whether to combine lower doses with a second agent or adjust dosing schedules. Lower starting doses are recommended for older patients. Lidocaine is available in a patch formulation, and topical creams can be prepared by compounding pharmacies. Lidocaine can be dramatically effective in providing pain relief, presumably by reducing the contributions from peripheral pain generators. The response of some patients to lidocaine suggests that peripheral pain generators are important in maintaining pain in some forms of painful neuropathy. Efficacy is dose dependent, and upward titration may be necessary to achieve
relief from pain. There is little information available about the drug levels resulting from this treatment, but caution is necessary when increasing dosages because there is the potential for systemic toxicity to include cardiac conduction block and cardiac arrest. Opioids are considered first-line agents for the treatment of neuropathic pain. They have been shown to be similar in efficacy to tricyclic antidepressants (TCAs) for the treatment of postherpetic neuralgia. Opioid medications have a long history. Efficacy, safety, and side effect profiles are well established. Escalating doses may be required in some circumstances but not in others. An alternative to dose escalation is opioid rotation,
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that is, switching to an equivalent dose of another opioid. Patients should be counseled regarding the potential for abuse, and many patients actively seek this information. The use of opiates in patients with a history of substance abuse should be approached with caution. If necessary, the patient should be contracted for proper use. Constipation resulting from opioids can be profound, and a bowel regimen must be instituted when opioid therapy begins. Alternatives for managing constipation include intermittent dosing and senna. Tramadol is a useful first-line agent for treatment of neuropathic pain. It has multiple mechanisms of action and thus it is a good alternative when other first-line agents are not fully effective. There is some risk that this medication is subject to abuse so that prescriptions should be monitored for signs of misuse (e.g., lost prescriptions, premature refill requests). In some patients tramadol provides much needed relief, but others are not able to tolerate the gastrointestinal side effects. Seizures are a potential serious side effect. TCAs have a long track record of efficacy in painful neuropathy, and their effectiveness is close to that of opioids. Because there is little abuse potential, they are an important alternative to narcotic medications. Although the doses used for treatment of neuropathic pain are generally much lower than those that were used for treatment of depression, it is necessary to monitor for side effects, especially cardiac dysrhythmias such as the tachyarrhythmias. Blood dyscrasias are a potential idiosyncratic side effect of TCAs, and a CBC should be checked with initiation of therapy; monitoring intervals are variable. An electrocardiogram has been recommended for patients older than 40 years of age who are beginning TCA treatment. Several of the selective serotonin reuptake inhibitors (SSRIs) interfere with TCA metabolism to the extent that toxicity can develop. This is often manifest as a tachycardia or nonpathologic increase in basal heart rate. The prevalence of SSRI usage mandates careful screening of patients for TCA use: in some patients the SSRI may be withdrawn, and in others a trial of a pain-relieving SSRI might be appropriate. When adding a second agent, target complementary mechanisms of action. Using two or more agents for the control of painful neuropathy is often a very successful strategy. Although it is essential to ensure that there are no harmful interactions and that a proper monitoring plan is in place, combination therapy can be the key to effective pain management. The benefits of combination therapy include using lower doses of either drug than would be effective as monotherapy, decreased side effects, and additive or synergistic symptom control. Second-line agents can be helpful in particular cases. There are particular syndromes for which second-line agents are especially effective. Examples of these include the use of carbamazepine and oxcarbazepine (Trileptal) for trigeminal neuralgia and lamotrigine (Lamictal) for HIV neuropathy. Other popular secondline agents include anticonvulsants and capsaicin cream (often poorly tolerated). Sympathetically mediated pain (SMP) is less common than small-fiber neuropathy. SMP is typically a burning
pain distally in a single extremity that is severe, develops over days to months, responds to sympathetic blockade, is often associated with hyperalgesia to light touch, and is worse with cold exposure. The principal reason for making the distinction between SMP and standard small-fiber neuropathy is that there are distinct treatment strategies. SMP is described in detail in the previous chapter.
Conclusions
The understanding of painful neuropathy is developing rapidly. Advances have been spurred by the measurement of epidermal nerve fibers in skin biopsy. This technique provides objective evidence to support an otherwise elusive diagnosis. There are studies underway using skin biopsy as an outcome measure, and it is anticipated that compounds promoting healthy nerve regeneration will be developed in the next 5 to 10 years. Although many effective therapies are available for symptom control in painful neuropathy, there are no compounds that reverse or slow the process of neuropathy. This remains an important research challenge. The clinical trials of nerve growth factor demonstrated that the doses sufficient for nerve regeneration also produced hyperalgesia and diffuse myalgias. Other growth factors have shown promise in laboratory models of neuropathy, and there is hope that these will be effective in patients. SUGGESTED READING
Boulton AJ, Kirsner RS, Vileikyte L: Clinical practice: neuropathic diabetic foot ulcers, N Engl J Med 351:48-55, 2004. Dworkin RH, Backonja M, Rowbotham MC, et al: Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations, Arch Neurol 60:1524-1534, 2003. England JD, Asbury AK: Peripheral neuropathy, Lancet 363: 2151-2161, 2004. Griffin JW, McArthur J, Polydefkis M, et al: Painful peripheral neuropathies and C fiber nociceptors. In Dostrovsky JO, Carr DB, Koltzenburg M, editors: Proceedings of the 10th World Congress on Pain: Progress in pain research and management, Seattle, 2003, IASP Press, 155-172.
PATIENT RESOURCES
http://www.neuro.wustl.edu/neuromuscular/sensory-pain.html http://www.neuropathy.org/ http://hiv.neuro.jhmi.edu/cutaneous/
The American Diabetes Association (ADA) estimates that 18.2 million Americans have diabetes, of which 5.2 million are undiagnosed. The problem is not just an American one, as the World Health Organization estimates that 220 million people worldwide will have diabetes by 2010. Type II diabetes accounts for 90% to 95% of cases, and its prevalence is increasing at an
368
that is, switching to an equivalent dose of another opioid. Patients should be counseled regarding the potential for abuse, and many patients actively seek this information. The use of opiates in patients with a history of substance abuse should be approached with caution. If necessary, the patient should be contracted for proper use. Constipation resulting from opioids can be profound, and a bowel regimen must be instituted when opioid therapy begins. Alternatives for managing constipation include intermittent dosing and senna. Tramadol is a useful first-line agent for treatment of neuropathic pain. It has multiple mechanisms of action and thus it is a good alternative when other first-line agents are not fully effective. There is some risk that this medication is subject to abuse so that prescriptions should be monitored for signs of misuse (e.g., lost prescriptions, premature refill requests). In some patients tramadol provides much needed relief, but others are not able to tolerate the gastrointestinal side effects. Seizures are a potential serious side effect. TCAs have a long track record of efficacy in painful neuropathy, and their effectiveness is close to that of opioids. Because there is little abuse potential, they are an important alternative to narcotic medications. Although the doses used for treatment of neuropathic pain are generally much lower than those that were used for treatment of depression, it is necessary to monitor for side effects, especially cardiac dysrhythmias such as the tachyarrhythmias. Blood dyscrasias are a potential idiosyncratic side effect of TCAs, and a CBC should be checked with initiation of therapy; monitoring intervals are variable. An electrocardiogram has been recommended for patients older than 40 years of age who are beginning TCA treatment. Several of the selective serotonin reuptake inhibitors (SSRIs) interfere with TCA metabolism to the extent that toxicity can develop. This is often manifest as a tachycardia or nonpathologic increase in basal heart rate. The prevalence of SSRI usage mandates careful screening of patients for TCA use: in some patients the SSRI may be withdrawn, and in others a trial of a pain-relieving SSRI might be appropriate. When adding a second agent, target complementary mechanisms of action. Using two or more agents for the control of painful neuropathy is often a very successful strategy. Although it is essential to ensure that there are no harmful interactions and that a proper monitoring plan is in place, combination therapy can be the key to effective pain management. The benefits of combination therapy include using lower doses of either drug than would be effective as monotherapy, decreased side effects, and additive or synergistic symptom control. Second-line agents can be helpful in particular cases. There are particular syndromes for which second-line agents are especially effective. Examples of these include the use of carbamazepine and oxcarbazepine (Trileptal) for trigeminal neuralgia and lamotrigine (Lamictal) for HIV neuropathy. Other popular secondline agents include anticonvulsants and capsaicin cream (often poorly tolerated). Sympathetically mediated pain (SMP) is less common than small-fiber neuropathy. SMP is typically a burning
pain distally in a single extremity that is severe, develops over days to months, responds to sympathetic blockade, is often associated with hyperalgesia to light touch, and is worse with cold exposure. The principal reason for making the distinction between SMP and standard small-fiber neuropathy is that there are distinct treatment strategies. SMP is described in detail in the previous chapter.
Conclusions
The understanding of painful neuropathy is developing rapidly. Advances have been spurred by the measurement of epidermal nerve fibers in skin biopsy. This technique provides objective evidence to support an otherwise elusive diagnosis. There are studies underway using skin biopsy as an outcome measure, and it is anticipated that compounds promoting healthy nerve regeneration will be developed in the next 5 to 10 years. Although many effective therapies are available for symptom control in painful neuropathy, there are no compounds that reverse or slow the process of neuropathy. This remains an important research challenge. The clinical trials of nerve growth factor demonstrated that the doses sufficient for nerve regeneration also produced hyperalgesia and diffuse myalgias. Other growth factors have shown promise in laboratory models of neuropathy, and there is hope that these will be effective in patients. SUGGESTED READING
Boulton AJ, Kirsner RS, Vileikyte L: Clinical practice: neuropathic diabetic foot ulcers, N Engl J Med 351:48-55, 2004. Dworkin RH, Backonja M, Rowbotham MC, et al: Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations, Arch Neurol 60:1524-1534, 2003. England JD, Asbury AK: Peripheral neuropathy, Lancet 363: 2151-2161, 2004. Griffin JW, McArthur J, Polydefkis M, et al: Painful peripheral neuropathies and C fiber nociceptors. In Dostrovsky JO, Carr DB, Koltzenburg M, editors: Proceedings of the 10th World Congress on Pain: Progress in pain research and management, Seattle, 2003, IASP Press, 155-172.
PATIENT RESOURCES
http://www.neuro.wustl.edu/neuromuscular/sensory-pain.html http://www.neuropathy.org/ http://hiv.neuro.jhmi.edu/cutaneous/
The American Diabetes Association (ADA) estimates that 18.2 million Americans have diabetes, of which 5.2 million are undiagnosed. The problem is not just an American one, as the World Health Organization estimates that 220 million people worldwide will have diabetes by 2010. Type II diabetes accounts for 90% to 95% of cases, and its prevalence is increasing at an
369
alarming rate, paralleling increases in obesity rates. Between 1991 and 2002, diabetes prevalence increased to 61% in the United States and is projected to more than double by 2050. Furthermore, type II diabetes, once a disease largely of old age, is affecting increasingly younger populations, even children. The U.S. Department of Health and Human Services estimates that one in three children born in 2000 will develop type II diabetes at some point in their lives. In 2002, the cost of diabetes was estimated at $132 billion/year, or $13,243 per person. These epidemiologic trends suggest that diabetic complications not only will continue to be prominent medical issues but will likely grow in importance in the coming decades. Diabetes affects nearly every organ system, and peripheral nerve involvement is common. Depending on the definition of neuropathy, and the method of detection used, abnormalities in peripheral nerve are present in 20% to 67% of people with diabetes, though the prevalence of symptomatic neuropathy in people with diabetes is not well established. This translates into diabetic neuropathies being among the most common neurologic conditions. Among complications in type II diabetes, neuropathy ranks third in terms of life-time costs of care, behind macrovascular disease and nephropathy but ahead of retinopathy. Diabetes can affect the peripheral nervous system at many levels, and the term diabetic neuropathy is a general one that encompasses these diverse syndromes that likely have different pathophysiologic processes. Each of these forms of neuropathy are discussed separately.
Diabetic Polyneuropathy
Diabetic polyneuropathy (DPN) is a predominantly sensory, length-dependent process that develops over months to years and typically has an insidious onset. It preferentially affects the distal ends of the longest peripheral nerves in the bodythe ones that project from the lumbosacral spine to the toes and feet. As the disease advances, symptoms and signs progress caudally. When involvement reaches the level of the knee, the distal upper extremities are typically affected. In advanced disease, the central chest and abdominal areas are involved in a shield pattern because this region represents the most distal innervation territory of intercostal nerves. The precise mechanism for peripheral nerve injury is debated but likely is multifactorial. Mechanisms involving inappropriate activation of protein kinase C, abnormal flux through the polyol pathway, increased advanced glycation end-product formation, increased hexosamine flux, or abnormal nerve growth factor levels all have been implicated. Although there is currently no agent approved by the U.S. Food and Drug Administration directed at the prevention, reversal, or slowing of DPN, numerous agents targeting each of these mechanisms are in the advanced stages of development. The first step in evaluating patients with distal sensory complaints is to confirm that the symptoms are attributable to DPN and not another condition such as
radiculopathy or intrinsic foot pathology such as plantar fascitis or tarsal tunnel syndrome. Electrophysiologic testing is invaluable in instances where this is not readily apparent clinically. Once a diagnosis of DPN is established, patient education is imperative. Patients are often concerned that their symptoms are harbingers of future paralysis or imminent wheelchair dependence. Because painful symptoms often increase with exercise or increased activity, patients are often also concerned that they may be causing damage. While the neurologist can allay such fears, the patients concern represents an opportunity to stress the importance of prevention. The only proven treatment to slow or prevent the course of DPN remains intensive glycemic control. The possibility of reversal of disease in such patients is realistically limited because only mild improvements are reported in patients undergoing pancreas transplantation. The importance of slowing progression of disease should not be underestimated, however, since DPN contributes to 82,000 amputations per year in the United States, or one amputation every 6 minutes. Delaying or preventing even a small fraction of these amputations clearly has prominent ramifications. In addition to glycemic control, patients should be educated on the importance of foot self-examinations, podiatry follow-up, and infection control. Counseling patients to wear comfortable, properly fitted shoes with sock liners helps prevent callous formation that has been demonstrated to predispose to ulcer formation and amputation. The goal is for friction to occur between the sock and shoe, not the foot and sock. Over the past several years, the entity of impaired glucose tolerance (IGT)-associated neuropathy has emerged. Although the concept that mild degrees of glucose dysmetabolism can cause diabetes complications is not new, traditional dogma has been that complications are the result of established, long-standing diabetes. The past 11 years have witnessed an increasing focus on the importance of glycemic control (Diabetes Complication and Control Trial), earlier diabetes diagnosis (the 1997 lowering of the ADA fasting blood glucose cut-off from 143 to 126 mg/dL), and prediabetes with the establishment of IGT as a diagnostic criteria (and the subsequent Diabetes Prevention Program). The emergence of IGT-associated neuropathy is consistent with this growing recognition of the importance of early and mild hyperglycemia. Patients presenting with painful neuropathy symptoms historically were often inappropriately screened for diabetes with glycated hemoglobin testing. The insensitivity of this test as a screening tool led to patients incorrectly having diabetes removed as an explanation for their neuropathy. When appropriately screened with fasting blood sugars or oral glucose tolerance tests, 50% to 60% of these patients were determined to have frank diabetes or IGT. This represents a twofold to threefold increased IGT prevalence compared to that reported by the National Health and Nutrition Examination Survey (NHANES) III for similarly aged people. Furthermore, the severity of IGT-associated neuropathy has been shown to be less severe than diabetes-associated neuropathy even after stratification for the duration of neuropathy symptoms.
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Aside from identifying a probable cause for the neuropathy, these findings have important implications for treatment. IGT is a well-established risk factor for the subsequent development of diabetes (at a rate of 7% per year). This progression can be slowed or reversed by instituting aggressive control of hyperglycemia through diet and exercise, or metformin treatment. The reversal of early diabetes or IGT offers the possibility that neuropathy associated with early, mild hyperglycemia may also be reversible. We have observed that patients with IGT neuropathy who do diet and exercise often experience resolution or dramatic improvement in their pain symptoms. An added motivation for aggressive treatment of IGT or early diabetes emanates from the Epidemiology of Diabetes Intervention and Complications (EDIC) study, which found that the rate of diabetes complications in the DCCT cohort continued to diverge among the intensive and conventional treatment groups despite the two groups glycated hemoglobin values quickly merging after the conclusion of the DCCT. This phenomenon, referred to as metabolic memory, emphasizes that early glycemic control is crucial not only to forestall the development of diabetes complications but also the long-term rate at which these complications accrue. TREATMENT OF SYMPTOMS Neuropathic pain is reported in approximately 10% of patients with DPN. This figure may represent an underestimate given that it excludes patients who were previously diagnosed with cryptogenic neuropathy but are now recognized to have occult diabetes or prediabetes. Why some patients with DPN develop pain while others are spared remains an important unanswered question. Patients with pain typically describe their symptoms as burning, electric shocks, stabbing, or a bothersome pins and needles tingling. These symptoms tend to be worse at night and can be associated with allodynia. In others, these symptoms are accompanied by restless legs syndrome. In general, the neuropathic pain in DPN is aggravated by prolonged standing or walking. In addition to positive symptoms, patients also complain of negative symptoms in the form of frank numbness. Neurologists typically see the subset of patients with positive symptoms of neuropathic pain. There are many choices of agents for treatment of pain in DPN. Although the process can be one of trial and error, no patient should remain in pain. It is important to establish both the need for pain control as well as engage the patient as a partner in a treatment plan. Visual analog scores (VASs) are helpful in assessing the need for analgesia as well as measuring changes over time. Patients who rate their pain as a 3 or below on the 0-10 Likert scale generally do not require chronic, prophylactic therapy. These patients are able to function normally and are typically content with an understanding of the underlying cause of their discomfort. If such patients experience periods of increased pain, a medication that does not require maintenance of chronic blood levels for analgesic effect is preferred. Tramadol or Ultracet on an as-needed basis is particularly helpful for such patients.
Patients with higher levels of pain benefit from chronic therapy. It is important to explain that an individuals response to a particular medication is difficult to predict, both in terms of side effects and efficacy. Genetic differences in pain-mediating pathways may explain why different classes of drugs, which selectively inhibit particular pathways, are effective in some patients but not in others. Such a discussion sets the stage for appropriate expectations and the likely possibility that several agents may be tried sequentially before success is attained. It is also appropriate to establish expectations for treatment. The goal of therapy is not necessarily to eliminate all discomfort but rather to reduce the level of discomfort to tolerable levels and return the patient to normal functioning. Most patients with painful DPN have type II diabetes, are older, and take other medications. This patient population is at high risk for drug interactions and side effects. The possibility of drug-induced side effects is dramatically reduced if agents are started at a low dose and gradually increased over time (start low and go slow). Target doses are generally reached only after a 2- to 3-week gradual titration period. Furthermore, it is the lowest effective dose that is sought: if adequate pain relief is achieved during the titration period, there is no need to proceed to higher doses. During the titration period, the possibility of side effects is further reduced by initiating dose increases at the evening time point and in 3- to 5-day intervals increase the dosage schedule to twice daily followed by three times a day. Subsequent dose increases should also follow this pattern, with increases occurring with the evening dose first. Close follow-up through short clinic visits or phone calls is helpful and reassuring to patients during this period. Communication is facilitated and progress can be monitored by having patients fax VAS score sheets periodically. Finally, analogous to antiepileptic drug use, monotherapy, with maximization of one agents dose, is recommended before adding a second agent or switching drugs. It is not uncommon for patients to report that multiple agents provided no benefit to them. Understandably, they are reluctant to revisit these medications. The details of these drugs past use should be pursued. More often than not, the initial dose may have been too high resulting in unacceptable side effects, or the maximum dose too low or given for an insufficient duration, to constitute an adequate trial. Reintroducing the drug at a low dose followed by slow titration is often successful in these instances. Several factors should be considered when selecting a neuropathic pain medication for DPN. These include possible interaction with other medications and side effects such as weight gain, peripheral edema, somnolence, and imbalance/fall risk. Weight gain is clearly counterproductive in patients with diabetes or IGT, whereas peripheral edema has been implicated as a risk factor for ulcer formation. Finally, anticholinergic and sedating properties can place patients at increased risk for falling, especially in the setting of diminished proprioceptive sensation. A crude but effective screening tool for identifying patients at increased fall risk is the
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timed get up and go test. Patients are asked to rise from a chair, walk 20 feet, turn, walk back to the chair and sit down. The patient should walk at a rapid but comfortable pace. A screen is considered positive if the patient takes longer than 20 seconds to complete the task. In patients on numerous medications, particularly ones metabolized by the cytochrome P450 pathway, the chance for drug interactions can be diminished by selecting medications that are not hepatically metabolized (gabapentin) or do not affect the P450 pathway (lamotrigene). There are numerous agents to choose from for the treatment of painful DPN. A partial list of agents is included in Table 1. Unfortunately, traditional nonsteroidal anti-inflammatory drugs are generally not helpful in painful DPN. Antiepileptic agents, particularly gabapentin, have emerged as a common, attractive choice. Tramadol, tricyclic antidepressants (TCAs), lidocaine patch, and opiates are also effective in many patients (discussed later). I generally use gabapentin as first-line therapy with the dose slowly titrated to 2700 mg/day. Patients who tolerate and experience benefit from this dose can continue to 3600 mg/day if needed. Patients who do not benefit from 2700 mg/day rarely do so at higher doses in my experience. In addition to somnolence and ataxia, weight gain and peripheral edema are side effects. A second generation form of gabapentin, pregabalin, was recently FDA approved for the treatment of painful diabetic neuropathy though experience with this agent is currently limited. Duloxetine is the only other agent to gain FDA approval for the indication of painful diabetic neuropathy. It has a dual mechanism acting as both a serotonin and norepinephrine reuptake inhibitor and has demonstrated efficacy in three large randomized controlled studies. Distinct advantages include a rapid onset and the option for a single daily dosing schedule. In my experience, patients most often experience pain relief at 30 or 60 mg/day. Doses of 60 mg BID are generally not associated with additional symptom relief, but do cause higher rates of side effects. As one might expect, duloxetine has antidepressant properties making it attractive
TABLE 1 Medications and Methods with Efficacy in Relieving Neuropathic Pain in DPN
Antidepressant, tricyclic Anticonvulsant Opiates Tramadol Mexiletine Levodopa Dextromethorphan Lidocaine transdermal patch Alpha lipoic acid Gamma linolenic acid Acupuncture
DPN, Diabetic neuropathy.
for patients who suffer from both conditions. Care should be taken before initiating duloxetine therapy in patients already being treated for depression. Another favorite agent is tramadol, which has a dual mechanism of action with mu-opioid and tricyclic properties. Again it is slowly titrated to a target dose of two tablets three times a day (four times a day in younger patients), or the lowest effective dose. If sedation or constipation is problematic, Ultracet, a combination of lower dose tramadol and acetaminophen, is an alternative. The combination has excellent analgesia with fewer side effects and, despite its opioid effect, is not addictive. Second-line agents include TCAs and lamotrigene. Among tricyclic agents, amitriptyline has been the most rigorously studied, although it has a high incidence of anticholinergic side effects. The dose should be started at 10 mg at night and slowly (10 mg/week) titrated to effect, with some patients requiring high doses. Other TCAs with demonstrated efficacy are nortriptyline, doxepin, desipramine, and imipramine. TCAs have been associated with cardiac conduction abnormalities. In most instances, these occur in the setting of large overdoses; however, it is prudent to obtain a baseline electrocardiogram to screen for existing conduction abnormalities prior to initiating therapy with a TCA. Lamotrigene is another antiepileptic agent with neuropathic analgesic properties. Again, slow titration, starting at 25 mg/day and gradually increasing to 100 mg twice daily over several weeks is essential. This medication is associated with rare but serious Stevens-Johnson syndrome reactions and should be immediately discontinued at the first sign of rash. For patients with focal pain, the lidocaine 5% patch is often helpful. This patch is 10 14 cm and can be cut to appropriate size. It is worn for a maximum of 12 hours in any 24-hour period (12 hours on, 12 hours off) and only about 3% of the topical agents is systemically absorbed. For patients with refractory pain, opiates are often required. Classic teaching dictated that opiates were not useful for neuropathic pain. This is no longer recognized to be true and I have found fentanyl patches to be helpful. The gradual-release preparation is particularly well tolerated. Patients should start at 25 g/hr every 3 days and slowly increase at 25 g/hr intervals every 2 to 3 weeks. Another agent worth mentioning is topiramate. In general, I have found topiramate is a poor choice for neuropathic pain treatment, though it does work well in a small subset of patients. What makes it more attractive, however, is the well-established side effect of weight loss. Therefore, it may have a role in treating patients with IGT-associated neuropathy. A few final agents worth mentioning are topical capsaicin cream and phenytoin. Both have been demonstrated to have neuropathic pain-relieving effects in double-blind, placebo-controlled trials, but both have neurotoxic effects. When applied intensively, topical capsaicin causes a distal pruning of small-caliber sensory nerve fibers that may not fully regenerate to baseline levels. This toxicity has been documented to be associated with increases in heat pain threshold that is probably not advantageous to patients with diabetes.
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Finally, long-term use of phenytoin also has been implicated as a cause of neuropathy as well as of osteomalacia and therefore there are better choices. AVOIDANCE OF OTHER TOXINS In addition to treatment of pain, it is useful to educate patients regarding potential toxic exposures. Although such exposures are generally not a cause for concern, patients with DPN represent a vulnerable population and are susceptible to acceleration of their neuropathy when exposed to additional insults. Unfortunately, medications are a common culprit. The Charcot-Marie-Tooth Association publishes a list of medications (Table 2) that have been implicated in worsening neuropathy. Although this list may be overzealous, there are generally acceptable alternatives for implicated medications. The most common culprits in my experience are excessive vitamin B6 and sustained colchicine use in addition to chemotherapy agents. Patients often associate B vitamins with beneficial nerve effects. High doses of vitamin B12 are innocuous, but high doses of vitamin B6 can be toxic and cause either a peripheral neuropathy or a sensory neuronopathy. Similarly, sustained colchicine use in the setting of DPN can produce a severe axonal neuropathy. Since colchicine is indicated for the acute treatment of gout only and not prophylactic treatment, attention should be given to minimize the duration of treatment in patients with diabetes.
Proximal Diabetic Neuropathy, or Bruns-Garland Syndrome, or Diabetic Amyotrophy

Proximal diabetic neuropathy has been associated with many names, including Bruns-Garland syndrome, diabetic myelopathy, diabetic amyotrophy, diabetic mononeuritis multiplex, diabetic polyradiculopathy, femoral or femoral-sciatic neuropathy of diabetes, diabetic motor or paralytic neuropathy, proximal diabetic neuropathy, diabetic lumbosacral plexopathy, and, most recently, diabetic lumbosacral radiculoplexus neuropathy (DLRPN). The many names used for this disorder reflect the confusion concerning anatomic localization and possible diversity of underlying causes. Recent work suggests that these conditions represent different manifestations of the same entity and, when taken together, likely are clinically underappreciated. There is also a condition with similar clinical features and pathology but is not associated with diabetes. This entity has been described relatively recently and given the name lumbosacral radiculoplexus neuropathy. Both symmetric and asymmetric forms of proximal diabetic neuropathy or DLRPN occur. Typically, patients are older and have type II diabetes. Classically, the condition is preceded or accompanied by substantial weight loss and is a pure motor, monophasic process characterized by the abrupt onset of unilateral pain followed by weakness and subsequent recovery. It can occur coincident with diabetes diagnosis. Pain of variable intensity is present in the back, buttock, perineal, and anterior thigh regions and is typically described as knifelike aching and burning. Recent evidence suggests a broader spectrum of presentation for this condition with more diffuse involvement that can include thoracic or rarely the upper extremities as well as sensory nerves. Similarly, the time course of progression to disease nadir and recovery can span the spectrum of weeks up to 18 months. Instances of diffuse involvement should raise other possibilities such as chronic inflammatory demyelinating polyneuropathy. The pathogenesis of proximal diabetic neuropathy is unknown, but both microvasculitis and altered immunity have been implicated. It is usually a self-limiting condition, with variable though sometimes complete recovery. The role of immunomodulatory and immunosuppressive therapy is debated, and both intravenous steroids and intravenous immunoglobulin (IVIg) are the focus of ongoing randomized clinical trials. Often, these patients are already recovering from the disease by the time they are seen by a neurologist, making the need for treatment less pressing. The hyperglycemic effect of corticosteroids as well as the increased risk of infection and poor wound healing need to be carefully balanced with any potential benefit. Similarly, people with diabetes are at risk for acute renal failure with IVIg, particularly patients with glomerular filtration rates (GFRs) below 50 mL/hr. The GFR should be formally calculated in any patient with diabetes in whom IVIg treatment is being contemplated. In those with low GRFs, the risk of nephrotoxicity can be reduced with slower infusion
TABLE 2 Charcot-Marie-Tooth Medication List: Drugs with Implicated Peripheral Nerve Toxicity
Alcohol Amiodarone Chloramphenicol Cisplatin Dapsone Diphenylhydantoin (Dilantin) Disulfiram (Antabuse) Doxorubicin (Adriamycin) Glutethimide (Doriden) Gold Hydralazine (Apresoline) Isoniazid (INH) Megadose of vitamin A* Megadose of vitamin B6 (pyridoxine)* Megadose of vitamin D* Metronidazole (Flagyl) Nitrofurantoin (Furadantin, Macrodantin) Nitrous oxide (chronic repeated inhalation) Penicillin (large IV doses only) Perhexiline (Pexid) Taxol Vincristine
*A megadose is defined as 10 times the recommended daily allowance. Lithium, misonidazole, and sertraline can be used with caution. From http://www.charcot-marie-tooth.org/site/content/medicalalert/index.asp.
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rates and increased hydration. The decision to treat with these agents is best made on an individual basis. Pain management, rehabilitation, and the need for supportive devices all are critical management issues. These patients frequently require narcotics for pain control, and rehabilitation, particularly in patients with protracted courses, is critical for optimal outcomes.
PATIENT RESOURCES
http://www.cdc.gov/diabetes/ http://www.diabetes.org/
Toxic Neuropathy
Diabetic Thoracoabdominal Neuropathy, or Truncal Radiculoneuropathy
Diabetic thoracoabdominal neuropathy affects thoracic or abdominal nerves and is characterized by pain in the lateral chest or abdomen. It is generally unilateral and can be misinterpreted as the prodrome to varicella zoster or even cholecystitis. Similar to proximal diabetic neuropathy, it can occur in the setting of weight loss or as a presenting symptom of diabetes. The syndrome is generally self-limited, with recovery taking place over several months. Analgesia is the most pressing issue in these patients, with the same agents being helpful as in DPN.
Diabetic Cranial Nerve III Palsy

The main symptoms associated with diabetic cranial nerve III palsy are diplopia and pain. The underlying process is thought to be an ischemic injury to the nerve. Classically, patients with diabetic cranial nerve III palsy spare pupil function as a result of the parasympathetic fibers orientation in the periphery of the nerve. As a result of the orientation, the fibers to the pupil have redundant blood supply from the vasovasorum and are spared. In reality, the clinical pearl is unreliable, and all patients with cranial nerve III palsies should undergo imaging as part of their evaluation to rule out a mass. An eye patch is helpful to treat the diplopia. Most patients experience partial or complete recovery within 2 or 3 months. SUGGESTED READING
Chaudhry V, Chaudhry M, Simmons-OBrien E, et al: Toxic neuropathy in patients with preexisting neuropathy, Neurology 60:337-340, 2003. DCCT: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus, N Engl J Med 329:977-986, 1993. Dyck PJ, Windebank AJ: Diabetic and nondiabetic lumbosacral radiculoplexus neuropathies: new insights into pathophysiology and treatment, Muscle Nerve 25:477-491, 2002. Knowler WC, Barrett-Connor E, Fowler SE, et al: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393-403, 2002. Polydefkis M, Griffin JW, McArthur J: New insights into diabetic polyneuropathy, JAMA 290:1371-1376, 2003. Singleton JR, Smith AG, Russell JW, Feldman EL: Microvascular complications of impaired glucose tolerance, Diabetes 52:2867-2873, 2003. Sumner CJ, Sheth S, Griffin JW, et al: The spectrum of neuropathy in diabetes and impaired glucose tolerance, Neurology 60:108-111, 2003. Johnson: Current Therapy in Neurologic Disease (7/E)
In clinical practice, toxic neuropathy is typically a diagnosis of exclusion. Exceptional cases are those where the patient has a known exposure to a specific toxin such as modeling glue, acrylamide, or even rat poison, but the practicing neurologist and even the subspecialist may never encounter any such patients. For practical purposes neurologists should be familiar with the types of toxins that may be associated with neuropathy and consider this possibility when no better explanation for the disorder is present. Certainly a comprehensive reference text should be accessible providing a list of potential neurotoxins and their manifestations. Peripheral neurotoxins can be categorized as biologic toxins, environmental toxins, and pharmacologic toxins. Common examples of each of these are listed in Tables 1 and 2. Patients exposed to these toxins present with recognizable clinical syndromes related to the effects on the peripheral nerve, the neuromuscular junction, or even the spinal motor neuron. A few such as botulism, puffer fish poisoning, and tick paralysis may present acutely with spectacular clinical findings that quickly require the attention of a specialist. Most patients with toxic neuropathies, however, develop symptoms gradually. These patients frequently seek neurologic evaluation only after other more common causes of their symptoms have been ruled out. Once the diagnosis of toxic neuropathy is made, the treatment is easyremove the offending agent and the neuropathy will slowly recede. Clinicians experienced with treating these patients understand, however, that several caveats apply to this simple approach: It may not be so easy to identify the offending toxin. Many patients present with multiple possible causes of their neuropathies, such as the combination of diabetes and colchicine, or human immunodeficiency virus (HIV) and antiretroviral agents. The neuropathies associated with these conditions and exposures may appear identical. Recovery after removal of the toxin may be delayed significantly (months) because of the phenomenon of coasting. After removal the neuropathy may worsen for a while and plateau before showing any signs of improvement. In the case of pharmacologic toxins it is sometimes difficult or impossible to stop the offending drug. This situation is encountered frequently in cancer patients being treated with a variety of chemotherapeutic drugs
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rates and increased hydration. The decision to treat with these agents is best made on an individual basis. Pain management, rehabilitation, and the need for supportive devices all are critical management issues. These patients frequently require narcotics for pain control, and rehabilitation, particularly in patients with protracted courses, is critical for optimal outcomes.
PATIENT RESOURCES
http://www.cdc.gov/diabetes/ http://www.diabetes.org/
Toxic Neuropathy
Diabetic Thoracoabdominal Neuropathy, or Truncal Radiculoneuropathy
Diabetic thoracoabdominal neuropathy affects thoracic or abdominal nerves and is characterized by pain in the lateral chest or abdomen. It is generally unilateral and can be misinterpreted as the prodrome to varicella zoster or even cholecystitis. Similar to proximal diabetic neuropathy, it can occur in the setting of weight loss or as a presenting symptom of diabetes. The syndrome is generally self-limited, with recovery taking place over several months. Analgesia is the most pressing issue in these patients, with the same agents being helpful as in DPN.
Diabetic Cranial Nerve III Palsy

The main symptoms associated with diabetic cranial nerve III palsy are diplopia and pain. The underlying process is thought to be an ischemic injury to the nerve. Classically, patients with diabetic cranial nerve III palsy spare pupil function as a result of the parasympathetic fibers orientation in the periphery of the nerve. As a result of the orientation, the fibers to the pupil have redundant blood supply from the vasovasorum and are spared. In reality, the clinical pearl is unreliable, and all patients with cranial nerve III palsies should undergo imaging as part of their evaluation to rule out a mass. An eye patch is helpful to treat the diplopia. Most patients experience partial or complete recovery within 2 or 3 months. SUGGESTED READING
Chaudhry V, Chaudhry M, Simmons-OBrien E, et al: Toxic neuropathy in patients with preexisting neuropathy, Neurology 60:337-340, 2003. DCCT: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus, N Engl J Med 329:977-986, 1993. Dyck PJ, Windebank AJ: Diabetic and nondiabetic lumbosacral radiculoplexus neuropathies: new insights into pathophysiology and treatment, Muscle Nerve 25:477-491, 2002. Knowler WC, Barrett-Connor E, Fowler SE, et al: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393-403, 2002. Polydefkis M, Griffin JW, McArthur J: New insights into diabetic polyneuropathy, JAMA 290:1371-1376, 2003. Singleton JR, Smith AG, Russell JW, Feldman EL: Microvascular complications of impaired glucose tolerance, Diabetes 52:2867-2873, 2003. Sumner CJ, Sheth S, Griffin JW, et al: The spectrum of neuropathy in diabetes and impaired glucose tolerance, Neurology 60:108-111, 2003. Johnson: Current Therapy in Neurologic Disease (7/E)
In clinical practice, toxic neuropathy is typically a diagnosis of exclusion. Exceptional cases are those where the patient has a known exposure to a specific toxin such as modeling glue, acrylamide, or even rat poison, but the practicing neurologist and even the subspecialist may never encounter any such patients. For practical purposes neurologists should be familiar with the types of toxins that may be associated with neuropathy and consider this possibility when no better explanation for the disorder is present. Certainly a comprehensive reference text should be accessible providing a list of potential neurotoxins and their manifestations. Peripheral neurotoxins can be categorized as biologic toxins, environmental toxins, and pharmacologic toxins. Common examples of each of these are listed in Tables 1 and 2. Patients exposed to these toxins present with recognizable clinical syndromes related to the effects on the peripheral nerve, the neuromuscular junction, or even the spinal motor neuron. A few such as botulism, puffer fish poisoning, and tick paralysis may present acutely with spectacular clinical findings that quickly require the attention of a specialist. Most patients with toxic neuropathies, however, develop symptoms gradually. These patients frequently seek neurologic evaluation only after other more common causes of their symptoms have been ruled out. Once the diagnosis of toxic neuropathy is made, the treatment is easyremove the offending agent and the neuropathy will slowly recede. Clinicians experienced with treating these patients understand, however, that several caveats apply to this simple approach: It may not be so easy to identify the offending toxin. Many patients present with multiple possible causes of their neuropathies, such as the combination of diabetes and colchicine, or human immunodeficiency virus (HIV) and antiretroviral agents. The neuropathies associated with these conditions and exposures may appear identical. Recovery after removal of the toxin may be delayed significantly (months) because of the phenomenon of coasting. After removal the neuropathy may worsen for a while and plateau before showing any signs of improvement. In the case of pharmacologic toxins it is sometimes difficult or impossible to stop the offending drug. This situation is encountered frequently in cancer patients being treated with a variety of chemotherapeutic drugs
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Toxic Neuropathy
TABLE 1 Biologic Toxins

Toxin Botulinum Source Ingestion of spoiled food in adults, colonization of GI tract by Clostridium botulinum in infants; local botulism from infected wound Puffer fish ingestion Clinical Manifestations Rapidly progressive paralysis; areflexia and retained sensory responses Mechanism Proteolytic cleavage of vesicle-associated membrane protein (VAMP) syntaxin, and SNAP-25, preventing vesicle fusion and neurotransmission Blockade of voltage-gated sodium channels Diagnostic Tests High-frequency repetitive nerve stimulation showing > 100% facilitation; clostridial culture from stool or wound Treatment Supportive
Tetrodotoxin
Ciguatoxin
Ingestion of toxic fish during algal blooms
Tick paralysis
Envenomation by tick bite; may be common dog or wood tick
Rapid onset of paresthesias, paralysis, diarrhea; areflexia and respiratory failure Rapid onset of paresthesias, paralysis, diarrhea; areflexia and respiratory failure Progressive paralysis, mostly in children
Supportive
Opening of sodium channels causing depolarization block Unknown; protein neurotoxin affecting presynaptic acetylcholine release and membrane conductance at the node of Ranvier Direct toxic effect to peripheral nerve fibers Unknown; probable energy failure due to effects on mitochondrial respiratory chain function Anemia, malnutrition Measurement in blood, urine, hair, and nails
Supportive
Remove tick
Environmental/Industrial Toxins Alcohol Chronic ingestion Arsenic Occupational/ environmental exposure from pesticides, wood preservatives, mining industries
Lead
Occupational exposure in manufacturing, smelting, construction Solvents, glue sniffing
Hexacarbons (n-hexane, methyl butyl ketone)
Distal numbness, burning, weakness Insidious onset of distal polyneuropathy; skin changes including sloughing on palms and soles; Mees lines in fingernails Motor-predominant neuropathy, classically affecting wrist extensors; weight loss and abdominal pain Progressive sensory/motor neuropathy, weight loss, inanition
Abstinence Chelation
Unknown; lead interferes with many enzyme systems with unknown consequences to nerve function Unknown; experimental hexacarbon neuropathy causes abnormalities in axonal transport and accumulation of neurofilaments
High levels in blood and urine; microcytic anemia Nerve biopsy shows paranodal axonal swellings in severe cases
Chelation
Removal of exposure
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TABLE 1 Biologic Toxinscontd

Toxin Organophosphates Source Insecticides and nerve gas exposure Clinical Manifestations Acute cholinergic response (diarrhea, sialorrhea fasciculations); chronic sensory/motor neuropathy Painful paresthesias, hair loss, autonomic dysfunction Mechanism Inhibition of neuropathy target esterase (NTE) Diagnostic Tests Treatment Removal of exposure
Thallium
Accidental or homicidal ingestion of rodenticides
Thallium levels in urine
Consider chelation
GI, Gastrointestinal.
TABLE 2
Drug
Pharmacologic Toxins
Indication Clinical Manifestations Mechanism Diagnostic Tests
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Treatment
Antineoplastic Drugs Paclitaxel Solid tumors of lung, breast, head and neck
Dose-dependent sensory > motor neuropathy; significant motor manifestations in severe cases Dose-dependent sensory and autonomic neuropathy; painful paresthesias in hands and feet Sensory neuropathy/ neuronopathy (sensory ataxia, areflexia, pain); may not show typical length dependence Acute paresthesias and cold-induced cramping within hours of dose; chronic length-dependent polyneuropathy
Vincristine/ vinblastine
Lymphoma/ leukemia, some solid tumors
Cisplatin
Small cell lung cancer, urogenital cancers
Polymerization of microtubules may interfere with axonal transport; also direct toxic effects on the axon Interference with microtubule assembly presumably disrupts axonal transport Direct toxicity to DRG neurons
Sensory/motor axonal neuropathy on EMG; Wallerianlike degeneration on nerve biopsy Sensory/motor axonal neuropathy on EMG; Wallerianlike degeneration on nerve biopsy Loss of sensory potentials on NCV studies; loss of large myelinated fibers on sural nerve biopsy Electrodiagnostic studies show peripheral nerve afterdischarges and neuromyotonia
Reduction of dose
Reduction of dose
Reduction of dose
Oxaliplatin
Colorectal cancer
Unknown; suspected acute symptoms are due to peripheral nerve hyperexcitability resulting from sodium channel opening Formation of drug-lipid complexes that
Reduction of dose; membranestabilizing drugs (anticonvulsants)
Amphiphilic Cationic Drugs Amiodarone Ventricular arrhythmias
Sensory/motor neuropathy with areflexia and ataxia;
Demyelinating changes on NCV; nerve biopsy
Cessation of drug
Continued
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TABLE 2
Drug
Pharmacologic Toxinscontd
Indication Clinical Manifestations not necessarily dose related Mechanism are lysosome resistant and toxic Diagnostic Tests Treatment
Chloroquine
Perhexiline
Malaria Neuromyopathy; may (prophylaxis be motor and treatment), predominant with connective significant tissue diseases weakness before sensory manifestations Angina pectoris Sensory/motor (not used in polyneuropathy United States) with areflexia and autonomic features
shows osmophilic granules in Schwann, endothelial, and perineurial cells Formation of Vacuolar drug-lipid myopathy; complexes that osmophilic are lysosome inclusions in resistant and Schwann, toxic endothelial, and perineurial cells Formation of Osmophilic drug-lipid cominclusions in plexes that are Schwann, lysosome resistendothelial, and ant and toxic perineurial cells Unknown; may interfere with mitochondrial function NCV/EMG shows distal axonal polyneuropathy; nerve biopsy shows nonspecific axonal degeneration
Cessation of drug
Cessation of drug
Antiretrovirals Zalcitabine HIV infection (ddC) Stavudine (d4T) Didanosine (ddI)
Painful, distal sensory polyneuropathy; sensory ataxia; more frequently seen in patients with AIDS; may complicate or uncover underlying HIVassociated neuropathy Neuromyopathy; paresthesias in hands and feet
Reduction in dose or cessation of drug
Miscellaneous Colchicine Gout and other rheumatologic disorders
Interferes with microtubule assembly, possibly affecting axonal transport
Thalidomide
Suppression of immunemediated disorders Antibiotic for leprosy and Pneumocystis pneumonia Megavitamin therapy for various disorders
Distally predominant sensory/motor polyneuropathy
Unknown
Dapsone
Pyridoxine (vitamin B6)
Motor > sensory neuropathy; may affect hands disproportionately Sensory neuropathy/ neuronopathy
Unknown
NCV/EMG Cessation of drug shows mild length-dependent axonal neuropathy irritable myopathy; vacuolar myopathy in patients with renal failure NCV/EMG Cessation of drug shows lengthdependent sensory/motor axonal polyneuropathy Motor axonal Cessation of drug neuropathy Pure sensory neuropathy Cessation of exposure; late neuropathy may not be reversible
Direct toxicity to DRG neurons
EMG, Electromyogram; DRG, dorsal root ganglion; NCV, nerve conduction velocity; HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome.
such as paclitaxel (Taxol), cisplatin, oxaliplatin, and vincristine. Similarly, patients treated with amiodarone for prevention of potentially fatal arrhythmias may not be able to be safely switched to a less neurotoxic agent.
The presence of an underlying neuropathic disorder increases susceptibility to toxic neuropathy. This generalization should be recognized when choosing potentially toxic drugs in patients with diabetes, HIV infection, or hereditary neuropathies. Toxic neuropathic
377
effects are likely additive, meaning that exposure to multiple neurotoxic agents increases the likelihood of symptoms and signs. Many drugs have been labeled as causing neuropathy. Patients reporting numbness or pins and needles during clinical trials frequently earn a drug this designation. However, only a few drugs have been adequately studied to provide data supporting this claim. SUGGESTED READING
Goetz CG: Neurotoxins in clinical practice, New York, 1985, SP Medical & Scientific. Massaro EJ, editor: Handbook of neurotoxicology, Totowa, NJ, 2002, Humana Press.
PATIENT RESOURCE
National Institute of Occupational Safety and Health (NIOSH) http://www.cdc.gov/niosh/srchpage.html/
Kleopas A. Kleopa, M.D., and Steven S. Scherer, M.D., Ph.D.
What Are Familial Neuropathies?

When inherited neuropathies occur in isolation, they are termed Charcot-Marie-Tooth disease (CMT), or alternatively, hereditary motor and sensory neuropathy (HMSN). The typical CMT phenotype consists of a slowly progressive, distal muscle weakness and atrophy with sensory loss. Different subtypes are classically recognized by their clinical, electrophysiologic, and pathologic findings (Table 1). The neuropathy is traditionally considered demyelinating (CMT-1/HMSN-I) if the forearm motor nerve conduction velocities (NCV) are less than 38 m/sec, or axonal (CMT-2/HMSN-II) if NCVs are greater than 38 m/sec. CMT-1 is more common, with clinical onset in the first or second decade of life and segmental demyelination/remyelination and secondary axonal loss in nerve biopsies. CMT-2 typically has a later onset and is associated with loss of myelinated axons, without much evidence of demyelination. Some phenotypes have been traditionally given different names but proved to be genetically related to CMT, including the hereditary neuropathy with liability to pressure palsies (HNPP), which is milder, and Dejerine-Sottas syndrome (DSS) and congenital hypomyelinating neuropathy (CHN), which are more severe. CMT-1, CMT-2, HNPP, and DSS/CHN are caused by mutations in different genes, and different mutations in the same gene can cause different phenotypes (see Table 1). For example, deletion of Peripheral Myelin
Protein 22-kD gene (PMP22) causes HNPP, PMP22 duplications cause CMT-1A, and various missense mutations cause HNPP, a CMT-1-like syndrome, or even DSS/CHN. Likewise, different mutations in Myelin Protein Zero (MPZ), Early Growth Response 2 (EGR2), and Neurofilament Light (NEFL) genes cause diverse phenotypes. Demyelinating neuropathies are Schwann cell autonomous: the myelinating cells express the mutated gene and are responsible for the initial damage. Similarly, mutations in genes that are expressed by neurons likely cause axonal neuropathies by cell autonomous effects. There may be exceptions, such as certain MPZ mutations that appear to cause an axonal neuropathy, even though neurons do not express MPZ. It is also possible that the direct effects of some mutant proteins in both Schwann cells and neurons independently contribute to the neuropathy, as in MTMR2 or GDAP1 mutations. Some syndromic axonal neuropathies, such as the familial amyloidotic neuropathies (FAPs), are caused by mutations in genes that are not expressed by either neurons or Schwann cells. In FAP, physiologically soluble mutant plasma proteins exit the circulation and are transformed into proteolytically resistant -structured fibrils. These fibrils accumulate in various organs, including peripheral nerve, causing dysfunction. In each type of amyloidosis a specific protein contributes to the subunit of these fibrils; the degree and distribution of organ involvement determine the clinical phenotype. Neuropathy is a prominent manifestation of the subtypes of inherited amyloidosis that are associated with mutations of transthyretin (TTR), gelsolin (AGel), and apolipoprotein AI (ApoAI) genes. In addition to FAP, neuropathy may be a prominent manifestation of many inherited syndromic disorders (Table 2), often overshadowed by other manifestations. A discussion of these disorders is outside the scope of this review.
15
Diagnosing Familial Neuropathies

The diagnosis of familial neuropathies is usually suggested by a family history or by the elucidation of a phenotype that is consistent with an inherited neuropathy (Figure 1). Median and ulnar motor NCVs are of particular value because the degree and uniformity of NCV slowing often confirm or refute the clinical diagnosis and may even suggest a specific diagnosis (e.g., HNPP). Nerve biopsies are not necessary except in problematic cases or for research purposes. If desired, a molecular diagnosis can be logically pursued according to the diagram in Figure 1. Until a more comprehensive battery becomes commercially available, some of the recently discovered causes of CMT-1 (LITAF), CMT-2 (KIF1B, RAB7, and GARS), and CMT-4 (MTMR2, MTMR13, KIAA1985, and NDRG1) may not be commercially available (listed in http://www.genetests.org/). Given the complexity and cost of genetic testing, it is reasonable to refer a patient with a suspected inherited neuropathy to a specialist.
377
effects are likely additive, meaning that exposure to multiple neurotoxic agents increases the likelihood of symptoms and signs. Many drugs have been labeled as causing neuropathy. Patients reporting numbness or pins and needles during clinical trials frequently earn a drug this designation. However, only a few drugs have been adequately studied to provide data supporting this claim. SUGGESTED READING
Goetz CG: Neurotoxins in clinical practice, New York, 1985, SP Medical & Scientific. Massaro EJ, editor: Handbook of neurotoxicology, Totowa, NJ, 2002, Humana Press.
PATIENT RESOURCE
National Institute of Occupational Safety and Health (NIOSH) http://www.cdc.gov/niosh/srchpage.html/
Kleopas A. Kleopa, M.D., and Steven S. Scherer, M.D., Ph.D.
What Are Familial Neuropathies?

When inherited neuropathies occur in isolation, they are termed Charcot-Marie-Tooth disease (CMT), or alternatively, hereditary motor and sensory neuropathy (HMSN). The typical CMT phenotype consists of a slowly progressive, distal muscle weakness and atrophy with sensory loss. Different subtypes are classically recognized by their clinical, electrophysiologic, and pathologic findings (Table 1). The neuropathy is traditionally considered demyelinating (CMT-1/HMSN-I) if the forearm motor nerve conduction velocities (NCV) are less than 38 m/sec, or axonal (CMT-2/HMSN-II) if NCVs are greater than 38 m/sec. CMT-1 is more common, with clinical onset in the first or second decade of life and segmental demyelination/remyelination and secondary axonal loss in nerve biopsies. CMT-2 typically has a later onset and is associated with loss of myelinated axons, without much evidence of demyelination. Some phenotypes have been traditionally given different names but proved to be genetically related to CMT, including the hereditary neuropathy with liability to pressure palsies (HNPP), which is milder, and Dejerine-Sottas syndrome (DSS) and congenital hypomyelinating neuropathy (CHN), which are more severe. CMT-1, CMT-2, HNPP, and DSS/CHN are caused by mutations in different genes, and different mutations in the same gene can cause different phenotypes (see Table 1). For example, deletion of Peripheral Myelin
Protein 22-kD gene (PMP22) causes HNPP, PMP22 duplications cause CMT-1A, and various missense mutations cause HNPP, a CMT-1-like syndrome, or even DSS/CHN. Likewise, different mutations in Myelin Protein Zero (MPZ), Early Growth Response 2 (EGR2), and Neurofilament Light (NEFL) genes cause diverse phenotypes. Demyelinating neuropathies are Schwann cell autonomous: the myelinating cells express the mutated gene and are responsible for the initial damage. Similarly, mutations in genes that are expressed by neurons likely cause axonal neuropathies by cell autonomous effects. There may be exceptions, such as certain MPZ mutations that appear to cause an axonal neuropathy, even though neurons do not express MPZ. It is also possible that the direct effects of some mutant proteins in both Schwann cells and neurons independently contribute to the neuropathy, as in MTMR2 or GDAP1 mutations. Some syndromic axonal neuropathies, such as the familial amyloidotic neuropathies (FAPs), are caused by mutations in genes that are not expressed by either neurons or Schwann cells. In FAP, physiologically soluble mutant plasma proteins exit the circulation and are transformed into proteolytically resistant -structured fibrils. These fibrils accumulate in various organs, including peripheral nerve, causing dysfunction. In each type of amyloidosis a specific protein contributes to the subunit of these fibrils; the degree and distribution of organ involvement determine the clinical phenotype. Neuropathy is a prominent manifestation of the subtypes of inherited amyloidosis that are associated with mutations of transthyretin (TTR), gelsolin (AGel), and apolipoprotein AI (ApoAI) genes. In addition to FAP, neuropathy may be a prominent manifestation of many inherited syndromic disorders (Table 2), often overshadowed by other manifestations. A discussion of these disorders is outside the scope of this review.
15
Diagnosing Familial Neuropathies

The diagnosis of familial neuropathies is usually suggested by a family history or by the elucidation of a phenotype that is consistent with an inherited neuropathy (Figure 1). Median and ulnar motor NCVs are of particular value because the degree and uniformity of NCV slowing often confirm or refute the clinical diagnosis and may even suggest a specific diagnosis (e.g., HNPP). Nerve biopsies are not necessary except in problematic cases or for research purposes. If desired, a molecular diagnosis can be logically pursued according to the diagram in Figure 1. Until a more comprehensive battery becomes commercially available, some of the recently discovered causes of CMT-1 (LITAF), CMT-2 (KIF1B, RAB7, and GARS), and CMT-4 (MTMR2, MTMR13, KIAA1985, and NDRG1) may not be commercially available (listed in http://www.genetests.org/). Given the complexity and cost of genetic testing, it is reasonable to refer a patient with a suspected inherited neuropathy to a specialist.
378
TABLE 1 Classification of the Nonsyndromic Inherited Neuropathies*

Disease (OMIM) Locus; Gene Clinical Features
CMT-1 (autosomal or X-linked dominant demyelinating) HNPP (162500) 17p11; PMP22 Episodic mononeuropathies at typical sites of compression; mild demyelinating neuropathy CMT-1A (118220) 17p11; PMP22 Onset in 1st-2nd decade; progressive distal weakness, muscle atrophy, and sensory loss CMT-1B (118200) 1q22-23; MPZ Similar to CMT-1A; severity varies according to mutation CMT-1C (601098) 16p13-12; Similar to CMT-1A LITAF/SIMPLE CMT-1D 10q21; EGR2 Similar to CMT-1A; severity varies according to mutation CMT-1X (302800) Xq13.1; GJB1 Similar to CMT-1A, distal atrophy more pronounced; men more (connexin32) affected than women, more sensory symptoms, CNS involvement possible CMT-2 (autosomal dominant axonal/neuronal) CMT-2A (118210) 1p35-36; KIF1B (608507) 1p36.2; MFN2 CMT-2B (600882) 3q13-22; RAB7 CMT-2C (606071) CMT-2D (601472)Allelic to HMN-V CMT-2E (162280) CMT-2F (no MIM) CMT-2G (604484) CMT-2-P0 (118200) 12q23-24 7p14; GARS 8p21; NEFL 7q11-21; HSPB1 3q13.1 1q22-23; MPZ Onset of neuropathy by 10 yr of age; progresses to distal weakness and atrophy in legs; mild sensory disturbance Onset 2nd-3rd decade; severe sensory loss with distal ulcerations; length-dependent weakness Vocal cord and diaphragmatic weakness Arm > leg weakness; onset in 2nd-3rd decade; sensory axons involved Variable onset and severity; ranging from DSS-like to CMT-2 phenotype Severe distal weakness, fasciculations Proximal > distal weakness Late-onset progressive neuropathy, pain, hearing loss, abnormally reactive pupils
CMT-3 (severe demyelinating, autosomal dominant or recessive phenotypes) DSS/HMSN-III PMP22, MPZ, GJB, Onset before 3 yr of age with delayed motor development, severe (145900) EGR2, NEFL weakness, atrophy, and sensory loss; motor NCVs < 10 m/sec; (dominant); dysmyelination on nerve biopsies PRX, MTMR2 (recessive) Congenital PMP22, MPZ Hypotonic at birth, developing into clinical picture often similar to DSS hypomyelinating (dominant); EGR2 neuropathy (CHN) (recessive) (605253) CMT-4 (autosomal recessive demyelinating neuropathy) CMT-4A (214400) 8q13-q21; GDAP1 Early-childhood onset, progression to wheelchair dependency; both demyelinating and axonal phenotypes CMT-4B1 (601382) 11q22; MTMR2 Early-childhood onset, may progress to wheelchair dependency; focally folded myelin sheaths CMT-4B2 (604563) 11p15; SBF2 Childhood onset; progressive; focally folded myelin sheaths; glaucoma CMT-4C (601596) 5q23-33; KIAA1985 Infantile to childhood onset; progressing to wheelchair dependency CMT-4D (Lom) 8q24; NDRG1 Childhood onset; severe disability by 50 yr; hearing loss, dysmorphic (601455) features CMT-4F (605260) 19q13; PRX Childhood onset; usually progression to severe disability; prominent sensory loss, pain AR-CMT-2 or CMT-2B (autosomal recessive axonal neuropathy) AR-CMT-2A (605588) 1q21; LMNA Onset of neuropathy in 2nd decade; progresses to severe distal weakness and atrophy Hereditary Sensory (and autonomic) Neuropathies (HSN or HSAN) HSN-I (162400) 9q22; SPTLC1 Onset 2nd-3rd decade; severe sensory loss (including nociception) with dominant distal ulcerations; distal weakness HSN-III (Riley-Day) 9q31; IKBKAP Congenital onset; dysautonomic crises; absence of fungiform papillae, (223900) recessive overflow tears HSN-IV (CIPA) 1q21-q22, NTRKA Congenital absence of sensory and sympathetic neurons cause (256800) recessive dysautonomia, loss of pain sensation HSN (608088) 3p22-p24 Adult-onset cough and sensory neuropathy; painless injuries and/or lancinating pains, gastroesophageal reflux
379
TABLE 1 Classification of the Nonsyndromic Inherited Neuropathies*contd

Disease (OMIM) Locus; Gene Clinical Features
Hereditary Motor Neuropathies (HMN) or distal spinal muscular atrophy (SMA) HMN-5 (600794) 7p; GARS Arm > leg weakness; onset in 2nd-3rd decade; no sensory involvement Allelic to CMT-2D HMN-7 (158580) 2q14 Vocal cord involvement SMARD-1 (604320) 11q13; IGHMBP2 Distal infantile SMA with diaphragm paralysis HMNJ (605726) 9p21.1-p12 Childhood-onset distal weakness (Jerash type) HMN (607641) 2p13; DCTN1 Progressive hand > leg weakness and atrophy, vocal fold paralysis, facial weakness
*Genetic classification of selected types according to the Online Mendelian Inheritance in Man (OMIM) (http://www.ncbi.nlm.nih.gov/Omim/). References can also be found in the website: http://molgen-www.uia.ac.be/CMTMutations/DataSource/MutByGene.cfm. CNS, Central nervous system; DSS, Dejerine-Sottas syndrome; NCV, nerve conduction velocity.
A high index of suspicion is required to diagnose systemic amyloidosis. For neurologists, a progressive painful neuropathy and/or autonomic neuropathy (e.g., impotence) could lead to this diagnosis, especially if there is clinical or subclinical evidence of renal, cardiac, or gastrointestinal dysfunction. Demonstrating amyloid deposits in biopsies of nerve, rectal mucosa, or minor salivary glands or in an abdominal fat aspirate establishes the diagnosis. After diagnosis, it is essential to determine the cause to provide counseling for the patient and family about inheritance, prognosis, and treatment. A family history of amyloidosis makes the acquired form (due to immunoglobulin-derived amyloid) unlikely, but the absence thereof does not exclude inherited amyloidosis. In certain situations, one may elect to perform genetic testing for amyloid-associated mutations (http://www.genetests.org/), particularly for the most common form caused by TTR mutations, without first demonstrating amyloid. Genetic counseling for familial neuropathies is important. Information regarding the pattern of inheritance, penetrance, genotype-phenotype correlations, and implications of the genetic testing need to be addressed. Where appropriate, the patient should be aided in making family planning decisions with updated information regarding the likelihood of transmitting the disease, availability of prenatal testing, preimplantation genetic diagnosis, sperm and egg donation, and adoption.
polyneuropathy (CIDP) causes individuals with CMT to worsen over weeks to months. Some of these patients responded to conventional treatments for CIDP. Liver transplantation is increasingly used to treat TTR amyloidosis (FAP-I, FAP-II). For many patients, plasma levels of mutant TTR fall rapidly, and disease progression stops after transplantation, although disease regression is rare. Individuals with certain mutations (e.g., Val30Met) may have better outcome than those with other mutations (e.g., Glu42Gly), perhaps depending on the degree of cardiac involvement at the time of transplantation. Carpal tunnel syndrome, spinal stenosis, neuropathic pain (see later), diarrhea, heart failure, and renal failure can be treated. Renal failure is the major cause of death in FAP-III, and several patients have had liver transplantation with encouraging early results. Renal dialysis is the major supportive therapy, and early treatment of hypertension is advocated. Treatment of FAP-IV is symptomatic. Lubricants should be used to avoid corneal ulceration when eyelid closure is incomplete. Corneal transplantation should be considered if vision is impaired by corneal dystrophy. Plasma gelsolin is synthesized mainly by skeletal muscle, so that liver transplantation offers little theoretical benefit. Lysosomal replacement (-galactosidase) is being used for Fabrys disease.
15
Treating the Causes of Familial Neuropathies

No medical or surgical therapies are known to alter the course of any form of CMT. In animal models of CMT-1A, the commonest form of CMT, two drugs reduce the expression of PMP22 and thereby ameliorate the degree of neuropathy. One is a progesterone receptor antagonist, onapristone, which is not well tolerated. The other is large weekly doses of vitamin C (ascorbic acid). Whether these agents will work in humans is unknown, and no data support their use in other forms of CMT (there are even theoretical objections to their use in HNPP). Finally, there are rare cases in which superimposed chronic inflammatory demyelinating
Treating the Complications of Familial Neuropathies

Progressive weakness and sensory loss affect mobility and activities of daily living. Physical and occupational therapists, physiatrists, podiatrists, and orthopedic surgeons all have roles. Physical therapists and physiatrists can help the patient maintain function while ensuring safety and protecting the joints and feet. Goals include developing a program of stretching, as well as strengthening and conditioning exercises. Occupational therapists can assess the disabilities and daily needs of the patient and recommend adaptive strategies and equipment. Podiatrists and orthotics are helpful in foot care and ambulation. In mildly affected patients, properly fitting shoes may suffice. With moderate weakness, custom shoe inserts/insoles may suffice instead of braces. When distal
380
TABLE 2
Selected Syndromic Familial Neuropathies*

Locus; Gene (Protein) Associated Features
Disease (OMIM) Demyelinating Dominant Wardeenburg type IV (602229) Demyelinating Recessive Metachromatic leukodystrophy (250100) Globoid cell leukodystrophy (Krabbes) (245200) Refsums disease (266500) Merosin deficiency (156225) Axonal Dominant Familial amyloidotic neuropathy (FAP-I, FAP-II; 176300) FAP-III (Iowa; 107680) FAP-IV (Finnish; 137350) Acute intermittent porphyria (176000) Coproporphyria (121300) Variegate porphyria (176200) Fabrys disease (301500) Hereditary neuralgic amyotrophy (HNA; 162100) Axonal Recessive Hereditary tyrosinemia type 1 (276700) Giant axonal neuropathy (256850) Abetalipoproteinemia (200100) Analphalipoproteinemia (Tangiers disease; 205400) Cowchocks syndrome (310490) Congenital cataracts, facial dysmorphism neuropathy (CCFDN; 604168)
22q13; SOX10
CNS and PNS dysmyelination; Hirschsprungs disease Optic atrophy, mental retardation, hypotonia Spasticity, optic atrophy, mental retardation Deafness, retinitis pigmentosa, ichthyosis, heart failure Neuropathy and muscular dystrophy Painful axonal neuropathy; other organs involved; FAP-II also causes carpal tunnel syndrome Nephropathy, liver disease Corneal lattice dystrophy, cranial neuropathies Acute neuropathy follows abdominal crises; psychosis; depression; dementia; seizures Skin photosensitivity, psychosis, crises of acute neuropathy and abdominal pain South Africa: founder effect; similar to acute intermittent porphyria Angiokeratoma, pain, renal failure, cardiomyopathy Painful episodes of brachial palsy, dysmorphic features Hepatic and renal disease, cardiomyopathy Mental retardation, spasticity, kinky/curly hair Ataxia, acanthocytosis Orange tonsils, organomegaly, atherosclerosis, painless ulcerations Mental retardation (60%), deafness Cataracts, microcornea, facial dysmorphism, skeletal deformities
22q13; ARSA (Arylsulfatase A) 14q31; GALC (Galactosylceramide -galactosidase) 10pter-p11.2; PAHX (Phytanoyl-CoA hydroxylase) and 7q21-22; PEX7 (Peroxin-1) 6q22; LAMA2 (laminin-2) 18q21; TTR (transthyretin) 11q23; ApoA1 (apolipoprotein A1) 9q32-q34; AGel (Gelsolin) 11q23.3; PBGD (Porphobilinogen deaminase) 3q12; CPO (Coproporphyrinogen 3 oxidase) 1q22; PPOX (Protoporphyrinogen oxidase) Xq22; GLA (-galactosidase) 17q25
15q23-q25; FAH (Fumaryl-acetoacetase) 16q24; GANI (Gigaxonin) 4q24; MTP (microsomal triglyceride transfer protein) 9q31; ABC1 (ATP-binding cassette transporter) Xq24-26 18q23-qter; CTDP1 (intron 6)
Classification according to the Online Mendelian Inheritance in Man (OMIM) (http://www.ncbi.nlm.nih.gov/Omim/). CNS, Central nervous system; PNS, peripheral nervous system; ATP, adenosine triphosphate.
weakness becomes severe, most patients require short leg braces or ankle-foot orthoses; these should be custommade of lightweight materials and fit intimately to provide good stability and prevent pressure sores. In growing children, braces need to be adjusted or replaced periodically. The goals of timely orthopedic interventions are to minimize and correct deformities, especially those causing instability, decreased balance/ ambulation, or pain. Different procedures include fasciotomies, plantar releases for high arches, osteotomies for bone deformities, and tendon transfers or fusion of interphalangeal joints for hammertoes. The morbidity and convalescence time associated with triple arthrodesis of the ankle make it problematic.
Neuropathic pain is relatively uncommon, although it may develop in some kinds of CMT-2 and even be a presenting symptom in some neuropathies (CMT-2-P0, FAP-I to III, and Fabrys disease). Other causes of pain, especially stemming from the orthopedic complications of a chronic neuropathy, can be mistaken for neuropathic pain; proper foot care and nonsteroidal anti-inflammatory medications may be effective. The principles of managing neuropathic pain are the same as in acquired neuropathies; no controlled trials have demonstrated the superiority of any given medication in painful inherited neuropathies. The clinician needs to help select the medication and advise on how to adjust the dose. The patient needs to accurately inform the clinician on the
Familial Neuropathies NON-SYNDROMIC INHERITED NEUROPATHY
381
DSS/CHN
CMT
HNPP
Clinical phenotype: history and examination
CMT1
CMT1X
CMT2
Electrophysiology: forearm motor NCV slowing
Severe (<10 m/s)
Moderate (1035 m/s)
Intermediate (2540 m/s)
Mild (4050 m/s or normal)
Focal and/or mild (4050 m/s)
Genetic testing
Autosomal recessive? CMT4 Sequence: PRX Moderate EGR2 NCV? MTMR2* MTMR13* KIAA 1985* NDRG1* GDAP1
Sequence: PMP22 MPZ EGR2 () GJB1 NEFL
Sequence: PMP22 duplication () GJB1 () Sequence: PMP22 MPZ GJB1 EGR2 LITAF NEFL
Sequence: MPZ GJB1 NEFL KIF1B* RAB7* GARS*
Autosomal recessive? AR-CMT2
PMP22 deletion () Sequence:
15
Sequence: GDAP1 LMNA
PMP22
FIGURE 1. Making the diagnosis of Charcot-Marie-Tooth (CMT) neuropathies. In cases of suspected hereditary neuropathy with liability to pressure palsies (HNPP), testing for the PMP22 deletion should be performed first, because this is by far the major cause. If this is negative, then PMP22 exons should be sequenced. In CMT patients with uniform slowing of motor nerve conduction velocity (NCV) between 10 and 35 m/sec, testing for the PMP22 duplication, the major cause of CMT-1, should be performed first. If the patient does not have the duplication, then MPZ, PMP22, GJB1, EGR2, LITAF, and NEFL genes should be sequenced. When CMT-1X is the most likely diagnosis, sequencing GJB1 alone is the appropriate initial test; if negative, consider testing for other cases of CMT-1 or CMT-2. In cases of suspected CMT-2, one may test for MPZ, GJB1, and NEFL mutations via commercial laboratories and for KIF1B, RAB7, and GARS through scientific investigators. In Dejerine-Sottas syndrome (DSS) with severely slowed NCV, testing for the duplication will usually be negative, and sequencing of the PMP22, MPZ, and EGR2 should be done; if these are negative, consider GJB1 and NEFL. In families with possible recessive inheritance (CMT-4) and severely slow NCV, one may test for PRX and EGR2 mutations via commercial laboratories, and MTMR2, MTMR13, KIAA1985, and NDRG1 through scientific investigators; if NCV is not severely slowed, consider GDAP1, GJB1, and NEFL. If recessive CMT-2 is suspected, LMNA and GDAP1 genes may be sequenced. Updated information on the availability of new genetic testing can be found on the website http://www.geneclinics.org/. CHN, Congenital hypomyelinating neuropathy; AR, autosomal recessive. *Currently not commercially available.
benefits and side effects of medication. Use one medication at a time. To minimize side effects, start at the low doses and increase as tolerated, over weeks if necessary. It is imperative to increase the dose until significant pain relief or side effects occur. Neuropathic pain often responds to one or more of the following medications, most of which have not been approved by the U.S. Food and Drug Administration for this purpose: 1. Tricyclic antidepressantsamitriptyline, nortriptyline or desipramine, in order of decreasing sedation.
The choice depends on whether the sedation would be unwanted (interferes with daily activities) or beneficial (when improved sleep would be desirable). Start at low doses (10 to 25 mg) 1 hour before sleep and increase weekly (by 10 to 25 mg) to minimize side effects; the optimal dose seldom exceeds 100 mg/day. Tricyclics typically take 2 to 4 weeks to become fully effective against pain, and the severity of their side effects often diminishes over time. Bupropion, a nontricyclic antidepressant, is also effective (150 mg SR every 12 hours) and has less anticholinergic side effects.
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Entrapment Neuropathies Phone: 800-572-1717 http://www.mdausa.org/ The Neuropathy Association 60 E. 42nd St., Suite 942 New York, NY 10165 Phone: 212-692-0662 http://www.neuropathy.org/ CMT Mutation Database: listing of all reported CMT mutations in each gene and in each phenotype: http://molgen-www.uia.ac.be/ CMTMutations/ Amyloid Research Group at Indiana University School of Medicine http://www.iupui.edu/~amyloid/ Amyloid Treatment and Research Program at Boston University Medical Center http://medicine.bu.edu/amyloid/amyloid1.htm Online Mendelian Inheritance in Man http://www.ncbi.nlm.nih.gov/Omim/ Gene Clinics: includes reviews of inherited disorders and lists laboratories offering genetic testing http://www.geneclinics.org/
2. Gabapentinthis has minimal interactions with other medications and appears to be as effective as tricyclics but is more expensive. The usual starting dose is 300 mg at bedtime with 300-mg daily increments, up to 3600 mg or more daily, divided into three daily doses. The relative amount absorbed decreases as the dose increases. 3. Sodium channel blockersthese may be particularly beneficial for paroxysmal or stabbing pains. a. Carbamazepinestart at 100 mg twice daily or 200 mg at bedtime and increase daily by 100 mg; take in four divided daily doses. It is recommended not to exceed 1200 mg/day. b. Oxcarbazepinethe starting dose is 300 mg every 12 hours; this can be increased weekly (by 300 to 600 mg/day) to a maximum of 1200 mg every 12 hours. c. Topiramatethe recommended starting dose is 50 mg/day; increase the dose by 50 mg/day each week (on an every-12-hour schedule), to a maximum of 400 mg/day. 4. Opiateslong-acting opiates are effective in most patients but should be reserved for chronic pain unresponsive to adequate trials of the above medications. a. MS Contin (the active ingredient is morphine; 15, 30, 60, 100 mg tablets)each dose is active for about 12 hours. In non-opioid-tolerant patients, start at 15 mg every 12 hours. b. OxyContin (the active ingredient is oxycodone; 10, 20, 40, 80 mg tablets)works for about 12 hours. In non-opioid-tolerant patients, start at 10 mg every 12 hours. c. Duralgesic patches (the active ingredient is fentanyl; comes in 25 g/hr (10 cm2), 50 g/hr (20 cm2), 75 g/hr (30 cm2), and 100 g/hr (40 cm2)one patch works for 2 to 3 days. In nonopioid-tolerant patients, start with the 25 g/hr (10 cm2) patch. SUGGESTED READING
Benson MD: Amyloidosis. In Scriver CR, Beaudet AL, Sly WS, et al, editors: The metabolic and molecular bases of inherited disease, ed 8, New York, 2001, McGraw-Hill, 5345-5378. Dyck PJ, Chance P, Lebo R, Carney JA: Hereditary motor and sensory neuropathies. In Dyck PJ, Thomas PK, Griffin JW, et al, editors: Peripheral neuropathy, ed 3, Philadelphia, 1993, WB Saunders, 1094-1136. Lupski JR, Garcia CA: Charcot-Marie-Tooth peripheral neuropathies and related disorders. In Scriver CR, Beaudet AL, Sly WS, et al, editors: The metabolic and molecular bases of inherited disease, ed 8, New York, 2001, McGraw-Hill, 5759-5788. Wrabetz L, Feltri ML, Kleopa K, Scherer SS: Inherited neuropathies: clinical, genetic, and biological features. In Lazzarini RL, editor: Myelin biology and disorders, San Diego, 2004, Elsevier, 905-951.
Yuen T. So, M.D.
PATIENT RESOURCES
Charcot-Marie-Tooth Association 601 Upland Avenue, Upland, PA 19015 Phone: 800-606-7487 Fax: 610-499-7487 http://www.charcot-marie-tooth.org/ Muscular Dystrophy Association (MDA) 3300 E. Sunrise Drive Tucson, AZ 85718
Physical injury to peripheral nerves arises under several clinical settings. Chronic nerve entrapment may occur within a constrained anatomic space such as the carpal tunnel. Compression may also occur along a vulnerable nerve segment where the nerve may be compressed against underlying bony structures with little padding from surrounding soft tissues. The consequences of nerve compression are likely the outcome of a combination of nerve ischemia and mechanical disruption to neural tissues. Ischemia occurs at a relatively low pressure when the external compressive pressure exceeds capillary perfusion pressure. Ischemic consequences are reversible as long as ischemia is brief, because nerve infarction occurs only after hours of ischemia (e.g., the familiar leg tingling after prolonged sitting). At a much higher pressure, direct mechanical injury is possible with irreversible deficits appearing after only 20 to 30 minutes of compression. This higher pressure is possible in the earlier-mentioned vulnerable regions where the external force can be concentrated over a small bony region (pressure = force/area). Common examples are the peroneal nerve at the fibular head and the radial groove in the upper arm.
General Principles
The key to the initial diagnosis is the temporal course of symptoms. An abrupt onset usually implies a traumatic cause. This may occur with external compression during prolonged sleep or unconsciousness or during periods of
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Entrapment Neuropathies Phone: 800-572-1717 http://www.mdausa.org/ The Neuropathy Association 60 E. 42nd St., Suite 942 New York, NY 10165 Phone: 212-692-0662 http://www.neuropathy.org/ CMT Mutation Database: listing of all reported CMT mutations in each gene and in each phenotype: http://molgen-www.uia.ac.be/ CMTMutations/ Amyloid Research Group at Indiana University School of Medicine http://www.iupui.edu/~amyloid/ Amyloid Treatment and Research Program at Boston University Medical Center http://medicine.bu.edu/amyloid/amyloid1.htm Online Mendelian Inheritance in Man http://www.ncbi.nlm.nih.gov/Omim/ Gene Clinics: includes reviews of inherited disorders and lists laboratories offering genetic testing http://www.geneclinics.org/
2. Gabapentinthis has minimal interactions with other medications and appears to be as effective as tricyclics but is more expensive. The usual starting dose is 300 mg at bedtime with 300-mg daily increments, up to 3600 mg or more daily, divided into three daily doses. The relative amount absorbed decreases as the dose increases. 3. Sodium channel blockersthese may be particularly beneficial for paroxysmal or stabbing pains. a. Carbamazepinestart at 100 mg twice daily or 200 mg at bedtime and increase daily by 100 mg; take in four divided daily doses. It is recommended not to exceed 1200 mg/day. b. Oxcarbazepinethe starting dose is 300 mg every 12 hours; this can be increased weekly (by 300 to 600 mg/day) to a maximum of 1200 mg every 12 hours. c. Topiramatethe recommended starting dose is 50 mg/day; increase the dose by 50 mg/day each week (on an every-12-hour schedule), to a maximum of 400 mg/day. 4. Opiateslong-acting opiates are effective in most patients but should be reserved for chronic pain unresponsive to adequate trials of the above medications. a. MS Contin (the active ingredient is morphine; 15, 30, 60, 100 mg tablets)each dose is active for about 12 hours. In non-opioid-tolerant patients, start at 15 mg every 12 hours. b. OxyContin (the active ingredient is oxycodone; 10, 20, 40, 80 mg tablets)works for about 12 hours. In non-opioid-tolerant patients, start at 10 mg every 12 hours. c. Duralgesic patches (the active ingredient is fentanyl; comes in 25 g/hr (10 cm2), 50 g/hr (20 cm2), 75 g/hr (30 cm2), and 100 g/hr (40 cm2)one patch works for 2 to 3 days. In nonopioid-tolerant patients, start with the 25 g/hr (10 cm2) patch. SUGGESTED READING
Benson MD: Amyloidosis. In Scriver CR, Beaudet AL, Sly WS, et al, editors: The metabolic and molecular bases of inherited disease, ed 8, New York, 2001, McGraw-Hill, 5345-5378. Dyck PJ, Chance P, Lebo R, Carney JA: Hereditary motor and sensory neuropathies. In Dyck PJ, Thomas PK, Griffin JW, et al, editors: Peripheral neuropathy, ed 3, Philadelphia, 1993, WB Saunders, 1094-1136. Lupski JR, Garcia CA: Charcot-Marie-Tooth peripheral neuropathies and related disorders. In Scriver CR, Beaudet AL, Sly WS, et al, editors: The metabolic and molecular bases of inherited disease, ed 8, New York, 2001, McGraw-Hill, 5759-5788. Wrabetz L, Feltri ML, Kleopa K, Scherer SS: Inherited neuropathies: clinical, genetic, and biological features. In Lazzarini RL, editor: Myelin biology and disorders, San Diego, 2004, Elsevier, 905-951.
Yuen T. So, M.D.
PATIENT RESOURCES
Charcot-Marie-Tooth Association 601 Upland Avenue, Upland, PA 19015 Phone: 800-606-7487 Fax: 610-499-7487 http://www.charcot-marie-tooth.org/ Muscular Dystrophy Association (MDA) 3300 E. Sunrise Drive Tucson, AZ 85718
Physical injury to peripheral nerves arises under several clinical settings. Chronic nerve entrapment may occur within a constrained anatomic space such as the carpal tunnel. Compression may also occur along a vulnerable nerve segment where the nerve may be compressed against underlying bony structures with little padding from surrounding soft tissues. The consequences of nerve compression are likely the outcome of a combination of nerve ischemia and mechanical disruption to neural tissues. Ischemia occurs at a relatively low pressure when the external compressive pressure exceeds capillary perfusion pressure. Ischemic consequences are reversible as long as ischemia is brief, because nerve infarction occurs only after hours of ischemia (e.g., the familiar leg tingling after prolonged sitting). At a much higher pressure, direct mechanical injury is possible with irreversible deficits appearing after only 20 to 30 minutes of compression. This higher pressure is possible in the earlier-mentioned vulnerable regions where the external force can be concentrated over a small bony region (pressure = force/area). Common examples are the peroneal nerve at the fibular head and the radial groove in the upper arm.
General Principles
The key to the initial diagnosis is the temporal course of symptoms. An abrupt onset usually implies a traumatic cause. This may occur with external compression during prolonged sleep or unconsciousness or during periods of
383
obvious mechanical trauma. The absence of a plausible explanation should prompt investigation into other acute etiologies such as vasculitis and inflammation. By contrast, the typical entrapment neuropathy presents insidiously, often with an intermittent nature to the symptoms. Careful history in such a patient may reveal a correlation between symptoms and physical activities or postures of the involved limb. For example, wrist and finger flexion increases the pressure within the carpal tunnel and may therefore precipitate symptoms. Such a history of exacerbation is useful in distinguishing entrapment neuropathies from the polyneuropathy of systemic diseases. The latter tends to present with sensory symptoms that are relatively constant. Sensory symptoms are almost universally present in entrapment neuropathies. The distribution of paresthesia is often felt over a wider area than expected from the innervation of the nerve. Published maps of cutaneous innervation therefore provide a rough guidance at best. Pain especially may be caused by non-neuropathic causes. Even when pain is caused by a nerve injury, its location may be distant from the site of nerve involvement due to the phenomenon of referred pain. Weakness and atrophy appear later in the course of entrapment neuropathies but are more reliable means for anatomic localization. Some patients may be inherently more susceptible to physical injuries of their nerves. Diabetic and uremic neuropathies predispose nerves to mechanical injuries. An even more dramatic example is a hereditary disorder called hereditary neuropathy with liability to pressure palsy linked to a heterozygous deletion of the PMP22 gene on chromosome 22. Other causes are presented in Table 1. Nerve conduction study (NCS) and electromyography (EMG) are essential in the diagnosis. Entrapment neuropathies manifest electrophysiologically with a variable combination of focal demyelination (slowing of conduction velocity sometimes with conduction block) and loss of axons (reduced amplitude of the response and denervation on EMG). Focal demyelination is especially useful in lesion localization because the site of slowing or conduction block corresponds to the
entrapment site. Axonal loss is more useful for assessment of severity and prognosis. A general approach to management of entrapment and compression neuropathies is suggested in Figure 1. A fundamental assumption is the establishment of an accurate diagnosis. Unless symptoms are trivial and the examination is normal, all patients should undergo NCS and EMG because the tests provide a degree of anatomic localization that is often impossible with clinical evaluation alone. After a diagnosis of chronic entrapment or acute compression is established, one can then proceed to deal with the mechanical factors inherent in the disorders as outlined in Figure 1 and the remainder of this chapter.
Specific Neuropathies
CARPAL TUNNEL SYNDROME The median nerve and the finger flexor tendons pass through the carpal tunnel. The transverse carpal ligament forms the roof of the tunnel. Women on average have smaller carpal tunnels than men; the difference explains in part the increased incidence of carpal tunnel syndrome. Conditions that may predispose to carpal tunnel syndrome are listed in Table 1. Carpal tunnel syndrome is frequently bilateral, and the dominant hand is usually more often and more severely affected. Paresthesia is the foremost symptom, typically most prominent in the median-innervated fingers, although about half of the patients may report tingling in all the fingers. Pain is usually localized to the hand and wrist but may also be referred to the forearm or even the shoulder. Prominent pain may suggest a superimposed condition like tenosynovitis or arthritis. Pain alone without paresthesia is seldom due to carpal tunnel syndrome. Although it is common for patients to complain of hand weakness or an increased tendency to drop objects held in the hand, objective weakness is either absent or mild. Weakness and atrophy of the thenar muscles (abductor pollicis brevis and opponens pollicis) are present primarily in advanced disease. The key to both diagnosis and treatment is the characteristic exacerbation of symptoms with the use of hands. Repetitive or forceful use of the hands and fingers exacerbate symptoms. Some patients have synovitis or tendonitis from overuse. There may also be superimposed rheumatoid or other inflammatory arthritis. Wrist flexion increases the intracarpal tunnel pressure. Because the wrist often falls into a posture of prolonged volar flexion during sleep, nocturnal paresthesia is a frequent and characteristic complaint. Focal slowing of sensory nerve conduction velocity at the carpal tunnel is an early as well as a specific sign. Other median nerve conduction abnormalities are present in more severe cases. Ulnar NCS should be performed as a control and should be normal unless a polyneuropathy or a concurrent ulnar neuropathy is present. NCSs are abnormal in about 70% to 90% of patients with unequivocal carpal tunnel syndrome. The yield is lower in patients with only mild symptoms.
15
TABLE 1 Conditions that Predispose or Mimic Entrapment Neuropathies

Increased Nerve Susceptibility Diabetes mellitus Uremia Hereditary neuropathy with liability to pressure palsy Reduced Space* Hypothyroidism Pregnancy Amyloidosis Multiple myeloma Acromegaly Mucopolysaccharidosis Mucolipidoses Mass Lesions Ganglion Cyst Tumor Old fractures, osteophytes Hematoma Anomalous muscles or tendons
*For example, increased fluid pressure or infiltrative disease.
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Mononeuropathy
FIGURE 1. General approach to patient management in entrapment and compression neuropathies. EMG, electromyogram; NCS, nerve conduction study.
History Examination EMG/NCS Anatomic localization
Exclude radiculopathy, neoplastic, inflammatory and neurodegenerative diseases
Subacute/chronic symptoms
Acute onset
Syndrome compatible with entrapment neuropathy
Syndrome compatible with compression neuropathy
Consider additional causative factors (Table 1)
Close monitor (see text)
Intermittent symptoms
Persistent symptoms and signs, EMG denervation, or severe NCS changes Not improved
Not improved
Improved
Conservative therapy (see text)
Improved
Consider imaging, surgical decompression/ exploration
Reconsider diseases not due to compression/ entrapment
Treatment For patients with mild symptoms and mild nerve conduction abnormalities, the first step is to find and eliminate potential predisposing systemic conditions and to identify physical activities that aggravate symptoms. It is often difficult to completely eliminate physical activities that exacerbate symptoms, but a few weeks of rest should at least provide temporary relief. Additional benefits may be possible with a 4-week trial of splinting the wrist during sleep. The splint keeps the wrist in a neutral or slightly dorsiflexed position and is especially effective in those with nocturnal paresthesia. Many clinicians use local injection of corticosteroid near the carpal tunnel (20 mg or equivalent of methylprednisolone with 1 mL of 1% lidocaine) after the conservative therapy fails. The needle is inserted just ulnar to the palmaris longus tendon about 1 cm proximal
to the proximal wrist crease. The needle is angled at 45 degrees and aimed distally toward the carpal tunnel, avoiding the transverse carpal ligament. As the needle approaches the proper location near the carpal tunnel, gentle wiggling of the patients digits will cause slight movement of the needle. Before instillation of the medications, one must be careful to avoid intraneural injection into the median nerve. The needle should be removed if it causes any median or ulnar paresthesia. Steroid injection provides symptom relief for only about 1 month, and more than three injections are to be avoided because steroid weakens the flexor tendons and predisposes them to rupture. A 2-week course of oral prednisone (20 mg daily the first week, 10 mg the second week) also may provide short-term but modest benefits. Nonsteroidal anti-inflammatory agents, systemic diuretics, vitamin B6 (pyridoxine), and therapeutic
385
ultrasonography are of limited or unproven benefits. Daily use of 100 mg or more of vitamin B6 should be avoided because it may cause a sensory neuropathy. Most patients with disabling symptoms and those with severe EMG or nerve conduction abnormalities eventually require surgical decompression. All that is needed is the division of the transverse carpal ligament. Most patients fully recover within 6 weeks. The use of endoscopic surgical technique speeds up postoperative recovery, though the neurologic outcome is probably the same. Incomplete relief of symptoms after surgery may be due to incorrect preoperative diagnosis, incomplete section of the transverse ligament, postsurgical fibrosis, or causal etiologies that are untreated. Other reasons include arthritis or tenosynovitis unrelated to carpal tunnel syndrome or complex regional pain syndrome after surgery. ULNAR NEUROPATHY Most ulnar nerve entrapment occurs at the elbow, although the nerve may also be compressed in its distal portion at or near the Guyons canal. In those localized to the elbow, the compression may be either at the ulnar (condylar) groove or in the cubital tunnel. As in carpal tunnel syndrome, diabetes and other conditions may worsen or mimic ulnar entrapment neuropathy (see Table 1). Ulnar neuropathy manifests as weakness and atrophy of the intrinsic hand muscles and tingling in the little and ring fingers. The presentation is variable. Some patients notice only paresthesia, whereas others present with weakness and atrophy. Frequently, patients come to attention only after a medical provider notices atrophy of the intrinsic hand muscles. Sensory disturbances are often intermittent and worsen with prolonged elbow flexion or with repetitive elbow flexion and extension. Pain, if present, is usually referred to the elbow. Muscle atrophy involves all the intrinsic hand muscles, with the exception of the thenar eminence. Weakness is demonstrable with abduction of the fingers. In ulnar neuropathies due to entrapment at the elbow, flexion of the ring and little fingers may also be weak. A definite diagnosis may be difficult on the basis of examination alone. A C8 radiculopathy, a lesion in the lower trunk or medial cord of the brachial plexus, polyneuropathy, and amyotrophic lateral sclerosis all mimic ulnar neuropathy to some degree. Electrodiagnostic studies help with further anatomic localization. The classic NCS findings of ulnar entrapment at the elbowfocal slowing of ulnar motor nerve conduction velocity across the elbow and selective loss of the ulnar sensory nerve action potentialare usually sufficient to confirm the diagnosis. Shortsegment incremental study sometimes permits further differentiation between a lesion at the condylar groove and one at the cubital tunnel. However, the diagnosis can be difficult at times. Other patterns of abnormalities, such as borderline slowing, pure axonal loss, superimposed polyneuropathy, or coexisting carpal tunnel syndrome often do not permit an easy localization of the lesion.
Treatment The first step of treatment is conservative. Potential causative factors like repeated leaning on the elbow (e.g., confinement to wheelchairs) or prolonged pressure on the palm (e.g., bicycling or use of crutches) may be alleviated with a change of activity and proper padding. Conservative therapy should be accompanied by careful follow-up. Patients with significant neurologic deficits and those who fail to improve with conservative treatment are candidates for surgery. Surgery should be preceded by electrodiagnostic confirmation and localization. If an ulnar neuropathy is localized to the elbow, I favor further testing with shortsegment incremental motor study to identify cubital tunnel compression if possible. A cubital tunnel entrapment, in theory, needs only a simple release by cutting the flexor carpi ulnaris aponeurosis, whereas a condylar groove entrapment will need anterior transposition of the ulnar nerve and cubital tunnel decompression. Another procedure, medial epicondylectomy, has also been advocated. None of these procedures have been compared in a vigorous manner by controlled clinical trials. THORACIC OUTLET SYNDROME The term thoracic outlet syndrome as it is used today likely refers to a heterogeneous group of disorders. One classic syndrome is sometimes called the neurogenic thoracic outlet syndrome. This is a rare disorder with paresthesia in the ulnar aspect of the hand and forearm, selective wasting of the thenar eminence, and lesser wasting of other intrinsic muscles of the hand. Another rare disorder is caused by angulation and compression of the subclavian artery over an anomalous cervical rib. This is often called the vascular thoracic outlet syndrome, with intermittent arm claudication, coldness of the limb, and occasional embolic phenomena as principal manifestations. The most common entity, however, fits neither syndrome. These patients have intermittent arm pain and paresthesia. Symptoms worsen with carrying heavy objects or holding the arm overhead for a long period. The clinical examination and electrodiagnostic studies are normal. Popular adjunct tests such as Adson, hyperabduction, and costoclavicular maneuvers are of dubious value because they may be positive in normal individuals. Surgical decompression of the thoracic outlet should be reserved only for those with true neurogenic or vascular syndromes. For all other patients without neurologic or vascular abnormalities, treatment begins with avoidance of activities that worsen symptoms. Exercises are then designed to promote proper shoulder and neck posture. These exercises consist of strengthening exercises of shoulder girdle muscles and range-ofmovement exercises of the shoulder and neck. UNCOMMON ENTRAPMENT NEUROPATHIES Several uncommon entrapment neuropathies are listed in Table 2. Detailed description of them is beyond
15
386
TABLE 2
Uncommon Entrapment Neuropathies

Syndrome Suprascapular neuropathy: insidious shoulder pain, and weakness of supraspinatus/ infraspinatus Meralgia paresthetica: pain and numbness over lateral thigh Tarsal tunnel syndrome: pain and numbness over sole or heel Piriformis syndrome: buttock pain and tenderness, symptoms and signs of sciatic neuropathy Entrapment Site Suprascapular or spinoglenoid notch Inguinal ligament Predisposing and Exacerbating Factors Pain with shoulder movements; pain may be absent with spinoglenoid lesion Obesity, pregnancy, tight belts or pants, diabetes; symptoms worse with standing, better with hip flexion Prior ankle trauma or arthritis; symptoms worse with weight bearing Symptoms worse with prolonged sitting, adduction and internal rotation of hip Comments Look for spinati atrophy in patients with shoulder pain Largely a clinical diagnosis
Nerve Suprascapular
Lateral femoral cutaneous Tibial
Tarsal tunnel at medial malleolus At or near piriformis muscle
Sciatic
Mimics polyneuropathy, but far less common in neurologists practice Overrated cause of sciatica and buttock pain; occurs rarely
the scope of this review. The management decisions are similar. Patients with minor symptoms and no neurologic deficits can be managed with conservative measures alone. The primary goals are to identify and eliminate the causative or exacerbating factors. In those with disabling symptoms or neurologic deficits, I try to localize the lesion as accurately as possible through clinical evaluation and electrodiagnostic studies (EMG and NCS). I then follow with magnetic resonance imaging of the suspected nerve segment looking for mass lesions or abnormal nerve signal. Surgical exploration and decompression are often indicated in such instances. ACUTE COMPRESSION NEUROPATHIES Several focal neuropathies present typically in an acute fashion. Common examples are the radial neuropathy in the upper arm (Saturday night palsy) and the peroneal neuropathy at the fibular head (foot drop). Most of these are not true entrapment neuropathies but rather are caused by external compression. They follow a monophasic time course. Depending on the severity of the initial injury, recovery can be expected within a few weeks to 3 or 4 months after the onset. A lack of
improvement in 4 months should prompt surgical exploration for neuroma or a serious consideration for nerve grafting. A relentlessly progressive course after the first insult with further nerve involvement may suggest causes other than trauma, such as vasculitis or other causes of mononeuropathy multiplex. True entrapment is seen only rarely, usually manifesting as a relapse months or years after remission from the initial event (e.g., entrapment of the common peroneal nerve at the fibular tunnel). SUGGESTED READING
Gerritsen AA, de Krom MC, Struijs MA, et al: Conservative treatment options for carpal tunnel syndrome: a systematic review of randomized controlled trials, J Neurol 249:272-280, 2002. Logigian EL, editor: Entrapment and other focal neuropathies, Neurol Clin 17:1, 1999. National Institute for Occupational Safety and Health: In Bernard BP, editor: Musculoskeletal disorders and workplace factors, Atlanta, 1997, Centers for Disease Control and Prevention. http://www.cdc.gov/niosh/ergosci1.html. Stewart JD: Focal peripheral neuropathies, ed 3, Philadelphia, 2000, Lippincott Williams & Wilkins.
SECTION 16
Neuromuscular Junction and Muscle Disease

Myasthenia Gravis
Andrea M. Corse, M.D.
Some patients have symptoms limited to ocular muscles, so-called ocular MG, whereas the majority of patients experience generalized MG. A hallmark of the disease is the fatigable nature of the weakness.
Diagnosis
Myasthenia gravis (MG) is one of the most well understood of the human autoimmune diseases. The pathogenesis is an antibody-mediated autoimmune attack against the nicotinic acetylcholine receptor, resulting in skeletal muscle weakness. The antibodies impair neuromuscular transmission by (1) blocking postsynaptic acetylcholine receptors; (2) accelerating complement-mediated receptor degradation; and (3) inducing morphologic alterations of the postsynaptic end plate. The prevalence of acquired, autoimmune MG is approximately 5 to 10:100,000 population. The disease can afflict all ages but has peak incidences in younger women and older men. Neonatal autoimmune MG occurs in about 15% of babies born to myasthenic mothers and results from the passive transfer of antibodies from the mother to the baby; it is a transient disorder. In contrast, congenital MG refers to a group of rare genetic syndromes that are not autoimmune but which result in impaired neuromuscular junction transmission; these rare genetic conditions are not discussed further in this chapter. With the advent and widespread use of immunomodulating and immunosuppressant therapies over the past 30 years, the prognosis of myasthenic patients has improved strikingly. The mortality associated with MG is approaching zero, and the morbidity is drastically reduced; most myasthenic patients can be returned to full, productive lives with proper therapy. The diagnosis is based on a typical history and examination consistent with fatigable weakness combined with laboratory confirmation, such as positive antiacetylcholine receptor (anti-AChR) or anti-muscle-specific receptor tyrosine kinase (MUSK) serologies or electrophysiologic evidence of decrement on repetitive nerve stimulation studies or abnormal jitter on single-fiber EMG (SF-EMG). Anti-AChR antibodies are detectable in 80% of patients with generalized MG and about 50% of patients with ocular MG. Anti-MUSK serology is positive in up to 70% of the AChR-antibody seronegative patients. Patients who have anti-AChR antibodies do not have anti-MUSK antibodies. Anti-MUSK serology testing is available commercially in the United States. The presence of the AChR or MUSK antibodies confirms the diagnosis of MG; however, their absence does not exclude the diagnosis. The most commonly used electrophysiologic technique for the diagnosis of MG is repetitive nerve stimulation, which has a sensitivity of nearly 90% in generalized MG and 68% in ocular MG. Slow rate (2 to 3 Hz) repetitive nerve stimulation studies should be performed on three nerve-muscle pairs, preferably recording from weak limb or facial muscles. Repetitive stimulation at baseline is performed in all three pairs and then every minute up to 5 minutes after 15 seconds of exercise in at least one nerve-muscle pair. A significant baseline decremental response typical of MG is a 10% reduction in the compound muscle action potential amplitude or area of the fourth response compared to the first. Typically in MG, there is a reduction in the decrement (so-called postexercise facilitation) immediately after exercise due to increased concentrations of calcium and increased mobilization of acetylcholine stores in the presynaptic terminal. 387
Clinical Features
Clinical features of MG include any combination of ptosis, diplopia, dysarthria, dysphagia, facial weakness, proximal more than distal limb weakness, and shortness of breath.
388
Myasthenia Gravis
This is followed by an increased decrement (so-called postexercise exhaustion) due to reduced presynaptic terminal calcium and acetylcholine concentrations. SF-EMG provides the highest sensitivity in the detection of neuromuscular junction defects, detecting abnormalities in 88% to 99% of patients with generalized MG. The hallmark feature of a neuromuscular junction defect by this electrophysiologic technique is increased jitter, where jitter is the varying time interval between the triggered muscle action potentials in two muscle fibers belonging to the same motor unit. In patients who are AChR and MUSK serology negative and in whom repetitive nerve stimulation is normal or equivocal, SF-EMG is an extremely valuable diagnostic tool. An edrophonium (Tensilon) test is a diagnostic test that involves intravenous administration of an acetylcholinesterase inhibitor to enhance neuromuscular junction transmission. However, due to the lack of specificity and typical unpleasant cholinergic side effects, Tensilon tests are performed less frequently. In cases of probable serology negative, ocular MG with negative electrophysiology, consultation with a neuroophthalmologist for intramuscular prostigmine testing with quantification of extraocular eye movements may be also helpful. An ice test is a simple additional diagnostic test if ptosis is present. Ice applied to the ptotic eyelid for 2 minutes results in an increase in the palpebral fissure in more than 75% of patients with MG as reported in a small sample; patients with ptosis that is not on the basis of MG do not show improvement with cooling. The differential diagnosis is broad, depending on the constellation of symptoms. The differential diagnosis would include familial ptosis, levator dehiscence, thyroid ophthalmopathy, brain tumors, mitochondrial cytopathies, muscular dystrophies (e.g., myotonic and oculopharyngeal muscular dystrophies), intrinsic brainstem disease, myositis, motor neuron disease, or progressive supranuclear palsy, among others. Patients diagnosed with MG should undergo highresolution chest computed tomographic imaging due to the increased incidence of thymoma and thymic hyperplasia. The presence of anti-striated muscle antibodies in patients with MG is associated with the presence of thymoma. In patients with respiratory complaints, spirometry to include forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and FVC/FEV1 is critical. A search for other autoimmune disease is indicated in a patient with MG, including screens for autoimmune thyroid disease (antithyroglobulin and antimicrosomal antibodies), rheumatologic diseases (antinuclear and double-stranded DNA serologies and rheumatoid factor), hematologic diseases (antiparietal cell antibodies), or myositis (serum creatine kinase level). Diagnosis of myasthenic crisis indicates either an inability to swallow safely or significant respiratory insufficiency (FVC < 1 L) and necessitates critical care monitoring with possible nasogastric tube feeding and either noninvasive (bilevel positive airway pressure) or invasive ventilatory support.
Therapy
There is a broad range of therapeutic strategies for MG depending on the severity of the symptoms. When the symptoms are mild, no treatment may be required. In rare cases with mild and relatively static diplopia, prisms may be effective. More often, patients require at a minimum first-line medical management with pyridostigmine (Mestinon), an oral acetylcholinesterase inhibitor that acts by slowing down the enzymatic degradation of acetylcholine at the neuromuscular junction. In many cases of MG, pyridostigmine provides mild clinical benefit, but additional therapeutic interventions are required. The next therapeutic step is the addition of some form of immunomodulation to the pyridostigmine therapy. There are numerous immunomodulatory therapies to choose from, including steroids, azathioprine, cyclosporine, mycophenolate mofetil, intravenous gamma globulin, plasmapheresis, and cyclophosphamide. Factors that help determine the best therapeutic approach include the severity of the MG symptoms, time to onset of response, comorbidities, patient compliance, and cost and availability. PYRIDOSTIGMINE Pyridostigmine monotherapy is inexpensive and may be sufficient to control mild symptoms. Initial dosage of pyridostigmine is 60 mg (one tablet) in the morning and mid-day. Eventually, dosing with 1 or 2 tablets every 3 to 4 hours during the day while awake is recommended, if necessary. Mestinon Timespan 180 mg taken as a single bedtime dose provides sustained release overnight. Pyridostigmine is very safe; relative contraindications are cardiac conduction defects or asthma. Pyridostigmine dosing is often limited by gastrointestinal side effects due to increased gut peristalsis causing abdominal cramping, frequent bowel movements, or diarrhea, although these can be managed with over-the-counter antidiarrheal preparations. Rarely, excessive amounts of anticholinesterases may cause increased weakness that is reversible after decreasing or discontinuing the drug. THYMECTOMY AND THYMOMECTOMY In patients with thymoma, thymomectomy is recommended. Thymomas should be removed at any age, if the patient is an operative candidate, due to the risk of local spread and invasion, although metastases are rare. A trans-sternal dissection is the recommended surgical technique for resection of thymomas to maximize the opportunity for complete resection. If thymomatous tissue is not completely excised, postoperative radiation therapy is administered. Thymectomy is a recommended therapy to increase the probability of remission or improvement in a select group of nonthymomatous MG patients, although the benefit of thymectomy has not been established conclusively. Patients between puberty and 50 years of age who are not adequately controlled with pyridostigmine monotherapy may benefit. Thymectomy appears likely to result in clinical improvement in probably 85%
Myasthenia Gravis
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of patients, with drug-free remission in up to 35% and reduced medication requirements in up to 50%. The benefit from thymectomy is delayed, rarely occurring within 6 months and requiring up to 2 to 5 years. There is no definitive evidence indicating the superiority of one surgical technique for thymectomy against another; the two most common techniques are the transcervical and trans-sternal approaches. Video-assisted thoracoscopic surgery also is being used. Risks of thymectomy or thymomectomy include injury to the phrenic or recurrent laryngeal nerves, atelectasis, pleural effusion, pneumonia, thoracic duct injury, myasthenic crisis, pulmonary embolism, impaired wound healing, and later sternal instability. Therefore, thymectomy always should be done in an institution where this procedure is performed expertly and regularly and where the staff is experienced in the anesthetic care and preoperative and postoperative management of MG. IMMUNOSUPPRESSIVE DRUGS Immunosuppressive therapy is indicated when MG symptoms are insufficiently controlled by anticholinesterase agents and are sufficiently disabling to the patient that the frequent side effects of these drugs are worth risking. Sufficient control is best defined functionally by each patient; for example, some patients are willing to live with moderate generalized weakness, whereas for others even mild ptosis is intolerable. Three agents are now considered as first-line drugs for chronic immunosuppressive therapy for MG prednisone, azathioprine, and cyclosporine. A newer agent, mycophenolate mofetil, is currently being investigated as another first-line chronic immunosuppressive agent in the treatment of MG. Plasmapheresis and intravenous immunoglobulin (IVIg) are effective shortterm immunomodulatory therapies for MG patients. The choice among these treatments is made by considering two facts: (1) how the toxicity profile fits the patient, and (2) how fast the patient has to improve. I see patients who are not immunosuppressed potently enough, not treated long enough, or are treated without adequate management of side effects or infections. The predictably poor outcomes may end up souring both the patient and physician on a particular drug or convincing both that it is ineffective when it could be effective. Before immunosuppression is begun, the patients history of tuberculosis exposure and, if appropriate, skin testing should be obtained and, if significant, alternative immunomodulatory therapies such as maintenance plasmapheresis or human IVIg therapy should be considered. CORTICOSTEROIDS Corticosteroids have been the mainstay of MG therapy for more than 30 years. More than 80% of myasthenic patients can be expected to improve with steroid therapy alone within 2 to 3 weeks, though maximal therapeutic benefit may not be realized for up to 6 months.
Steroids have a rapid onset of improvement measured in weeks and are inexpensive. There are no absolute contraindications to the use of steroid therapy; however, relative contraindications include diabetes mellitus, obesity, ulcer disease, uncontrolled hypertension, osteoporosis, or ongoing infections. Some of these problems can be circumvented by medical measures. Chronic steroid therapy requires medical attention by an experienced physician; patients who are unwilling to be followed closely should never be treated with steroids or any other immunosuppressive therapy. Nursing mothers should be warned that steroids can pass into breast milk. The most common errors observed in the use of steroid therapy in MG patients are the initiation of therapy with doses too high and too rapid withdrawal of the steroid. Patients with moderate to severe generalized weakness or significant respiratory insufficiency or bulbar weakness are at risk of a transient steroid-induced exacerbation. Nearly 50% of such patients have an exacerbation, which lasts days and occurs most commonly during the second 5 days of induction. The cause of the initial steroid-induced deterioration is not clear. Prednisone is begun at a dosage of 15 to 20 mg/day taken as a single daily dose in the morning and gradually increased by 5 mg every 3 days, until the patient reaches a satisfactory clinical response or reaches the level of 60 mg daily. Only if the patient is already on a ventilator, then high-dose therapy will be initiated without dose escalation. A single alternate-day morning dose schedule mimics the normal diurnal cortisol cycle, reduces side effects, and facilitates eventual tapering of total dose. Corticosteroids should not be used in divided daily dosesthis need arises mainly in painful, inflammatory, arthritic, or vasculitic diseases but never in MG. High-dose prednisone is maintained until clinical improvement levels off, or 3 months, whichever comes first. The dosage and schedule are then gradually tapered toward an alternate-day regimen typically by reducing the alternate-day dose by 10% every 6 weeks as tolerated as determined by the patients index symptoms and quantitatively measured signs that served as the original indication for immunotherapy. Eventually an alternate-day regimen is established in most patients; occasionally a small dose of prednisone must be given on the off day to prevent fluctuations in strength. When the patient reaches a plateau of improvement on an alternate-day regimen, the gradual steroid taper is resumed to seek the smallest effective dose. The goal of the steroid taper is not to eliminate the medication entirely; steroid therapy may need to be continued indefinitely in many patients, though the dose may be substantially reduced. It usually takes up to 2 years to determine the minimum requirement for a given patient. It is extremely important to taper the steroids very gradually because the disease may exacerbate with too rapid a taper. The consequences of lowering the dose too fast may not be apparent for several months, and higher doses may be needed to achieve the same effect as before the exacerbation. Physicians must make their patients familiar with the unfortunately long list of side effects of chronic steroid
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therapy and the potential serious side effects. Most patients develop some side effects; almost every patient gains weight and develops part of the cushingoid habitus. Some of the side effects can be minimized with alternateday dosing and scrupulous attention to follow-up. I routinely monitor weight, blood pressure, the lens, glucose, and electrolytes. Preventive treatment against osteoporosis, especially in postmenopausal women, includes exercise, calcium supplements 1500 mg/day (Tums and Rolaids double as antacids), and vitamin D (50,000 units twice weekly). Use of etidronate should be considered in patients who develop osteopenia detected by monitoring quantitative bone mineral densitometry. Low maintenance steroid doses should be doubled during periods of acute stress to prevent symptoms of adrenal insufficiency. The following patients should be considered for other forms of immunotherapy and thymectomy if not already performed: those who have an exacerbation when prednisone is slowly tapered; those who fail to respond; those requiring more than 40 to 50 mg every other day; and those in whom toxicity exceeds benefit. AZATHIOPRINE Azathioprine is used as (1) an alternative firstline chronic immunosuppressant; (2) an additional therapy in patients whose MG has not been adequately controlled by thymectomy and corticosteroids; or (3) a steroid-sparing agent. Because the beneficial effects of azathioprine may take more than 6 months to appear, the combination of azathioprine and steroids or azathioprine and IVIg affords the relatively rapid onset of immunosuppression produced by the steroids or IVIg and allows more successful tapering of steroids as demonstrated in a randomized, double-blinded, placebo-controlled trial of prednisolone alone or with azathioprine. Since a completely intact immune response requires antigen processing and presentation (dependent in part on RNA synthesis) as well as proliferation and differentiation of immunocompetent cells (dependent on DNA and RNA synthesis), purine analogs like azathioprine can interrupt the immune response potently at multiple sites. A tight relationship exists between azathioprine dose and biologic effects on dividing cells like lymphoid and erythroid cells. Leukopenia and macrocytosis occur predictably and are monitored as guides to azathioprine dosing. Azathioprine is extensively oxidized and methylated in liver and red blood cells. Concurrent administration of allopurinol (for treatment of gout) can increase the toxicity of azathioprine by interfering with its metabolism by xanthine oxidase, an important degradative pathway. Therefore, azathioprine dosage must be reduced by as much as 75% in patients who take allopurinol. As many as 10% to 20% of patients are unable to tolerate azathioprine because of abnormal liver function, bone marrow depression, or an idiosyncratic reaction consisting of flulike symptoms of fever and myalgias. The question of a small increased risk of malignancy in azathioprine-treated patients has
not been resolved; experience with azathioprine in organ transplantation suggests an increased risk of malignancy. However, patients with MG and rheumatoid arthritis have been treated for years with the drug and no increase in the incidence of malignancies has been found. Azathioprine is begun at a test dose of 50 mg/day; the dose is advanced by 50 mg weekly toward a usual target dose of 2 to 3 mg/kg. Weekly monitoring of the white blood cell (WBC) count, differential, platelet count, and liver function tests is continued until the maintenance dose is achieved, then monthly surveillance is continued indefinitely even after a stable nontoxic dose is reached. To establish the optimum dose, several endpoints may be used. A rise in the red blood cell mean corpuscular volume to greater than 100 fl provides a useful gauge of biologic activity and in MG usually correlates with clinical improvement; macrocytosis, therefore, is not an indication for discontinuation of therapy. A total WBC count of 3000 to 4000/mm3 is also a safe endpoint. Azathioprine should be briefly discontinued if the WBC count falls below 2500/mm3 or the absolute neutrophil count is less than 1000/mm3, then reintroduced as a lower dose. This measure cannot be used in patients receiving prednisone, because of the steroid-induced leukocytosis. In that situation, an absolute lymphocyte count of 5% to 10% is an appropriate target. An adequate therapeutic trial of azathioprine therapy must last 1 to 2 years, since the lag to onset of effect may range from 3 to 12 months, and the point of maximum benefit may be delayed 1 to 3 years. Although azathioprine is decidedly slow to act, it is well tolerated by most patients. Although most myasthenic patients require lifelong immunosuppression, it is worthwhile to attempt to very slowly taper azathioprine to establish a minimal effective dose usually only after years of clinical stability. Azathioprine increases susceptibility to opportunistic infections as with other immunosuppressant agents. The hematologic toxicity, including leukopenia, anemia, and thrombocytopenia, all are reversible on reduction of the dose of azathioprine. Hepatic toxicity, with mild elevation of transaminases, is common and responds to lowering the dose. Gastrointestinal discomfort with nausea and anorexia is usually mild and responds to the use of divided doses taken with meals. CYCLOSPORINE Unlike the cytotoxic effects of corticosteroids and azathioprine, cyclosporine provides a relatively selective immunomodulatory action. Cyclosporine inhibits the activation of helper inducer (CD4+) T cells and their production of interleukin (IL)-1 and IL-2, while relatively sparing suppressor (CD8+) T cells. Its therapeutic effect in MG is thus explained, because the activation of B cells and production of anti-AChR antibodies are T-cell dependent. Cyclosporine is metabolized by the liver and excreted in the bile. This accounts for its ability to potentiate greatly the risk of necrotizing myopathy or myoglobinuria due to lovastatin, which also depends on biliary excretion. Because P450-mediated oxidation of the
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drug is extensive, hepatic dysfunction or concurrent administration of agents that affect the cytochrome P450 system can cause dramatic changes in the elimination of cyclosporine. Cyclosporines independent mechanism of action produces an effect that is additive to that of corticosteroids; corticosteroids increase plasma cyclosporine levels. Because of evidence that the combination of cyclosporine and azathioprine and prednisone for suppression of organ rejection causes an increased risk of malignancies and infectious complications, most centers prefer to use only prednisone in combination with cyclosporine. Cyclosporine has been shown to be effective primary immunotherapy for the treatment of MG in a prospective, double-blinded, randomized, placebo-controlled trial. Improvement began in about 2 weeks, with maximal improvement by 4 months, correlating with a reduction in the AChR antibody levels. The efficacy of cyclosporine relates to the lowest (trough) plasma levels, whereas toxicity depends on peak concentration. The drug is given in a divided dosage schedule, twice a day. Because it is lipid soluble and variably absorbed, cyclosporine should be taken with a fat-containing meal or snack. The initial dose is 2.5 mg/kg twice a day. Although the dose is eventually guided by clinical efficacy, it is initially adjusted by monitoring (1) plasma trough cyclosporine levels and (2) side effects. Plasma levels should be measured every 3 weeks until stable and then approximately monthly. Trough levels are measured in the morning 12 hours after the last dose. The reported levels depend on the method of assay; using the radioimmunoassay with a specific monoclonal antibody, the trough level should be maintained between 100 and 200 ng/mL. The blood pressure, serum creatinine, and blood urea nitrogen are monitored, and the dose of cyclosporine is decreased if the creatinine level rises above 1.4 times the baseline level. Cyclosporine has less frequent serious chronic toxicity compared to corticosteroids. The most worrisome side effects are hypertension and nephrotoxicity (seen in 25% of patients), especially in elderly patients. Nonsteroidal anti-inflammatory drugs that inhibit prostaglandin generation potentiate cyclosporine nephrotoxicity. Other side effects include facial hirsutism, gastrointestinal disturbance, headache, tremor, convulsions, and, rarely, hepatotoxicity. These are related to the drug level and reversible with dose reduction. Hypertension may respond to either dose reduction or, if the cyclosporine blood levels are appropriate, to institution of weight reduction, salt restriction, and an antihypertensive drug. Calcium channel blockers are preferred. As with other immunosuppressive agents, there is a theoretically possible increase in the long-term risk of malignancy. MYCOPHENOLATE MOFETIL Mycophenolate mofetil is an immunosuppressant agent approved by the U.S. Food and Drug Administration in 1995 as a drug to prevent rejection in renal transplant. It has been reported in small, uncontrolled open clinical trials to be effective in the treatment of MG. Mycophenolate mofetil inhibits the proliferation of B
and T cells by interfering with purine biosynthesis similar to azathioprine. Proliferating lymphocytes appear to use the de novo pathway for purine synthesis that is selectively inhibited by mycophenolate mofetil in contrast to the less specific inhibition of purine synthesis produced by azathioprine. The usual dose of mycophenolate mofetil is 2 or 3 gm/day in two divided doses. It is highly protein bound. There is no drug interaction with allopurinol, unlike azathioprine. The cost of the drug is considerably higher than either azathioprine or cyclosporine. Therefore, pending the results of a controlled clinical trial of mycophenolate mofetil in MG, use of this drug is limited. In my practice I tend to reserve it for adjuvant therapy in combination with cyclosporine and prednisone therapy or for older patients in whom there are relative contraindications for the other immunosuppressant agents. Use of mycophenolate mofetil rarely causes nephrotoxicity or hepatotoxicity, and the side effects are generally mild and seldom require discontinuation of the drug. The most frequently reported side effects or adverse effects include gastrointestinal complaints, hematologic toxicity with pancytopenia, and opportunistic infections. SHORT-TERM IMMUNOTHERAPIES Plasmapheresis, which depletes circulating antibodies, has been shown to produce short-term benefit in up to 100% of patients with MG. It is used primarily to stabilize patients in myasthenic crisis or for short-term management of patients undergoing thymectomy, to avoid perioperative corticosteroids and other immunosuppressants. Less commonly, it is used as an adjuvant therapy in severely ill patients who are slow to respond to immunosuppressants. Repeated plasmapheresis as a chronic form of therapy either because the patient is intolerant or unresponsive to conventional immunosuppressant treatment is rarely indicated. Plasmapheresis works rapidly with improvement measurable within days of treatment. The beneficial effects of plasmapheresis are temporary, lasting only days to weeks, unless concomitant immunosuppressive agents are used. Five plasma exchanges over a 2-week period are a typical protocol. The major risks are due to problems with vascular access. Blood flow from peripheral veins is frequently insufficient for processing by modern high-volume hemapheresis machines. Therefore, indwelling catheters in large veins are used and can cause infection, thrombosis, perforation, and even pneumothorax. Sepsis, arrhythmia, anaphylactic shock, pulmonary embolism, and systemic hemorrhage from disseminated intravascular coagulation, among other hazards, have also been reported. The benefit of plasma exchange must be weighed against problems of vascular access, the risks of pheresis, and the high cost of the procedure. The indications for the use of intravenous human immune globulin (HIG) are the same as those for plasma exchange, that is, to produce rapid improvement so as to get the patient through a difficult period of
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Muscular Dystrophies Schneider C, Gold R, Reiners K, Toyka KV: Mycophenolate mofetil in the therapy of severe myasthenia gravis, Eur Neurol 46:79-82, 2001.
myasthenic weakness. A review of the efficacy of HIG in numerous published series indicates an overall improvement in more than 70% of the patients. The usual dose is 400 mg/kg/day on each of 5 consecutive days. When patients respond, the onset is within 4 or 5 days and the maximal response occurs within 1 to 2 weeks. The effect may be sustained for weeks to months, allowing for intermittent chronic therapy. The mechanism of action of HIG in MG is unknown, but possible mechanisms include (1) blockade of Fc receptors on macrophages and other cells, and (2) inhibition of the immune response to AChR by specific anti-idiotypic antibodies in the HIG pool. HIG is generally well tolerated. Adverse reactions occur in fewer than 10% of patients and are generally mild, including headache, fluid overload, and various gastrointestinal complaints. Patients with selective IgA deficiency with antibodies against IgA should not receive HIG due to serious risks of allergic reaction. A rare adverse effect is renal failure, especially in patients older than 65 years of age, with baseline creatinine greater than 1.4, or in the setting of diabetes mellitus. Gamma globulin preparations containing sucrose have been implicated most often. The process of preparation of HIG has been shown to inactivate human immunodeficiency virus and hepatitis B. HIG is quite expensive, and this factor as well as possible risks should be carefully weighed against the potential of rapid benefit.
PATIENT RESOURCES
Muscular Dystrophy Association 3300 East Sunrise Drive Tucson, Arizona 85718-3208 Phone: 800-572-1717 E-mail: mda@mdausa.org http://www.mdausa.org Myasthenia Gravis Foundation of America 1821 University Ave., W., Suite S256 St. Paul, MN 55104 Phone: 651-917-6256 or 800-541-5454 E-mail: mgfa@myasthenia.org http://www.myasthenia.org/
Kathryn R. Wagner, M.D., Ph.D., and Richard T. Moxley III, M.D.
Comparisons
Each immunomodulatory treatment has its own advantages and disadvantages. Steroids generally act rapidly, are tried and true, but are beset by the problems of prevention and treatment of side effects. Azathioprine is safe and moderately effective but slow. Cyclosporine is about equal to azathioprine in effectiveness; it is rapid in onset but expensive to use. Cyclophosphamide is potent but potentially more toxic, and it is therefore reserved for special cases. Mycophenolate mofetil is the newest addition to the immunosuppressant options; however, limited clinical data in MG are available, and it is the most expensive of the oral pharmacologic options. Plasmapheresis or IVIg is often useful for the short-term management of acute problems or as preoperative or postoperative therapy. However, the effects of both are transient, and their costs are extremely high. These therapeutic options provide a broad spectrum of effective treatment modalities. However, more specific and long-lasting treatments are still needed. SUGGESTED READING
Ciafaloni E, Sanders D: Advances in myasthenia gravis, Curr Sci 2:89-95, 2002. Gronseth G, Barohn R: Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review), Neurology 55:7-15, 2000. Palace J, Newsom-Davis J, Lecky B: Myasthenia Gravis Study Group. A randomized double-blinded trial of prednisolone alone or with azathioprine in myasthenia gravis, Neurology 50:1778-1783, 1998.
Muscular dystrophies are hereditary diseases of muscle that are marked by progressive weakness and wasting. Currently, there are more than 40 diseases of muscle in which the responsible genetic mutation has been identified. In this chapter, we discuss some of the common goals in treating patients with muscular dystrophy as well as specifics related to the most prevalent forms. In general, these diseases require a multidisciplinary approach where the neurologist is often central in recognizing the need for other services for the patient. Muscular Dystrophy Association clinics throughout the country facilitate such an approach. While there has been an explosion in our understanding of the molecular basis of the muscular dystrophies in recent years, there are currently no drugs approved by the U.S. Food and Drug Administration for use in muscular dystrophy. Specific therapies aimed at correcting the underlying pathophysiology are still in preclinical and early clinical studies. Further along in development are clinical trials aimed at stimulating muscle growth and regeneration. Corticosteroids have been proven in multiple clinical trials to have a moderate benefit in one disorder, Duchennes muscular dystrophy (DMD). Other than corticosteroids for DMD, we do not recommend any drugs or supplements specifically for muscle growth that have not been proven to be beneficial in controlled clinical trials. Despite the current lack of available pharmacologic agents, attentive care and treatment as outlined in this chapter provide significant benefit to patients with muscular dystrophy, increasing the quality and often the extent of their lives, by improving function. There are several aspects to the care of dystrophic diseases that are similar for the various disorders, including exercise, maintaining flexibility, and minimizing immobility.
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Muscular Dystrophies Schneider C, Gold R, Reiners K, Toyka KV: Mycophenolate mofetil in the therapy of severe myasthenia gravis, Eur Neurol 46:79-82, 2001.
myasthenic weakness. A review of the efficacy of HIG in numerous published series indicates an overall improvement in more than 70% of the patients. The usual dose is 400 mg/kg/day on each of 5 consecutive days. When patients respond, the onset is within 4 or 5 days and the maximal response occurs within 1 to 2 weeks. The effect may be sustained for weeks to months, allowing for intermittent chronic therapy. The mechanism of action of HIG in MG is unknown, but possible mechanisms include (1) blockade of Fc receptors on macrophages and other cells, and (2) inhibition of the immune response to AChR by specific anti-idiotypic antibodies in the HIG pool. HIG is generally well tolerated. Adverse reactions occur in fewer than 10% of patients and are generally mild, including headache, fluid overload, and various gastrointestinal complaints. Patients with selective IgA deficiency with antibodies against IgA should not receive HIG due to serious risks of allergic reaction. A rare adverse effect is renal failure, especially in patients older than 65 years of age, with baseline creatinine greater than 1.4, or in the setting of diabetes mellitus. Gamma globulin preparations containing sucrose have been implicated most often. The process of preparation of HIG has been shown to inactivate human immunodeficiency virus and hepatitis B. HIG is quite expensive, and this factor as well as possible risks should be carefully weighed against the potential of rapid benefit.
PATIENT RESOURCES
Muscular Dystrophy Association 3300 East Sunrise Drive Tucson, Arizona 85718-3208 Phone: 800-572-1717 E-mail: mda@mdausa.org http://www.mdausa.org Myasthenia Gravis Foundation of America 1821 University Ave., W., Suite S256 St. Paul, MN 55104 Phone: 651-917-6256 or 800-541-5454 E-mail: mgfa@myasthenia.org http://www.myasthenia.org/
Kathryn R. Wagner, M.D., Ph.D., and Richard T. Moxley III, M.D.
Comparisons
Each immunomodulatory treatment has its own advantages and disadvantages. Steroids generally act rapidly, are tried and true, but are beset by the problems of prevention and treatment of side effects. Azathioprine is safe and moderately effective but slow. Cyclosporine is about equal to azathioprine in effectiveness; it is rapid in onset but expensive to use. Cyclophosphamide is potent but potentially more toxic, and it is therefore reserved for special cases. Mycophenolate mofetil is the newest addition to the immunosuppressant options; however, limited clinical data in MG are available, and it is the most expensive of the oral pharmacologic options. Plasmapheresis or IVIg is often useful for the short-term management of acute problems or as preoperative or postoperative therapy. However, the effects of both are transient, and their costs are extremely high. These therapeutic options provide a broad spectrum of effective treatment modalities. However, more specific and long-lasting treatments are still needed. SUGGESTED READING
Ciafaloni E, Sanders D: Advances in myasthenia gravis, Curr Sci 2:89-95, 2002. Gronseth G, Barohn R: Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review), Neurology 55:7-15, 2000. Palace J, Newsom-Davis J, Lecky B: Myasthenia Gravis Study Group. A randomized double-blinded trial of prednisolone alone or with azathioprine in myasthenia gravis, Neurology 50:1778-1783, 1998.
Muscular dystrophies are hereditary diseases of muscle that are marked by progressive weakness and wasting. Currently, there are more than 40 diseases of muscle in which the responsible genetic mutation has been identified. In this chapter, we discuss some of the common goals in treating patients with muscular dystrophy as well as specifics related to the most prevalent forms. In general, these diseases require a multidisciplinary approach where the neurologist is often central in recognizing the need for other services for the patient. Muscular Dystrophy Association clinics throughout the country facilitate such an approach. While there has been an explosion in our understanding of the molecular basis of the muscular dystrophies in recent years, there are currently no drugs approved by the U.S. Food and Drug Administration for use in muscular dystrophy. Specific therapies aimed at correcting the underlying pathophysiology are still in preclinical and early clinical studies. Further along in development are clinical trials aimed at stimulating muscle growth and regeneration. Corticosteroids have been proven in multiple clinical trials to have a moderate benefit in one disorder, Duchennes muscular dystrophy (DMD). Other than corticosteroids for DMD, we do not recommend any drugs or supplements specifically for muscle growth that have not been proven to be beneficial in controlled clinical trials. Despite the current lack of available pharmacologic agents, attentive care and treatment as outlined in this chapter provide significant benefit to patients with muscular dystrophy, increasing the quality and often the extent of their lives, by improving function. There are several aspects to the care of dystrophic diseases that are similar for the various disorders, including exercise, maintaining flexibility, and minimizing immobility.
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Exercise is important to prevent disuse atrophy. However, dystrophic muscle undergoes continuous rounds of degeneration and regeneration and may eventually lose its ability to regenerate. Therefore, strenuous exercise, which leads to muscle breakdown, particularly exercises that involve lengthening and simultaneous contraction of muscle (eccentric exercise), such as in weight lifting, should be avoided. We recommend aquatic therapy three to four times a week as a safe form of exercise that is often enjoyable for the patient because of the increased abilities provided by buoyancy. As muscle tissue and tendons become fibrotic, their flexibility decreases, leading to contractures. Twice-daily stretching cannot be overemphasized to maintain flexibility and function. Joints requiring stretching vary by disease, as does the degree of contracture formation, but frequently the ankles and hips are more severely involved. The clinician or physical therapist should demonstrate proper stretching techniques. Atrophy and the formation of contractures are both accelerated during periods of immobility such as casting. Since weakness frequently causes falls and fractures, it is important that periods of immobility are as brief as possible.
Duchennes Muscular Dystrophy

DMD is the most common muscular dystrophy, estimated at affecting 1:3500 live male births. The disease results from mutations in the gene for dystrophin, which is located on the short arm of the X chromosome (Xp21). Boys are thus primarily affected, but girls and women, who carry the mutation, occasionally develop mild or moderate limb weakness and infrequently can have significant cardiomyopathy. DMD is a devastating disorder. Typically, boys begin to show signs of leg weakness between 2 to 4 years of age with difficulty running and climbing steps. Neck flexors, anterior abdominal muscles, hip extensors and abductors, and external rotators of the arms are disproportionately affected while facial muscle function is relatively preserved. Weakness progresses inexorably, leading to the loss of ambulation in the preteen years. Respiratory muscle weakness and its complications along with cardiomyopathy are the major causes of death, usually in teenage to young adult years. DMD can be diagnosed by a commercially available DNA blood test in approximately two thirds of cases. This test checks the most common large deletions and insertions in the dystrophin gene. In the past few years major advances have occurred in genetic screening for mutations in DMD. Now there are economical methods available to detect duplications of one or more exons and to identify point mutations. This advance in DNA analysis allows identification of more than 95% of the DMD mutations and should soon become widely available. If there is a high clinical suspicion for DMD and DNA testing is negative, patients undergo muscle biopsy. In DMD there is an absence of dystrophin by immunohistochemical staining and immunoblot analysis. Class I clinical trials demonstrate that corticosteroid treatment increases strength and improves function in
boys with DMD. The mechanism of action is unknown. We use prednisone at 0.75 mg/kg/day. The goal is to maintain ambulation for as long as possible, which is not only important for social interactions and independence but delays severe contracture formation and scoliosis. Long-term corticosteroid therapy also delays the development of respiratory muscle failure and may have an temporizing effect on cardiac function. However, there are many potential side effects to this treatment. Those that occur commonly include increased appetite with weight gain and a cushingoid appearance. Decreased linear growth, bone density loss, behavioral changes, and delayed secondary sexual characteristics also occur. Increased susceptibility to infections, diabetes, gastrointestinal bleeding, and hypertension are rare. Cataracts occur occasionally with prednisone but do not usually require treatment. Deflazacort is an alternative corticosteroid that is available in some countries but not in the United States. Deflazacort at 0.9 mg/kg/day improves strength in DMD; it causes less weight gain than prednisone but leads to significantly more cataracts. When to begin and when to stop treatment with corticosteroids has not been adequately addressed in clinical trials. Due to the side effects, we begin treatment at approximately 5 years of age. We observe improvement in timed function testing (time to travel 30 ft, arise from supine to standing, and to climb 4 steps) within 3 to 6 months after initiating treatment. We also expect to see improvement in strength within 6 months of beginning treatment as measured by handheld dynamometry. Strength may then plateau for some time before it begins to decline. We continue steroid treatment during this period, with the assumption that steroids slow the rate of decline. Patients are followed every 4 months while on prednisone with neuromuscular assessments as well as side effect monitoring of weight, blood pressure, and fasting glucose. Prednisone is usually discontinued in the event of a serious side effect, such as a gastrointestinal bleed. We attempt to maintain patients on corticosteroids, especially those who have been able to control their weight, even after they have entered a wheelchair fulltime. Many have reaped additional benefits, especially maintaining their upper extremity function for an extended period and maintaining a forced vital capacity over 1 L. In some patients additional weight gain after they have lost their ability to ambulate makes it difficult to transfer them in and out of their wheelchair and bed and increases the risk to caretakers in moving them. In these patients we discontinue corticosteroid therapy. Management of weight gain is a major challenge in all patients with DMD whether or not they receive corticosteroids. Dietary counseling is needed early in childhood for all these patients. The development of contractures may become the limiting factor in walking as weakness progresses. For that reason, considerable emphasis is placed on minimizing contractures of the ankles, knees, and hips. Without such emphasis, patients more quickly develop toe walking with profound lordosis. In addition to twicedaily stretching as discussed earlier, boys with DMD can benefit from night splints to keep their ankles at 90 degrees. These are generally unpopular with children
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and we usually recommend to the parents that the child try to fall asleep with them on but if they are taken off in the middle of the night not to force them back on. Despite stretching and splinting, contractures of the Achilles tendon frequently develop eventually due to the strength imbalance of foot plantar flexors over dorsiflexors. If contractures are limiting to ambulation, serial casting in walking casts is recommended by an orthopedic surgeon with experience in muscular dystrophy. Rarely is surgical lengthening of the Achilles tendon recommended. Scoliosis invariably develops in patients with DMD. Within 2 years of entering a wheelchair fulltime, scoliosis usually develops rapidly. There are only a few long-term trials of corticosteroids that have followed patients after they become limited to a wheelchair, and they suggest that corticosteroid therapy delays the onset of severe scoliosis. More studies are needed to prove this possibility. However, untreated scoliosis not only produces significant discomfort for patients confined to a wheelchair but also decreases what may already be compromised respiratory function. Boys should have a scoliosis film series every year after becoming wheelchair bound and more frequently if clinical findings suggest a rapidly progressing curve. Referral to an orthopedic specialist with experience in muscular dystrophy is recommended for consideration of spinal fusion when the major curve exceeds 20 degrees. In the late stages of DMD, as many as 90% of patients may develop cardiomyopathy with cardiac ejection fractions falling to 10% to 20%. Patients should have a cardiac investigation including echocardiogram and electrocardiogram (ECG) on diagnosis, every 2 years to age 10 and annually thereafter. There is limited information about the effect of corticosteroid treatment on the heart in the late stages of DMD, but the data that are available indicate that there is less severe cardiomyopathy. However, heart failure related to cardiomyopathy in DMD is difficult to manage and requires cardiology consultation to guide care. Early treatment with afterload reduction therapy is important. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockade are typically advanced to the maximal dose tolerated without symptomatic hypotension. If left ventricular dysfunction persists or worsens, beta-blocker therapy is frequently added. Occasionally, ventricular and/or atrial clots are present, and long-term anticoagulation therapy is initiated. Respiratory insufficiency due to restrictive ventilatory defect is common in the late stages of DMD and is a major risk factor for anesthesia and postoperative care. Respiratory problems may begin with night-time hypoventilation or with pneumonia. Early discussions with families concerning the degree of intervention most appropriate for the patient are essential. In consultation with pulmonologists, many patients benefit from biphasic inspiratory positive airway pressure (BiPAP) at night as well as assisted coughing devices. Influenza and pneumococcal vaccinations are essential, and upper respiratory infections are aggressively treated with antibiotics. Gastrointestinal complications of DMD frequently include constipation due to chronic intestinal hypomotility. Constipation may even decrease total lung
volume and decrease the forced vital capacity, tidal volume during sleep, and the power of coughing. Good hydration, a balanced dietary intake, and regular bowel habits are the mainstays of treatment for this problem. Infrequently, acute gastric dilation occurs as a complication of late-stage DMD. This typically occurs in association with an idiopathic metabolic acidosis and responds rapidly to nasogastric tube decompression of the stomach and intravenous hydration. Caution must be used with intravenous repletion of potassium because in the late stages of the disease the muscle mass of the patient is considerably diminished and is not available to buffer an acute rise in extracellular potassium.
Beckers Muscular Dystrophy

Beckers muscular dystrophy (BMD), like DMD, results from a mutation in the gene for dystrophin. However, although DMD is marked by the absence of dystrophin, patients with BMD typically express a reduced amount of dystrophin as can be seen on muscle biopsy or immunoblot analysis. The disease is milder than DMD, with onset after 5 years of age and ambulation continuing beyond 13 years of age. While DMD is fairly uniform in its severity and progression, there is a wide range of severity in BMD, including some patients who are not symptomatic until adulthood. Many of the problems and management options are similar in DMD and BMD. A severe BMD is treated as a child with DMD and is placed on daily prednisone. There have been no clinical trials of long-term steroid use in mild to moderate BMD, and we do not use it in this setting. Contractures are less common in BMD compared with DMD, but Achilles tendon contractures may occur and are minimized with stretching, splinting, and serial casting as necessary. Scoliosis is also less common but is monitored by scoliosis radiographic series with referral to an orthopedic surgeon for spinal fusion as necessary. Cardiomyopathy is common in BMD and frequently develops out of proportion to the severity of the skeletal muscle involvement. BMD patients need an echocardiogram and ECG at diagnosis and then need screening at least at 5-year intervals. Similar to DMD, BMD patients with cardiomyopathy require management with ACE inhibitors under the care of a cardiologist. Many BMD patients with severe cardiomyopathy but only moderate limb weakness have successfully undergone heart transplantation. Respiratory problems are uncommon until the late stages of BMD and then are managed as with DMD.
Myotonic Muscular Dystrophy

The myotonic muscular dystrophies are multisystemic disorders that exhibit myotonia, weakness, and other organ system involvement. Myotonic dystrophy type 1 (MD-1) is the most common form of myotonic dystrophy and is the most common muscular dystrophy in adults.
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It is due to an abnormal enlargement of an unstable trinucleotide repeat expansion in the 3 untranslated region of the DM1 gene on chromosome 19. Disease severity is related to the size of the trinucleotide repeat expansion. Successive generations with DM-1 often have greater numbers of repeats with increased severity and earlier age of onset, a phenomenon termed anticipation. The onset of MD-1 can occur in adult life, childhood, or infancy, as the severe congenital form of disease. Another form of myotonic dystrophy, DM-2, results from an unstable nucleotide repeat expansion, a CCTG repeat, in the zinc finger 9 protein gene at the 3q21 locus. Severe congenital and infantile forms of DM-2 have not been described. Genetic testing with leukocyte DNA analysis is commercially available for both MD-1 and DM-2. Children with congenital myotonic dystrophy (MD-1) present at birth with respiratory failure, poor feeding, generalized hypotonia, clubfoot deformity, and an increased risk of intracerebral hemorrhage and eventration of the diaphragm. During gestation there are often decreased fetal movements and a history of polyhydramnios. Not uncommonly a failed labor develops and requires urgent cesarean section. There is also an increased frequency of placenta previa and miscarriage. Electrodiagnostic and clinical signs of myotonia are absent in neonates and infants. Myotonia appears later in childhood. Careful evaluation of the mother is necessary to search for signs of DM since almost all babies born with MD-1 have mothers rather than fathers with the disease. During infancy and childhood certain problems can occur in patients with MD-1 that require active management. During the perinatal period infants with MD-1 often require continuous ventilator support. These infants are at risk for both anoxia and cerebral (germinal matrix) hemorrhage. Those requiring longer than 4 weeks of ventilator support have a poor prognosis for survival. Feeding tubes are often necessary during the first 6 months of life to maintain nutrition, and frequent evaluations by the pediatrician are useful to detect early signs of aspiration of respiratory infections. During the first 2 years of life children with MD-1 are also at increased risk for aspiration pneumonitis as well as difficulties with feeding. Mental retardation and learning disabilities are common in congenital and childhood forms of MD-1. Assessing the degree of cognitive deficit requires careful clinical evaluation. The patients have marked facial weakness, are unable to speak and communicate well, and have an increased incidence of hearing deficit, and for these reasons may appear more cognitively limited than they are. Clubfoot deformities are common in infant and childhood MD-1 and require several months of treatment with molded plastic foot orthoses. The symptoms of the childhood form of myotonic dystrophy (MD-1) typically relate to nonskeletal muscle manifestations. These manifestations include intellectual deficiency, difficulty with speech and hearing, clumsiness, and, rarely, cardiac arrhythmia or postoperative apnea. Patients with myotonic dystrophy have an increased sensitivity to sedative medications, especially
barbiturates and opiates, and may develop delayedonset apnea. Other nonmuscular manifestations (e.g., gastrointestinal hypomotility) and intermittent urinary tract symptoms (e.g., urgency) are common in childhood DM. After obtaining an ECG as well as blood counts and liver function tests, we give a 4- to 6-week trial of mexiletine, 50 to 75 mg twice daily , for gastrointestinal hypomotility. Teenage- and adult-onset MD-1 is marked by distal and less marked proximal weakness. Light-weight fiberglass and Velcro ankle-foot orthotics may prevent tripping due to dorsiflexor weakness. Even where strength is adequate, myotonia may inhibit good function. After obtaining an ECG to exclude heart block, we begin treatment of myotonia with mexiletine, 150 mg twice a day. If necessary to ameliorate stiffness, we advance the dose to 200 mg and the frequency to three times a day. Patients take mexiletine with food to lessen side effects, which are primarily mild gastrointestinal discomfort and lightheadedness. Mexiletine is usually more effective than older-generation antimyotonia drugs, such as phenytoin and procainamide, but these are also options. Patients with MD-1 are frequently bothered by hypersomnolence. This can decrease their ability to learn at school, complete assignments, and later, to function on the job. Sleep apnea is prevalent in MD-1 and contributes to daytime somnolence. A sleep study should be performed and night-time BiPAP should be a consideration. However, even in the absence of sleep apnea, patients with MD-1 have hypersomnolence likely of central origin. Modafenil (Provigil) beginning at 50 mg a day and increasing to 100 mg twice a day is highly effective in this population. Cardiac complications in MD-1 include cardiac arrhythmias and, less commonly, cardiomyopathies. All patients should have an ECG and echocardiogram at diagnosis, with annual ECGs thereafter. In the event of ECG abnormalities suggestive of intrahisian or infrahisian atrioventricular conduction disturbances and/or symptoms including dizziness or syncope, cardiac consultation for electrophysiologic studies (EPSs) are recommended. Given the high rate of sudden death in MD-1, a lower threshold for EPS is justified. Pacemaker and cardioverter-defibrillator implantations may be required. Severe respiratory compromise is a less common cause of death in this population but should be monitored by yearly pulmonary function testing with referral to a pulmonologist for positive-pressure ventilation as appropriate. Other organ system involvement includes ocular with early cataract formation, ptosis, and eye closure weakness. The incidence of diabetes is higher in this population and should be monitored by periodic glucose tolerance testing. Gastrointestinal problems include reflux, treated with elevation of the head of the bed and avoidance of late evening meals, and difficultly swallowing. Dysphagia is likely a combination of smooth muscle weakness and myotonia. A trial of mexiletine 150 mg two or three times a day is recommended. Late in the disease, a percutaneous endogastric tube may be required to help with drugs and nutrition.
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DM-2 is also marked by weakness, mainly involving proximal muscles, the hip extensors, and flexors. DM-2 can also cause distal weakness in the deep flexors of the fingers. Early-onset cataracts (< 50 years of age) are common and identical in appearance to MD-1. Myotonia is usually not as severe as in MD-1 and frequently does not require treatment. However, muscle pain is a common and often disabling symptom in this group of patients. On occasion, muscle pain is improved with treatment with mexiletine or carbamazepine but frequently requires traditional pain management.
PATIENT RESOURCES
Several promising treatments entering clinical trials include gene therapy, cell therapy, and pharmacologic approaches to increase muscle mass. Information concerning these trials as well as resources available to patients and their families is easily accessible on a variety of private foundation websites such as those listed here. FSH Society, Inc. 3 Westwood Road Lexington, MA 02420 Phone: 781-860-0501 http://www.fshsociety.org/ Muscular Dystrophy Association National Headquarters 3300 E. Sunrise Drive Tucson, AZ 85718 Phone: 800-572-1717 http://www.mdausa.org/ Parent Project Muscular Dystrophy 1012 North University Blvd. Middletown, OH 45042 Phone: 800-714-5437 http://www.parentprojectmd.org/
Facioscapulohumeral Muscular Dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common inherited disease of muscle following DMD and DM-1. FSHD is caused by a deletion of repeat elements (D4Z4) in the subtelomeric region of chromosome 4, and it is inherited in an autosomal dominant fashion. More severe clinical manifestations are loosely associated with larger deletions and fewer remaining repeat elements. Genetic testing using leukocyte DNA analysis is commercially available. As the name of the disease implies, patients with FSHD have prominent weakness of facial muscles and muscles of scapular fixation. The deltoid muscle is relatively spared but is ineffective due to the unstable scapula leading to winging of the scapula with attempted arm abduction. Some patients with good deltoid strength benefit from surgical fixation of the scapula to the rib cage. Scapula fixation should usually be done on one side only and by surgeons experienced with FSHD. Cardiac disease is uncommon in FSHD. Patients should be screened with an echocardiogram and ECG at diagnosis, but frequent screening is not indicated. Respiratory insufficiency is also less common, and many patients have a near-normal life expectancy.

The inflammatory myopathies comprise three major and distinct subsets: polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). Although the presence of moderate to severe muscle weakness and endomysial inflammation are common features in all these conditions, unique clinical, immunopathologic, and histologic criteria along with different prognosis and response to therapies characterize each subset. DM develops subacutely and affects skin and proximal muscles. The skin manifestations accompany or precede the muscle weakness and include a heliotrope rash (blue-purple discoloration) on the upper eyelids with edema; a flat red rash on the face, knees, elbows, malleoli, neck, anterior chest (in a V sign), or on the back and shoulders (shawl sign); and erythema of the knuckles with a raised, violaceous, scaly eruption (Gottrons rash). Dilated capillary loops at the base of the fingernails with irregular, thickened, and distorted cuticles, or cracked, dirty horizontal lines at the lateral and palmar areas of the fingers (mechanics hands) are characteristic for the disease. PM almost always begins after 16 years of age, has a subacute onset, affects proximal muscles, and spares facial and eye muscles. As a stand-alone entity, PM is an uncommon disorder but mimics many other myopathies and remains a diagnosis of exclusion. A patient with PM should not have a family history of a neuromuscular
Other Muscular Dystrophies

The diagnosis of less common forms of muscular dystrophy is aided by determining the age of onset, rate of progression, pattern of weakness, and associated symptoms. Often the diagnosis is not easy. For example there are approximately 15 distinct limb girdle muscular dystrophies recognized, but only three for which there is a commercially available DNA blood test. Most patients suspected of having a rare form of muscular dystrophy need to undergo a muscle biopsy with immunohistochemical staining for different muscle proteins known to be implicated in the pathogenesis of various muscular dystrophies. In reality, few of these patients obtain a molecular diagnosis more specific than muscular dystrophy. The treatment of these patients then revolves around the general care of dystrophic muscle as outlined earlier as well as vigilance for possible associated disorders, especially cardiomyopathies and cardiac arrhythmias.
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DM-2 is also marked by weakness, mainly involving proximal muscles, the hip extensors, and flexors. DM-2 can also cause distal weakness in the deep flexors of the fingers. Early-onset cataracts (< 50 years of age) are common and identical in appearance to MD-1. Myotonia is usually not as severe as in MD-1 and frequently does not require treatment. However, muscle pain is a common and often disabling symptom in this group of patients. On occasion, muscle pain is improved with treatment with mexiletine or carbamazepine but frequently requires traditional pain management.
PATIENT RESOURCES
Several promising treatments entering clinical trials include gene therapy, cell therapy, and pharmacologic approaches to increase muscle mass. Information concerning these trials as well as resources available to patients and their families is easily accessible on a variety of private foundation websites such as those listed here. FSH Society, Inc. 3 Westwood Road Lexington, MA 02420 Phone: 781-860-0501 http://www.fshsociety.org/ Muscular Dystrophy Association National Headquarters 3300 E. Sunrise Drive Tucson, AZ 85718 Phone: 800-572-1717 http://www.mdausa.org/ Parent Project Muscular Dystrophy 1012 North University Blvd. Middletown, OH 45042 Phone: 800-714-5437 http://www.parentprojectmd.org/
Facioscapulohumeral Muscular Dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common inherited disease of muscle following DMD and DM-1. FSHD is caused by a deletion of repeat elements (D4Z4) in the subtelomeric region of chromosome 4, and it is inherited in an autosomal dominant fashion. More severe clinical manifestations are loosely associated with larger deletions and fewer remaining repeat elements. Genetic testing using leukocyte DNA analysis is commercially available. As the name of the disease implies, patients with FSHD have prominent weakness of facial muscles and muscles of scapular fixation. The deltoid muscle is relatively spared but is ineffective due to the unstable scapula leading to winging of the scapula with attempted arm abduction. Some patients with good deltoid strength benefit from surgical fixation of the scapula to the rib cage. Scapula fixation should usually be done on one side only and by surgeons experienced with FSHD. Cardiac disease is uncommon in FSHD. Patients should be screened with an echocardiogram and ECG at diagnosis, but frequent screening is not indicated. Respiratory insufficiency is also less common, and many patients have a near-normal life expectancy.

The inflammatory myopathies comprise three major and distinct subsets: polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). Although the presence of moderate to severe muscle weakness and endomysial inflammation are common features in all these conditions, unique clinical, immunopathologic, and histologic criteria along with different prognosis and response to therapies characterize each subset. DM develops subacutely and affects skin and proximal muscles. The skin manifestations accompany or precede the muscle weakness and include a heliotrope rash (blue-purple discoloration) on the upper eyelids with edema; a flat red rash on the face, knees, elbows, malleoli, neck, anterior chest (in a V sign), or on the back and shoulders (shawl sign); and erythema of the knuckles with a raised, violaceous, scaly eruption (Gottrons rash). Dilated capillary loops at the base of the fingernails with irregular, thickened, and distorted cuticles, or cracked, dirty horizontal lines at the lateral and palmar areas of the fingers (mechanics hands) are characteristic for the disease. PM almost always begins after 16 years of age, has a subacute onset, affects proximal muscles, and spares facial and eye muscles. As a stand-alone entity, PM is an uncommon disorder but mimics many other myopathies and remains a diagnosis of exclusion. A patient with PM should not have a family history of a neuromuscular
Other Muscular Dystrophies

The diagnosis of less common forms of muscular dystrophy is aided by determining the age of onset, rate of progression, pattern of weakness, and associated symptoms. Often the diagnosis is not easy. For example there are approximately 15 distinct limb girdle muscular dystrophies recognized, but only three for which there is a commercially available DNA blood test. Most patients suspected of having a rare form of muscular dystrophy need to undergo a muscle biopsy with immunohistochemical staining for different muscle proteins known to be implicated in the pathogenesis of various muscular dystrophies. In reality, few of these patients obtain a molecular diagnosis more specific than muscular dystrophy. The treatment of these patients then revolves around the general care of dystrophic muscle as outlined earlier as well as vigilance for possible associated disorders, especially cardiomyopathies and cardiac arrhythmias.
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disease, exposure to myotoxic agents, endocrine disease, dystrophy, or IBM. IBM has a slow onset and progression, affects both the proximal and the distal muscles, and results in significant weakness and atrophy. The muscles of swallowing are also affected, and choking episodes are frequent. Although IBM is commonly suspected when a patient with presumed PM does not respond to therapy, involvement of distal muscles, especially foot extensors and deep finger flexors, in almost all cases may be a clue to early diagnosis. The weakness and atrophy may be asymmetric, with selective involvement of the quadriceps, iliopsoas, triceps, biceps, and forearm flexor muscles. Patients with IBM account for most of the patients older than 50 years of age referred for PM unresponsive to therapy. The diagnosis of these disorders is based on the combination of clinical presentation, determination of serum muscle enzymes, electromyography (EMG) , and muscle biopsy. The creatine kinase (CK) level is elevated in all three subsets, but it can be normal or only slightly elevated in DM and IBM. The EMG is myopathic in all three conditions. The muscle biopsy is characterized by endomysial inflammation that has unique features in each case: in DM the inflammation is perivascular or at the periphery of the fascicle and is often associated with perifascicular atrophy; in PM and IBM the inflammation is in the endomysial parenchyma and it is characterized by CD8+ T cells that invade healthy muscle fibers expressing MHC-I antigen; the MHC/DC8 complex is characteristic and important for the diagnosis. An additional feature in IBM is the presence of vacuoles containing 12 to 16 nanometers tubulofilaments with tiny deposits of amyloid and amyloid-related proteins.
As a result, the current immunotherapies are not selectively targeting the relevant, pathogenic T cells. Further, most of them are empirical or uncontrolled. In IBM, the picture is complicated even further by the presence of degenerative features, such as vacuoles and accumulation of amyloid or amyloid-related proteins, in fibers not invaded by T cells, suggesting the presence of two processes acting independently or in concert with each othera primary immune process and a degenerative one.
Goals of Therapy and Clinical Assessment

The goal of therapy in inflammatory myopathies is to improve muscle strength and activities of daily living. Although when the strength improves, the serum CK falls concurrently, the reverse is not always true because most of the immunosuppressive therapies can result in a decrease of serum muscle enzymes without necessarily improving muscle strength. Unfortunately, this has been misinterpreted as chemical improvement, and has formed the basis for the common habit of chasing or treating the CK level instead of the muscle weakness, a practice that has led to a prolonged use of unnecessary immunosuppressive drugs and erroneous assessment of their efficacy. It is prudent to discontinue these drugs if an adequate trial has led only to a reduction in CK and not to an objective improvement in muscle strength. The level of CK is helpful only as an auxiliary measure and not as a guide to start or monitor therapy. On assessing strength, it is also useful to keep in mind that some patients under-report changes in their strength, others overinterpret a feeling of well-being as improvement, and still others over-report or elaborate extensively on their symptoms. For these reasons, it is informative to ask the patients specific questions about changes in performing routine physical tasks at home or work and activities of daily living. In a patient who responds to steroid therapy, the ultimate goal is to find the lowest dose that controls the disease with the least adverse effects. When this goal is reached, it is quite appropriate to consider adding a steroid-sparing drug while lowering the amount of steroid, without a breakthrough of disease. I do not advocate a concurrent use of steroids with another immunosuppressant from the outset of treatment except if the disease has a highly aggressive course and the patient is rapidly worsening. Patients with DM have a high incidence of malignancy, especially in older-age groups. In these circumstances, a thorough work-up is needed from the outset and yearly thereafter, especially the first 3 years. The most common cancers are those of the ovaries, gastrointestinal tract, lung, breast, non-Hodgkin lymphomas, and, in Asian populations, nasopharyngeal cancer. In patients without risk factors, expensive radiologic blind search for occult malignant diseases is not practical or fruitful. A complete annual physical examination with pelvic, breast (mammogram if indicated), rectal (colonoscopy
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Immunopathology and Prospects for Specific Immunotherapy

The cause of PM, DM, and IBM is unknown, but autoimmune mechanisms are strongly implicated. In spite of the progress made in elucidating the specificity of the immune response, a number of fundamental issues remain unanswered hindering the prospects of specific immunotherapy. In DM, complement in the form of membranolytic attack complex is deposited on the endomysial capillaries leading to their destruction and muscle ischemia. The target antigen on the endothelial cell wall, where the complementmediated attack complex is directed against, remains unknown. In PM and IBM, antigen-driven, CD8+ cytotoxic T cells with rearrangement of their T-cell receptor (TCR) profile and unique sequences of the antigen-binding region of the TCR, invade intact muscle fibers leading to muscle fiber destruction. Up-regulation of costimulatory molecules, adhesion molecules, metalloproteinases, cytokines, and chemokines on the muscle fibers and the autoinvasive T cells is a consistent finding. Although this knowledge has identified targets for semispecific immunotherapy, the prospects for specific immunotherapeutic interventions are remote because the antigen(s) remain still unknown.
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according to age or family history), and chest radiograph should suffice. It has not been determined if screening with PET scan justifies the cost.
Initial Treatment for PM and DM: The Use of Corticosteroids

In the initial treatment of PM and DM, prednisone is the first-line drug based on experience but not on controlled trials. Because the effectiveness and relative safety of prednisone therapy will determine the future need for stronger immunosuppressive drugs, my preference is to start with a high-dose prednisone beginning early in the disease. A high dose, at least 1 mg/kg or 60 to 80 mg/day, as a single daily morning dose (after breakfast) for an initial period of 3 to 4 weeks is preferable. Another option, especially in patients with severe PM or DM and systemic manifestations, is to start treatment with intravenous methylprednisolone 1 gm/day for 3 to 5 days and continue with the oral prednisone regimen, as mentioned earlier. After 1 month of high-dose, oral, daily prednisone, I start a slow tapering over a 10-week period, to reach a 60 to 80 mg single daily, alternate-day dose. This is accomplished by gradually reducing the alternate, off-day dose by 10 mg per week, or faster if necessitated by side effects, though this carries a greater risk of breakthrough of disease. If there is evidence of efficacy and there are no serious adverse effects, the dosage is reduced gradually by 5 to 10 mg every 3 to 4 weeks until the lowest possible dose that controls the disease is reached. In a patient responding to prednisone, a maintenance dose of 10 to 25 mg every other day may be needed to secure stability. On the other hand, if by the time the dosage has been reduced to 60 to 80 mg every other day (14 weeks after initiating therapy), there is no objective benefit (defined as increased muscle strength and not as lowering of the CK or a subjective feeling of increased energy), the patient may be considered unresponsive to prednisone, and tapering is accelerated while the next immunosuppressive drug in the line of preference is started. The single-dose, alternate-day program minimizes adverse effects while adequately maintaining control of the underlying disease. It is my preference to give the prednisone as a single dose in the morning because it is less likely to suppress the evening secretion of adrenocorticotropic hormone and more likely to secure a normal endogenous cortisol secretion the next morning. Further, the higher morning concentration of natural cortisol results in a competitive decrease in the metabolism of the administered prednisone and decreased clearance of the unbound (active) prednisone and, theoretically, greater effectiveness. To minimize side effects, every patient is requested from the beginning of steroid therapy to start a strict low-carbohydrate, low-salt, high-protein diet. Antacids may be added, preferably a calcium-containing one such as Tums, between meals. Cimetidine (Tagamet), ranitidine (Zantac), omeprazole (Prilosec), or the other similar drugs, are alternatives. Coadministration of calcium
supplement (1 gm/day) and vitamin D (50,000 units per week) may be useful. In postmenopausal women, when long-term therapy is required, I prefer alendronate (Fosamax), once per week, because of its proved efficacy in the prophylaxis of steroid-related osteoporosis. Patients at high risk of exposure to tuberculosis, those with a recently documented positive purified protein derivative test, and those with a previous history of tuberculosis may be given isoniazid prophylaxis. STEROID MYOPATHY VERSUS DISEASE ACTIVITY The long-term use of prednisone may theoretically cause worsening of muscle strength associated with a normal or unchanged CK level, referred to as steroid myopathy. The term is a misnomer because steroids do not cause histologic signs of myopathy but rather selective atrophy of type II muscle fibers. Contrary to what is believed, the condition is not common. Rarely, it may be difficult to distinguish a developing steroid-induced myopathic weakness from the increased weakness related to disease activity or to other factors such as decreased mobility, infections, or a concomitant systemic illness. The decision to adjust the prednisone dosage in a patient with myositis who has previously responded to treatment may be influenced by reviewing the past 1 to 2 months history of strength, mobility, serum CK, medication changes, and associated medical conditions. For example, in a patient who for the past 1 to 2 months has had increased CK levels, no new overt signs of steroid toxicity with reduced or unchanged dosage of steroids, and no evidence of a systemic illness or infection, increasing muscle weakness is most likely due to worsening of the disease that may require more prednisone or has become steroid resistant. When these signs are not clear, one may arbitrarily raise the prednisone dosage and wait for the answer, which can be evident in about 2 to 8 weeks, according to the change in the patients strength. A clinical sign that I have found to be of some help in a few patients is the strength of neck extensor muscles, which usually worsens with exacerbation of the disease but remains unchanged with steroid-induced muscle intoxication. EMG seeking for increased spontaneous activity is a sign suggestive of active disease. TREATMENT OF RELAPSES WHILE ON MAINTENANCE STEROID THERAPY Relapses may occur while the steroid dose is decreased below a critical level for a given patient, or in patients who are seemingly stable but decompensate after a viral illness, concurrent infections, or for unknown factors. Most such patients can be controlled if the dose of prednisone is increased to a high single daily dose (as high as the initial), or to a high alternate day (if the relapse is mild), for a period of 1 month following by a slow taper. Often, however, severe relapses require more aggressive strategies, such as intravenous immunoglobulin (IVIg) and addition of an immunosuppressant, as described in the following sections.
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Steroid-Resistant Cases and Steroid-Sparing Regimens: Second-Line Therapy Using Immunosuppressants or IVIg
Although almost all the patients with bona fide PM and DM respond to steroids to some degree and for some period of time, a number of them fail to respond or become steroid resistant. The decision to start an immunosuppressive drug or IVIg in these patients is based on the following factors: (1) its steroid-sparing effect when, in spite of steroid responsiveness, the patient has developed significant complications; (2) attempts to lower a high steroid dosage have repeatedly resulted in worsening of muscle strength; (3) adequate doses of prednisone for at least a 2- to 3-month period have been ineffective; and (4) the disease is rapidly progressive with evolving severe weakness and respiratory failure. IMMUNOSUPPRESSANTS The preference for selecting an immunosuppressive drug is empirical because control studies have not been conducted. The choice is usually based on our own prejudices or personal experience with each drug and our own assessment of the relative efficacy/safety ratio. My own preference depends on disease severity, clinical setting, and other conditions. In general, I use the immunosuppressive drugs, either alone or in combination, in the following order: First tierazathioprine, methotrexate or mycophenolate mofetil Second tiercyclosporine, rituximab, or cyclophosphamide First Tier
AZATHIOPRINE. Although lower doses (1.5 to 2 mg/kg) are
thrombocytopenia, renal toxicity, hepatotoxicity, and malignancies. Because it acts faster than azathioprine, I use it early in the therapeutic plan as a steroidsparing agent.
MYCOPHENOLATE MOFETIL. This is a morpholinoethylester of
mycophenolic acid that blocks de novo purine synthesis and acts on both B and T cells. It is an antipurine antimetabolite, like azathioprine, but it does not cause significant bone marrow suppression or hepatoxicity. It is now emerging as a promising and well-tolerated drug when used at doses up to 2 gm/day. There is anecdotal evidence that mycophenolate may be of benefit not only to patients with PM and DM but also to some IBM patients. However, it does not work as fast as initially thought, and it may take at least 3 months to see any clinical benefit. Second Tier
CYCLOSPORINE. It affects T-cell-mediated immunity by inhibiting transcription of certain genes, mostly the IL2 gene, resulting in reduced interleukin (IL)-2 and other cytokines. At doses of 150 mg twice a day (not more than 5 mg/kg/day) and monitoring of the optimal trough serum level (100 to 200 mg/mL), this drug can be given without major complications. The kidney function should be closely monitored, and nonsteroidal anti-inflammatory drugs (e.g., ibuprofen) are avoided. The concomitant use of ketoconazole (which inhibits the P480 cytochromal enzyme in the liver) allows for a lower (80%) dose with less toxicity. The advantage of cyclosporine compared to azathioprine is that it acts faster, and it may be more effective, although more toxic. RITUXIMAB. This is a monoclonal antibody against CD20+
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commonly used, I prefer higher doses of azathioprine, up to 3 mg/kg, for effective immunosuppression. Because azathioprine is usually effective after 6 months of treatment, patience is required before it is concluded that the drug is ineffective. The major side effects of azathioprine include thrombocytopenia, anemia, leukopenia, pancytopenia, drug fever, nausea, and liver toxicity. An elevation of liver enzymes, if slight, needs only observation. Azathioprine, which is metabolized by xanthine oxidase, if given concurrently with allopurinol, can be severely toxic to the liver or bone marrow, and combined use of these two drugs is not recommended.
METHOTREXATE. An antagonist of folate metabolism,
B cells resulting in B-cell depletion that lasts for at least 6 months. There is evidence based on a small series of seven patients that rituximab at 375 g/mg2 once a week for 4 weeks can be beneficial to patients with DM resistant to therapies.
CYCLOPHOSPHAMIDE. I use cyclophosphamide in patients who have interstitial lung disease and severe clinical myopathy at doses of 0.5 to 1 mg/m2 monthly intravenously. Adequate hydration the day before and antiemetics are helpful. Adverse reactions include nausea, vomiting, alopecia, hemorrhagic cystitis, bone marrow suppression, secondary malignancies, and sterility. It is critical to monitor the neutrophil count (no less than 1500 to 2000) and the lymphocyte count (no less than 1000) at 7, 10, 14, and 21 days and perform frequent urinalysis even after the drug was stopped. OTHER, NEWER AGENTS. Formerly known as FK-506,
methotrexate is a useful drug. I prefer the oral route starting at 7.5 mg weekly for the first three weeks (given in a total of 3 doses, 2.5 mg every 12 hours), increasing it gradually by 2.5 mg per week up to a total of 25 mg weekly. A relevant side effect is methotrexate pneumonitis, which can be difficult to distinguish from the interstitial lung disease seen in some patients with inflammatory myopathies. Other adverse effects include stomatitis, gastrointestinal symptoms, leukopenia,
tacrolimus is structurally different from cyclosporine, although both share the ability to selectively inhibit the transcription of cytokines and specifically IL-2. There is anecdotal evidence that tacrolimus is effective in some difficult cases of PM. Formerly known as rapamycin, sirolimus inhibits the proliferation of both T and B cells and the production of
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cytokines, especially IL-2. However, in contrast with cyclosporine and tacrolimus, which inhibit transcription of IL-2, sirolimus prevents the translation of messenger RNA for key cytokines and has an effect on T cells even after their activation. Its use in PM and DM is limited, but in experienced hands this drug may be an option for difficult cases. HIGH-DOSE IVIG IVIg has multiple mechanisms of action, most of which include inhibition of cytokines, competition with autoantibodies, inhibition of complement deposition, interference with Fc receptor binding on macrophages or the immunoglobulins on B cells, blocking the Fc receptors on target antigens, and interference with antigen recognition by sensitized T cells. More than one of these actions are probably responsible for the observed benefit. The dose is 2 gm/kg, given in two to five divided daily doses, every 5 to 8 weeks as clinically required. In a double-blind study we conducted in patients with refractory DM, IVIg significantly improved the patients strength compared to placebo. The improvement is noticeable about 15 days after the first IVIg infusion and becomes clear and definitive after the second infusion. Marked improvement is also noticed in the active violaceous rash or the chronic scaly eruptions on the knuckles. Repeated infusions often required every 6 to 12 weeks to maintain improvement. In several patients I have been able to lower the prednisone and keep only a low maintenance dose. Some patients with DM who had become unresponsive to steroids may respond again to prednisone after a few IVIg infusions. I have observed such a phenomenon of restoring responsiveness to steroids not only in DM but also in some cases of CIDP (Chronic Inflammatory Demyelinating Polyneuropathy). Because DM responds to steroids, IVIg therapy is best reserved for steroid-resistant patients, either as a second-line therapy or as a third-line add-on therapy in patients who are not adequately controlled with combination of steroids and methotrexate or azathioprine and for patients in whom immunosuppressants are contraindicated. In children and in patients with aggressive disease, I use it always as a second-line drug after steroids. The beneficial effect of IVIg in PM has been documented only in open-label trials. A controlled study we had started 10 years ago was never completed. It is my experience and that of others, however, that IVIg is effective in most patients with PM. IVIg or Immunosuppressants as a SecondLine Therapy? The excellent effect of IVIg in many DM and PM patients and the limited beneficial effect achieved by the other immunosuppressants have changed the order by which I personally use these agents. If steroids are inadequate, I go directly to IVIg followed by the addition of one of the aforementioned immunosuppressants. An algorithm for the treatment of PM and DM is shown in Figure 1.
Treatment of Inclusion Body Myositis

In spite of immunopathologic features identical with PM, IBM patients are difficult to treat. Although a number of patients may transiently respond to steroids, most do not. Methotrexate in a controlled study was not better than placebo. Cyclosporine, azathioprine, or total lymphoid irradiation are ineffective. IVIg may provide some benefit to a small number of patients for a period, especially those with dysphagia, as demonstrated in a controlled study. Although no statistically significant differences were noted in the strength of the limb muscles between placebo and IVIg, significant differences were noted regionally in certain muscle groups, especially the muscles of swallowing. Dysphagia appears to be the main symptom that improves consistently, as documented on subsequent open-label trials. Because dysphagia is life threatening, I use IVIg in patients with significant swallowing difficulties and choking episodes. Collectively, my approach to the treatment of patients with IBM is sequentially as follows: (1) coenzyme Q10, Vitamin E, creatine, and a systematic exercise program; (2) low-dose, every-other-day prednisone combined with mycophenolate mofetil in some patients hoping for disease stability; and (3) a trial with IVIg if there is significant worsening of muscle strength or life-threatening dysphagia.
Prognosis
DM responds more favorably to therapy than PM. Overall, most patients improve, and many of them make a full functional recovery that is sustained with maintenance therapy. However, up to 30% of the patients may be left with residual muscle weakness or calcifications. The 5-year survival rate for treated patients with PM and DM is now approaching 80%. On the other hand, IBM is predictably disabling. Most of these patients require the use of an assistive device such as a cane, walker, or wheelchair. The older the age of onset, the more rapidly progressive the course of IBM appears to be.
New Agents and Ongoing Trials

The prospects for semispecific immunotherapy are heightened by the identification of the following agents, currently available or in ongoing trials, directed against the following targets: 1. Blocking the signal transduction in T lymphocytes. Two such drugs have been tried or are being tested in patients with IBM: (a) a humanized monoclonal antibody called CAMPATH, directed against the CD52 molecule associated with T-cell activation. CAMPATH causes T-cell depletion and is investigated at the National Institutes of Health in an ongoing clinical trial; and (b) anti-T-lymphocyte globulin, which in a semicontrolled study showed promising results in some IBM patients
Reevaluate; challenge original diagnosis; consider IBM or other disease; consider repeat muscle biopsy No No No Satisfactory objective benefit found? Yes Add IVIg or an immunosuppressant, (AZA, MTX, mycophenolate); accelerate tapering of prednisone
Polymyositis
High-dose prednisone 6080 mg/d for 4 weeks followed by tapering to every other day Yes Taper prednisone dose gradually Yes Objective improvement present? No Initiate trial of high-dose IVIg Reevaluate at 8 weeks No Patient responding to IVIg? Yes Add an immunosuppressant (MTX, cyclosporine, cyclophosphamide rituximab) Reevaluate muscle strength Continue prednisone at lowest possible maintenance dose
Patient responding after 3 months (while prednisone at 6080 mg every other day?)
Add AZA, MTX, mycophen (3 mg/kg); accelerate tapering of prednisone Yes
Johnson: Current Therapy in Neurologic Disease (7/E) Continue prednisone at lowest possible maintenance dose High-dose prednisone 6080 mg/d for 4 weeks followed by tapering to every other day Patient responding to IVIg? Repeat infusion of IVIg every 68 weeks; maintain low-dose prednisone every other day Continue Tx and monitor CoEnzyme Q 10, vitamin E, creatine, physical therapy Rapid Yes High-dose worsening with IVIg for 3 dysphagia? months Objective response noted? No No Yes Consider every other day prednisone along with azathioprine or mycophenolate Patient showing objective response? Yes Continue treatment and monitor Slowly progressive weakness Yes Repeat infusion of IVIg every 68 weeks Discontinue all drug therapies
Suspected inflammatory myopathy
Dermatomyositis
Inclusion-body myositis
FIGURE 1. Treatment of inflammatory myopathies. IBM, inclusion body myositis; IVIg, intravenous immunoglobulin; AZA, azathioprine; MTX, methotrexate; MYCOPHEN, mycophenolate mofetil; Tx, treatment.
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2. Immunomodulating cytokines. These include (a) antitumor necrosis factor alpha strategies, using etanercept (Enbrel) or the monoclonal antibody infiximab (Remicade), both of which are being tested in patients with DM and PM and IBM; and (b) interferon beta-1a, for which a pilot study with Avonex was ineffective in IBM. 3. Agents against costimulatory and adhesion molecules. These include (a) monoclonal antibodies against lymphocyte function-associated antigen (LFA)-1 (Rectiva) and LFA-3 (Alefacept), which block the interaction of LFA with intercellular adhesion molecules; and (b) anti-integrins and their receptors, such as the monoclonal antibody against beta-4 integrins (Antegren), which interfere with transmigration of activated T cells.
Supportive Therapy
I recommend physical therapy early in the disease to preserve existing muscle function, avoid disuse atrophy of the weak muscles, and prevent joint contractures. Evaluation of swallowing function is also recommended because dysphagia is common, especially in IBM. Speech pathologists provide practical tips on how to prevent choking episodes and diminish the anxiety of an impending aspiration not only for the patient but also for the immediate family. Occupational and rehabilitation therapists help the patients with their ambulation by providing canes, braces or wheelchairs according to the stage of their disease or by teaching them how to walk without falling (i.e., locking on the knees or by using light braces) and how to perform easier fine motor tasks. Proper emotional support to accept these aids is essential; the patients and their families should be convinced that these means are not demoralizing but realistic approaches to improve transportation and socialization. Emotional support is also fundamental for young women with DM who are discouraged by a disfiguring rash and calcifications. Reassurance that these symptoms improve with aggressive therapies is important.
Calcinosis, a manifestation of DM, does not resolve with immunotherapies. New calcium deposits, however, may be prevented if the primary disease responds to the available therapies. Diphosphonates, aluminum hydroxide, probenecid, colchicine, low doses of warfarin, and surgical excision all have been tried without success. If prednisone or the other immunosuppressive therapies have not helped or have become ineffective in improving the patients strength, they should be discontinued to avoid severe, irreversible adverse effects because, contrary to common belief, there is no evidence that their continuation maintains stability or prevents further disease progression. Patients with interstitial lung disease may have a more difficult disease and require aggressive treatment with cyclophosphamide. Physical therapy to preserve existing muscle function, avoid disuse atrophy of the weak muscles, and prevent joint contractures should start early in the disease. When treatment of PM is unsuccessful, the patient should be reevaluated and the muscle biopsy reexamined. A new biopsy might be considered to make sure that the diagnosis is correct and that the diagnosis of IBM has not been overlooked. The disorders most commonly mistaken for PM are IBM, sporadic limb-girdle dystrophy with endomysial inflammation resembling PM (such as dysferlinopathies), metabolic myopathy (e.g., phosphorylase deficiency), endocrinopathy, drug-induced myopathies with some secondary inflammatory features, and neurogenic muscular atrophies. The major pitfalls leading to failure of steroid or immunosuppressive treatment include (1) inadequate initial dose of prednisone or cytotoxic drugs; (2) short duration of therapy or quick tapering; (3) early discontinuation of prednisone without keeping a maintenance low-dose therapy; (4) early development of preventable side effects necessitating early discontinuation of prednisone; and (5) wrong diagnosis. SUGGESTED READING
Dalakas MC: Intravenous immunoglobulin in autoimmune neuromuscular diseases, JAMA 291:2367-2375, 2004. Dalakas MC: Polymyositis, dermatomyositis, and inclusion body myositis, N Engl J Med 325:1487-1498, 1991. Dalakas MC: Therapeutic approaches in patients with inflammatory myopathies, Semin Neurol 23:199-206, 2003. Dalakas MC, Hohlfeld R: Polymyositis and dermatomyositis, Lancet 362:971-982, 2003. Mastaglia FL, Garlepp MJ, Phillips BA, Zilko PJ: Inflammatory myopathies: clinical, diagnostic, and therapeutic aspects, Muscle Nerve 27:407-425, 2003.
Practical Therapeutic Considerations

In light of the information presented earlier, the following observations and practical tips regarding management may be useful: Patients with bona fide PM and DM should almost always respond to prednisone to a certain degree and for some period of time. A patient with presumed PM who has not responded to any form of immunotherapy most likely has IBM or another disease. In these cases, a repeat muscle biopsy and a more vigorous search for the other disease are recommended.
PATIENT RESOURCE
Patients with PM, DM, and IBM can get services from the Muscular Dystrophy Association and the MDA Clinic (http://www. mdusa.org/): MDA-USA 3300 E. Sunrise Drive Tucson, AZ 85718 Phone: 800-572-1717 Johnson: Current Therapy in Neurologic Disease (7/E)
The Periodic ParalysesCurrent Therapy A major source of educational updates is provided by The Myositis Association, a nonprofit organization (http://www.myositis.org/). A newsletter updates ongoing therapeutic trials and provides information on new publications.
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Diagnosis is based on the characteristic clinical presentation, as well as family history and DNA testing. The prolonged exercise test shows a progressive drop in the compound muscle action potential (CMAP) amplitude by about 50% over 20 to 40 minutes, with most of the decline occurring in the first 20 minutes. TREATMENT AND MANAGEMENT (Figure 1)
The Periodic Paralyses Current Therapy

Barbara E. Shapiro, M.D., Ph.D., and Robert L. Ruff, M.D., Ph.D.
Recent mutational and genetic linkage analyses have identified the molecular basis for several of the periodic paralyses, resulting in the classification of these disorders based on a specific ion channel (channelopathy). Myotonia, an inability of a muscle to relax quickly after contraction, occurs in several channelopathies. We review the major periodic paralyses and current therapeutic options.
Hyperkalemic Periodic Paralysis

Hyperkalemic periodic paralysis (HyperPP) is associated with mutations of the human voltage-gated skeletal muscle sodium channel a-subunit (SCN4A) on chromosome 17q and is inherited in an autosomal dominant fashion. Three variants exist: (1) HyperPP without myotonia, (2) HyperPP with clinical or electromyographic (EMG) evidence of myotonia, and (3) HyperPP with paramyotonia (paramyotonia congenita). Patients present in early childhood with attacks of periodic weakness provoked by rest after exercise, fasting, emotional stress, cold, or potassium loading. Weakness generally occurs on awakening from sleep. Some patients can forestall an impending attack with mild exercise. Attacks of weakness are usually brief, lasting from minutes to hours, and usually are accompanied by hyporeflexia. Rare patients experience prolonged attacks of weakness. Weakness is usually generalized, sparing facial and respiratory muscles. The potassium level is usually elevated during attacks, although in some patients it is normal. The frequency of attacks often lessens in middle age, and some patients develop fixed progressive proximal weakness in adulthood. If myotonia is present, it may be detected only on EMG testing in some patients, whereas in others myotonia is elicited on physical examination. In HyperPP with paramyotonia, patients experience muscle stiffness brought on by repeated muscle contractions or exercise, and symptoms are extremely cold sensitive. These patients also experience periodic paralysis, in some induced by cold or exercise while in others the attacks are spontaneous without obvious provocative factors.
Management of HyperPP with or without myotonia is directed toward preventing or reducing the frequency of paralytic attacks, and treating major paralytic attacks once they occur. To prevent attacks, we advise patients to eat regular meals, especially carbohydrate-rich, lowpotassium meals, and avoid situations that precipitate attacks, such as strenuous activity followed by rest, emotional stress, cold, and potassium-rich foods, or drinks. For patients with frequent attacks, thiazide diuretics such as hydrochlorothiazide (HCTZ) or the carbonic anhydrase inhibitor acetazolamide are effective as preventive therapy in reducing the frequency and severity of attacks in most patients. The advantage of diuretics is that they can be taken daily or intermittently as needed, using the lowest dose and frequency needed to prevent attacks. HCTZ can be started at 12.5 mg orally once a day, and slowly titrated up in 12.5 mg increments up to 100 mg a day, though some patients may require higher doses, up to 200 mg a day. Acetazolamide therapy can be started at 125 mg orally twice a day and slowly increased as tolerated and as needed up to 250 mg orally four times a day, though some patients may require a higher dose, up to 1500 mg a day, to prevent attacks or reduce the severity of attacks. Side effects include nausea, anorexia, and paresthesias. Rash has been reported. Patients should be warned about the formation of kidney stones, especially at higher doses. Liver function studies and blood count should be monitored. Dichlorphenamide, a potent carbonic anhydrase inhibitor, also reduces the frequency and severity of attacks in HyperPP and can be used at a starting dose of 25 mg orally twice a day, slowly increasing to 25 to 50 mg two or three times a day. The side effect profile is similar to acetazolamide. Some patients report confusion. Unfortunately, preventing attacks does not preclude later development of fixed proximal weakness. Depolarizing muscle relaxants should be avoided during anesthesia, which aggravates myotonia and may cause adverse anesthesia-related events. Many patients can forestall an impending attack by engaging in mild exercise, ingesting carbohydrates such as a candy bar, or inhaling a beta-adrenergic agent once they note an impending attack. Acute paralytic attacks that are severe or associated with life-threatening hyperkalemia require more aggressive treatment than ingesting carbohydrates or inhaling a beta-adrenergic agent. Intravenous glucose and insulin can be used to lower the potassium level, but this must be done under strict supervision, preferably in an intensive care unit, with electrocardiographic (ECG) and serum electrolyte monitoring. Patients with HyperPP and paramyotonia often do not require daily treatment, as they learn to avoid situations
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The Periodic ParalysesCurrent Therapy A major source of educational updates is provided by The Myositis Association, a nonprofit organization (http://www.myositis.org/). A newsletter updates ongoing therapeutic trials and provides information on new publications.
403
Diagnosis is based on the characteristic clinical presentation, as well as family history and DNA testing. The prolonged exercise test shows a progressive drop in the compound muscle action potential (CMAP) amplitude by about 50% over 20 to 40 minutes, with most of the decline occurring in the first 20 minutes. TREATMENT AND MANAGEMENT (Figure 1)
The Periodic Paralyses Current Therapy

Barbara E. Shapiro, M.D., Ph.D., and Robert L. Ruff, M.D., Ph.D.
Recent mutational and genetic linkage analyses have identified the molecular basis for several of the periodic paralyses, resulting in the classification of these disorders based on a specific ion channel (channelopathy). Myotonia, an inability of a muscle to relax quickly after contraction, occurs in several channelopathies. We review the major periodic paralyses and current therapeutic options.
Hyperkalemic Periodic Paralysis

Hyperkalemic periodic paralysis (HyperPP) is associated with mutations of the human voltage-gated skeletal muscle sodium channel a-subunit (SCN4A) on chromosome 17q and is inherited in an autosomal dominant fashion. Three variants exist: (1) HyperPP without myotonia, (2) HyperPP with clinical or electromyographic (EMG) evidence of myotonia, and (3) HyperPP with paramyotonia (paramyotonia congenita). Patients present in early childhood with attacks of periodic weakness provoked by rest after exercise, fasting, emotional stress, cold, or potassium loading. Weakness generally occurs on awakening from sleep. Some patients can forestall an impending attack with mild exercise. Attacks of weakness are usually brief, lasting from minutes to hours, and usually are accompanied by hyporeflexia. Rare patients experience prolonged attacks of weakness. Weakness is usually generalized, sparing facial and respiratory muscles. The potassium level is usually elevated during attacks, although in some patients it is normal. The frequency of attacks often lessens in middle age, and some patients develop fixed progressive proximal weakness in adulthood. If myotonia is present, it may be detected only on EMG testing in some patients, whereas in others myotonia is elicited on physical examination. In HyperPP with paramyotonia, patients experience muscle stiffness brought on by repeated muscle contractions or exercise, and symptoms are extremely cold sensitive. These patients also experience periodic paralysis, in some induced by cold or exercise while in others the attacks are spontaneous without obvious provocative factors.
Management of HyperPP with or without myotonia is directed toward preventing or reducing the frequency of paralytic attacks, and treating major paralytic attacks once they occur. To prevent attacks, we advise patients to eat regular meals, especially carbohydrate-rich, lowpotassium meals, and avoid situations that precipitate attacks, such as strenuous activity followed by rest, emotional stress, cold, and potassium-rich foods, or drinks. For patients with frequent attacks, thiazide diuretics such as hydrochlorothiazide (HCTZ) or the carbonic anhydrase inhibitor acetazolamide are effective as preventive therapy in reducing the frequency and severity of attacks in most patients. The advantage of diuretics is that they can be taken daily or intermittently as needed, using the lowest dose and frequency needed to prevent attacks. HCTZ can be started at 12.5 mg orally once a day, and slowly titrated up in 12.5 mg increments up to 100 mg a day, though some patients may require higher doses, up to 200 mg a day. Acetazolamide therapy can be started at 125 mg orally twice a day and slowly increased as tolerated and as needed up to 250 mg orally four times a day, though some patients may require a higher dose, up to 1500 mg a day, to prevent attacks or reduce the severity of attacks. Side effects include nausea, anorexia, and paresthesias. Rash has been reported. Patients should be warned about the formation of kidney stones, especially at higher doses. Liver function studies and blood count should be monitored. Dichlorphenamide, a potent carbonic anhydrase inhibitor, also reduces the frequency and severity of attacks in HyperPP and can be used at a starting dose of 25 mg orally twice a day, slowly increasing to 25 to 50 mg two or three times a day. The side effect profile is similar to acetazolamide. Some patients report confusion. Unfortunately, preventing attacks does not preclude later development of fixed proximal weakness. Depolarizing muscle relaxants should be avoided during anesthesia, which aggravates myotonia and may cause adverse anesthesia-related events. Many patients can forestall an impending attack by engaging in mild exercise, ingesting carbohydrates such as a candy bar, or inhaling a beta-adrenergic agent once they note an impending attack. Acute paralytic attacks that are severe or associated with life-threatening hyperkalemia require more aggressive treatment than ingesting carbohydrates or inhaling a beta-adrenergic agent. Intravenous glucose and insulin can be used to lower the potassium level, but this must be done under strict supervision, preferably in an intensive care unit, with electrocardiographic (ECG) and serum electrolyte monitoring. Patients with HyperPP and paramyotonia often do not require daily treatment, as they learn to avoid situations
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REDUCE PARALYTIC ATTACK FREQUENCY 1) Eat regular meals high in carbohydrates and low in K, 2) Avoid strenuous exercise followed by rest, emotional stress and cold.
FIGURE 1. Treatment strategies for paralytic attacks and altered muscle tone in patients with hyperkalemic periodic paralysis (HyperPP). HCTZ, Hydrochlorothiazide.
IF PARALYTIC ATTACKS REMAIN FREQUENT 1) Start oral HCTZ diuretic, with initial dose of 12.5 mg/day and increasing slowly in increments of 12.5 mg to a final dose of 100200mg/day. 2) If HCTZ alone is not sufficient initiate an oral carbonic anhydrase inhibitor. The preferred agent is acetazolamide, with the initial dose of 125 mg twice a day and increasing as needed to final dose of 250 mg four times a day (some will need a total daily dose of 1500 mg). An alternative carbonic anhydrase inhibitor is dichlorphenamide starting at 25 mg twice a day and increasing to 2550 mg two to three times a day. Note that carbonic anhydrase inhibitors may precipitate weakness in patients with HyperPP and paramyotonia.
ABORT PARALYTIC ATTACKS 1) Ingest high carbohydrate food such as candy bar, 2) Use beta-adrenergic agonist inhaler. For severe attacks I.V. glucose and insulin can be administered in a carefully monitored setting.
IF PARAMYOTONIA AND STIFFNESS ARE PRESENT 1) Mexiletine 150 mg twice a day increasing to 300 mg three times a day to reduce stiffness. 2) Tocainide is a second line agent if mexiletine fails; however blood counts must be monitored due to the risk of bone marrow suppression. The dose of tocainide is 4001200 mg per day.
such as exposure to the cold, especially during exercise, that provoke symptoms of stiffness and weakness. For patients who require treatment, mexiletine is especially helpful in preventing or alleviating stiffness and weakness induced by cold, as well as the periodic weakness experienced by some patients. We generally begin dosing at 150 mg orally twice a day, increasing slowly as needed and tolerated up to 300 mg three times a day. Common potential side effects include gastrointestinal distress, lightheadedness, and tremor that reverse with dose reduction. Rash has been reported. Patients with HyperPP and paramyotonia who experience cold-induced stiffness as well as spontaneous attacks of periodic weakness that are not cold induced usually require preventive treatment and may benefit from a combination of mexiletine with HCTZ. Mexiletine is used to reduce the cold-induced stiffness, whereas HCTZ is used to prevent spontaneous attacks of weakness that are not precipitated by cold or exercise, presumably by lowering the potassium level. Tocainide can reduce stiffness and weakness in some patients with paramyotonia congenita, at doses of 400 to 1200 mg orally daily. However, it should not be used as a firstline drug, and only with extreme caution, because of the potential for bone marrow suppression. Acetazolamide, either alone or in combination with mexiletine, has proved beneficial in some patients with periodic weakness that is not cold induced. Acetazolamide can be started at 125 mg orally twice a day, slowly increasing to 250 mg three or four times a day, as required, and as tolerated by the patient. Some patients may require
doses up to 1500 mg a day. Common side effects and warnings were described earlier. However, acetazolamide has provoked weakness in some patients with paramyotonia congenita and cold-induced weakness, probably by lowering the potassium level. It is therefore crucial to determine whether weakness is temperature dependent, since there are clear implications regarding treatment options. Acetazolamide is best avoided in patients with paramyotonia congenita and cold-induced weakness. As with other myotonic disorders, depolarizing muscle relaxants should be avoided during anesthesia because they aggravate myotonia and may cause adverse anesthesia-related events.
Hypokalemic Periodic Paralysis, Types I and II

Hypokalemic Periodic Paralysis (HypoPP)-I is the most common of the inherited periodic paralyses. It is an autosomal dominant inherited disorder with reduced penetrance in women, associated with mutations in the a-subunit of a voltage-sensitive muscle calcium channel gene (CACNA1S) on chromosome 1q. In contrast, HypoPP-II (also dominant) is associated with loss-offunction sodium channel mutations in the a-subunit of the sodium channel gene on chromosome 17q. This small group of patients is clinically indistinguishable from those with HypoPP-I. Patients present in adolescence with attacks of periodic weakness. Attacks are provoked by cold,
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carbohydrate ingestion, alcohol, emotional stress, and rest after exercise. Some patients can forestall an impending attack with mild exercise. Paralytic attacks may be prolonged and severe, generally occurring on awakening from sleep, and rarely involving respiratory muscles. Weakness is often accompanied by hyporeflexia. The potassium level is usually low during attacks, although in some cases it is normal. There is no associated myotonia. Attacks are more frequent in males than females. Females are often so minimally affected by periodic weakness that they are unaware that they have the disorder. All patients, however, invariably develop progressive proximal weakness during adulthood, whether they have had attacks of periodic paralysis or not. Diagnosis is based on the characteristic clinical presentation, as well as family history and DNA testing. The prolonged exercise test shows a progressive drop in the CMAP amplitude by about 50% over 20 to 40 minutes, with most of the decline occurring in the first 20 minutes. TREATMENT AND MANAGEMENT (Figure 2) Management of HypoPP is directed toward preventing attacks and aggressively treating major paralytic attacks once they occur. We advise patients to follow a low-carbohydrate, low-sodium diet and avoid situations that precipitate attacks, such as strenuous activity followed by rest, high-carbohydrate meals, or alcohol. Most patients require some form of maintenance therapy to prevent attacks. Acetazolamide is effective in reducing the frequency and severity of attacks and reducing interattack weakness in most patients. A reasonable starting dose is 125 mg orally twice a day, that can be
slowly increased as tolerated to 250 mg orally three to four times a day as needed to prevent attacks or reduce the severity of attacks. Some patients may require doses up to 1500 mg a day. Common side effects and warnings were described earlier. Rare patients with HypoPP worsen with acetazolamide and must be watched closely when beginning treatment. Dichlorphenamide, another carbonic anhydrase inhibitor, can be used at a starting dose of 25 mg orally twice a day, and slowly increased to 25 to 50 mg two or three times a day. The side effect profile is similar to acetazolamide. Some patients report confusion. Patients who do not respond to carbonic anhydrase inhibitors may respond to potassium-sparing diuretics such as triamterene and spironolactone, although these must be used with caution in patients who are also taking oral potassium supplements. We start at the lowest possible dose and slowly titrate up as tolerated and needed to prevent attacks. Daily maintenance therapy with oral potassium chloride, either alone or in conjunction with a carbonic anhydrase inhibitor, is often useful in preventing or reducing the frequency and severity of attacks. Acute paralytic attacks are treated with oral potassium chloride, 0.25 mEq/kg body weight, repeating every 30 minutes until weakness improves. Electrolyte monitoring should be done in the hospital during severe attacks requiring extensive potassium supplementation. Intravenous potassium is best avoided, unless oral potassium cannot be administered, and should always be done with close ECG and serum potassium monitoring, preferably in the intensive care unit. Intravenous potassium may exacerbate the hypokalemia when mixed in a solution of glucose and saline or may cause acute hyperkalemia when given as a continuous infusion.
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FIGURE 2. Treatment strategies for paralytic attacks in patients with hypokalemic periodic paralysis (HypoPP). EKG, Electrocardiogram.
REDUCE PARALYTIC ATTACK FREQUENCY 1) Follow a low carbohydrate and sodium restricted diet. 2) Avoid precipitating factors such as strenuous exercise followed by rest, high carbohydrate meals or alcohol.
MEDICATION TO REDUCE ATTACK FREQUENCY 1) Initiate an oral carbonic anhydrase inhibitor. The preferred agent is acetazolamide, with the initial dose of 125 mg twice a day and increasing as needed to final dose of 250 mg four times a day (some will need a total daily dose of 1500 mg). An alternative carbonic anhydrase inhibitor is dichlorphenamide starting at 25 mg twice a day and increasing to 2550 mg two to three times a day. Note that some HypoPP patients worsen with carbonic anhydrase inhibitors. 2) If carbonic anhydrase inhibitors are not successful, a K-sparing diuretic such as triamterene or spironolactone may help. 3) Supplemental oral K alone or combined with a carbonic anhydrase inhibitor may prevent paralytic attacks.
ABORT PARALYTIC ATTACKS 1) Oral KCl 0.25 mEq/kg repeating every half hour until the weakness improves. Carefully monitor electrolytes and EKG in an intensive care setting. Avoid intravenous KCl unless KCl cannot be given orally. Avoid giving glucose and insulin as this will worsen paralysis. Johnson: Current Therapy in Neurologic Disease (7/E)
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MEDICATION TO REDUCE ATTACK FREQUENCY Initiate an oral carbonic anhydrase inhibitor. The preferred agent is acetazolamide, with the initial dose of 125 mg twice a day and increasing as needed to final dose of 250 mg four times a day. An alternative carbonic anhydrase inhibitor is dichlorphenamide starting at 25 mg twice a day and increasing to 2550 mg two to three times a day. Monitor cardiac function.
FIGURE 3. Treatment strategies for patients with Andersen-Tawil syndrome.
TREATMENT OF ARRHYTHMIAS Arrhythmias may respond poorly to anti-arrhythmic agents. Imipramine may be useful. Manage with a cardiologist.
Andersen-Tawil Syndrome
Andersen-Tawil syndrome (AS) is characterized by a clinical triad of periodic paralysis, ventricular arrhythmias, and dysmorphic facial features. This is an autosomal dominant inherited disorder, in some families associated with mutations in the Kir2.1 subunit of the inward rectifying potassium channel gene on chromosome 17q, resulting in dysfunctional inward rectifier potassium channels. Patients present in childhood or adolescence, with some or all features of the clinical triad of periodic paralysis, prolonged QT interval and ventricular arrhythmias, and distinctive physical features. Characteristic physical features include short stature, high-arched palate, low-set ears, broad nose, micrognathia, hypertelorism, clinodactyly of the fingers, short index finger, and syndactyly of the toes. Scoliosis may be present. Patients may have generalized limb and neck flexor weakness between paralytic attacks. There is no clinical or EMG myotonia. Paralytic attacks may occur spontaneously or may be triggered by rest after exercise or alcohol. Some patients report intermittent muscle pain without attacks of weakness and can work through the muscle pain with mild exercise. Prolonged QT interval is present in about 80% of patients and may be the only finding in some individuals. Prolonged QT interval may only manifest with stress testing. The long QT interval may be asymptomatic or can precipitate childhood cardiac arrest prior to onset of
periodic paralysis. Diagnosis is based on the characteristic clinical presentation as well as family history. The prolonged exercise test shows a progressive drop in the CMAP amplitude by about 50% over 20 to 40 minutes, with most of the decline occurring in the first 20 minutes. TREATMENT AND MANAGEMENT (Figure 3) Treatment of AS is empiric, and complicated by the fact that both skeletal and cardiac muscles are involved; treatment of one set of symptoms may exacerbate the other, through paradoxical responses to changes in potassium levels. Additionally, cardiac arrhythmias may be refractory to standard antiarrhythmic agents. Treatment with carbonic anhydrase inhibitors (acetazolamide, dichlorphenamide) may be helpful in controlling periodic weakness while only minimally lowering the potassium level. A reasonable starting dose of acetazolamide is 125 mg orally twice a day that can be slowly increased to the lowest dose needed to prevent or reduce the severity of attacks while monitoring cardiac function closely. The dose may need to be increased to 250 mg orally three to four times a day. Common side effects and warnings were discussed earlier. Dichlorphenamide can be used alternatively, at a starting dose of 25 mg orally twice a day, and slowly increased to the lowest dose needed to control paralytic attacks while monitoring cardiac function. The side
PRIMARY TREATMENT IS TO CORRECT HYPERTHYROIDISM. When it is not possible to correct thyrotoxicosis, treatment with propranolol may reduce the frequency of paralytic attacks as may the treatments used to reduce the frequency of paralytic attacks in patients with HypoPP. Carbonic anhydrase inhibitors are not effective for treating TPP.
FIGURE 4. Treatment strategies for patients with thyrotoxic periodic paralysis (TPP). HypoPP, Hypokalemic periodic paralysis; EKG, electrocardiogram.
ABORT PARALYTIC ATTACKS Administer oral KCl 0.25 mEq/kg repeating every half hour until the weakness improves. Carefully monitor electrolytes and EKG in an intensive care setting. Avoid intravenous KCl unless KCl cannot be given orally. Avoid giving glucose and insulin as this will worsen paralysis. Intravenous propranolol, given with EKG monitoring may be useful in treating acute paralytic attacks in TPP when hyperthyroidism has not yet been addressed. Johnson: Current Therapy in Neurologic Disease (7/E)
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effect profile is similar to acetazolamide, though some patients report confusion. Arrhythmias are poorly responsive to commonly used antiarrhythmic agents, including tocainide, procainamide, flecainide, quinidine, sotalol, and amiodarone, which may also worsen the weakness or prolong the QT interval. Imipramine, a mild antiarrhythmic, has been used successfully in some patients, without exacerbating weakness. Patients should be evaluated by a cardiologist for close cardiac monitoring and coordination of treatment.
Fax: 626-337-1966 E-mail: info@periodicparalysis.org http://www.periodicparalysis.org/ NINDS Periodic Paralyses Information Page http://www.ninds.nih.gov, then search for periodic paralysis

Thyrotoxic Periodic Paralysis

Thyrotoxic periodic paralysis (TPP) is seen in a subset of patients with thyrotoxicosis. Patients present with attacks of weakness associated with hypokalemia. The syndrome is clinically indistinguishable from primary HypoPP, except for age of presentation, which is generally in adulthood. Similar to primary HypoPP, attacks may be provoked by a high-carbohydrate meal, rest after exercise, or cooling of the limb. It occurs more commonly in males than females, despite the fact that thyrotoxicosis is more prevalent in women. Just as in the primary periodic paralyses, the prolonged exercise test results in a progressive decline in the CMAP amplitude. The incidence is highest in adults of Asian origin, although it has been reported in all races. Susceptibility to developing TPP may be transmitted in an autosomal dominant fashion. Periodic paralysis and hypokalemia may be the initial presentation of thyrotoxicosis, without any of the usual features of hyperthyroidism. TREATMENT AND MANAGEMENT (Figure 4) Treatment of TPP consists of correcting the thyrotoxicosis. In some patients propranolol may prevent attacks of weakness. Acetazolamide is not effective in preventing periodic weakness in TPP. As in primary HypoPP, acute attacks are treated with oral potassium. Untreated, TPP may result in progressive myopathy. SUGGESTED READING
Renner DR, Ptacek LJ: Periodic paralyses and nondystrophic myotonias, Adv Neurol 88:235-252, 2002. Shapiro BE, Brown RH: Myotonia and periodic paralysis. In Samuels MA, Feske S, editors: Office practice of neurology, ed 2, Philadelphia, 2003, Churchill Livingstone. Shapiro BE, Ruff RL: Disorders of skeletal muscle membrane excitability: myotonia congenita, paramyotonia congenita, periodic paralysis, and related syndromes. In Katirji B, Kaminski HJ, Preston D, et al, editors: Neuromuscular disorders in clinical practice, Boston, 2002, Butterworth Heinemann.
The restless legs syndrome (RLS) is characterized by an irresistible urge to move the legs, usually associated with unpleasant sensations located mainly in the calves and around the ankles. Moving the affected leg(s) or walking brings temporary relief from these symptoms. Because symptoms are brought on by inactivity, significant distress attends situations requiring prolonged immobility such as plane travel, prolonged car rides or attending school, meetings, or theater. Symptoms peak in the evening and at night, thereby interfering with sleep onset and maintenance. RLS has been referred to as the most common disorder never heard of and by Thomas Willis as a place of greatest torture. Nonetheless, RLS is diagnosed in only 8% to 12% of patients reporting symptoms to their primary care physician. The Swedish physician Karl-Axel Ekbom provided the first comprehensive description in 1945 and emphasized several principal features, including (1) a prevalence of at least 5%; (2) a proclivity to affect pregnant women; (3) families with a dominant mode of inheritance; and (4) a favorable response to iron supplementation. A second advance came with recognition that periodic limb movements (PLMs) in sleep are evident in the anterior tibialis in 85% to 95% of RLS subjects, making them a useful parameter for diagnosis and assessing treatment adequacy. The third major advance has come with discovery of treatments, most notably dopaminergics and opioids. A fourth, and most recent, advance is the discovery that brain iron delivery appears critical to the pathophysiology of RLS, as evidenced by depressed iron acquisition in in vivo and postmortem brains.
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Definition and Epidemiology

Four consensus criteria comprise those necessary to establish a diagnosis of RLS, although 5% to 7% of subjects deny symptom alleviation with movement (Table 1). High prevalences (5% to 12%) in the United Sates and Europe contrast with low prevalences in individuals of African or Asian descent. Prevalence varies significantly by age and sex, affecting 3% of 30-year-old adults and 20% aged 80 and older, and women more often than men in a roughly 6:4 ratio. Peak symptom onset occurs in the 2nd or 3rd decade (Figure 1). Nearly one third of patients experience
PATIENT RESOURCES
Periodic Paralysis Association (PPA) 1024 Royal Oaks Drive, #620 Monrovia, CA 91016 Phone: 626-303-3244 Johnson: Current Therapy in Neurologic Disease (7/E)
407
effect profile is similar to acetazolamide, though some patients report confusion. Arrhythmias are poorly responsive to commonly used antiarrhythmic agents, including tocainide, procainamide, flecainide, quinidine, sotalol, and amiodarone, which may also worsen the weakness or prolong the QT interval. Imipramine, a mild antiarrhythmic, has been used successfully in some patients, without exacerbating weakness. Patients should be evaluated by a cardiologist for close cardiac monitoring and coordination of treatment.
Fax: 626-337-1966 E-mail: info@periodicparalysis.org http://www.periodicparalysis.org/ NINDS Periodic Paralyses Information Page http://www.ninds.nih.gov, then search for periodic paralysis

Thyrotoxic Periodic Paralysis

Thyrotoxic periodic paralysis (TPP) is seen in a subset of patients with thyrotoxicosis. Patients present with attacks of weakness associated with hypokalemia. The syndrome is clinically indistinguishable from primary HypoPP, except for age of presentation, which is generally in adulthood. Similar to primary HypoPP, attacks may be provoked by a high-carbohydrate meal, rest after exercise, or cooling of the limb. It occurs more commonly in males than females, despite the fact that thyrotoxicosis is more prevalent in women. Just as in the primary periodic paralyses, the prolonged exercise test results in a progressive decline in the CMAP amplitude. The incidence is highest in adults of Asian origin, although it has been reported in all races. Susceptibility to developing TPP may be transmitted in an autosomal dominant fashion. Periodic paralysis and hypokalemia may be the initial presentation of thyrotoxicosis, without any of the usual features of hyperthyroidism. TREATMENT AND MANAGEMENT (Figure 4) Treatment of TPP consists of correcting the thyrotoxicosis. In some patients propranolol may prevent attacks of weakness. Acetazolamide is not effective in preventing periodic weakness in TPP. As in primary HypoPP, acute attacks are treated with oral potassium. Untreated, TPP may result in progressive myopathy. SUGGESTED READING
Renner DR, Ptacek LJ: Periodic paralyses and nondystrophic myotonias, Adv Neurol 88:235-252, 2002. Shapiro BE, Brown RH: Myotonia and periodic paralysis. In Samuels MA, Feske S, editors: Office practice of neurology, ed 2, Philadelphia, 2003, Churchill Livingstone. Shapiro BE, Ruff RL: Disorders of skeletal muscle membrane excitability: myotonia congenita, paramyotonia congenita, periodic paralysis, and related syndromes. In Katirji B, Kaminski HJ, Preston D, et al, editors: Neuromuscular disorders in clinical practice, Boston, 2002, Butterworth Heinemann.
The restless legs syndrome (RLS) is characterized by an irresistible urge to move the legs, usually associated with unpleasant sensations located mainly in the calves and around the ankles. Moving the affected leg(s) or walking brings temporary relief from these symptoms. Because symptoms are brought on by inactivity, significant distress attends situations requiring prolonged immobility such as plane travel, prolonged car rides or attending school, meetings, or theater. Symptoms peak in the evening and at night, thereby interfering with sleep onset and maintenance. RLS has been referred to as the most common disorder never heard of and by Thomas Willis as a place of greatest torture. Nonetheless, RLS is diagnosed in only 8% to 12% of patients reporting symptoms to their primary care physician. The Swedish physician Karl-Axel Ekbom provided the first comprehensive description in 1945 and emphasized several principal features, including (1) a prevalence of at least 5%; (2) a proclivity to affect pregnant women; (3) families with a dominant mode of inheritance; and (4) a favorable response to iron supplementation. A second advance came with recognition that periodic limb movements (PLMs) in sleep are evident in the anterior tibialis in 85% to 95% of RLS subjects, making them a useful parameter for diagnosis and assessing treatment adequacy. The third major advance has come with discovery of treatments, most notably dopaminergics and opioids. A fourth, and most recent, advance is the discovery that brain iron delivery appears critical to the pathophysiology of RLS, as evidenced by depressed iron acquisition in in vivo and postmortem brains.
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Definition and Epidemiology

Four consensus criteria comprise those necessary to establish a diagnosis of RLS, although 5% to 7% of subjects deny symptom alleviation with movement (Table 1). High prevalences (5% to 12%) in the United Sates and Europe contrast with low prevalences in individuals of African or Asian descent. Prevalence varies significantly by age and sex, affecting 3% of 30-year-old adults and 20% aged 80 and older, and women more often than men in a roughly 6:4 ratio. Peak symptom onset occurs in the 2nd or 3rd decade (Figure 1). Nearly one third of patients experience
PATIENT RESOURCES
Periodic Paralysis Association (PPA) 1024 Royal Oaks Drive, #620 Monrovia, CA 91016 Phone: 626-303-3244 Johnson: Current Therapy in Neurologic Disease (7/E)
408
TABLE 1 Diagnostic Features of Restless Legs Syndrome

A distressing need or urge to move the legs (akathisia), usually accompanied by an uncomfortable/unpleasant sensation in the leg Symptoms begin or worsen during periods of rest or inactivity such as while lying down or sitting The sensations are partially or totally relieved by movement such as walking or stretching Symptoms are worst in the evening or night as compared with the day and especially a protected window around 10 AM
symptoms before 20 years of age, so it is important to query for this disorder in children and adolescents where it can mimic attention deficit hyperactivity disorder. Variability in symptom expressivity is the rule rather than exception. Symptoms are mild and infrequent (e.g., two or three nights/month) at onset and together with symptom-free periods delay presentation to the 4th to 6th decades of life. Increasingly, PLMs in the absence of subjective symptoms are recognized as a forme fruste of RLS. A familial component to RLS exists given that 20% to 60% of first-degree relatives are affected, autosomal dominant transmission patterns occur in many families, and monozygotic twins exhibit at least 80% concordance. Operationally, RLS is divided into primary and secondary forms. The former
is remarkable for age of onset at younger than 45 years of age; 2:1 female/male ratio; a slow, fluctuating, progressive course; limited relation to body iron status; exacerbation by pregnancy and alcohol; and a 25% risk in first-degree relatives. Secondary RLS occurs less often in families; exhibits a 1:1 female/male ratio; is more rapidly progressive; more often correlated with body iron status; or associated with identifiable factors such as neuropathy, radiculopathy, myelopathy, neurodegenerative diseases, arthritic conditions, cervical spondylosis, end-stage renal disease, and diabetes (Table 2). The underlying pathophysiology of RLS remains unknown. The final common pathway mediating RLS/PLMs are neural elements intrinsic to the spinal cord given their frequent unveiling below the level of brainstem infarction, or spinal cord pathology. The principal deficit manifests as spinal reflex hyperexcitability that is state dependent (viz., a reduced threshold and segmental spread of the flexor-reflex during sleep). Waking electromyographic (EMG) activity, resting motoneuron excitability, simple reflexes, and sensory evoked potentials are usually normal. Diffuse peripheral nerve dysfunction is nonetheless common and likely modifies RLS/PLMs expression. The most powerful influences impacting on RLS/PLMs originate from outside the spinal cord, in supraspinal premotor circuits. Major susceptibility loci have been reported on chromosomes 12q, 14q, and 9p in several families from diverse ethnic backgrounds. Thus, RLS appears to be a complex disorder influenced by several acquired and genetic factors.
DISTRIBUTION OF RLS POPULATION BY SEX AND AGE OF ONSET 25 Males Females
FIGURE 1. Distribution of restless legs syndrome (RLS) by sex and age of onset from 650 Icelandic RLS subjects and their affected relatives responding to a newspaper advertisement.
20
Percent of RLS population
15
10
0 09 1019 2029 3039 4049 5059 6069 >70 Age of onset (years) Johnson: Current Therapy in Neurologic Disease (7/E)
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TABLE 2 Known or Suspected Exacerbators of RLS/PLMs
EVALUATION/ASSESSMENT The most important consideration is a review of social and medication histories because there are several recognized provocateurs of RLS/PLMs (see Table 2). Alcohol, caffeine, and nicotine use should be minimized. Antidepressants with serotonin and/or norepinephrine reuptake blocking activity can exacerbate RLS/PLMs; yet, the frequency of this complication in the RLS or general neuropsychiatric patient populations is not established. Other common aggravators are nonspecific antihistamines such as those in over-the-counter cold remedies and sleeping aids, antiemetics, and metaclopramide (Reglan). Because RLS has been associated with anemia, uremia, pregnancy, iron deficiency (even in the absence of anemia), myelopathies, neuropathies, and neurodegenerative conditions (Table 3), these entities should be screened for and treated, when present. Recent interest has focused on iron deficiency because it is common in older RLS patients, brain iron deficiency may be a critical factor in the pathology of RLS, and iron repletion can lead to long-term clinical improvement. Testing for iron deficiency that includes a serum ferritin level should therefore be performed routinely, particularly in the older patient. Serum ferritin levels in the range of 20 g/L and iron saturations of less than 20% are indicative of significant iron depletion, with values lower than 50 g/L still suggestive. Formal polysomnography to confirm the presence of PLMs is rarely indicated, given (1) the night-to-night variability in expression, (2) the substantial cost of polysomnography, and (3) that PLMs are not specific for RLS. Accelerometer-based, actigraphic devices are simple to use and practical alternatives for measuring PLMs in the patients home over many nights. Although not yet in routine, widespread use, these devices capture internight PLMs variability and provide an objective gauge for disease course and treatment efficacy. Evaluation for PLMs either by polysomnography or actigraphy is indicated when perceived or witnessed limb jerking, sleep
Type of Exacerbators Environmental
Specific Exacerbator Boredom Sleep deprivation (sleepiness) Caffeine Nicotine Alcohol Diphenhydramine (Benadryl) and other OTC cold remedies Metoclopramide (Reglan) Prochlorperazine (Compazine) Chlordiazepoxide (Librium) Traditional antipsychotics (e.g., phenothiazines) Atypical neuroleptics Antidepressants (especially having serotonin or norepinephrine reuptake blockade)
Medications
RLS, Restless legs syndrome; PLM, periodic limb movements; OTC, over the counter.
16
Diagnosis
RLS remains a diagnosis based solely on clinical judgment (see Table 1). The general and neurologic examinations are usually normal, although severely affected individuals often have difficulties remaining still and on rare occasions appear to have a hyperkinetic movement disorder. DIFFERENTIAL DIAGNOSIS RLS should be distinguished from nocturnal leg cramps (systremma), generalized or neuroleptic-induced anxiety/ akathisia, and hypotensive akathisia manifesting as leg fidgeting in autonomic failure. Nocturnal leg cramps are thought to reflect muscle spasms secondary to excessive muscular fatigue and salt loss and are typically treated with quinine, electrolyte repletion, or skeletal muscle relaxants, more or less successfully. Some patients with RLS experience leg cramps as well but are able to distinguish them from RLS symptoms. Generalized akathisia can be differentiated from RLS as it is perceived of as an inner, generalized, psychic sensation versus a focal, sensorimotor disturbance and fails to demonstrate a circadian pattern of expression. Hypotensive akathisia typically occurs only while seated (vs. lying) and fails to demonstrate a circadian pattern of expression. Painful legs with moving toes is a nosologic entity that has been differentiated from RLS secondary to its noncircadian nature and frequent association with neuropathy. A drug response profile that mimics that for RLS and the presence of PLMs suggest rather that this entity may represent a phenotypic variant of RLS/PLMs.
TABLE 3 Frequency of RLS in Some Medical and Neurologic Conditions
Condition Anemia Blood donation Men Women Renal failure/hemodialysis Whites African Americans Pregnancy, especially 3rd trimester Charcot-Marie-Tooth type 2 Spinocerebellar ataxias (SCA) types 1-3 Parkinsons disease Insomnia Attention deficit hyperactivity disorder
RLS, Restless legs syndrome.
RLS Prevalence, % (?)common 15 25 70 50 30 35 30 20 20 12
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RLS symptoms
Differential diagnosis
1 RLS
2 RLS
Refractory RLS
Possible RLS
Identify and treat aggravators and associated conditions (iron deficiency/neuropathy/insomnia)
Actigraphy and/or Short-term trial of Levodopa/ carbidopa or DA agonist
Infrequent < 1x/week
Frequent > 2x3x/week
Disease progression
Augmentation
PRN Levodopa/ carbidopa Sedatives/ hypnotics Opioid
Pain/ neuropathy/ neurodegenerative disease
No pain or associated condition
Titrate to maximum dose
Discontinue Levodopa/carbidopa Additional DA agonist doses earlier
Gabapentin
Dopamine agonist
Inadequate/ poor response
Respond
Nonresponder
Add or switch to gabapentin or opioid
Switch DA agonist
Respond
Nonresponder
Minimize DA agonist Add or switch to gabapentin or opioid
FIGURE 2. Treatment algorithm for restless legs syndrome (RLS). DA, dopamine.
fragmentation, or significant daytime sleepiness persists despite resolution of subjective RLS symptoms.
Treatment
NONPHARMACOLOGIC APPROACH A plethora of nonmedical therapies have been advocated to relieve the discomfort of RLS, including surgical repair of varicose veins, transcutaneous nerve stimulators, acupuncture, and herbal remedies. There is no
scientific evidence to date that has demonstrated that any of these approaches are effective. Symptom alleviation has been noted with mental distraction, alerting environments, moderate exercise, and exposure of the legs to extremes of hot or cold, but no specific programs have been systematically investigated. PHARMACOLOGIC APPROACH When identified, iron deficiency is treated with 65 mg of elemental iron (e.g., 325 mg of ferrous sulfate) together
411
with 100 mg of vitamin C on an empty stomach one to three times a day. Oral supplementation is continued for 3 to 4 months until ferritin levels exceed 50 g/L and iron saturations surpass 20%. Some patients will be able to discontinue symptomatic relief once iron has been repleted. The pharmacologic agents employed to alleviate RLS are symptomatic, not curative, and because RLS is progressive, diagnosis portends a life of pharmacotherapy, potential medication side effects, and treatment-related complications (see later). Ropinirole (Requip) is the only agent presently with U.S. Food and Drug Administration approval for RLS. Other agents are also well tolerated and efficacious at doses lower than those customary for their primary indications. Choice of agent and dosing depends on the timing, frequency, and quality of symptoms (Figure 2). There are four well-established treatments for PLMs/RLS: dopaminergics, gabapentin, opioids, and benzodiazepines (Table 4). The newer nonergot-derived dopamine agonists are widely considered the first line of treatment for idiopathic RLS/PLMs. Gabapentin and opioids also suppress RLS/PLMs, whereas benzodiazepines improve sleep continuity only by decreasing arousals with minimal effects on PLMs.
TABLE 4 Pharmacologic Treatment for RLS/PLM
Medication Dopamine precursor Carbidopa/levodopa Carbidopa/levodopa CR Dopamine agonists Pramipexole (Mirapex) Ropinirole (Requip) Pergolide (Permax) Cabergoline (Dostinex; Cabaser) Anticonvulsants Gabapentin (Neurontin) Opioids Tramadol HCl (Ultram) Propoxyphene HCl (Darvon) Propoxyphene napsylate (Darvon-N) Hydromorphone (Dilaudid) Oxycodone-XR (OxyContin) Methadone Opioid/analgesic combinations Oxycodone (Percocet; OxyContin) Hydrocodone (Lortab; Vicodin) Sedative hypnotics Zolpidem (Ambien) Zaleplon (Sonata) Triazolam (Halcion) Temazepam (Restoril) Clonazepam (Klonopin) Miscellaneous Carbamazepine (Tegretol) Clonidine (Catapres) Bromocriptine (Parlodel) Iron Magnesium
RLS, Restless legs syndrome; PLM, periodic limb movement.
Carbidopa/levodopa is an excellent choice for patients with sporadic, infrequent symptoms given a short delay (15 to 20 minutes) to reach effectiveness when taken on an empty stomach. Intermittent use of short-acting benzodiazepines, benzodiazepine receptor agonists, or opioids are also a reasonable choice in this setting. Chronic, daily use of carbidopa/levodopa should be avoided because early-morning symptom rebound, or augmentation, occurs in about 30% and 80% of subjects, respectively, after initial improvement. Augmentation manifests as RLS symptoms occurring earlier in the day, increased symptom intensity, and/or spread of symptoms to the arms. The risk of augmentation may be less with intermittent use (e.g., less than three times a week), but this has not been firmly established. Patients should be warned about the phenomenon, because taking additional doses of levodopa further exacerbates augmentation. If augmentation occurs, the drug should be discontinued and another agent substituted. In patients with moderate to severe RLS/PLMs occurring more often than three nights a week, long-term efficacy has been well established with several non ergot-derived dopamine agonists such as pramipexole (mean effective dose ~ 0.375 mg) and ropinirole (mean effective dose ~ 2 mg). Ergot-derived agonists such as
16
Initial Dose
Maximal Dosage (in 2-3 divided doses) 25/100 mg tid-qid 50/200 mg 1.5 mg 4 mg 1 mg 4 mg 3600 mg 200-400 mg 195 mg 300 mg 8 mg 20-30 mg 20 mg 20-30 mg 20-30 mg 15 mg 15 mg 0.5 mg 30 mg 3 mg 600 mg 0.9 mg 15 mg tid 840 mg
25/100 mg 25/100 mg 0.125 mg 0.5 mg 0.05 mg 0.5 mg 300 mg 50 mg 65 mg 100 mg 2 mg 10 mg 2.5 mg 5 mg 5 mg 5 mg 5 mg 0.125 mg 15 mg 0.5 mg 200 mg 0.1 mg 2.5 mg 325 mg ferrous sulfate 100 mg/day
412
pergolide (mean effective dose ~ 0.5 mg) and cabergoline also demonstrate good efficacy but carry attendant risks of multiorgan fibrosis and valvular heart damage at unknown rates with prolonged usage. Divided dosing (dinner and bedtime), and dosing several hours before typical symptom onset is preferable, because dopamine agonists take at least 2 hours to reach their peak effect. Dosing should be titrated to subjective relief, although increasingly it is recognized that some degree of PLMs may still exist (manifesting as fragmented sleep or daytime sleepiness). Common side effects include nausea and orthostatic hypotension, with insomnia, nasal congestion, and peripheral edema encountered less frequently. Augmentation has been less frequently encountered with dopamine agonists after 9 to 12 months of treatment (10% to 30%). In patients in whom pain is a predominant symptom, or in those who have neuropathy or neurodegenerative disease, we advocate the use of gabapentin (300 to 3600 mg in divided doses). The use of opioids is also reserved for patients with a prominent component of pain or in those who are refractory to the
earlier-mentioned approaches. Several other treatments have been proposed for RLS/PLMs, but few of them have been systematically evaluated (see Table 4). Benzodiazepines at least 1 hour before bedtime are a useful adjunct treatment in those patients who present with a component of psychophysiologic insomnia possibly reflecting years of inadequate treatment. SUGGESTED READING
Earley CJ: Restless legs syndrome, N Engl J Med 348:2103-2109, 2003. Silber MH, Ehrenberg BL, Allen RP, et al: An algorithm for the management of restless legs syndrome, Mayo Clin Proc 79:916-922, 2004.
PATIENT RESOURCE
Restless Legs Syndrome Foundation 4410 19th Street, NW, Suite 201 Rochester, MN 55901-6624 http://www.rls.org/
SECTION 17
General Issues in Therapy

Linda P. Fried, M.D., M.P.H.
is increasingly thought to be the core physiology of frailty, a consequence of aggregate alterations in function of multiple physiologic systems, including elevated inflammation, neuroendocrine dysregulation, and a wastingtype syndrome with loss of muscle mass (sarcopenia). There does not appear to be one specific physiologic system that is fully explanatory of the vulnerability of frailty, an observation that is important in considering therapies. Although the underlying vulnerability is the core physiology, the clinical presentation of frailty is that of a wasting syndrome, with evidence for the concurrent presence of at least several of the following: undernutrition and perhaps weight loss, loss of muscle mass with resulting declines in strength and exercise tolerance, low energy, slowed motor performance, and low physical activity. There is clinical face validity to considering frailty to be a self-perpetuating cycle, and, in fact, there is strong scientific evidence for pair-wise associations between the characteristics listed above, such as low strength and exercise tolerance, and slowed motor performance (e.g., walking speed) predicting declines in physical activity; undernutrition leading to loss of muscle mass, and so forth. Such a clinical picture, jointly with this supporting evidence, has led to the hypothesis that the clinical presentation of frailty may be both a final common pathway and a vicious cycle (Figure 2). In addition to the presentation related to energetics that is most commonly recognized clinically, there are many hypotheses that declines in cognitive reserves may also be a component of the frailty syndrome, but this remains undefined. A recently operationalized clinical phenotype of frailty (Table 1) has been validated as predicting the adverse outcomes associated with frailty: falls, disability, hospitalization, and death, as well as having the properties consistent with a medical syndrome. The presence of three or more of five criteria, as listed in Table 1, can be used as an initial screening approach to identify older adults who are frail and to identify appropriate preventive or therapeutic approaches (see Figure 1). Of import from the point of view of screening for primary prevention, those who have only one or two of these criteria have been shown to be at high risk of progression to having three or more (i.e., clinically apparent frailty) over 3 years and may constitute an additional risk group who would benefit from careful attention at times of stress, such as acute illness, and be candidates for prevention of onset of frailty. 413
Frailty is not a classic disease but rather is a medical syndrome that is seen clinically as the background substrate of individuals that is associated with their inherent vulnerability as well as prognosis. Frailty appears to result from physiologic changes associated with aging (primary frailty) or is part of the endstage manifestation of certain diseases such as congestive heart failure, advanced cancers, dementia, and acquired immunodeficiency syndrome (AIDS). It appears clinically that this syndrome develops in a chronic, progressive manner and has different degrees of severity, from a latent stage to a clinically manifest phenotype to endstage frailty that presages death (Figure 1). The mounting interest in frailty is due to (1) its likely increasing prevalence with the aging of the population (it is estimated that at least 7% of community-dwelling adults older than 65 years of age and at least 25% of those older than 80 years are frail, whereas most nursing home patients5% of older adults in the United Statesare considered frail); (2) frailty marking a subset of older adults who are highly vulnerable to stressors, such as acute illness, and at high risk of a range of adverse health outcomes, including falls, disability, risk of hospitalization as well as low tolerance of the stressors of hospitalization and death; and (3) increasing evidence that the earlier and mid-stages of frailty may be responsive to both therapeutic and preventive interventions. In marked contrast to clinical thinking about disease as the foreground of attention diagnostically and therapeutically, frailty could be thought of as a biologic syndrome of decreased reserve and resistance to stressors, resulting from cumulative declines in multiple physiologic systems. With such decrements in ability to maintain homeostasis, frailty becomes manifest as the underlying vulnerability of the individual on which acute illnesses or injuries can be superimposed (as well as causative) and which modifies the outcomes associated with such stressors. This underlying vulnerability
414
Robust Presentation Active older adult
Latent frailty ibid
Clinical phenotype Sarcopenia, weakness, decreased energy and exercise tolerance, low physical activity, slowed motor speed, weight loss
Endstage frailty Severe end of clinical phenotype; wasting and metabolic abnormalities; low albumin, cholesterol
FIGURE 1. The continuum of frailty in older adults and potential therapies appropriate to stage.
Vulnerabilities
Decompensation in presence of stressors
Treatment Prevention
Resistance exercise
Resistance exercise; tai chi; prevention of adverse outcomes: falls, disability
Palliative care, quality of life
Treatment and Prevention of Frailty

The syndrome of frailty may be precipitated by a number of risk factors, including diseases that contribute to wasting, such as congestive heart failure; AIDS, tuberculosis, and other chronic infections; advanced cancers; thyroid disease ; diabetes mellitus; dementia; and
depression and grief. Chronic inflammatory diseases such as temporal arteritis can also cause a frailty-type presentation. It is not known whether clinical therapy for these chronic diseases prevents the development of frailty. However, recognition of potential underlying causes and effective treatment to minimize progression of a disease and its adverse outcomes, including frailty, is a reasonable approach. In addition, vaccination to
Disease Environment Medications
Chronic undernutrition
Disease Medications Aging-related changes
Total energy expenditure
Cycle of frailty
Sarcopenia
Insulin sensitivity Resting metabolic rate Walking speed Strength and power Impaired balance Osteopenia
Activity
VO2 max
Disability
Immobilization
Dependency
Falls and injuries
. FIGURE 2. Hypothesized cycle of frailty. VO2max, maximum oxygen consumption. (From Fried LP, Walston J: Frailty and failure to thrive. In Hazzard WR, Blass JP, Ettinger WH Jr, et al, editors: Principles of geriatric medicine and gerontology, ed 5, New York, 2003, McGraw-Hill, 1487-1502.)
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TABLE 1 Validated Screening Criteria Used to Identify Frail Older Adults in the Cardiovascular Health Study*
Frailty identified by presence of 3 of the following 5 criteria: 1. Weight loss 10 pounds lost unintentionally in prior year 2. Low grip strength Lowest quintile in kilogram (by gender, body mass index [BMI]): Men Women BMI Kg cutoff BMI Kg cutoff 24 29 23 17 24.1-26 30 23.1-26 17.3 26.1-28 30 26.1-29 18 3. Slow usual walking speed Over 15-ft course Men Height >173 cm 6 sec else 7 sec Women Height >159 cm 6 sec else 7 sec 4. Exhaustion By self-report: I felt that everything I did was an effort, or I could not get goinganswered as a moderate amount of time (3-4 days) or most of the time in the last week 5. Low physical activity Males < 383 kcal/wk; females <270 kcal/wk
Adapted from Fried LP, Tangen CM, Walston J, et al: Frailty in older adults: evidence for a phenotype [abstract], J Gerontol Med Sci 56A:M146-M156, 2001. *Based on the short version of the Minnesota Leisure Time Activities Questionnaire, asking about frequency and duration of participation, each week, in walking, chores (moderately strenuous), mowing of lawn, raking, gardening, hiking, jogging, biking, exercise cycling, dancing, aerobics, bowling, golf, singles tennis, doubles tennis, racquetball, calisthenics, swimming. See the Center for Epidemiological Studies-Depression scale. Kilocalories per week are calculated using a standardized algorithm: for calculation of physical activity in kilocalories: low physical activitylowest quintile of physical activity based on kilocalories expended, for each sex.
17
minimize risk of acute infections is highly appropriate, as is close attention to prevention of adverse outcomes of falls, delirium, disability, and hospitalization when possible. In addition, health behaviors including low physical activity and inadequate nutrition are core risk factors for the development of frailty (see Figure 2) and should be minimized. There is strong evidence that resistance or weight-lifting exercise can be highly effective in frail older adults, including frail nursing home patients, in improving muscle mass, strength, exercise tolerance, and walking speed. Use of nutritional supplements enhances the effect of resistance exercise but does not appear effective without exercise. Tai chi also has been shown to be beneficial in preventing falls and is a useful adjunct to strengthening exercise. Overall, there is evidence that early detection matters even after someone is already frail. For example, weight-lifting exercise has been shown to improve muscle strength in frail older adults but is most effective in those who are weak but not yet manifesting severe muscle atrophy. Notably, the increases in strength with resistance exercise are greater than with hormonal replacement, such as with growth hormone, in those who are clinically deficient. There is mounting evidence that frailty results from dysregulation of multiple physiologic systems. Because it is the cumulative dysregulation across many systems that appears to be related to both the clinical phenotype and the vulnerability of frailty, it is likely that treatment of a single system will not affect the onset or progression of frailty. There is no evidence at this time that enhancement of levels of a biomediator in a single system, such as a hormone, when there is not a clinical deficiency, will be effective in preventing or treating frailty.
LATENT PHASES The evidence, discussed earlier, that those with only one or two of five criteria for frailty are at risk of progression to the full clinical phenotype suggests that there may be benefit from early identification of those at risk. The goal of such early identification would be, first, to recommend preventive approaches, primarily resistance exercise. Research indicates that high-intensity strength training in older adults has highly anabolic effects and may prevent the development of sarcopenia and clinical frailty. Research is needed to discover other approaches to identifying those with this heightened vulnerability and to determine whether approaches such as prehabilitation prior to elective surgery minimize the development of frailty and optimize recovery afterward. There is increasing evidence for distinct physiologic and potential genetic and/or molecular etiologies, but no support exists for therapies directed at this level.
Management of High-Risk Situations and Stressors

Overall, the central issue for those who are already frail and, potentially, those in a latent phase of frailty, is their vulnerability to stressors such as acute illness and injury, and to the stressors of new situations such as hospitalization. It is likely that this group is also particularly at risk for iatrogenesis, including from invasive procedures, dehydration, and adverse drug effects and interactions resulting from polypharmacy. Additionally, this is a patient subset likely at high risk of falls and delirium at the time of acute illness or recovery. These vulnerabilities
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warrant particular vigilance at times of acute illness to minimize adverse outcomes of frailty, through attention to minimizing immobilization and unnecessary bed rest and low activity, inadequate nutrition and weight loss, use of catabolic and sedating medications, and polypharmacy, and implementing effective approaches to prevention of falls and delirium. Prehabilitation to optimize strength and exercise tolerance prior to an elective procedure should be considered in this patient population. Rehabilitation likely also is essential to minimize loss of muscle mass and maximize recovery of strength and function. In frail patients, the period of recovery will likely be prolonged. Geriatric models of care delivery have been particularly designed to improve health outcomes for frail older adults, both at times of acute stressors such as hospitalization and for general prevention of adverse outcomes for which frail persons are at risk. These models are designed to provide patient-centered care, taking into account patient and family goals, analyzing both the multiple components of physical health status and physical functioning and the environmental issues, from housing to caregiving support and access to care, and services and education needed to support optimal outcomes. Generally, multidisciplinary teams of providers, including geriatricians, nurses, and social workers, are the models of care for comprehensive geriatric assessment and management in outpatients or in acute care for the elderly inpatient units. These care models have been shown to decrease adverse outcomes for frail older adults and improve functional recovery. There are several clinical studies indicating that those presenting with endstage frailty (see Figure 1)whether due to endstage disease or severe primary frailtyare not responsive to therapy and are at high risk of death over the subsequent 6 to 12 months. In these patients, palliative care goals are highly appropriate, with a focus on comfort, symptom relief, supporting/maintaining functional status, improving overall sense of well-being, maximizing the quality of life, and minimizing time in the hospital. SUGGESTED READING
Ferrucci L, Penninx BW, Volpato S, et al: Change in muscle strength explains accelerated decline of physical function in older women with high interleukin-6 serum levels, J Am Geriatr Soc 50: 1947-1954, 2002. Fiatarone MA, ONeill EF, Ryan ND, et al: Exercise training and nutritional supplementation for physical frailty in very elderly people, N Engl J Med 330:1769-1775, 1994. Fried LP, Tangen CM, Walston J, et al: Frailty in older adults: evidence for a phenotype [abstract], J Gerontol Med Sci 56A: M146-M156, 2001. Fried LP, Walston J: Frailty and failure to thrive. In Hazzard WR, Blass JP, Ettinger WH Jr, et al, editors: Principles of geriatric medicine and gerontology, ed 5, New York, 2003, McGraw-Hill, 1487-1502.

Characteristics of Corticosteroids and Pharmacologic Effects

The effects of corticosteroids are legion, yet the details of their mechanisms of action in many diseases are not fully known. The immunosuppressive and antiinflammatory actions of corticosteroids probably occur mainly via the following known effects on immune cells. First, corticosteroids induce lymphocytopenia by redistributing lymphocytes out of circulation into other compartments less accessible to sites of immunoreactivity. Second, corticosteroids reduce differentiation and proliferation of lymphocytes. In both of these mechanisms, T lymphocytes are affected and depleted more prominently than are B lymphocytes and plasma cells. Third, and perhaps most important in an autoimmune disease, corticosteroids disrupt the intercellular communication among leukocytes through interference with the production or function of numerous lymphokines, especially interleukin (IL)-1, IL-2, tumor necrosis factor, and migration-inhibitory factor. These actions potently inhibit the recruitment of leukocytes and macrophages in an immune response. Fourth, corticosteroids inhibit many functions of macrophages, including elaboration of IL-1 (hence all its downstream effects on lymphocytes), the action of migration-inhibitory factor (hence promoting the egress of macrophages), phagocytosis, and the processing and display of antigen that are facilitated by gamma interferon. Thus, in all these ways, not only are cell numbers reduced, but phagocytosis, migration, antigen processing and presentation, and all aspects of the inflammatory response are suppressed. Many of the immunosuppressive effects of corticosteroids may last far longer than the maximal suppression of adrenocorticotropic hormone (ACTH) secretion by the pituitary. This allows effective alternate-day therapy in myasthenia gravis or inflammatory myopathies, for example, a strategy that may work less well in painful inflammatory arthritic disorders (rheumatoid arthritis, systemic lupus erythematosus) or severe life-threatening forms of vasculitis, in which even divided daily doses may be required. If the drug is administered as a single dose in the morning at a time when the endogenous circadian cortisol level would peak, by evening the administered dose is no longer present in the circulation and the hypothalamus-pituitary-adrenal axis should secrete ACTH. This, in turn, will stimulate secretion of endogenous cortisol the next morning. The longer immunopharmacologic effect maintains control of disease, and the single-morning-dose schedule mimics the normal diurnal cortisol cycle. An alternateday schedule further reduces side effects and facilitates eventual tapering of total dose.
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warrant particular vigilance at times of acute illness to minimize adverse outcomes of frailty, through attention to minimizing immobilization and unnecessary bed rest and low activity, inadequate nutrition and weight loss, use of catabolic and sedating medications, and polypharmacy, and implementing effective approaches to prevention of falls and delirium. Prehabilitation to optimize strength and exercise tolerance prior to an elective procedure should be considered in this patient population. Rehabilitation likely also is essential to minimize loss of muscle mass and maximize recovery of strength and function. In frail patients, the period of recovery will likely be prolonged. Geriatric models of care delivery have been particularly designed to improve health outcomes for frail older adults, both at times of acute stressors such as hospitalization and for general prevention of adverse outcomes for which frail persons are at risk. These models are designed to provide patient-centered care, taking into account patient and family goals, analyzing both the multiple components of physical health status and physical functioning and the environmental issues, from housing to caregiving support and access to care, and services and education needed to support optimal outcomes. Generally, multidisciplinary teams of providers, including geriatricians, nurses, and social workers, are the models of care for comprehensive geriatric assessment and management in outpatients or in acute care for the elderly inpatient units. These care models have been shown to decrease adverse outcomes for frail older adults and improve functional recovery. There are several clinical studies indicating that those presenting with endstage frailty (see Figure 1)whether due to endstage disease or severe primary frailtyare not responsive to therapy and are at high risk of death over the subsequent 6 to 12 months. In these patients, palliative care goals are highly appropriate, with a focus on comfort, symptom relief, supporting/maintaining functional status, improving overall sense of well-being, maximizing the quality of life, and minimizing time in the hospital. SUGGESTED READING
Ferrucci L, Penninx BW, Volpato S, et al: Change in muscle strength explains accelerated decline of physical function in older women with high interleukin-6 serum levels, J Am Geriatr Soc 50: 1947-1954, 2002. Fiatarone MA, ONeill EF, Ryan ND, et al: Exercise training and nutritional supplementation for physical frailty in very elderly people, N Engl J Med 330:1769-1775, 1994. Fried LP, Tangen CM, Walston J, et al: Frailty in older adults: evidence for a phenotype [abstract], J Gerontol Med Sci 56A: M146-M156, 2001. Fried LP, Walston J: Frailty and failure to thrive. In Hazzard WR, Blass JP, Ettinger WH Jr, et al, editors: Principles of geriatric medicine and gerontology, ed 5, New York, 2003, McGraw-Hill, 1487-1502.

Characteristics of Corticosteroids and Pharmacologic Effects

The effects of corticosteroids are legion, yet the details of their mechanisms of action in many diseases are not fully known. The immunosuppressive and antiinflammatory actions of corticosteroids probably occur mainly via the following known effects on immune cells. First, corticosteroids induce lymphocytopenia by redistributing lymphocytes out of circulation into other compartments less accessible to sites of immunoreactivity. Second, corticosteroids reduce differentiation and proliferation of lymphocytes. In both of these mechanisms, T lymphocytes are affected and depleted more prominently than are B lymphocytes and plasma cells. Third, and perhaps most important in an autoimmune disease, corticosteroids disrupt the intercellular communication among leukocytes through interference with the production or function of numerous lymphokines, especially interleukin (IL)-1, IL-2, tumor necrosis factor, and migration-inhibitory factor. These actions potently inhibit the recruitment of leukocytes and macrophages in an immune response. Fourth, corticosteroids inhibit many functions of macrophages, including elaboration of IL-1 (hence all its downstream effects on lymphocytes), the action of migration-inhibitory factor (hence promoting the egress of macrophages), phagocytosis, and the processing and display of antigen that are facilitated by gamma interferon. Thus, in all these ways, not only are cell numbers reduced, but phagocytosis, migration, antigen processing and presentation, and all aspects of the inflammatory response are suppressed. Many of the immunosuppressive effects of corticosteroids may last far longer than the maximal suppression of adrenocorticotropic hormone (ACTH) secretion by the pituitary. This allows effective alternate-day therapy in myasthenia gravis or inflammatory myopathies, for example, a strategy that may work less well in painful inflammatory arthritic disorders (rheumatoid arthritis, systemic lupus erythematosus) or severe life-threatening forms of vasculitis, in which even divided daily doses may be required. If the drug is administered as a single dose in the morning at a time when the endogenous circadian cortisol level would peak, by evening the administered dose is no longer present in the circulation and the hypothalamus-pituitary-adrenal axis should secrete ACTH. This, in turn, will stimulate secretion of endogenous cortisol the next morning. The longer immunopharmacologic effect maintains control of disease, and the single-morning-dose schedule mimics the normal diurnal cortisol cycle. An alternateday schedule further reduces side effects and facilitates eventual tapering of total dose.
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Available oral and intravenous corticosteroid preparations differ pharmacologically mainly in rates of absorption, metabolism, and solubility, and these may legitimately drive therapy. However, glucocorticoid and mineralocorticoid side effects (sodium and fluid retention, potassium wasting) are not well dissociated in various steroid preparations. Yet certain corticosteroid drugs have become associated by habit or tradition with treatment of particular conditions, without a strong pharmacologic basis for the practice. Examples in neurology are the use of dexamethasone for treating cerebral edema or the sharply declining use of ACTH in acute exacerbations of multiple sclerosis or infantile spasms. The main historic advantage of ACTH is that adrenal gland responsiveness is maintainable during therapy (although pituitary suppression does occur when usage is prolonged). The disadvantages of ACTH are the parenteral route, unpredictable magnitude and slowness of the response, and substantial mineralocorticoid effects. Furthermore, long-acting preparations of ACTH, despite maximal adrenal stimulation, are incapable of producing more than about 300 mg of cortisol daily, equivalent to 60 mg of prednisone. Consequently, potency and route drive therapeutic considerations in the choice of a corticosteroid preparation. At least in multiple sclerosis, studies in small numbers of patients have suggested that high-dose intravenous methylprednisolone is similar in efficacy to equivalent doses of oral methylprednisolone, equivalent to or better than ACTH alone, and better than lower doses of intravenous methylprednisolone. This is likely to be true in most autoimmune or inflammatory diseases. Toxicities of the various corticosteroid forms may also drive therapeutic choice. Oral prednisolone is chosen over prednisone only if a problem in the hepatic metabolism of prednisone to prednisolone is known or suspected. This can be surmised but not proved if at high doses of prednisone no cushingoid effects occur at all.
TABLE 1 Adverse Effects of Corticosteroids

Organ/Anatomic Area Blood vessels, fluid and electrolytes Bone Brain More Common Adverse Effects* Hypertension Capillary fragility and bruising Sodium retention, fluid retention Hypokalemia Osteoporosis Avascular necrosis of bone Insomnia Mood disordersdepression, hypomania, euphoria Anxiety, irritability Psychosis Weight gain, cushingoid habitus Hyperglycemia, diabetes mellitus Hypercholesterolemia Secondary adrenal insufficiency Growth retardation Menstrual irregularities Increased intraocular pressure Cataract Peptic ulcer Exacerbation of gastroesophageal reflux disease Oral thrush General increased susceptibility to infections Skeletal muscle atrophy (so-called myopathy) Acute quadriplegic myopathy (associated with the combination of corticosteroids and neuromuscular blocking agents) Skin thinning, fragility, and bruising Poor wound healing (2-3 times prolonged) Increased sweating, especially night sweats
Endocrine glands
Eye Gastrointestinal tract
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Immune system Muscle
Skin
Adverse Effects and Monitoring

The patient, internist, and treating neurologist must join efforts to prevent and detect adverse effects related to corticosteroid therapy as early as possible, because toxicity is potentially serious. Of course, not every patient develops every symptom, but most patients have some side effects; almost every patient gains weight and develops part of the cushingoid habitus. The more common adverse effects (Table 1) may occur rather early in treatment, are more frequently seen with divided doses, and are generally reversible with dose reduction or elimination. Routine tuberculin skin testing is recommended prior to instituting corticosteroid therapy. Once therapy is begun, patients are followed scrupulously to monitor caloric intake, weight gain, blood pressure, quantitative and functional strength assessment, and routine laboratory tests, including serum electrolytes and glucose. Much of the toxicity can be prevented. Biannual ophthalmologic examination is advised to screen for cataracts and glaucoma. Proton pump inhibitors or H2 blockers
*These are relatively common, often occur early during use, are more common with divided doses, and are generally reversible with dose reduction or elimination, except as noted. Rare, not reversible, may require surgery. A reason to discontinue corticosteroids urgently. Extremely common after 10-20 years of use of corticosteroids.
may be required to treat peptic ulcer or esophageal reflux; potassium supplements may be needed. In secondary adrenal insufficiency during steroid withdrawal or chronic low-dose usage, one generally doubles any lowmaintenance steroid doses (or returns to a minimum of 20 to 25 mg of prednisone daily or its equivalent) during acute periods of physical stress (for example, just before and after surgery). An empirical strategy for prevention of corticosteroidinduced osteoporosis is best in all patients from the beginning, especially in postmenopausal women, because the greatest loss of bone density may occur within the first month of therapy. That plan is as follows: exercise, calcium supplements (1500 mg per day, usually as Tums to double as antacid), vitamin D (50,000 units twice weekly,
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or equivalent is given if the monitored serum 25-OH vitamin D level is less than 40 ng/mL), and monitoring 24-hour urinary calcium (if hypercalciuria is detected, initiation of a thiazide and potassium-sparing diuretic, e.g., amiloride-hydrochlorothiazide, is recommended to reduce calcium clearance). Replacement of gonadal hormones is controversial. Use of calcitonin, etidronate, or newer biphosphonates should be considered in patients who develop steroid osteopenia (detected by monitoring baseline and follow-up quantitative bone mineral densitometry) or fractures. Because of adverse effects, the continual goal of therapy in most diseases should be to use the least effective dose, to use no more than once-daily therapy if possible, and to switch gradually to alternate-day dosing when possible. CORTICOSTEROID-INDUCED MUSCLE ATROPHY AND ITS DIFFERENTIAL DIAGNOSIS Corticosteroid muscle atrophy may result from prolonged exposure to elevated endogenous or exogenous corticosteroid levels. Although all synthetic glucocorticoids can cause it, the incidence is somewhat higher in patients treated with the 9-alpha fluorinated corticosteroids. Doses higher than or equivalent to 30 mg of prednisone per day increase vulnerability, whereas significant atrophy rarely occurs with doses of 10 mg per day or less and is far less frequent with alternate-day regimens. Differential Diagnosis Muscle weakness and atrophy usually occur insidiously and predominantly affect proximal muscles. The legs are usually more severely affected than the arms, and bulbar muscles are usually spared. Reflexes are normal except with severe muscle weakness. Myalgia is uncommon. This pattern of weakness is indistinguishable from that of polymyositis. Patients with corticosteroid atrophy may display other clinical stigmata typical of adrenocorticoid excess, including obesity, facial plethora, or easy bruisability, for example. As in other endocrine myopathies (except hypothyroidism), the serum creatine kinase (CK) is normal. Needle electromyographic (EMG) studies are normal, except in severe cases in which type I fibers are affected. In such cases, small-amplitude, short-duration polyphasic motor unit action potentials and early recruitment patterns may be seen. However, insertional activity is normal and fibrillation potentials are absent, owing to the lack of muscle fiber necrosis. The primary histologic finding in corticosteroid atrophy is type II fiber atrophy. The electron microscopic appearance of atrophic myofibers reveals loss of myofibrils, redundant folding of basal lamina secondary to the atrophy, an increase in lipid droplets and subsarcolemmal glycogen, and enlarged mitochondria. A common diagnostic dilemma occurs when patients with inflammatory myopathies experience a worsening of weakness after an initial positive response to corticosteroids. In such a scenario, the physician must
distinguish between steroid toxicity and refractory disease (in which case an increase in dosing might be warranted). Because the serum CK is normal in corticosteroid muscle atrophy, an elevation in serum levels of muscle enzymes suggests that the inflammatory myopathy remains active, in part; EMG may also be valuable. In patients with inflammatory myopathies, the presence of fibrillation potentials and positive sharp waves suggests that muscle fiber necrosis is ongoing and that the myopathy is not responding to the current steroid dose. Finally, muscle biopsy can distinguish inflammatory myopathy from steroid atrophy if the muscle sample contains active inflammation. Nevertheless, both conditions may coexist, so that a clinical trial of corticosteroid dose reduction or switching to another immunotherapy may be required. Included among the conditions that do not respond to steroids is the syndrome of inclusion body myopathy, a morphologically distinctive vacuolar inflammatory myopathy most commonly seen in older men. When high-dose corticosteroids are combined with neuromuscular blocking agents, the syndrome of acute quadriplegic myopathy may occur, attributable to a selective loss of myosin thick filaments. Treatment The most effective treatments of corticosteroid myopathy are to reduce the dose to the lowest level possible, switch to a nonfluorinated corticosteroid, or switch to alternate-day dosing. Full recovery usually takes at least several weeks, but an effective dose reduction by half should noticeably affect strength within 2 weeks. Inactivity may worsen corticosteroid myopathy; thus, exercise may be useful in lessening and treating the effects of glucocorticoids on muscle.
Use of Corticosteroids
GENERAL CONTRAINDICATIONS There are no absolute contraindications to the use of corticosteroids. Relative contraindications include severe obesity, diabetes mellitus, uncontrolled hypertension, ulcer disease, osteoporosis, and ongoing infections. These problems can usually be circumvented by appropriate medical measures. Long-term treatment with steroids requires medical attention by an experienced physician; patients who are unable or unwilling to be followed closely should never be treated with steroids. Nursing mothers should be warned that steroids may pass into breast milk. If prednisone provides no quantitative improvement in function, if relapses recur with lower steroid doses, or if corticosteroid toxicity outweighs the benefit, a steroid-sparing intervention is usually required. Most commonly, steroid therapy is continued and a second immunosuppressive agent (methotrexate, azathioprine, cyclosporine, or mycophenolate mofetil) is added for combination therapy. If steroid toxicity is severe, prednisone can be tapered as an alternative immunosuppressive therapy is initiated.
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TABLE 2 Disease Differences in Corticosteroid Therapy

Disease Unique Issues Dose Recommendations
Autoimmune, Vasculitic, and Granulomatous Disorders Polymyositis, Rule out other mimicking conditions: drugdermatomyositis induced myopathy, sarcoidosis, HIV- or HTLV-1-associated myositis, pyomyositis, eosinophilic fasciitis, and acid maltase deficiency, because all have elevated CK; successful therapy is based on functional gains, not CK changes; pattern of weakness in corticosteroid atrophy mimics the inflammatory myopathy itself; corticosteroid failure often indicates diagnosis of inclusion body myopathy Myasthenia gravis Induction with high-dose corticosteroids may (MG) cause transient exacerbation and respiratory insufficiency within 5-10 days of therapy in nearly half of patients who have moderate to severe disease; vital capacity must be monitored; diplopia frequently responds especially well to steroids
Prednisone 1 mg/kg/day until stable clinical response, or 2-3 mo, then switch to alternate day; steroid-sparing regimens (methotrexate, azathioprine, cyclosporine, or mycophenolate mofetil) often necessary; most patients improve within 3-6 mo
Lambert-Eaton myasthenic syndrome Vasculitic neuropathy
Treat underlying cancer (usually lung) Usually corticosteroids alone are insufficient and cyclophosphamide is required; undiagnosed or uncontrolled diabetes may cause neuropathy that confuses the clinical picture; presence of HIV or hepatitis B or C can complicate treatment Acute steroid psychosis may be mistaken as lupus cerebritis Corticosteroids alone are usually insufficient Treatment is particularly urgent, even if necessary before biopsy confirmation, because blindness, if it occurs, is usually irreversible; dramatic improvement often occurs within 0.5-4 days; ESR, CRP normalize within 2-4 wk Effective dose and duration of therapy depend on region of the nervous system affected
Usual starting dose: prednisone 15-20 mg/day, increased q 2nd-3rd day by 5 mg until satisfactory response; improvement begins within 2-3 wk, but max response may take 3-6 mo; for mild or ocular MG, begin with prednisone 10 mg/day and increase by 5 mg/day q wk until satisfactory response or 1 mg/kg/day is reached; azathioprine, cyclosporine, and mycophenolate mofetil are also first-line agents, but prednisone is fastest acting Prednisone 60 mg/day is effective within weeks; convert to alternate-day therapy and taper dose Pulse with IV methylprednisolone 1000 mg/day for 3-5 days, followed by high-dose oral prednisone 1 mg/kg, divided twice daily, plus cyclophosphamide 2 mg/kg/day Various regimens have been used, including pulse with IV methylprednisolone 1000 mg/day for 3-5 days High-dose pulse IV methylprednisolone plus cyclophosphamide With visual symptoms: admit to hospital and treat presumptively with IV methylprednisolone 1000 mg/day for 3 days, followed by oral prednisone Without visual symptoms: prednisone 1 mg/kg/d PO; blindness rarely occurs once a patient is on established dose of prednisone exceeding 15-20 mg/day or equivalent Prednisone 0.5-1.5 mg/kg/day, depending on severity; higher for optic or auditory nerve involvement; treatment often needs to be prolonged and at higher doses in granulomatous meningitis, parenchymal disease, neuropathy, or myopathy IV methylprednisolone 1000 mg/day for 3-7 days, depending on severity, followed by prednisone 1 mg/kg/day and tapering course of oral prednisone for a total exposure of 2 wk Cranial MR imaging should be obtained, and neurologic evaluation for possible MS completed; white matter hyperintensities indicate a significant risk of progressing to definite MS
Continued
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Systemic lupus erythematosus Cerebral vasculitis Giant cell arteritis
Neurosarcoidosis
Optic neuritis
Vision recovers more rapidly with IV methylprednisolone followed by oral prednisone than with oral prednisone alone. However, long-term recovery is similar to untreated patients; use of oral prednisone alone was associated with twofold increased risk of relapse of optic neuritis and progression to MS in the Optic Neuritis Treatment Trial
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TABLE 2 Disease Differences in Corticosteroid Therapycontd

Disease Multiple sclerosis (MS) Unique Issues See optic neuritis Dose Recommendations See Chapter 43 for immunomodulatory regimens and steroid-sparing approaches; many corticosteroid approaches, but common approach is IV methylprednisolone 1000 mg for 3-5 days, followed by rapid taper with oral prednisone 1.5 mg/kg/day, decreasing by 20 mg q 2 days, limited to 2 wk; IVIg or plasmapheresis are options for steroidrefractory exacerbations or where steroids are contraindicated Pediatric meningitis: IV methylprednisolone 0.15 mg/kg for 3 days
Other Disorders Bacterial meningitis
Bells palsy Vestibular neuritis Duchennes muscular dystrophy Spinal cord trauma
Useful in pediatric cases and tuberculous meningitis; remains controversial in adult bacterial meningitis, because corticosteroids reduce the beneficial inflammatory response associated with infection Short course only; even without treatment, more than 75% of patients recover completely within a few weeks Controlled clinical trial showed benefit of methylprednisolone but no added benefit of antiviral therapy In nonambulatory patients, corticosteroid risks probably exceed potential benefits; uncontrollable obesity and growth retardation with long-term use Use of corticosteroids is confirmed as effective in controlled clinical trials
Famciclovir 500 mg tid and oral prednisone 1 mg/kg for 10 days Short-term 2-wk tapering course of methylprednisolone, begun with 100 mg/day Prednisone 0.75 mg/kg/day, switching to 1-2 mg/kg on alternate days Methylprednisolone bolus IV infusion of 30 mg/kg of body weight over 15 min within 8 hr of acute closed spinal cord injury, followed 45 min later by an infusion of 5.4 mg/kg of body weight per hr for 23 hr Treatment is controversial At beginning of cluster period, oral prednisone 40-100 mg/day, with rapid taper over 1-2 wk, often combined with verapamil or other agents Optimal dose, length of therapy, and effect on long-term outcomes are unclear
Head trauma Acute disseminated encephalomyelitis Migraine and cluster headache Infantile spasms
Use of corticosteroids is not confirmed as efficacious in randomized, controlled trial Disease may remit spontaneously; parainfectious, so any active, proved bacterial or viral disease is treated simultaneously Use of IV corticosteroids limited to rare use as rescue therapy in status migrainosus, when triptans or IV dihydroergotamine fail ACTH probably as effective in resolution of hypsarrhythmia as short-term treatment
ACTH, Adrenocorticotropic hormone; HIV, human immunodeficiency virus; HTLV, human T-cell lymphotropic virus; CK, creatine kinase; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; IVIg, intravenous immunoglobulin.
USE IN SPECIFIC DISEASES Distinct disease categories differ widely in optimal corticosteroid usage and raise some unique issues. These considerations are summarized in Table 2. The reader also is referred to the other chapters in which diseasespecific treatment for those disorders is discussed.
Principles to Avoid Misuse

1. If at all possible, corticosteroids should not be used without pathologic confirmation of a diagnosis that provides a correct indication for therapy, because
toxicity can be quite problematic and requires the intense collaborative effort of patient and physician to monitor and prevent it. 2. There is always a differential diagnosis to be considered before undertaking the risk of corticosteroid therapy in any disease. 3. Initial rapid dramatic improvements without objective measurements are misleading in any corticosteroid usage because of both placebo effects and relative drug-induced euphoria. 4. Corticosteroid therapy intended for short-term rescue in diseases (e.g., migraine or multiple sclerosis) must never be used chronically.
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5. Unsupervised chronic use of corticosteroids without monitoring and active prevention of deleterious side effects is a prescription for disaster. 6. Use of corticosteroids for longer than about 2 weeks, or, for example, a 5-day intravenous course followed by a 10-day taper, risks severe adrenosuppression.

Benjamin Greenberg, M.D., and Vinay Chaudhry, M.D.
Intravenous immunoglobulin (IVIg) and plasmapheresis (plasma exchange [PE]) have become common therapeutic interventions in a variety of immune-mediated neurologic diseases. Both modalities are effective for a short duration (weeks to months) and require a plan for longer-term immune modulation. The natural history of neurologic diseases, patient-specific factors, costs, availability, specific adverse event profiles of each therapy, and a long-term plan for immune modulation must be taken into consideration before embarking on IVIg or PE therapy. In addition, the efficacy and side effects of each therapy need to be closely monitored by health care professionals knowledgeable about the disease and the therapies. This chapter describes each therapy separately in terms of mechanism of action, indications for use, and potential adverse events. Those discussions are followed by a brief description of individual neurologic diseases and our preference of treatment. We then offer an algorithm for deciding between these two therapies for diseases in which both approaches are known to be equally effective.
Intravenous Immunoglobulin
IV immunoglobulin is commonly referred to as IVIg even though the correct nomenclature is IGIV if it follows the U.S. Food and Drug Administration accepted terminology of drug (Ig) followed by route of administration (IV). In this chapter we use the more common term of IVIg. IVIg was licensed in the United States in 1981, but its origins date back to the late 19th century. In 1890 Emil von Behring produced the first serum therapy for diphtheria. By the late 20th century refinement methods were established for concentrating Ig from donor serum. In the last 20 years a variety of IVIg preparations have become available, and the indications for use in neurologic disease have broadened.
IVIg is composed primarily of IgG, one of the five classes of human antibodies. Although IgG is the predominate antibody present, IgM and IgA remain present in most preparations of commercially available IVIg. There are two main classes of IVIg: pooled (most commonly used for neurologic diseases) and hyperimmune. Pooled IVIg is derived from the plasma of unselected donors, whereas hyperimmune IVIg is created from target donors with increased resistance to specific pathogens (i.e., hepatitis B, tetanus, varicella, rabies). A single bottle of pooled IVIg contains antibodies from more than 2000 donors. Plasma from donors is screened for evidence of transmissible infection and subjected to a filtration process meant to remove infectious agents. The various preparations of pooled IVIg (Carimune, Gamunex, Gammagard, Gammar-P, Polygam, Flebogamma, and Octagam) have significant differences in terms of preparation and relative levels of Igs but have no proved difference in terms of efficacy (Table 1). Most manufacturers use Cohn-Oncley ethanol fractionation (fraction II) as an initial step in the preparation of IVIg. In this process, pooled plasma is mixed with cold liquid ethanol and fractions are separated by ionic strength, ph, temperature, ethanol concentration, and concentration of protein. Other steps include removal of aggregates; inactivation of viruses; and addition of a variety of stabilizing agents including albumin, glycine, sucrose, glucose, or maltose. IVIgs are currently available in either liquid or lyophilized form. Lyophilized formulations are considered more time consuming to prepare and less convenient than liquids, although some liquid formulations may require refrigerated storage. Concentration has a direct impact on volume load. A 10% solution can cut volume load in half compared with a 5% solution and may be preferred in congestive heart failure, neonates, and the elderly. A higher concentration may also significantly reduce infusion time. On the other hand, a lower concentration product may be preferred in patients with renal failure or those with risk of thromboembolic episodes. The major contributors to osmolarity/osmolality include sodium, sugars, and contaminating proteins such as albumin. Sugar-stabilized products tend to have higher osmolarities than sugar-free preparations. Patients who have selective IgA deficiency and the ability to produce antibodies may be at risk for developing IgE or IgG anti-IgA antibodies, which may result in an adverse reaction. Although anaphylaxis is a theoretical risk, it is rare, and routine screening for anti-IgA antibodies in IVIg recipients is not routinely recommended. Sugarstabilized preparations tend to have a higher osmolality than sugar-free products. Most of the renal failure cases have been reported with products containing sucrose as a stabilizer. Sodium content varies widely in available preparations. Concerns about increased salt concentration and its association with significant adverse events and thromboembolic complications have been raised. High sodium content may be inappropriate for patients with congestive heart failure or renal dysfunction and for neonates, young children, or elderly patients. Tolerability of a product impacts the rate of infusion.
17
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5. Unsupervised chronic use of corticosteroids without monitoring and active prevention of deleterious side effects is a prescription for disaster. 6. Use of corticosteroids for longer than about 2 weeks, or, for example, a 5-day intravenous course followed by a 10-day taper, risks severe adrenosuppression.

Benjamin Greenberg, M.D., and Vinay Chaudhry, M.D.
Intravenous immunoglobulin (IVIg) and plasmapheresis (plasma exchange [PE]) have become common therapeutic interventions in a variety of immune-mediated neurologic diseases. Both modalities are effective for a short duration (weeks to months) and require a plan for longer-term immune modulation. The natural history of neurologic diseases, patient-specific factors, costs, availability, specific adverse event profiles of each therapy, and a long-term plan for immune modulation must be taken into consideration before embarking on IVIg or PE therapy. In addition, the efficacy and side effects of each therapy need to be closely monitored by health care professionals knowledgeable about the disease and the therapies. This chapter describes each therapy separately in terms of mechanism of action, indications for use, and potential adverse events. Those discussions are followed by a brief description of individual neurologic diseases and our preference of treatment. We then offer an algorithm for deciding between these two therapies for diseases in which both approaches are known to be equally effective.
Intravenous Immunoglobulin
IV immunoglobulin is commonly referred to as IVIg even though the correct nomenclature is IGIV if it follows the U.S. Food and Drug Administration accepted terminology of drug (Ig) followed by route of administration (IV). In this chapter we use the more common term of IVIg. IVIg was licensed in the United States in 1981, but its origins date back to the late 19th century. In 1890 Emil von Behring produced the first serum therapy for diphtheria. By the late 20th century refinement methods were established for concentrating Ig from donor serum. In the last 20 years a variety of IVIg preparations have become available, and the indications for use in neurologic disease have broadened.
IVIg is composed primarily of IgG, one of the five classes of human antibodies. Although IgG is the predominate antibody present, IgM and IgA remain present in most preparations of commercially available IVIg. There are two main classes of IVIg: pooled (most commonly used for neurologic diseases) and hyperimmune. Pooled IVIg is derived from the plasma of unselected donors, whereas hyperimmune IVIg is created from target donors with increased resistance to specific pathogens (i.e., hepatitis B, tetanus, varicella, rabies). A single bottle of pooled IVIg contains antibodies from more than 2000 donors. Plasma from donors is screened for evidence of transmissible infection and subjected to a filtration process meant to remove infectious agents. The various preparations of pooled IVIg (Carimune, Gamunex, Gammagard, Gammar-P, Polygam, Flebogamma, and Octagam) have significant differences in terms of preparation and relative levels of Igs but have no proved difference in terms of efficacy (Table 1). Most manufacturers use Cohn-Oncley ethanol fractionation (fraction II) as an initial step in the preparation of IVIg. In this process, pooled plasma is mixed with cold liquid ethanol and fractions are separated by ionic strength, ph, temperature, ethanol concentration, and concentration of protein. Other steps include removal of aggregates; inactivation of viruses; and addition of a variety of stabilizing agents including albumin, glycine, sucrose, glucose, or maltose. IVIgs are currently available in either liquid or lyophilized form. Lyophilized formulations are considered more time consuming to prepare and less convenient than liquids, although some liquid formulations may require refrigerated storage. Concentration has a direct impact on volume load. A 10% solution can cut volume load in half compared with a 5% solution and may be preferred in congestive heart failure, neonates, and the elderly. A higher concentration may also significantly reduce infusion time. On the other hand, a lower concentration product may be preferred in patients with renal failure or those with risk of thromboembolic episodes. The major contributors to osmolarity/osmolality include sodium, sugars, and contaminating proteins such as albumin. Sugar-stabilized products tend to have higher osmolarities than sugar-free preparations. Patients who have selective IgA deficiency and the ability to produce antibodies may be at risk for developing IgE or IgG anti-IgA antibodies, which may result in an adverse reaction. Although anaphylaxis is a theoretical risk, it is rare, and routine screening for anti-IgA antibodies in IVIg recipients is not routinely recommended. Sugarstabilized preparations tend to have a higher osmolality than sugar-free products. Most of the renal failure cases have been reported with products containing sucrose as a stabilizer. Sodium content varies widely in available preparations. Concerns about increased salt concentration and its association with significant adverse events and thromboembolic complications have been raised. High sodium content may be inappropriate for patients with congestive heart failure or renal dysfunction and for neonates, young children, or elderly patients. Tolerability of a product impacts the rate of infusion.
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TABLE 1 Preparations of Pooled Intravenous Immunoglobulin(IVIg)

Brand Name of IVIg Product Factors Manufacturer Form Concentration Osmolality IgA, g/mL Sugar Salt Time to infuse 70 gm, hr Shelf life, mo pH
Polygam/ Gammagard Gammar-P Carimmune Gamunex Octagam Flebogamma
ARC/Baxter Powder 5-10% 636-125 (5-10%) <2.4 20-40 mg glucose 8.5-17 mg/mL 1.2-5 hr 24 mo 6.4-7.2
Aventis Powder 5% 309 <25 50 mg/mL sucrose 5 mg/ml 5.6 hr 24 mo 6.4-7.2
CSL Freeze dried 3-12% 192-1074 (3-12%) 720 1.6 sucrose/gm <20 mg <6.6 hr (6%) 24 mo 6.4-6.8
Bayer Liquid 10% 258 46 None Trace 2 hr 36 mo 4-4.5
Octapharma Liquid 5% 310-380 100 Maltose 0 4.6 hr 24 mo 5.1-6
Grifols Liquid 5% 240-350 50 5% sorbitol 3.1 hr 24 mo 5-6
The recommended infusion rates (0.03 to 0.13 mg/kg/min) vary for different preparations, and these should be followed. For some products, a patient may not be able to tolerate the highest recommended infusion rate. Careful consideration of past tolerability experiences and medical condition is essential. Shelf lives of currently available products range from 24 to 36 months. A longer shelf life could be more cost effective and convenient and therefore may be preferable. Some reports suggest a possible association between low pH and the occurrence of phlebitis. Several potential mechanisms of action exist for pooled IVIg. Although IVIg was originally used to prevent infections in various immunodeficient states, its neurologic use is limited to its immune modulation properties, including the ability to neutralize pathogenic autoantibodies; suppress pathogenic autoantibody production; inhibit complement binding; block Fc binding mediated phagocytosis; suppress cytokines, chemokines, and adhesion molecules; and alter activation, differentiation, and effector functions of T-helper cells. The neurologic indications (off-label) for IVIg therapy include Guillain-Barr syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN), dermatomyositis, polymyositis, stiff person syndrome, Lambert-Eaton myasthenic syndrome (LEMS), myasthenia gravis (MG), transverse myelitis (TM), multiple sclerosis (MS), and intractable pediatric epilepsy (Table 2). In some instances, such as CIDP, GBS, MMN, stiff person syndrome, and dermatomyositis, there are randomized, double-blind, placebo-controlled studies available to support the use of IVIg. In others, the support comes from small trials and case reports. IVIg dosage is 2 gm/kg infused over 2 to 5 days (0.4 gm/kg/day for 5 days, 0.4 gm/kg on day 1 followed by 0.8 gm/kg on days 2 and 3, or 1 gm/kg/day for 2 days). Patients who require maintenance therapy should have their frequency of administration decided by relapse of symptoms. In general, patients require treatment every 4 to 8 weeks. Lower daily dosing and slower infusion rates may decrease complications. Response to IVIg usually
begins toward the end of the complete dose administration but may be delayed by as much as 1 to 2 weeks. Adverse reactions vary considerably in severity but in general are quite rare. Minor self-limited reactions include headache, chills, myalgias, fever, chest discomfort, and low back pain. These episodes occur early in the infusion and usually abate if the infusion rate is reduced or stopped temporarily. Moderately severe reactions including aseptic meningitis and skin rash (urticaria, lichenoid lesions, pruritus, petechiae) occur within days of the infusion and generally require no treatment. More serious reactions are fortunately rare and include anaphylaxis (in patients with severe IgA deficiencywho should be screened prior to administration); renal failure (in patients with preexisting renal disease and volume depletion); thromboembolic episodes, such as stroke, myocardial infarction, and pulmonary embolism (in patients with increased risk such as elderly, diabetic, thrombocytic, with hypergammaglobulinemia); and volume overload (necessitating caution in congestive heart failure patients). Although there is always a risk of infectious agent transmission, the screening, inactivation, and removal procedures are stringent. Clinical judgment must be used when deciding to treat a patient with IVIg, taking into account comorbid medical conditions such as heart disease, renal disease, pulmonary disease, and previous IVIg reactions.
Plasma Exchange
PE is a procedure that reduces the amount of circulating antibodies in a patient through filtration. A patients blood is removed and the plasma is separated from the red blood cells, which are returned with 5% serum albumin or human donor plasma. Albumin is preferred over plasma as a source of replacement colloid because it is pasteurized, can be given without regard to blood type, and does not require thawing prior to use. Angiotensinconverting enzyme inhibitors are to be avoided because there are reports of hypotension with certain lots
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TABLE 2 Neurologic Indications for Intravenous Immunoglobulin (IVIg) Therapy and Plasma Exchange
Factors Indications IVIg Refractory seizures Stiff person syndrome MS Transverse myelitis GBS CIDP MMN LEMS Isaacs syndrome Myasthenia gravis Inflammatory myopathy 2 gm/kg over 2-5 days Anaphylaxis, flulike (headache, fever, chills, nausea, vomiting, myalgia), renal failure, aseptic meningitis, CHF, pulmonary embolus, MI, stroke IgA deficiency, renal dysfunction, CHF, previous thrombotic episodes 1. Easily available, including weekends, home, office 2. Repeated administration easy to achieve 3. Less risks 4. Works for everything that PE works for and more 5. Can be used as a maintenance therapy 1. Expensive 2. Insurance approval may be difficult for off-label indications 3. Thrombotic events a serious adverse event PE Stiff person syndrome MS Transverse myelitis GBS CIDP MMN worse with PE LEMS Authors Preference IVIg IVIg, PE PE IVIg IVIg IVIg PE/IVIg IVIg
Average dose Side effects
50 mL/kg every other day 5 Line sepsis, pneumothorax, hypotension, paresthesias Line sepsis, preexisting coagulopathy, large bleeds (GI, cerebral) 1. Works better in crisis situations, e.g., respiratory failure in myasthenic crisis 2. If PE fails, can still try IVIg
Relative contraindications Advantages
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1. Line sepsis 2. Line placement may be a problem 3. Reserved for hospitalized patients; not available on weekends, home, office
Disadvantages
PE, Plasma exchange; MS, multiple sclerosis; GBS, Guillain-Barr syndrome; CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; LEMS, LambertEaton myasthenic syndrome; CHF, congestive heart failure; MI, myocardial infarction; GI, gastrointestinal.
of albumin. In patients with preexisting bleeding disorders, however, serum, rather than plasma, should be considered as the replacement fluid. Beneficial effects are usually seen when about two plasma volumes have been exchanged. Usual PE regimen occur every other day for five sessions (10 days). A similar list of neurologic conditions responds to PE as to IVIg. GBS, CIDP, MG, and LEMS all have responses to PE. Antibody depletion lasts for approximately 3 to 4 weeks, which is similar to the length of IVIgs efficacy. For chronic conditions, repeated treatments may be required. PE requires a different set-up than IVIg administration. Not all medical institutions have the ability to provide PE, whereas IVIg can be administered almost anywhere. PE requires the ability to gain adequate IV accessspecifically, two large-bore peripheral IV lines in veins able to withstand the pressures associated with pheresis or a large double-lumen central line. Furthermore, an institution would need personnel trained in operating pheresis equipment. The complications related to pheresis can be broken down into two categories: those related to catheter placement and maintenance and those related to the PE process itself. The central line-associated complications
include placement events (i.e., hematomas, pneumothoraces) and sepsis. Pheresis, however, can cause electrolyte abnormalities and coagulopathies because of the inadvertent removal of albumin and clotting factors. Episodic hypotension is also a potential complication as large volumes are filtered from patients. This is especially important in conditions where there may be autonomic dysfunction due to the neurologic illness (e.g., GBS). After a patients plasma is filtered, the red blood cells are returned to the patient with albumin solution or donor plasma. The incidence of adverse reactions (e.g., urticarial reactions) is higher if plasma is used as the replacement fluid. Protein-bound medications can have abnormal metabolism during PE, and care should be taken to monitor levels when appropriate.
Neurologic Conditions for Intravenous Immunoglobulin/ Plasma Exchange Use

GBS is an acute inflammatory disorder of the peripheral nerves that is characterized by the rapid onset of progressive weakness and sensory loss in the legs, arms, and face.
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Areflexia and albuminocytologic dissociation within the cerebrospinal fluid are typically noted. The target antigen is unknown, but the presence of antiglycolipid and antiganglioside antibodies, increased T-cell activation, and cytokine production confirms that immune mechanisms are involved. PE and high-dose Ig therapy are both effective and proved treatments for GBS. Combining the two treatments produces no incremental benefit. We prefer IVIg treatment to PE since the latter is not so readily available and has the potential of greater adverse effects. If a patient does not respond or continues to progress within the first 4 weeks of onset despite IVIg infusion, we would consider giving a repeat IVIg infusion. We reserve PE for those who have a contraindication to receiving IVIg. CIDP is immunopathologically and clinically similar to GBS with progressive weakness, sensory loss, and areflexia. However, rather than being a monophasic illness of GBS, CIDP is slowly progressive (> 8 weeks) and/or becomes a relapsing disease that requires long-term therapy to maintain improvement. Although corticosteroids, IVIg, and PE all have been shown to be beneficial treatment for CIDP, we prefer IVIg as the first-line therapy, especially in the early inflammatory phase of the disease. Long-term IVIg is also an attractive therapy, given the serious adverse effects of prolonged therapy with other immunomodulatory drugs. Although the frequency of administration can be variable, most patients would require IVIg, 2 gm/kg, every 6 to 8 weeks. In patients who have a CIDP phenotype but have diabetes and/or paraproteinemia, we would consider PE as an alternate first-line therapy and use long-term immune medications with steroids, azathioprine, or cyclosporine. MMN is an immune-mediated neuropathy that presents as progressive distal asymmetrical weakness predominantly in the upper extremities. Multifocal motor conduction block is the diagnostic hallmark, and most patients have elevated anti-GM1 antibodies. Unlike other diseases discussed in this chapter, MMN does not respond to PE or steroids and may in fact be made worse by these modalities. IVIg is unequivocally the first-line and long-term maintenance therapy of choice. The disease, however, may continue to progress slowly over many years despite this therapy. MG is the most common disorder affecting the neuromuscular junction. It is an autoimmune disorder caused by antibodies to the muscle acetylcholine receptors (AChRs) at the neuromuscular junction in voluntary muscles. Characteristic presentations include fluctuating weakness or fatigability of extraocular, bulbar, respiratory, or limb muscles. PE can produce a striking though temporary improvement in most patients with MG and is our preferred treatment for myasthenic crisis (respiratory muscle weakness requiring ventilation in MG) and in patients with severe myasthenic weakness. We use IVIg in lieu of PE only in patients where PE is not possible (for access reasons) or when there are relative contraindications. We have also used IVIg for MG in the following situations: (1) in a newly diagnosed myasthenic patient (not in crisis) during the time when immune drugs have not
had a chance to take effect; (2) mild MG exacerbations (secondary to changes of medications, infection, thyroid disease, and so forth) in patients otherwise on chronic stable medication regimens; and (3) in preparation for thymectomy. LEMS is an autoimmune disorder with pathogenic antibodies against voltage-gated calcium channel antibodies directed against the presynaptic terminals. Most patients present with weakness in the legs and generalized fatigue. In about 60% of the patients, the disorder is paraneoplastic, with small cell lung cancer being the most common underlying neoplasm. Treatment is individually tailored, taking into account the treatment of underlying cancer and response to aminopyridine drugs. In cases where no underlying malignancy is detected and the weakness is moderate, immunomodulation with either PE or IVIg may be considered. Given that chronic treatment is generally required, we prefer IVIg unless the patient has severe weakness requiring hospitalization, in which case we would treat with PE. Inflammatory myopathies include polymyositis and inclusion body myositis, both mediated by cytotoxic CD8+ T cells and dermatomyositis, mediated by complement. Polymyositis and dermatomyositis present with the subacute onset of progressive proximal muscle weakness. Inclusion body myositis is a more insidious onset of weakness in quadriceps (frequent falls) and forearm flexors. The diagnosis of the disease is confirmed by serum creatine kinase, electromyogram, and muscle biopsy. IVIg is an important mode of treatment for patients with dermatomyositis and polymyositis. We do not use this as a first-line therapy but as an adjunct to conventional immunosuppressive therapies. We do not use PE in these conditions. Inclusion body myositis is notoriously resistant to all immune manipulation. However, we do give a trial of IVIg for IBM patients since about 10% of the patients are responsive despite the reportedly negative trials. MS is an immune disease of white matter of the central nervous system. It is thought to be mediated by T-helper CD4+ autoreactive lymphocytes with activated macrophages, complement, and antibodies involved in the demyelination. A variety of pathologic patterns have been observed in autopsy specimens suggesting the existence of defined subtypes within the rubric of MS. Common symptoms include visual loss, double vision, numbness or tingling, weakness or fatigue, unsteady gait, urinary incontinence, and incoordination. IVIg has several effects on the immune system that could have a beneficial influence on disease processes in MS. A meta-analysis of four double-blind trials in relapsing-remitting MS showed a significant beneficial effect on the annual relapse, on the proportion of relapsefree patients, and a change in the Expanded Disability Status Scale (EDSS) score. We would use IVIg as an alternative treatment of relapsing-remitting MS in patients who do not tolerate or are unwilling to take the approved injectable interferons and glatiramer acetate. IVIg has not been shown to be efficacious in secondary progressive forms of MS. We would consider using PE only in a situation in which a patient has an acute,
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Choice of IVIg v. PE neurological condition
Myasthenic crisis Transverse myelitis MS severe relapse (not responding to steroids)
MMN Refractory PM, DM, IBM Stiff person, MG relapse MS (intolerant to interferons or glatiramer)
GBS, CIDP, MG, LEMS
PE
IVIG
Presence of IgA deficiency, renal dysfunction, CHF or previous thrombotic episodes
Absence of IgA deficiency, renal dysfunction, CHF or previous thrombotic episodes
PE
IVIg
FIGURE 1. Choice of intravenous immunoglobulin (IVIg) versus plasma exchange (PE) to treat a neurologic condition. MS, Multiple sclerosis; MMN, multifocal motor neuropathy; PM, polymyositis; DM, dermatomyositis; IBM, inclusion body myositis; MG, myasthenia gravis; GBS, Guillain-Barr syndrome; CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; LEMS, Lambert-Eaton myasthenic syndrome; CHF, congestive heart failure.
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severe relapse with persistent disability despite treatment with an extended course of corticosteroids. TM is a focal demyelinating event of the spinal cord. Unlike MS it is characterized by its lack of distribution in space and time. Classically it occurs only once (with recurrence being rare) and causes only focal damage (unlike the multitude of white matter lesions observed in patients diagnosed with MS). The other defining factor for this disease is its location within the spinal cord causing classic spinal syndromes depending on the location of disease. Sensory level, motor weakness, and bowel and bladder difficulties all are prominent features of this condition. There is evidence linking this condition to aberrant immune responses with associated abnormal cytokine levels and to various autoimmune conditions. We would use PE (to IVIg) for patients with moderate to severe TM (inability to walk, markedly impaired autonomic function, and sensory loss) if they have not responded to IV steroids. Stiff person syndrome is a rare neurologic disorder characterized by persistent and usually symmetrical rigidity of axial muscles with superimposed episodic painful spasms. An autoimmune basis for stiff person syndrome is suggested by its association with antibodies against glutamic acid decarboxylase in the serum and cerebrospinal fluid of many affected patients. These antibodies inhibit the activity of gamma aminobutyric acid, an inhibitory neurotransmitter. We consider immunomodulation with IVIg in patients whose response to diazepam or baclofen is limited.
The duration of the beneficial effects of immune globulin varies from 6 weeks to 1 year. Since diabetes is frequently present in patients with stiff person syndrome, close monitoring for renal functions is needed. We use PE only if there are relative contraindications to the use of IVIg. For other conditions, although IVIg or PE has been reported to be of use in refractory childhood epilepsy, Rasmussens encephalitis, Isaacs syndrome, vasculitis, acute disseminated encephalitis, paraneoplastic conditions, antiphospholipid syndrome, and TM, our experience for the use of either modalities in these conditions is too limited to offer any formal recommendations.
Treatment Algorithm
In general we tend to use IVIg more often than PE for autoimmune neurologic conditions (Figure 1). There are a variety of reasons for this, including relative safety, universal availability, and, in many cases, superior efficacy. Certain circumstances are relative contraindications to IVIg. These include previous hypersensitivity reactions, IgA deficiency, and concerns about excessive volume shifts in renal or cardiac disease. Contraindications for PE include line sepsis, preexisting coagulopathies, medical conditions that could be worsened by bleeding (e.g., large gastrointestinal bleeds, cerebral hemorrhages) and inability for a facility to properly place and care for a central line.
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Depression in Neurologic Disorders

Laura Marsh, M.D., and Paul Rosenberg, M.D.
Comorbid depressive syndromes figure prominently in neurologic disorders. Prevalence rates vary across neurologic conditions, affecting at least one third to one half of patients with chronic central nervous system disturbances such as epilepsy, multiple sclerosis, cerebrovascular accidents, and neurodegenerative diseases such as Parkinsons or Alzheimers disease. Peripheral nervous system disorders are also associated with depressive syndromes, especially when there is chronic pain. Depressive disorders often link to underlying brain pathology, but medication effects and psychosocial issues can also be important etiologic factors. Recognition of comorbid depressive disorders is critical for comprehensive management of the neurologic patient. In addition to causing suffering and despair, depressive disorders have significant adverse effects, contributing to further neurologic disability, caregiver strain, and reduced quality of life. There is also a risk of suicide in the setting of depression; this is of particular concern in multiple sclerosis and epilepsy, in which suicide attempts occur at higher rates than in the general population. Unfortunately, depressive disorders are often undetected in clinical neurologic practices. Even if the neurologist does not provide treatment for depression, its recognition is important since effective treatment of depression improves functioning, reduces excess morbidity, and influences management of the primary neurologic disorder.
Diagnosis
Distinguishing normal emotional variations and depressed feelings from a depressive disorder can be challenging. Proper diagnosis of a depressive syndrome requires clarification of the mood phenomena and their
time course and inquiry into associated nonmood cognitive and somatic changes. It is important to encourage patients to describe what mood symptoms they have and not just provide interpretations of why they feel a certain way. This is especially relevant because the term depression is frequently used when other states, such as disgust, anger, anxiety, apathy, and fatigue, may be more applicable. The clinical manifestations of depressive disorders in neurologic illnesses are generally the same as those for primary (idiopathic) depressive disorders. Core features of depressive syndromes include sadness, tearfulness, and an inability to enjoy oneself or take an interest in usual activities. Negative or pessimistic ruminations, especially about oneself, morbid thoughts about death (especially ones own), and inappropriate feelings of guilt are also common. Intellectual symptoms such as poor concentration and attention and physical symptoms such as aches and pains, disrupted sleep and appetite, and decreased energy are nonspecific but are usually worse when there is significant depression. Likewise, ineffective coping and poor adjustment occur in the absence of a depressive disorder but are invariably aggravated when the patient has a depressive disorder. Depressive disorders should be suspected in patients who report greater disability than is evident on examination. It is often helpful to interview a spouse, caretaker, or other informant who knows the patient well since poor insight and cognitive impairment are associated with depressive disorders. The differential diagnosis of depressive disturbances includes normal states of grief or demoralization, interpersonal difficulties, adjustment disorder, major depressive episode, nonmajor depressive syndrome, apathetic syndromes, anxiety disorders, bipolar disorder, pathologic tearfulness (emotionalism), depression secondary to a general medical condition, delirium, dementia, and substance abuse or intoxication. The neurologist needs to be aware of this differential, since primary neurologic symptoms can overlap with depressive symptoms and confound diagnosis and treatment planning. Table 1 lists common confounding symptoms. In general, major depressive episodes are circumscribed mood syndromes requiring the presence of five
TABLE 1 Common Neurologic Features that Mimic Depressive Phenomena

Neurologic Feature Bradykinesia Masked face Pathologic tearfulness Expressive aphasia or decreased verbal fluency Receptive aphasia Executive dysfunction Inattention Depressive Phenomena Psychomotor retardation Apathy; slow affective response Depressed, tearful affect Severe psychomotor retardation, apathy Decreased interest in social events, lack of motivation Impaired concentration and/or loss of interest Impaired concentration and/or loss of interest, indecisiveness Neurologic Disorders Parkinsons disease Parkinsons disease Progressive supranuclear palsy, multiple sclerosis, midbrain lesions, delirium Stroke, Alzheimers disease, frontotemporal dementia Stroke Dementias, delirium, medication toxicity Dementias, delirium, epileptic seizure, medication toxicity
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TABLE 2 Major Depressive Episode: Summary of DSM-IV Criteria
DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (Washington, DC, 2000, American Psychiatric Association).
of nine criteria most of the day, nearly every day for at least 2 weeks and not in the context of delirium or substance abuse. Table 2 provides the criteria for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Major Depressive Episode. Many depressed patients with primary neurologic disorders have fewer or less consistent symptoms, yet these nonmajor depressive disturbances, also referred to as minor or subsyndromal depression, still merit attention. Nonmajor depressive disorders are associated with increased functional disability, but their response to pharmacologic treatment is inconsistent. Depressive disturbances in neurologic illnesses can involve unique mood or affective changes that are disease specific and related to the underlying neurologic disorder or its treatment. Examples include irritability due to phenytoin, phenobarbital, or levetiracetam; discrete dysphoria manifest during an off state (nonmotor fluctuation) in a patient with Parkinsons disease; and ictal tearfulness (dacrystic seizures). Delirium (also termed toxic-metabolic encephalopathy) is one of the most common conditions to mimic mood disorders. Delirious patients who are somnolent or subdued often go unnoticed or are misdiagnosed as depressed. Delirium usually has an acute onset, and there is a fluctuating mental status and state of consciousness. By contrast, depressive disorders tend to have a more insidious onset and a stable mental state. Delirium may be due to the primary neurologic disorder itself (e.g., postictal delirium). More commonly, the delirium is due to other medical illness such as a urinary tract infection, pneumonia, metabolic abnormality, or effects of psychoactive medications such as opiates, anticholinergics, or benzodiazepines. Clinically significant depressive disturbances can be missed in the hubbub of a busy clinical practice where there tends to be a focus on physical signs and symptoms and treatment of the primary neurologic condition and diagnostic tests. Depressive symptom scales (e.g., Beck Depression Inventory or the Geriatric Depression Scale)
may help identify patients who need further assessment or track treatment response. Such tools do not substitute for careful history taking and consideration of the differential diagnosis, especially since many signs of depression are nonspecific and overlap with primary neurologic signs. Selection of depression rating scales, if used, may vary according to the neurologic disorder or degree of cognitive impairment (e.g., a clinician-rated scale for a patient with dementia rather than a self-report scale). Another diagnostic dilemma is that depression in neurologic illness may not always involve a primarily depressed mood. For example, patients with Alzheimers disease or related dementias may present with agitation and paranoia rather than complaints of feeling sad or blue. In such cases, the diagnosis of depression is based largely on the changes in motivation, enjoyment of activities, socialization, and psychomotor changes in sleep and energy. Clinicians can also miss the diagnosis of depression when they overidentify with the patient and assume that depression is a normal and inevitable reaction under the circumstances (e.g., who wouldnt be depressed if they have multiple sclerosis?) In fact, there is no medical condition in which all patients are depressed, and patients vary greatly in their resilience and flexibility in the face of disability and loss. Patients may also withhold information about mood changes, with stigma and limited education about the role of psychiatry in medical illnesses contributing to underdiagnosis.
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Treatment
Treatment of depression in neurologic illness depends on accurate diagnosis. Once the diagnosis of a depressive disorder is established, treatment is recommended if The patient has a depressive syndrome such as a Major Depressive Episode (see Table 2) or The patient has a sustained mood change that affects function. In neurologic disorders, consider emotional
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function as well as cognitive and motor functioning. Comparable to major depressive disorder, the clinician should look for a sustained and/or pervasive mood change over weeks, not due to a grief reaction, medical illness, or substance abuse. If a depressive syndrome requiring treatment is diagnosed, the choices are medications and psychosocial treatments. In clinical practice, there is a tendency to use medications as a primary treatment, but psychosocial interventions can be equally effective and safer. This is especially the case for nonmajor depressive disturbances. Watchful waiting is appropriate to determine whether the patient has persistent and pervasive depressive symptoms versus a more situational mood disturbance. ANTIDEPRESSANT MEDICATIONS Choice Table 3 lists the main antidepressant medications used to treat depressive disorders in patients with neurologic illness. There is little evidence that one antidepressant is more effective than any other, and the choice of antidepressants should be based on tolerability and side effects. Important side effects are sexual dysfunction, decreased sleep or increased sleep, decreased sedation or increased sedation, anxiety, gastrointestinal distress,
TABLE 3 Antidepressant Medications
Initial Dose, mg 10 25 10 10 5 37.5 75 7.5
confusion, and drug interactions. To comment further on Table 3, Selective serotonin reuptake inhibitors (SSRIs) are often used as first-line treatment. Among the SSRIs, fluoxetine should be used with caution due to its prolonged half-life and insidious increase in serum levels leading to side effects, particularly in fragile elderly patients. Amitriptyline is not recommended for routine treatment of depression. It has the most potent anticholinergic effects among the tricyclic antidepressants with concomitant side effects; its metabolite nortriptyline has similar efficacy and significantly less anticholinergic potency. Psychostimulants such as methylphenidate are probably underused. Although there are concerns of substance abuse, this is in fact uncommon in clinical practice. Psychostimulants, when effective, have a rapid onset of action and are especially helpful in patients with medical comorbidities who have fatigue, inattention, and lack of motivation and can enhance daily functioning. Duration of Treatment and Dosing Start at lowest dose possible (see Table 3), usually with an SSRI. In elderly patients, starting doses may be
Drug Fluoxetine Sertraline Paroxetine Citalopram Escitalopram Venlafaxine (long acting) Bupropion (long acting) Mirtazapine
Class SSRI SSRI SSRI SSRI SSRI SNRI Dopamine uptake blockade Alpha2 antagonist; modulates serotonin and norepinephrine release SNRI TCA Psychostimulant
Recommended Maximum Dose, mg 20-40 200 20-40 20-40 20 225 450 60
Side Effects GI distress, anxiety, insomnia GI distress, anxiety, insomnia GI distress, anxiety, insomnia, confusion, dry mouth GI distress, anxiety, insomnia GI distress, anxiety, insomnia Hypertension Seizures at supratherapeutic doses only Weight gain, sedation
Comment Long acting with increased risk of side effects May be calming and helpful for sleep
Enantiomer of citalopram More stimulating than SSRIs Dopaminergic effect may also be more stimulating than SSRIs Use at bedtime; used as hypnotic Best choice among tricyclic antidepressants due to favorable side effect profile May be helpful for apathy and fatigue; limited research base
Nortriptyline
10
100
Constipation, dry mouth Insomnia, dyskinetic movements
Methylphenidate, Dexedrine
20 (divided at breakfast and midday)
SSRI, Selective serotonin reuptake inhibitor; SNRI, serotonergic and norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant.
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even lower. Increase the dose at an increment of the lowest dose every 1 to 2 weeks until (1) the patient improves, (2) the maximum dose is achieved, or (3) side effects ensue. If side effects limit dose, decrease by one dose increment and continue treatment. A therapeutic trial of antidepressant should last for a total of 8 to 12 weeks at the maximum dose tolerated. Titrate to clinical effect; in younger patients this results in doses similar to those recommended for medically healthy adults. Elderly or brain-damaged patients generally exhibit both clinical response and side effects at lower antidepressant doses. If the patient does not improve after a full therapeutic trial of an antidepressant medication, switch medications and consider switching to a medication of a different class. Most important, patients should be reassessed in no less than 1 month and preferably in 2 weeks. Many patients have persistent depressive syndromes because they are undertreated, and clinical response to the antidepressant has not been evaluated. Psychosocial Support Neurologic patients often suffer an accumulation of losses due to disability, and support and advice in the neurology clinic can be done briefly and often to good effect. A basic principle is that adaptive coping strategic will facilitates resilience. The clinicians role is to encourage and identify opportunities for adaptation and maximal function. Some principles of adaptive support include the following: Identify the patients strengths and encourage them to use these strengths to overcome obstacles and solve problems (i.e., physical disability may be countered by pursuing intellectual and social pursuits, cognitive disability may be countered by improving socialization and exercise, and so forth). Help patients redefine goals that are realistic and achievable. Prescribe rehabilitative therapies (i.e., physical, occupational, speech, cognitive, and recreational). These therapies focus on maximizing or maintaining realworld function and help build confidence and solve problems in daily living that can lead to demoralization if unsolved. They are an invaluable component of care to patients with neurologic illnesses, especially when a depressive disorder has contributed to increased disability and physical deconditioning. Encourage opportunities for active coping and emotional adaptation, such as exercise, educational programs, patient support groups, advocacy programs, and other social relationships. Note the constantly shifting need for psychological and physical adaptation in life and in the patients neurologic illness. For example, multiple sclerosis often forces changes in family relationships due to physical dependency, incontinence, changes in sexual function, and so forth. Acquisition of new deficits triggers new responses, and adaptationspositive or negativeensue. Persistent and pervasive depressive symptoms, despite efforts to maximize coping, often suggest a need for pharmacologic therapy to address the
depressive syndrome. Patients may be resistant to pharmacotherapy because they can live with how things are or dont believe in taking medicines for depression. It may be important to remind such patients of the significant adverse impact of depressive disorders on their neurologic syndrome, including that an ongoing depressive disorder trumps coping.
Indications for Psychiatric Referral and Consultation

Indications for psychiatric referral and consultation include the following: Suicidal thoughts, feelings, or attempt Presence of isolated depressive emotions without other symptoms may be appropriate for psychotherapy Significant diagnostic uncertainty or lack of mood improvement after two therapeutic trials of antidepressant medication Need for more frequent follow-up of psychiatric symptoms than can be managed in a neurology practice 17
Conclusions
Patients with neurologic disorders frequently suffer from depressive disorders that add significantly to functional disability and difficulties coping with the primary neurologic disorder. The overlap of depressive and neurologic symptoms contributes to under-recognition of depressive disorders. Since treatment of depressive disorders affects neurologic treatment, the possibility of a comorbid depressive disorder should be considered in the assessment of all patients. Antidepressant medications and supportive psychosocial interventions can treat depression in patients with neurologic disorder, decrease stress for patients and caregivers, and improve coping skills and rehabilitative potential. SUGGESTED READING
Baldwin RC, Anderson D, Black S, et al, Faculty of Old Age Psychiatry Working Group, Royal College of Psychiatrists: Guideline for the management of late-life depression in primary care, Int J Geriatr Psychiatry 18:829-838, 2003. Reich SG, Marsh L: Ten most commonly asked questions about the psychiatric aspects of Parkinsons disease, Neurologist 9:50-56, 2003. Salzman C: Mood disorders. In Coffey CE, Cummings JL, editors: Textbook of geriatric neuropsychiatry, Washington, DC, 2000, American Psychiatric Press. (Note: Practicing neurologists may find the entire volume useful because other chapters address neuropsychiatric aspects of specific neurologic conditions, e.g., Alzheimers disease, Parkinsons disease, stroke, and so forth.) Williams LS, Jones WJ, Shen J, et al: Prevalence and impact of depression and pain in neurology outpatients, J Neurol Neurosurg Psychiatry 74:1587-1589, 2003.
PATIENT RESOURCES
Alzheimers Association National Office 225 N. Michigan Ave., Fl. 17 Chicago, IL 60601
430
Depression in Neurologic Disorders Depression and Related Affective Disorders Association (DRADA) 2330 West Joppa Road, Suite 100 Lutherville, MD 21093 Phone: 410-583-2919 E-mail: drada@jhmi.edu http://www.drada.org/
24/7 Nationwide Contact Center Helpline Phone: 800-272-3900 http://www.alz.org/ American Neuropsychiatric Association 700 Ackerman Road, Suite 625 Columbus, OH 43202 Phone: 614-447-2077 Fax: 614-263-4366 E-mail: anpa@osu.edu http://www.anpaonline.org/
Index
Note: Page numbers followed by f refer to illustrations; page numbers followed by t refer to tables.
A Abacavir, in HIV infection, 147t Abetalipoproteinemia, 297, 298t, 380t Abscess brain, 169172, 170f fungal, 161162, 168 treatment of, 117t, 169171, 170f epidural, 171172 spinal, 171172 Absence seizures, 3033 atypical, 30, 33 diagnosis of, 3031 management of, 3133, 32t33t typical, 30 Absence status epilepticus, 31 Acetazolamide in absence seizures, 33, 33t in Andersen-Tawil syndrome, 406 in cerebellar ataxia, 301 in Chiari malformation I, 95 in hyperkalemic periodic paralysis, 403, 404f in hypokalemic periodic paralysis, 405, 405f in idiopathic intracranial hypertension, 334 Acoustic neuroma, 109 Acquired immunodeficiency syndrome. See Human immunodeficiency virus (HIV) infection Activa stimulator, in dystonia, 306 Acute confusional state, 2t Acute disseminated encephalomyelitis, corticosteroids in, 420t Acute prolonged vertigo, 56, 5t Acyclovir, in herpes virus infection, 121 Adefovir, in HIV infection, 147t Adrenocorticotrophic hormone, in infantile spasms, 23, 25, 106 Adrenoleukodystrophy, 298299 Adrenomyeloneuropathy, 298t Adult neuronal ceroid-lipofuscinosis, 297 Agammaglobulinemia, enteroviral infection in, 141142 Aggression, in Huntingtons disease, 294 Agitation, in Alzheimers disease, 313 AIDS. See Human immunodeficiency virus (HIV) infection Airway in intracerebral hemorrhage, 222 in subarachnoid hemorrhage, 227 Akathisia, restless legs syndrome vs., 409 Akinetic mutism, 2t Albumin, in plasma exchange, 422423 Alcohol chronic ingestion of, 374t intoxication with, 343, 344t withdrawal from, 343344, 344t
Alefacept, in inflammatory myopathy, 402 Almotriptan, in migraine, 69t Alprazolam, in essential tremor, 291 Alprostadil, in erectile dysfunction, 200 Altered states of consciousness, 14, 2t, 3t. See also Unconsciousness Alternative medicine in dystonia, 306 in multiple sclerosis, 194 Alzheimers disease, 311314 abuse in, 314 agitation in, 313 anxiety and, 313 depression and, 313 hallucinations in, 313314 incontinence in, 314 initial therapy in, 311312, 312t long-term management of, 314 misdiagnosis of, 315 neglect in, 314 psychosis in, 313314 sleep disturbance in, 312313 Amanita phalloides poisoning, 355t, 357358 Amantadine in cerebellar ataxia, 301 in Huntingtons disease, 292, 293f in Parkinsons disease, 283f, 284 Amaurosis fugax, in giant cell arteritis, 233 American Spinal Injury Association, 241 Aminoglycosides, ototoxicity of, 8 Amiodarone, toxicity of, 375t376t Amitriptyline in amyotrophic lateral sclerosis, 327t in childhood headache prevention, 79, 80t in diabetic polyneuropathy, 371 in painful neuropathy, 367t in postherpetic neuralgia, 86 Amnesia, in Korsakoffs psychosis, 346 Amphetamine, in attention deficit hyperactivity disorder, 117t Amphotericin B, 164165, 164t in cryptococcal meningitis, 152, 153t intrathecal, 165 lipid formulations of, 165 nephrotoxicity of, 165 Amprenavir, in HIV infection, 147t Amyloidosis, 377, 379 Amyotrophic lateral sclerosis, 322328, 325f anxiety in, 326327 clinical manifestations of, 322, 323t counseling in, 323 depression in, 326327 diagnosis of, 322323, 323t, 324t epidemiology of, 322 frontotemporal degeneration and, 315, 316 gait in, 324
Amyotrophic lateral sclerosis (Continued) nutrition in, 326 occupational therapy in, 324 patient questions about, 327328 pharmacotherapy in, 323324, 325f, 326t, 327t physical therapy in, 324 respiratory therapy in, 326 speech therapy in, 325326 Analphalipoproteinemia, 380t Andersen-Tawil syndrome, 406407, 406f Anemia in giant cell arteritis, 233 in malaria, 184 of autonomic failure, 12 Anesthesia dolorosa, 83 Aneurysm, intracranial, 228232 endovascular obliteration of, 228, 229, 230, 230f rupture of. See Hemorrhage, subarachnoid unruptured, 229, 230f Angiitis, 235236. See also Vasculitis clinical features of, 236237, 237t diagnosis of, 237238, 237t treatment of, 238239, 238t Angiofibromata, in tuberous sclerosis complex, 103104 Angiography in arteriovenous malformation, 231, 231f in primary vasculitis, 237 in subarachnoid hemorrhage, 225 in unconsciousness, 2 Angioma, in neurofibromatosis 1, 99 Angiomyolipomata, in tuberous sclerosis complex, 104 Angiotensin blockers, orthostatic hypotension with, 10t Angiotensin-converting enzyme (ACE) inhibitors, orthostatic hypotension with, 10t Antegren, in inflammatory myopathy, 402 Anterior ischemic optic neuropathy, 233 Anti-CV2 antibodies, 277 Anti-Hu antibodies, 275t, 276, 277 Anti-integrins, in inflammatory myopathy, 402 Antibiotics in brain abscess, 117t, 169171, 170f in epidural abscess, 172 in Lyme disease, 177179, 180f in meningitis, 156158, 157t inhibitory quotient of, 156 minimal inhibitory concentration of, 156
431 1
432
Index Anxiety Alzheimers disease and, 313 in amyotrophic lateral sclerosis, 326327 in Parkinsons disease, 286t nightmares and, 17 vertigo and, 5, 5t Aorta, coarctation of, in neurofibromatosis 1, 101 Apathy, in Huntingtons disease, 294 Apneustic breathing, 4 Apomorphine, in Parkinsons disease, 285 Arbovirus infection, 129137 bunyavirida, 129, 132t133t diagnosis of, 130, 136 flavivirida, 129, 131t132t management of, 136137 reovirida, 129, 134t135t symptomatic, 130 togavirida, 129, 133t134t Arousal parasomnias, 1314, 13t, 15t, 17 Arrhythmias in Andersen-Tawil syndrome, 406, 407 in myotonic muscular dystrophy, 395 in unconsciousness, 1 Arsenic, 374t Artemether, in malaria, 183 Artemisinin, in malaria, 183 Arteriovenous fistula, 232 Arteriovenous malformation, 231, 231f Arteritis, giant cell, 232235, 233f. See also Giant cell arteritis Artesunate, in malaria, 183 Arthritis, in Lyme disease, 177 Ash leaf spots, 103 Aspergillus infection, 162t, 164t, 168 Aspiration in brain abscess, 171 in ischemic stroke, 215216, 217 Aspirin in stroke prevention, 217 in Sturge-Weber syndrome, 110 in transient ischemic attack, 210212, 212t Assistive communication devices, in amyotrophic lateral sclerosis, 325326 Astemizole, drug interactions of, 166t Astrocytoma anaplastic, 257, 257f, 262, 263f, 264 fibrillary, 256257, 257f in neurofibromatosis 1, 101 in tuberous sclerosis complex, 104, 105 low-grade, 256257, 264 pilocytic, 256257, 257f retinal, 104 Ataxia autoimmune disorders and, 300 cerebellar, 295302 acquired, 295t, 299300 autoimmune-mediated, 300 autosomal dominant, 198t, 295296, 295t, 296t, 297t autosomal recessive, 198t, 295t, 296297, 296t, 297t counseling in, 301 differential diagnosis of, 295, 295t idiopathic, 300 management of, 300301 mitochondrial, 198t, 295t, 296t, 297t, 299 X-linked, 198t, 295t, 296t, 297299, 297t demyelinating lesions and, 299 FGF14 generelated, 296, 296t, 297t Friedreichs, 296297, 296t, 297t, 298t, 391 heavy metal exposures and, 299 in idiopathic cerebellar degeneration, 300 Ataxia (Continued) in mitochondrial disorders, 198t, 295t, 296t, 297t, 299 in multisystem atrophy, 300 in Wernickes disease, 345 infection and, 299 paraneoplastic, 298t, 299 Purkinje cell degeneration in, 300 spinocerebellar, 295296, 296t, 297t vitamin deficiencies and, 299 Ataxia-telangiectasia, 297 Ataxic breathing, 4 Atomoxetine in attention deficit hyperactivity disorder, 117t, 118 in cataplexy, 22 Atovaquone-proguanil, in malaria, 183 Atrial fibrillation cardioembolism and, 218219, 220 transient ischemic attack and, 210, 212 Atrial myxoma, cardioembolism and, 221 Atrial thrombus, cardioembolism and, 219 Attention deficit hyperactivity disorder, 114119 evaluation of, 114, 115t, 116f in autism, 113 in Sturge-Weber syndrome, 110 learning disability in, 118 Tourettes syndrome and, 307, 309 treatment of, 114118, 117t Autism, 111114 diagnosis of, 111112 differential diagnosis of, 112 genetic factors in, 111 laboratory testing for, 112 screening for, 111 treatment of, 112113, 113f Autoimmune disorders. See also Multiple sclerosis; Myasthenia gravis ataxia and, 300 vertigo and, 5t Autonomic dysreflexia, after spinal cord injury, 244, 244t Autonomic neuropathy, in HIV infection, 150 Axonotmesis, 246f, 247, 247t, 251 Azathioprine in inflammatory myopathy, 399 in multiple sclerosis, 191 in myasthenia gravis, 389, 390 Azoles, 166, 166t B B virus infection, 126t, 129 Bacillus anthracis infection, 155 Back pain. See also Failed back syndrome in epidural spinal cord compression, 268 Baclofen in amyotrophic lateral sclerosis, 327t in cerebellar ataxia, 300 in dystonia, 305 in Tourettes syndrome, 308t Bacteroides fragilis infection, 158 Bannwarths syndrome, 178 Barbiturate, in migraine, 68t Barbiturate coma, in status epilepticus, 48 Bariatric surgery, in idiopathic intracranial hypertension, 334 Batsons plexus, 268 Beckers muscular dystrophy, 394 Behavior disorders, in frontotemporal degeneration, 316, 317, 318, 318t Bells palsy, 122, 123t, 207208, 208f corticosteroids in, 420t Lyme disease vs., 181
Antibodies anti-AChR, 387 anti-B. burgdorferi, 177 anti-CV2, 277 anti-ganglioside, 300 anti-gliadin, 300 anti-Hu, 275t, 276, 277 anti-MUSH, 387 paraneoplastic, 274276, 275t, 277 Anticholinergics, in Parkinsons disease, 284285 Anticoagulation in brain tumorrelated thromboembolism, 262 in ischemic stroke, 214215 Anticonvulsants discontinuation of, 38 drug interactions of, 38 folate with, 38 in autism, 113, 113f in brain tumor, 261262 in childhood headache prevention, 79, 80t in complex partial seizures, 3438, 35t36t, 37t in frontotemporal degeneration, 317, 317t in generalized seizures, 40, 4244, 42t, 43f in glossopharyngeal neuralgia, 8182 in migraine, 6869, 69t in mitochondrial encephalopathy, 339 in neonatal encephalopathy, 9091 in pharmacoresistant epilepsy, 4445 in postherpetic neuralgia, 8486 in pregnancy, 38 in Sturge-Weber syndrome, 109110, 109f in trigeminal neuralgia, 8182 in tumor-related seizures, 256 teratogenicity of, 38 Antidepressants, 427429, 428t in attention deficit hyperactivity disorder, 117t in cataplexy, 22 in Chiari malformation I, 95 in childhood headache prevention, 79, 80t in complex regional pain syndromes, 65 in diabetic polyneuropathy, 371, 371t in familial neuropathy, 380381 in painful neuropathy, 367t, 368 in postherpetic neuralgia, 86 orthostatic hypotension with, 10t Antiemetics, in migraine, 68t Antiepileptics. See Anticonvulsants Antifungals, 163166 Antihypertensives, orthostatic hypotension with, 10t Antioxidants in cerebellar ataxia, 301 in mitochondrial disorders, 340t, 341 Antipsychotics in autism, 113, 113f in frontotemporal degeneration, 317, 317t in Huntingtons disease, 294 Antipyretics, in febrile seizures, 28 Antiretrovirals drug interactions with, 148t in HIV dementia, 146147, 147t Antivenims jellyfish, 357 snake, 357 stonefish, 357 Antivirals in herpes virus infection, 121 in postherpetic neuralgia, 84
Index Benign paroxysmal positional vertigo, 5t, 68, 7f Benzodiazepines abuse of, 350 in cocaine overdose, 350 in dystonia, 305 in ethanol withdrawal, 343344, 344t in febrile seizures, 25, 28 in gamma-hydroxybutryic acid withdrawal, 351 in Huntingtons disease, 293 in sleep terrors, 14 in vertigo, 8 Benztropine mesylate, in Parkinsons disease, 284 Beta blockers in childhood headache prevention, 79, 80t in migraine, 69, 70t orthostatic hypotension with, 10t Bilateral vestibular hypofunction, 8 Bilevel positive airway pressure, in amyotrophic lateral sclerosis, 326 Biopsy brain in glioma, 261 in primary vasculitis, 237238 in prion diseases, 321 muscle, in inflammatory myopathy, 402 skin, in painful neuropathy, 365 temporal artery, 234 Biots breathing, 4 Black widow spider, 355t, 358 Blackwater fever, 184 Bladder disorders in Alzheimers disease, 314 in multiple sclerosis, 193, 193t, 197198, 198f in Parkinsons disease, 286t, 287 in spinal cord injury, 243, 244 Blastomyces dermatitidis infection, 162t, 164t Blindness in giant cell arteritis, 232233 in idiopathic intracranial hypertension, 333 Blood ethanol levels in, 343, 344t lead levels in, 352, 353t Blood-brain barrier, in meningitis, 156 Blood-CSF barrier, in meningitis, 156 Blood pressure high. See Hypertension in intracerebral hemorrhage, 222224, 224t in ischemic stroke, 215 in subarachnoid hemorrhage, 226, 230 low. See Hypotension; Neurogenic orthostatic hypotension Blood transfusion in malaria, 184 in subarachnoid hemorrhage, 226 Bone disorders after peripheral nerve injury, 252 in neurofibromatosis 1, 99t, 101 Borreliosis, Lyme. See Lyme disease Botulinum toxin in dystonia, 305 in essential tremor, 291 in migraine, 69 poisoning with, 374t Bradycardia, in unconsciousness, 1 Brain. See also Brain tumors abscess of, 169172, 170f fungal, 161162, 168 treatment of, 117t, 169171, 170f Brain (Continued) biopsy of in glioma, 261 in primary vasculitis, 237238 in prion diseases, 321 fungal infection of, 161162, 162t, 168 resuscitation of, 4 Brain tumors, 255265. See also specific tumors differential diagnosis of, 256t incidence of, 255 location of, 255, 256t metastatic, 265267 prognosis for, 260261 seizures and, 256 staging of, 260 supportive care in, 261262 thromboembolic disease and, 262 treatment of, 255 Brainstem, glioma of, 257258 Bran, in neurogenic orthostatic hypertension, 10 Breathing apneustic, 4 ataxic, 4 Biots, 4 Cheyne-Stokes, 4 in intracerebral hemorrhage, 222 Brevetoxin, 356 British antilewisite, 353354, 353t, 354t Bromocriptine, in restless legs syndrome, 411t Bruns-Garland syndrome, 372 Bunyaviridae infection, 129, 132t133t diagnosis of, 130, 136 management of, 136137 Buprenorphine, in opiate dependence, 347 Bupropion in attention deficit hyperactivity disorder, 117t in depression, 428t Burns, peripheral nerve injury and, 250 1,4-Butanediol abuse, 351 C C-reactive protein, in giant cell arteritis, 233 Cabergoline, in restless legs syndrome, 411412, 411t Cache Valley virus infection, 133t Caf` au lait spots, 98, 99, 99t e Caffeine, in neurogenic orthostatic hypertension, 10 Calcinosis, in dermatomyositis, 402 Calcium channel blockers in migraine, 69, 70t orthostatic hypotension with, 10t Calcium disodium versenate, 353354, 353t, 354t California virus encephalitis, 133t CAMPATH, 400 Cancer brain. See Brain tumors metastatic. See Metastases paraneoplastic syndromes in, 274279. See also Paraneoplastic neurologic syndromes Candida infection cerebral, 162t, 163, 164t meningeal, 162t, 163, 164t, 167168 Capsaicin in complex regional pain syndromes, 65 in diabetic polyneuropathy, 371 in postherpetic neuralgia, 86
433
Carbamazepine drug interactions of, 166t in complex partial seizures, 35t, 37, 37t in familial neuropathy, 381 in glossopharyngeal neuralgia, 81 in REM sleep behavior disorder, 16 in restless legs syndrome, 411t in trigeminal neuralgia, 81 Carbidopa/levodopa in dystonia, 304 in Huntingtons disease, 292 in Parkinsons disease, 282284, 283f, 283t in restless legs syndrome, 411, 411t orthostatic hypotension with, 10t Cardiac output, in subarachnoid hemorrhage, 227 Cardioembolism, 218221, 219f atrial fibrillation and, 218219, 220 atrial myxoma and, 221 atrial thrombi and, 219 depressed ejection fraction and, 219220 endocarditis and, 220221 nonbacterial thrombotic endocarditis and, 221 patent foramen ovale and, 221 postmyocardial infarction, 220 primary prevention of, 218220 prosthetic valves and, 219, 220 secondary prevention of, 220221 Cardiomyopathy in Beckers muscular dystrophy, 394 in Duchennes muscular dystrophy, 394 in myotonic muscular dystrophy, 395 Carnitine deficiency of, 340t, 341 in mitochondrial disorders, 340t, 341 Carotid artery stenosis, transient ischemic attack with, 210, 211212 Carotid endarterectomy, 217 transient ischemic attack with, 210 Carpal tunnel syndrome, 383384, 384f Caspofungin, 163 Cataplexy, 18. See also Narcolepsy diagnosis of, 19, 20f treatment of, 22 Cataracts, in myotonic muscular dystrophy, 395, 396 Catheterization, urinary, in multiple sclerosis, 197198 Cavernous malformation, 232 Ceftriaxone, in Lyme disease, 179 Central neurogenic hyperventilation, 4 Cephalosporins, in bacterial meningitis, 157, 157t Cerebellar ataxia. See Ataxia, cerebellar Cerebellar atrophy, in HIV infection, 153 Cerebral perfusion pressure, in intracerebral hemorrhage, 223 Cerebral salt wasting in CNS fungal infection, 168 in subarachnoid hemorrhage, 226, 227228, 230 Cerebrospinal fluid (CSF) examination of in bacterial meningitis, 155 in brain abscess, 169 in chronic inflammatory demyelinating polyneuritis, 361 in febrile seizures, 26 in fungal infection, 162, 163t in leptomeningeal metastases, 271, 272 in Lyme disease, 177 in malaria, 182 in neurosarcoidosis, 202
434
Index Chronic inflammatory demyelinating polyneuropathy, 361363, 361f, 424, 425f Chronic paroxysmal hemicrania, 72f, 72t, 73 Cidofovir, in herpes virus infection, 121 Ciguatera, 354, 355t, 356, 374t Circulation, in intracerebral hemorrhage, 222 Cisapride, drug interactions of, 166t Cisplatin, toxicity of, 375t Citalopram, in depression, 428t Clarithromycin, in cerebral toxoplasmosis, 151 Claudication, in giant cell arteritis, 232 Clindamycin, in cerebral toxoplasmosis, 151, 151t Clonazepam in absence seizures, 33t in dystonia, 305 in REM sleep behavior disorder, 16 in restless legs syndrome, 411t in Tourettes syndrome, 308t Clonidine in attention deficit hyperactivity disorder, 117t, 118 in autism, 113, 113f in opiate dependence, 348 in restless legs syndrome, 411t in Tourettes syndrome, 308t Cluster headache, 6970 chronic, 7173, 72t, 73t corticosteroids in, 420t Coasting, 373 Cocaine abuse, 349350 Coccidioides immitis infection, 162t, 164t, 167 Codeine abuse, 347348 Coenzyme Q10 deficiency of, 298t, 299, 338t in cerebellar ataxia, 301 in Huntingtons disease, 294 in mitochondrial disorders, 340t, 341 in Parkinsons disease, 282 Coffee, in neurogenic orthostatic hypertension, 10 Cognition disorders of. See Dementia in multiple sclerosis, 194 Colchicine, toxicity of, 372, 376t Colorado tick fever, 134t135t Coma, 14, 2t, 3t. See also Unconsciousness in CNS fungal infection, 168 pentobarbital, in status epilepticus, 48 Compartment syndromes, 250 Complex partial seizures, 3339 absence seizures vs., 30 diagnosis of, 34 treatment of, 3438, 35t36t, 37t Complex regional pain syndromes, 6466, 64f, 252 Compression garments in neurogenic orthostatic hypotension, 1011 in spinal cord injury, 243 Computed tomography in brain abscess, 169, 171 in epidural spinal cord compression, 268 in failed back syndrome, 59 in intracerebral hemorrhage, 221 in ischemic stroke, 213 in myasthenia gravis, 388 in neonatal encephalopathy, 89 in normal-pressure hydrocephalus, 335 in paraneoplastic neurologic syndromes, 277 in Sturge-Weber syndrome, 108 in subarachnoid hemorrhage, 225, 228 in unconsciousness, 2 Computed tomography myelography in syringomyelia, 96 in transverse myelitis, 195 COMT inhibitors, in Parkinsons disease, 283f, 284 Cone snails, 355t, 357 Confusional arousals, 1314, 13t, 15t Confusional state, 2t Congenital cataracts, facial dysmorphism neuropathy (CCFDN), 380t Congenital hypomyelinating neuropathy, 377 Connective tissue disease, transverse myelitis in, 195 Consciousness altered states of, 14, 2t, 3t. See also Unconsciousness level of, 3 Constipation in acute transverse myelitis, 196t in Duchennes muscular dystrophy, 394 in multiple sclerosis, 193 in spinal cord injury, 243 in subarachnoid hemorrhage, 227 Contractures, in Duchennes muscular dystrophy, 393394 Coproporphyria, 380t Coral snake, 355t, 357 Corneal response test, 3 Corticobasal-ganglionic degeneration, Parkinsons disease vs., 281 Corticosteroids, 416421 adverse effects of, 417418, 417t contraindications to, 418 dosing schedule for, 416 guidelines for, 420421 immune cell effects of, 416 in acute disseminated encephalomyelitis, 420t in bacterial meningitis, 157, 420t in Bells palsy, 207208, 208f, 420t in brain tumors, 255, 265 in carpal tunnel syndrome, 383384 in cerebral vasculitis, 419t in chronic inflammatory demyelinating polyneuritis, 361362, 361f in cluster headache, 72, 73t, 420t in dermatomyositis, 398, 401f, 419t in Duchennes muscular dystrophy, 393, 420t in epidural spinal cord compression, 269 in giant cell arteritis, 234, 419t in head trauma, 420t in infantile spasms, 420t in inflammatory myopathy, 398, 401f in Lambert-Eaton myasthenic syndrome, 419t in leptomeningeal metastases, 272 in migraine, 420t in multiple sclerosis, 420t in myasthenia gravis, 419t in neurosarcoidosis, 205206, 205f, 419t in optic neuritis, 186187, 419t in polymyositis, 398, 401f, 419t in primary angiitis, 238, 238t in spinal cord injury, 241, 420t in subarachnoid hemorrhage, 226 in systemic lupus erythematosus, 419t in transverse myelitis, 195 in tuberculous meningitis, 160f, 161 in vasculitic neuropathy, 419t in vestibular neuritis, 420t lymphocytopenia with, 416 misuse of, 420421 muscle atrophy and, 417t, 418 osteoporosis and, 417418, 417t
Cerebrospinal fluid (CSF) (Continued) in paraneoplastic neurologic syndromes, 277 in primary vasculitis, 237 in prion diseases, 321 in spinal epidural abscess, 172 in syphilis, 173 in transverse myelitis, 195 in tuberculous meningitis, 158159 in unconsciousness, 2 in viral meningitis, 138 hypocretin in, 20 pressure of. See Intracranial hypertension Cerebrotendinous xanthomatosis, 297, 298t Cervical spondylosis, 6164 classification of, 62 manifestations of, 6162 outcomes of, 6364 pathophysiology of, 6263 treatment of, 63 Cervical traction, in cervical spondylitic radiculopathy, 63 Channelopathy, 296, 296t, 297t Charcoal lavage, 2 Charcot-Marie-Tooth disease, 377382, 378t, 381f Chelation therapy, in lead poisoning, 353354, 353t, 354t Chemotherapy in brain tumors, 255, 262264, 263f, 267 in epidural spinal cord compression, 270 in leptomeningeal metastases, 272274, 273f intrathecal, 272, 273f toxicity of, 375t Cheyne-Stokes breathing, 4 Chiari malformation, 9297 type I, 9293, 93t complicating conditions in, 94, 94t evaluation of, 9394, 94t management of, 9597, 97f posterior fossa decompression in, 9596, 96t Chiari zero, 94 Childhood absence epilepsy, 3031 Children arousal parasomnias in, 1314, 13t, 15t, 17 confusional arousals in, 1314, 13t, 15t headache in, 7780, 78f, 80t prevention of, 7980, 80t treatment of, 7779, 78f meningitis in, 77 migraine in, 77 nightmares in, 17 psychogenic seizures in, 53 sleep terrors in, 14, 15t sleepwalking in, 14, 15t China white, 347348 Chiropractic therapy, in cervical spondylosis, 63 Chloroquine, toxicity of, 376t Cholinesterase inhibitors, in frontotemporal degeneration, 316317 Chorea, Huntingtons, 292, 293f Chromosome 1p, 261, 264 Chromosome 19q, 261, 264 Chronic daily headache, 7076 definition of, 70 epidemiology of, 70 evaluation of, 70, 71t, 72f long-duration, 72f, 7476, 74t, 75t, 76t medication overuse headache and, 7476, 75t, 76t secondary, 70, 71t short-duration, 7174, 73t
Index Corticosteroids (Continued) preparations of, 417 side effects of, 255 Countermaneuvers, in neurogenic orthostatic hypotension, 10 Cowchocks syndrome, 380t Coxsackievirus infection, 138141 Cranial nerve examination, in unconsciousness, 1, 3 Craniopharyngioma, 259 Creatine kinase, in amyotrophic lateral sclerosis, 322, 324t Cruetzfeldt-Jakob disease, 319 diagnosis of, 320321 treatment of, 321 variant, 320 Cryptococcus neoformans infection, 151152, 153t, 162t, 164t, 167 Cyclophosphamide drug interactions of, 238239 in chronic inflammatory demyelinating polyneuritis, 363 in inflammatory myopathy, 399 in multiple sclerosis, 192 in neurosarcoidosis, 205f, 206 in primary angiitis, 238239, 238t in transverse myelitis, 196 Cyclosporine in inflammatory myopathy, 399 in myasthenia gravis, 389, 390391 in neurosarcoidosis, 205f, 206 Cyproheptadine, in childhood headache prevention, 79, 80t Cysts, renal, in tuberous sclerosis complex, 104 Cytarabine, in leptomeningeal metastases, 272 Cytomegalovirus infection, 124t125t, 127128 congenital, 128 in HIV infection, 153154 peripheral nervous system, 125t, 128 retinal, 124t125t, 128, 154 D Daclizumab, in multiple sclerosis, 192 Dapsone, toxicity of, 376t Datura spp., 355t, 357 Decerebrate (extensor) posturing, 4 Decorticate (flexor) posturing, 4 Decubitus ulcers ischemic stroke and, 217 spinal cord injury and, 243 Deep brain stimulation in cluster headache, 73 in essential tremor, 291292 in Parkinsons disease, 288 Deep vein thrombosis ischemic stroke and, 217 spinal cord injury and, 243 Dehydration, in malaria, 184 Dejerine-Sottas syndrome, 377 Delavirdine, in HIV infection, 147t Delirium, 2t, 427 Delirium tremens, 344, 344t Dementia in Alzheimers disease, 311314, 312t in frontotemporal degeneration, 315319, 317t, 318t in human immunodeficiency virus infection, 144147, 145f in Parkinsons disease, 286t, 287 REM sleep behavior disorder and, 16 semantic, 315, 318t Demyelinating polyneuropathy, inflammatory, 361363, 361f in HIV infection, 149150 Demyelination. See also Multiple sclerosis ataxia and, 299 Dentatorubral-pallidoluysian atrophy, 296, 296t, 297t Depression, 426430 after peripheral nerve injury, 253 Alzheimers disease and, 313 clinical manifestations of, 426, 426t diagnosis of, 426427, 426t, 427t differential diagnosis of, 426, 426t in amyotrophic lateral sclerosis, 326327 in frontotemporal degeneration, 316 in Huntingtons disease, 293 in multiple sclerosis, 191, 192193, 193t in Parkinsons disease, 286287, 286t psychiatric referral for, 429 psychosocial support in, 429 subsyndromal, 427 treatment of, 427429, 428t Dermatomyositis, 396 corticosteroids in, 419t cytokines in, 402 immunopathology of, 397 immunosuppressants in, 399400 intravenous immunoglobulin in, 400 paraneoplastic, 278, 278t prognosis for, 400 treatment of, 397402, 401f, 424, 425f Desipramine, in painful neuropathy, 367t Desmopressin (DDAVP) in multiple sclerosis, 198 in neurogenic orthostatic hypotension, 11t Detoxification, in opiate dependence, 348 Dexamethasone in brain tumors, 255, 265 in epidural spinal cord compression, 269 in migraine, 68t in primary angiitis, 238, 238t in tuberculous meningitis, 160f, 161 Dexedrine, in depression, 428t Dextromethorphan abuse, 350351 Dextrose, thiamine with, 345346 Diabetes mellitus amyotrophy in, 372 cranial nerve III palsy in, 373 in myotonic muscular dystrophy, 395 lumbosacral radiculoplexus neuropathy in, 372 polyneuropathy in, 369370 pain treatment in, 370371, 371t toxin avoidance in, 371372, 372t proximal neuropathy in, 372 thoracoabdominal neuropathy in, 372373 Diastat, in febrile seizures, 25, 28 Diazepam, in febrile seizures, 25, 28 Dichlorphenamide in Andersen-Tawil syndrome, 406407 in hyperkalemic periodic paralysis, 403, 404f in hypokalemic periodic paralysis, 405, 405f Didanosine in HIV infection, 147t mitochondrial disorders with, 339 toxicity of, 376t Diet in Guillain-Barr syndrome, 359 in idiopathic intracranial hypertension, 334 in neurogenic orthostatic hypertension, 910 in Parkinsons disease, 285 Diffuse infiltrative lymphocytosis syndrome, in HIV infection, 150
435
Diffuse Lewy body disease, Parkinsons disease vs., 281 Digitalis, in idiopathic intracranial hypertension, 334 Dihydroergotamine in cluster headache, 72, 73t in migraine, 67, 68t Diltiazem, in migraine, 69, 70t Dimenhydrinate, in migraine, 68t Dimercaprol, 353354, 353t, 354t Dimercaptosuccinic acid (DMSA), 353354, 353t, 354t Disequilibrium, 4, 5, 5t definition of, 5 in Chiari malformation I, 93 treatment of, 8 Distal sensory polyneuropathy, in HIV infection, 149, 149f, 150t Distal symmetrical peripheral neuropathy, 363, 365 Diuretics in hyperkalemic periodic paralysis, 403, 404f in idiopathic intracranial hypertension, 334 orthostatic hypotension with, 10t Divalproex sodium, in migraine, 69t Dix-Hallpike maneuver, 7 Dizziness, 4. See also Disequilibrium; Vertigo Domoic acid, 356 Donepezil, in Alzheimers disease, 311312, 312t Dopamine, in intracerebral hemorrhage, 223t Dopamine agonists, in Parkinsons disease, 283f, 283t, 284 Dopamine D2 agonists, orthostatic hypotension with, 10t Dopamine receptor antagonists, in dystonia, 304305 Dopamine2-receptor blockers, in Tourettes syndrome, 308t Doxycycline, in malaria, 183, 183t Driving complex partial seizures and, 34 narcolepsy and, 22 Drugs. See also specific drugs abuse of, 346352 anticonvulsant drug interactions with, 38 antiretroviral interactions with, 148t azole interactions with, 166, 166t dyskinesias with, 285 implantable pump for, 61 neuropathy with, 371372, 372t, 373, 375t376t nightmares and, 17 orthostatic hypotension with, 9, 10t ototoxicity of, 8 REM sleep behavior disorder and, 16 Dry eyes, in Parkinsons disease, 286t Duchennes muscular dystrophy, 393394, 420t Dysarthria, 328 Dyskinesias, drug-induced, in Parkinsons disease, 285 Dysphagia, 328331 clinical examination of, 329331, 330f, 331f in inclusion body myositis, 400, 402 in myotonic muscular dystrophy, 395 in stroke, 215216, 217, 329331, 331f oromotor examination in, 329, 330f treatment of, 331 videofluoroscopic studies in, 330331, 331f
436
Index Encephalitis (Continued) enteroviral, 138141, 140f herpes simplex virus, 122, 123t neonatal, 122, 123t St. Louis, 131t sarcoid, 202t, 204 Toxoplasma, 151, 151t, 152f varicella zoster virus, 124t, 127 West Nile, 130 Western equine, 134t Encephalomyelitis, disseminated, corticosteroids in, 420t Encephalomyelopathy, demyelinating, 299 Encephalomyopathy, mitochondrial, 337341, 338t, 340t. See also Mitochondrial disorders Encephalopathy febrile seizures vs., 26 Hashimotos, 320 in Lyme disease, 177 malarial, 181184, 182t, 183t neonatal, 8991, 90t hypoxic-ischemic, 90 severity of, 90, 90t Wernickes, 345 Endocarditis, cardioembolism and, 220221 Endolymphatic hydrops (Menieres disease), 5t, 6 Entacapone, in Parkinsons disease, 283f, 284 Enterovirus infections, 137142 encephalitic, 138141, 140f epidemiology of, 137, 138t meningeal, 137138, 138t, 139f paralytic, 141 persistent, 141142 rhombencephalitic, 138141 Entrapment neuropathy, 382386, 383t at carpal tunnel, 383384, 384f at elbow, 384385, 384f at fibular head, 385386 at thoracic outlet, 385 at uncommon sites, 385, 386t at upper arm, 385386 Enzyme-linked immunoabsorbent assay, in Lyme disease, 177 Ependymoma, 258, 258f Ephedrine, in neurogenic orthostatic hypotension, 12 Epidural abscess, 171172 Epilepsy, 4245, 42t, 43f, 44f. See also Seizures febrile seizures vs., 26, 2728 in neurofibromatosis 1, 100 myoclonic, ataxia and, 297, 298t pharmacoresistant, 4445 psychogenic nonepileptic seizures vs., 50t, 5152, 51t risk for, afebrile seizures and, 2728, 28t status, 4549, 47f Epley maneuver, 7, 7f Epstein-Barr virus infection, 126t, 129 Erectile dysfunction, in multiple sclerosis, 193, 199200, 199t Ergotamines drug interactions of, 166t in cluster headache, 73t in migraine, 67 Ergotamines, in migraine, 68t Eros-CTD, 200 Erythema migrans, 177, 177t Erythrocyte sedimentation rate, in giant cell arteritis, 233 Erythropoietin, in chronic anemia of autonomic failure, 11t, 12 Escherichia coli infection, meningeal, 158 Esmolol, in intracerebral hemorrhage, 223t Etanercept, in inflammatory myopathy, 402 Ethambutol, in tuberculous meningitis, 160, 160f Ethanol in essential tremor, 291 intoxication with, 343, 344t withdrawal from, 343344, 344t Ethopropazine, in Parkinsons disease, 284 Ethosuximide, in absence seizures, 31, 32t Excessive daytime sleepiness, in Parkinsons disease, 285286, 286t Exercise in frailty prevention, 415 in neurogenic orthostatic hypotension, 10 Exophthalmos, in neurofibromatosis 1, 100 Extensor (decerebrate) posturing, 4 Eye(s) dry, in Parkinsons disease, 286t examination of, in idiopathic intracranial hypertension, 332333 pain in, in optic neuritis, 185 spontaneous opening of, in coma, 3 Eyelids, ptosis of, in mitochondrial disorders, 339340 F Fabrys disease, 380t Face angiofibromata of, 103104 pain in. See Glossopharyngeal neuralgia; Trigeminal neuralgia port-wine stain of, 109110 Facial nerve, decompression of, 208 Facial palsy idiopathic (Bells palsy), 108f, 207208 in Lyme disease, 178, 181 in neurosarcoidosis, 202t, 204 Facioscapulohumeral muscular dystrophy, 396 Failed back syndrome, 5861 evaluation of, 5859, 59f psychological evaluation in, 5859 radiography in, 59 treatment of, 5961 Fainting. See Disequilibrium; Vertigo Familial amyloidotic neuropathy, 377, 379, 380t Familial neuropathy, 377382, 378t379t, 380t Fampridine, in transverse myelitis, 196 Fanconis syndrome, in mitochondrial disorders, 340 Fansidar, in malaria, 183, 183t Fatigue in acute transverse myelitis, 196t in cerebellar ataxia, 300 in Lyme disease, 177 in multiple sclerosis, 192, 193t Febrile seizures, 2529 differential diagnosis of, 26 duration of, 27 epilepsy vs., 26, 2728, 28t evaluation of, 26, 26f immediate response to, 2526 long-term outcome of, 2627, 29 prevention of, 28 recurrence of, 27, 27t, 29 resources on, 29 risk for, 25, 25t viral infection vs., 26 Fecal incontinence in Alzheimers disease, 314 in multiple sclerosis, 193
Dystonia, 302306 baclofen in, 305 benzodiazepines in, 305 botulinum toxin injection in, 305 carbidopa/levodopa in, 304 cervical, 305 classification of, 302, 302t clinical evaluation of, 302303 counseling in, 304 denervation in, 305 diagnosis of, 302304 dopamine receptor antagonists in, 304305 etiology of, 303t focal, 302, 302t generalized, 302, 302t multifocal, 302, 302t physical therapy in, 304 segmental, 302, 302t surgery, 305306 trihexyphenidyl in, 305 E Eastern coral snake, 355t, 357 Eastern equine encephalitis, 133t134t Echovirus infection, 138141 Ecstasy, 349 Edema in ischemic stroke, 217 pulmonary, in opiate overdose, 347 Edrophonium test, 388 Efavirenz, in HIV infection, 147t Electrical burns, peripheral nerve injury and, 250 Electroencephalography in absence seizures, 30 in autism, 113 in complex partial seizures, 34 in dystonia, 303 in generalized seizures, 40, 42 in infantile spasms, 23 in neonatal encephalopathy, 90 in prion diseases, 321 in psychogenic nonepileptic seizures, 51, 51t in status epilepticus, 49 in unconsciousness, 2 Electromyography in amyotrophic lateral sclerosis, 322, 323t in corticosteroid-induced muscle atrophy, 418 in dystonia, 303 in entrapment neuropathy, 383 in inflammatory myopathy, 397 in myasthenia gravis, 388 in peripheral nerve injury, 245, 248 in REM sleep behavior disorder, 16 Electron microscopy, in corticosteroidinduced muscle atrophy, 418 Electroneurography, in Bells palsy, 207 Eletriptan, in migraine, 67, 69t Embolism cardiac, 218221, 219f pulmonary, subarachnoid hemorrhage and, 227 Empyema, subdural, 171 Enalapril, in intracerebral hemorrhage, 223t Encephalitis brainstem, 138141 California, 133t coxsackievirus, 138141 cytomegalovirus, 125t, 153154 Eastern equine, 133t134t echovirus, 138141
Index Feeding, orthostatic hypotension after, 12 Felbamate, in complex partial seizures, 35t, 37 Fentanyl abuse of, 347348 in painful neuropathy, 367t Ferrous sulfate in chronic anemia of autonomic failure, 12 in restless legs syndrome, 410411, 411t Fertility, after spinal cord injury, 244 Fever, in subarachnoid hemorrhage, 225226, 230 FGF14 generelated ataxia, 296, 296t, 297t Fiber, in neurogenic orthostatic hypertension, 10 Fibrin glue, in peripheral nerve injury, 250 Fibroblast growth factor 14 gene mutation, ataxia and, 296, 296t, 297t Fibroma, ungual, 104 Fibula, in neurofibromatosis 1, 101 Fish poisoning, 354, 355t, 356, 357, 374t Fistula, arteriovenous, 232 FK-506, in inflammatory myopathy, 399 Flaccidity, 4 Flaviviridae infection, 129, 131t132t diagnosis of, 130, 136 management of, 136137 Flexor (decorticate) posturing, 4 Fluconazole, 164t, 166, 166t in cryptococcal meningitis, 153t Flucytosine, 165 in cryptococcal meningitis, 152, 153t Fludrocortisone in neurogenic orthostatic hypotension, 11, 11t in Parkinsons disease, 287 in subarachnoid hemorrhage, 226 Fluid intake, in neurogenic orthostatic hypertension, 9 Fluid therapy in delirium tremens, 344, 344t in malaria, 184 in subarachnoid hemorrhage, 226, 227, 228 in unconsciousness, 1 Flumazenil, in unconsciousness, 2 Flunarizine, in essential tremor, 291 Flunitrazepam abuse, 350 Fluorescent treponemal antibodyabsorbed (FTA-ABS) test, 174, 174f, 175f Fluorodeoxyglucose positron emission tomography, in paraneoplastic neurologic syndromes, 277 Fluoxetine in cataplexy, 22 in childhood headache prevention, 79, 80t in depression, 428t Fluphenizine, in Tourettes syndrome, 308t FMR1 gene, 298 Folate (folic acid) in giant cell arteritis, 235 in mitochondrial disorders, 340t with antiepileptic drugs, 38 Foscarnet, in herpes virus infection, 121 Fosphenytoin in glossopharyngeal neuralgia, 82 in intracerebral hemorrhagerelated seizures, 224, 224t in status epilepticus, 46, 48 in trigeminal neuralgia, 82 Fragile X syndrome, 112 Fragile X tremor/ataxia syndrome, 297298, 298t Frailty, 413416 continuum of, 413, 414f latent phase of, 415 mortality and, 416 pathophysiology of, 413, 414f prevention of, 414415 screening for, 413, 415t stressor management in, 415416 treatment of, 414415 Freckles, 99, 99t Friedreichs ataxia, 296297, 296t, 297t, 298t, 391 Frontotemporal degeneration, 315319 animal models of, 319 behavior disorders in, 316, 317, 318, 318t clinical features of, 315316 pathology of, 316 pulmonary function in, 318319 treatment of, 316319, 317t Frovatriptan, in migraine, 67, 69t Fundus photography, in idiopathic intracranial hypertension, 333 Fungal infection, 161168 cerebral, 161162, 168 clinical presentation of, 161162, 162t complications of, 168 diagnosis of, 162163, 163t meningeal, 161, 162t, 167168 primary vs. secondary, 161 seizures with, 168 treatment of, 163166, 164t, 166t Furosemide, in idiopathic intracranial hypertension, 334 G Gabapentin in childhood headache prevention, 79, 80t in cluster headache, 73t in complex partial seizures, 35t, 37, 37t in complex regional pain syndromes, 65 in diabetic polyneuropathy, 371, 371t in essential tremor, 291 in familial neuropathy, 381 in glossopharyngeal neuralgia, 81 in migraine, 69t in painful neuropathy, 366, 367t in postherpetic neuralgia, 8485 in restless legs syndrome, 411t in trigeminal neuralgia, 81 Gait ataxic. See Ataxia in amyotrophic lateral sclerosis, 324 in cervical spondylosis, 62 Galantamine, in Alzheimers disease, 311312, 312t Gamma-butyrolactone abuse, 351 Gamma-hydroxybutyric acid (GHB) abuse, 351 Gangiclovir, in herpes virus infection, 121 Ganglion blocks, in complex regional pain syndromes, 65 Gangliosides, antibodies to, ataxia and, 300 Gastric dilation, in Duchennes muscular dystrophy, 394 Gaze, in altered states of consciousness, 3 Gene therapy, in brain tumor, 264 Generalized anxiety disorder, Tourettes syndrome and, 307308 Generalized epilepsy and febrile seizures plus (GEFS+), 26 Generalized seizures, 3942 counseling for, 40, 42 diagnosis of, 3940 recurrent, 4245, 42t, 43f treatment of, 40, 41f, 4244
437
Gentamicin, in Menieres disease, 6 Geriatric patient. See Frailty Germ cell tumors, 259, 260f Gerstmann-Strussler-Scheinker syndrome, 320 GHB (gamma-hydroxybutyric acid) abuse, 351 Giant axonal neuropathy, 380t Giant cell arteritis, 232235, 233f biopsy in, 234 corticosteroids in, 419t diagnosis of, 233234, 234t differential diagnosis of, 233 ocular manifestations of, 233, 234 treatment of, 234235, 235f Glasgow Coma Scale, 3 Glatiramer acetate, in multiple sclerosis, 190t, 191 Glaucoma in port-wine stain, 110 in Sturge-Weber syndrome, 108 Gliadin, antibodies to, ataxia and, 300 Glioblastoma, 257, 257f, 262 Glioma, 260265 brainstem, 257258 clinical presentation of, 261 in neurofibromatosis 1, 99t, 100101 prognosis for, 260261 staging of, 260 supportive care in, 261262 thromboembolic disease and, 262 treatment of, 262264, 263f Globoid cell leukodystrophy, 380t Glossopharyngeal neuralgia, 8183, 82f Glucose, in ischemic stroke, 215 Glue sniffing, 374t Glycopyrrolate, in amyotrophic lateral sclerosis, 327t Growth hormone deficiency, in mitochondrial disorders, 340 Guanfacine in attention deficit hyperactivity disorder, 117t, 118 in Tourettes syndrome, 308t Guillain-Barr syndrome, 126t, 359360, 423424 Guyons canal syndrome, 384385, 384f Gyromitrin, 355t H Hallucinations hypnagogic, 19, 22 hypopompic, 19 in Alzheimers disease, 313314 in Parkinsons disease, 286t, 288 Halstead-Reitan Test Battery, 52 Hamartomata cardiac, 104 cortical, 104, 105 retinal, 104 Hand-foot-and-mouth disease, 138, 139 Hashimotos encephalopathy, 320 Head impulse (head thrust) test, 5 Head injury corticosteroids in, 420t psychogenic nonepileptic seizures and, 53 Head-up tilt, in neurogenic orthostatic hypotension, 10 Headache acute, persistent, 72f, 76 Chiari, 9293, 93t cluster, 6970 chronic, 7173, 72t, 73t daily, 7076. See also Chronic daily headache
438
Index Herpes zoster, 8386, 85f, 123t124t, 127 clinical presentation of, 8384 treatment of, 84, 85f Herpes zoster ophthalmicus, 127 Hexacarbon exposure, 374t Hexosaminidase A deficiency, 297, 298t Histoplasma capsulatum infection, 162t, 164t, 167 HMG CoA reductase inhibitors, in stroke prevention, 212 Horners syndrome, 3, 247 Human herpesvirus 6 infection, 125t126t, 128129 Human immunodeficiency virus (HIV) infection, 144154 antiretroviral therapy in, 146147 autoimmune diseases in, 151 autonomic neuropathy in, 150 cerebellar atrophy in, 153 cryptococcal meningitis in, 151152, 153t, 167 cytomegalovirus infection in, 128, 153154 dementia in, 144147, 145f diffuse infiltrative lymphocytosis syndrome in, 150 distal sensory polyneuropathy in, 149, 149f inflammatory demyelinating neuropathy in, 149150 lymphoma in, 153 meningeal, 144 mononeuritis multiplex in, 149 myelopathy in, 148149 myopathy in, 150 neurosyphilis in, 154 progressive multifocal leukoencephalopathy in, 153 progressive polyradiculopathy in, 150 syphilis and, 173174 Toxoplasma encephalitis in, 151, 151t, 152f Human leukocyte antigen, in narcolepsy, 18 Huntingtons disease, 292294 behavioral care in, 293294 cognitive impairment in, 292 motor impairment in, 292, 293f neuroprotection in, 294 Hydralazine, in intracerebral hemorrhage, 223t Hydrocephalus in cryptococcal meningitis, 152, 167 in intracerebral hemorrhage, 223 in neurosarcoidosis, 206 in subarachnoid hemorrhage, 228, 229 normal-pressure, 299, 335337, 335f Hydrochlorothiazide, in hyperkalemic periodic paralysis, 403, 404f Hydrocodone abuse of, 347348 in painful neuropathy, 367t in restless legs syndrome, 411t Hydromorphone abuse of, 347348 in restless legs syndrome, 411t Hydrops, endolymphatic (Menieres disease), 5t, 6 Hydroxychloroquine, in neurosarcoidosis, 205f, 206 Hyperglycemia, in ischemic stroke, 215 Hyperparasitemia, in malaria, 184 Hypersomnolence, in myotonic muscular dystrophy, 395 Hypertension after spinal cord injury, 244, 244t in intracerebral hemorrhage, 222224, 224t in neurofibromatosis 1, 101 in subarachnoid hemorrhage, 226 in unconsciousness, 1 intracranial, idiopathic, 331335, 332t diagnosis of, 332333, 332t treatment of, 333335 supine, orthostatic hypotension and, 12 treatment of, in stroke prevention, 212 Hyperthermia in ischemic stroke, 215 in unconsciousness, 1 MDMA-related, 349 Hyperventilation, neurogenic, central, 4 Hypnic headache, 74 Hypocretin (orexin), 18, 20 Hypoglycemia in ethanol intoxication, 343 in malaria, 184 Hypokalemia, in delirium tremens, 344 Hypomelanotic macules, in tuberous sclerosis complex, 103 Hyponatremia in delirium tremens, 344 in subarachnoid hemorrhage, 227228, 230 Hypoparathyroidism, in mitochondrial disorders, 340 Hypotension drug-related, 9, 10t in Guillain-Barr syndrome, 359 in intracerebral hemorrhage, 222224, 224t in unconsciousness, 1 orthostatic in Parkinsons disease, 286t, 287 neurogenic, 813. See also Neurogenic orthostatic hypotension Hypothermia, in unconsciousness, 1 Hypothyroidism, in mitochondrial disorders, 340 Hypoxia, in ischemic stroke, 216 I Ibuprofen, in migraine, 68t Idiopathic cerebellar degeneration, 300 Idiopathic intracranial hypertension, 331335, 332t diagnosis of, 332333, 332t treatment of, 333335 Imipramine, in attention deficit hyperactivity disorder, 117t Immobilization, in spinal cord injury, 241 Immunoblot, in Lyme disease, 177 Immunocompromised patient. See also Human immunodeficiency virus (HIV) infection cytomegalovirus infection in, 125t, 128 herpes simple virus infection in, 123t126t, 126 Immunoglobulin intravenous, 421422 adverse reactions to, 422 contraindications to, 425 dosage for, 422 in agammaglobulinemia, 142 in chronic inflammatory demyelinating polyneuritis, 361f, 362 in dermatomyositis, 400 in Guillain-Barr syndrome, 360 in inclusion body myositis, 400 in multiple sclerosis, 192 in myasthenia gravis, 389, 391392 in polymyositis, 400
Headache (Continued) hypnic, 74 in children, 7780, 78f, 80t in giant cell arteritis, 232 in glioma, 261 in idiopathic intracranial hypertension, 333 in meningitis, 77 in Sturge-Weber syndrome, 110 in subarachnoid hemorrhage, 224 in West Nile virus infection, 136 migraine, 6769, 68t, 69t vestibular, 5t, 6 rebound, 7476, 75t, 76t in children, 80 tension-type, 76 Hearing in Bells palsy, 207 in Menieres disease, 6 in mitochondrial disorders, 340 in vertigo, 5 Heart hamartomata of, 104 rhabdomyomata of, 104 Heart failure in Duchennes muscular dystrophy, 394 in subarachnoid hemorrhage, 230231 in tuberous sclerosis complex, 104 Hematocrit, in subarachnoid hemorrhage, 226 Hematoma evacuation of, 223 volume of, 222 Hemicrania continua, 72f, 73 Hemoglobin, in subarachnoid hemorrhage, 226 Hemophilus influenzae infection, 155158, 157t Hemorrhage in arteriovenous malformation, 231, 231f intracerebral, 221224 complications of, 224, 224t diagnosis of, 221222 evaluation of, 222224, 223f intracranial pressure in, 223224, 223t management of, 222224, 223f, 224t seizures with, 224, 224t ventriculostomy in, 223 subarachnoid, 224228, 225t, 226t, 229231 complications of, 227228, 230231 etiology of, 224 grade of, 116t, 225, 225t hydrocephalus in, 228, 229 management of, 225227 prognosis for, 225, 225t rebleeding in, 225, 226, 228 seizures in, 226 sentinel hemorrhage in, 224 vasospasm in, 227 Heparin in brain tumorrelated thromboembolism, 262 in ischemic stroke, 214215 in spinal cord injury, 243 Hereditary motor and sensory neuropathy, 377382, 379t Hereditary neuralgic amyotrophy, 380t Hereditary sensory neuropathy, 377, 378t Heroin abuse, 347348 Herpes B virus infection, 126t, 129 Herpes simplex virus infection, 121126, 122t126t encephalitic, 122, 123t facial nerve, 122, 123t meningeal, 122, 123t
Index Immunoglobulin (Continued) in West Nile virus infection, 136 indications for, 422, 423425, 423t, 425f mechanisms of action of, 422 preparations of, 421422, 422t rabies, 144 Immunotherapy in brain tumor, 264 in paraneoplastic neurologic syndromes, 276 Impaired glucose toleranceassociated neuropathy, 369370 Implantable drug pump, in failed back syndrome, 61 Inclusion body myositis, 397 cytokines in, 402 immunopathology of, 397 prognosis for, 400 treatment of, 400, 401f, 424, 425f Indinavir drug interactions with, 148t in HIV infection, 147t Indomethacin in chronic paroxysmal hemicrania, 73 in cluster headache, 73t in hemicrania continua, 73 Infantile spasms, 2325, 24f corticosteroids in, 420t in tuberous sclerosis complex, 105106 Infectious mononucleosis, 126t, 129 Infiximab, in inflammatory myopathy, 402 Inflammatory demyelinating polyneuropathy, 361363, 361f in HIV infection, 149150 Inflammatory myopathy, 396403, 401f clinical features of, 396397 corticosteroids in, 398, 401f diagnosis of, 397 failed treatment of, 402 immunopathology of, 397 immunosuppressants in, 399400, 401f prognosis for, 400 treatment of, 397402, 401f, 424, 425f vs. corticosteroid-induced muscle atrophy, 418 Infliximab, in neurosarcoidosis, 205f, 206 Inhibitory quotient, 156 Injury head corticosteroids in, 420t psychogenic nonepileptic seizures and, 53 peripheral nerve, 244253. See also Peripheral nerve injury sleepwalking and, 14 spinal cord, 241244. See also Spinal cord injury Insect bite, erythema migrans vs., 177, 177t Insomnia fatal, 320 in Alzheimers disease, 312313 in Parkinsons disease, 285286, 286t Interferon-, in arboviral infection, 136 Interferon beta-1a in inflammatory myopathy, 402 in multiple sclerosis, 187189, 188f, 190191, 190t Intracerebral hemorrhage, 221224, 223f, 224t Intracranial hypertension, idiopathic, 331335, 332t diagnosis of, 332333, 332t treatment of, 333335 Intracranial pressure idiopathic elevation of, 331335, 332t in brain tumor, 256 in CNS fungal infection, 167, 168 in cryptococcal meningitis, 167 in intracerebral hemorrhage, 223224, 223t in ischemic stroke, 216217 in neurosarcoidosis, 206 Intubation, in Guillain-Barr syndrome, 359 Iron deficiency, in restless legs syndrome, 409 Irritability, in Huntingtons disease, 294 Isoniazid, in tuberculous meningitis, 159, 160f Isosorbide dinitrate, orthostatic hypotension with, 10t Itraconazole, in cryptococcal meningitis, 153t J Jamestown Canyon virus infection, 133t Jellyfish, 355t, 357 Joint disorders, after peripheral nerve injury, 252 Juvenile absence epilepsy, 3031, 33 Juvenile myoclonic epilepsy, 3031, 33 K Karnofsky scale, 96t Kearns-Sayre syndrome, 298t, 299, 338t, 339, 340 Ketamine abuse, 350351 Kidneys amphotericin B effects on, 165 angiomyolipomata of, 104 cysts of, 104 in idiopathic intracranial hypertension, 333334 in mitochondrial disorders, 340 Klebsiella infection, 158 Korsakoffs psychosis, 345346 Krabbes leukodystrophy, 380t Kufs disease, 297 L La Crosse virus infection, 132t133t Labetalol, in intracerebral hemorrhage, 223t Labyrinth, infarction of, 5, 5t Labyrinthitis, 56, 5t Lafora disease, 297 Lambert-Eaton myasthenic syndrome, 274, 276, 278, 278t treatment of, 419t, 424, 425f Lamivudine, in HIV infection, 147t Lamotrigine in absence seizures, 31, 32t33t, 33 in complex partial seizures, 35t, 37, 37t, 38 in glossopharyngeal neuralgia, 81 in migraine, 69t in trigeminal neuralgia, 81 Laser therapy, in port-wine stain, 110 Lateral femoral cutaneous neuropathy, 386t Latrotoxins, 355t, 358 Lead poisoning, 352354, 374t chelation therapy in, 353354, 353t, 354t Learning disability in attention deficit hyperactivity disorder, 118 in neurofibromatosis 1, 100 in Sturge-Weber syndrome, 110 Leber hereditary optic neuropathy, 338t, 339 Leighs syndrome, 298t, 299, 338t, 339, 340 Lennox-Gastaut syndrome, 31, 33
439
Leptomeninges lymphoma of, 271 metastases to, 270274, 273f evaluation of, 271 signs and symptoms of, 271 treatment of, 271274, 273f Leucovorin, in leptomeningeal metastases, 272 Leukoencephalitis, sarcoid, 202t, 204 Levetiracetam in complex partial seizures, 35t, 37, 37t in glossopharyngeal neuralgia, 82 in migraine, 68, 69t in trigeminal neuralgia, 82 in tumor-related seizures, 256 Levodopa. See also Carbidopa/levodopa in REM sleep behavior disorder, 16 Lidocaine in diabetic polyneuropathy, 371 in glossopharyngeal neuralgia, 82 in painful neuropathy, 366367, 367t in postherpetic neuralgia, 86 in trigeminal neuralgia, 82 Light-headedness, 4. See also Disequilibrium; Vertigo Limb girdle muscular dystrophy, 396 Lisch nodules, in neurofibromatosis 1, 99t, 100 Listeria monocytogenes infection, 158 Lithium, in cluster headache, 70, 73, 73t Liver transplantation, in amyloidosis, 379 Locked-in syndrome, 2t Lorazepam in amyotrophic lateral sclerosis, 327t in Huntingtons disease, 293 in malaria-related seizures, 184 in neonatal encephalopathy, 91 in status epilepticus, 46 LP shunt, in idiopathic intracranial hypertension, 334 Lumbar facet denervation, in failed back syndrome, 60 Lumbar puncture. See also Cerebrospinal fluid (CSF) in idiopathic intracranial hypertension, 334 in normal-pressure hydrocephalus, 336 Lungs lymphangiomatosis of, 104 small-cell cancer of anti-Hu antibodies in, 275t, 276, 277 Lambert-Eaton myasthenic syndrome in, 274, 276 Lyme disease, 176181 amyotrophic lateral sclerosis vs., 322 arthritis in, 177 clinical manifestations of, 177, 177t diagnosis of, 176, 177178, 177t, 179t, 180f encephalopathy in, 177 erythema migrans in, 177, 177t facial palsy in, 177, 181 fatigue in, 177 inflammation in, 179180 laboratory testing in, 177 meningitis in, 177 misdiagnosis of, 180181 possible, 181 radiculoneuropathy in, 177 travel history in, 177 treatment of, 178181, 180f Lymphangiomatosis, pulmonary, in tuberous sclerosis complex, 104 Lymphocytes, corticosteroid effects on, 416
440
Index Menadiol diphosphate, in mitochondrial disorders, 340 Menieres disease (endolymphatic hydrops), 5t, 6 Meningioma, in neurofibromatosis 2, 109 Meningitis bacterial, 155158 clinical aspects of, 155 corticosteroids in, 420t diagnosis of, 155 pathophysiology of, 156 treatment of, 156158, 157t cryptococcal, 151152, 153t, 162t, 164t, 167 febrile seizures vs., 26 fungal, 161, 162t diagnosis of, 162163, 163t treatment of, 164t, 167168 headache in, 77 hemorrhagic, 155 herpes simplex virus, 122, 123t HIV, 144 in Lyme disease, 177 meningococcal, 155158, 157t pneumococcal, 155158, 157t sarcoid, 202, 202t, 204 streptococcal, 155158, 157t tuberculous, 158161 diagnosis of, 158159, 159f multidrug-resistant, 160, 160f treatment of, 159161, 160f varicella zoster virus, 124t, 127 viral, aseptic, 137138, 138t, 139f Lyme disease vs., 181 West Nile, 130 Meningoencephalitis, varicella zoster virus, 124t, 127 Mental retardation in myotonic muscular dystrophy, 395 in Sturge-Weber syndrome, 110 in tuberous sclerosis complex, 105, 106 Meperidine abuse, 347348 Meralgia paresthetica, 386t Mercaptoethane sulfonate, in primary angiitis, 238 Mercury poisoning, 299 Merosin deficiency, 380t Mesna, in primary angiitis, 238 Metachromatic leukodystrophy, 297, 298t, 380t Metastases brain, 265267 leptomeningeal, 270274, 273f spinal, 268270, 269f Methadone in opiate dependence, 347 in postherpetic neuralgia, 86 Methamphetamine abuse, 348349 Methazolamide, in Chiari malformation I, 95 Methotrexate in giant cell arteritis, 234235 in inflammatory myopathy, 399 in leptomeningeal metastases, 272 in multiple sclerosis, 191 in neurosarcoidosis, 205f, 206 Methsuximide, in absence seizures, 33, 33t Methylcellulose, in neurogenic orthostatic hypertension, 10 Methylenedioxymethamphetamine, 349 3-Methylfentanyl abuse, 347348 Methylphenidate in attention deficit hyperactivity disorder, 117t in autism, 113, 113f in depression, 428t Methylprednisolone in acute prolonged vertigo, 6 in epidural spinal cord compression, 269 in giant cell arteritis, 234 in multiple sclerosis, 417 in neurosarcoidosis, 205206, 205f in optic neuritis, 186187 in primary angiitis, 238, 238t in spinal cord injury, 241 in transverse myelitis, 195 Methysergide, in cluster headache, 70, 73, 73t Metoclopramide, in migraine, 68t Metronidazole, in bacterial meningitis, 157t, 158 Mexiletine in hyperkalemic periodic paralysis, 404 in myotonic muscular dystrophy, 395 Midazolam, in status epilepticus, 48 Midodrine in neurogenic orthostatic hypotension, 1112, 11t in Parkinsons disease, 287 Migraine, 6769 acute therapy for, 67, 68t, 69t chronic, 72f, 74, 74t corticosteroids in, 420t in children, 77 in Sturge-Weber syndrome, 110 preventive therapy for, 6769, 69t transformed, 74, 74t in children, 80 transient ischemic attack vs., 209, 210t vestibular, 5t, 6 MINGIE (mitochondrial neurogastrointestinal encephalomyopathy) syndrome, 338t, 339, 340 Minimal inhibitory concentration, 156 Ministroke, 209 Minnesota Multiphasic Personality Inventory, in psychogenic nonepileptic seizures, 52 Mirtazapine in depression, 428t in Huntingtons disease, 293 Mitochondrial disorders, 337341, 338t, 340t ataxia in, 198t, 295t, 296t, 297t, 299 counseling in, 341 drug-induced, 339 genetics of, 337 treatment of, 339341, 340t Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome, 298t, 299, 338, 338t, 340 Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome, 338t, 339, 340 Mitoxantrone, in multiple sclerosis, 190t, 191192 Mobilization, after spinal cord injury, 243 Modafinil, in narcolepsy, 2021, 21t Monoclonal antibodies in multiple sclerosis, 192 in neurosarcoidosis, 205f, 206 Mononeuritis multiplex, in HIV infection, 149 Mood disorders. See also Depression in cerebellar ataxia, 301 Motor examination, in unconsciousness, 1, 34 Mucormycosis, 162, 162t, 164t Multifocal motor neuropathy, 363, 424, 425f
Lymphoma in HIV infection, 153 leptomeningeal, 271 M Macrocephaly, in neurofibromatosis 1, 100 Magnesium, in restless legs syndrome, 411t Magnetic resonance imaging in amyotrophic lateral sclerosis, 322, 322t in arboviral infection, 130, 136 in Bells palsy, 207 in brain metastases, 265 in dystonia, 303 in epidural spinal cord compression, 268 in failed back syndrome, 59 in generalized seizures, 40 in glioma, 261 in idiopathic intracranial hypertension, 332 in intracerebral hemorrhage, 221 in ischemic stroke, 213 in leptomeningeal metastases, 271 in neonatal encephalopathy, 89 in neurofibromatosis 1, 100, 102 in neurosarcoidosis, 201202 in normal-pressure hydrocephalus, 335, 336 in optic neuritis, 186, 187, 187f in paraneoplastic neurologic syndromes, 277 in primary vasculitis, 237 in prion diseases, 321 in Sturge-Weber syndrome, 108 in syringomyelia, 92, 94, 94t, 96 in transverse myelitis, 195 in tuberous sclerosis complex, 106, 106t in unconsciousness, 2 in Wernickes disease, 345 Malaria, 181184, 182t, 183t diagnosis of, 182, 182t fluid therapy in, 184 hemolytic disorders in, 184 hypoglycemia in, 184 neurologic complications of, 184 seizures in, 182, 183184 treatment of, 182183, 183t Malarone, in malaria, 183 Malignant hyperthermia, MDMA-related, 349 Malignant peripheral nerve sheath tumor, in neurofibromatosis 1, 100 Mannitol, in ciguatoxin exposure, 356 Marine toxins, 354358, 355t MDMA (methylenedioxymethamphetamine), 349 Meals, orthostatic hypotension after, 12 Mechanical ventilation, in status epilepticus, 48 Meclizine, in vertigo, 8 Medication overuse headache, 7476, 75t, 76t in children, 80 Medulloblastoma, 258259, 259f Mefloquine, 184 MELAS (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes) syndrome, 338, 338t, 340 Melatonin in cluster headache, 73t in REM sleep behavior disorder, 16 Memantine, in Alzheimers disease, 311312, 312t Memory loss of. See also Alzheimers disease; Dementia in Korsakoffs psychosis, 346 in multiple sclerosis, 194
Index Multiple sclerosis, 189194 alternative therapies in, 194 ataxia in, 299 CHAMPS trial in, 187188 cognitive problems in, 194 constipation in, 193 corticosteroids in, 420t depression in, 191, 192193, 193t diagnosis of, 189 erectile dysfunction in, 199200, 199t exacerbations of, 192, 192t fatigue in, 192, 193t fecal incontinence in, 193 glatiramer acetate in, 190t, 191 immunomodulatory therapy in, 189192, 190t interferon beta-1a in, 187189, 188f, 190191, 190t intravenous immunoglobulin in, 424425, 425f mitoxantrone in, 190t, 191192 neurogenic bladder in, 193, 193t, 197198, 198f nonpharmacologic therapy in, 189 optic neuritis in, 185, 187, 187f. See also Optic neuritis pain in, 193t, 194 paroxysmal disorders in, 193t, 194 plasma exchange in, 424425, 425f sexual function in, 193, 198200, 199t spasticity in, 193, 193t treatment of, 417 tremor in, 194 Multiple sleep latency (MSL) test, 1920, 20f Multisystem atrophy ataxia in, 300 Parkinsons disease vs., 281 REM sleep behavior disorder and, 16 Multivitamin, in Wernickes disease, 345 Muscarin, 355t Muscle(s) atrophy of, 245 corticosteroid-induced, 417t, 418 biopsy of, in inflammatory myopathy, 402 examination of, in peripheral nerve injury, 245 Muscular dystrophy, 392396 Beckers, 394 Duchennes, 393394, 420t facioscapulohumeral, 396 limb girdle, 396 myotonic, 394396 Mushroom poisoning, 355t, 357358 Mutism, akinetic, 2t Myasthenia gravis, 387392 azathioprine in, 389, 390 clinical features of, 387 corticosteroids in, 389390, 419t cyclosporine in, 389, 390391 diagnosis of, 387388 intravenous immunoglobulin in, 389, 391392, 424, 425f mycophenolate mofetil in, 389, 391 paraneoplastic, 278, 278t plasma exchange in, 389, 391, 424, 425f prevalence of, 387 pyridostigmine in, 388 thymectomy in, 388389 thymomectomy in, 388389 Mycophenolate mofetil in inflammatory myopathy, 399 in multiple sclerosis, 191 in myasthenia gravis, 389, 391 Myelitis herpes simplex virus, 123t transverse, 194197, 196t varicella zoster virus, 124t, 127 Myelography, in epidural spinal cord compression, 268 Myelopathy in HIV infection, 148149 radiation-induced, 270 sarcoid, 202t, 204 spondylitic, cervical, 6263, 64 tumor-induced, 268270, 269f Myocardial infarction, cardioembolism after, 220 Myoclonic epilepsy and ragged-red fibers (MERRF) syndrome, 298t, 299, 338, 338t Myopathy in HIV infection, 150 in mitochondrial disorders, 340 inflammatory, 396403, 401f. See also Inflammatory myopathy sarcoid, 202t, 204 steroid, 398 Myotonic muscular dystrophy, 394396 N Nails, fibromas of, 104 Naloxone in opiate overdose, 347 in unconsciousness, 2 Naltrexone, in opiate dependence, 347348 Naproxen, in migraine, 68t Naratriptan, in migraine, 69t Narcolepsy, 1822 behavioral treatments of, 22 diagnosis of, 1920, 20f pathophysiology of, 18 pharmacologic treatment of, 2022, 21t Natalizumab, in multiple sclerosis, 192 Nausea, in CNS fungal infection, 168 Neck pain, in cervical spondylosis, 62, 63 Neglect, in Alzheimers disease, 314 Neisseria meningitidis infection, 155158, 157t Nelfinavir drug interactions with, 148t in HIV infection, 147t Neonate. See also Children encephalopathy in, 8991, 90t herpes simplex virus encephalitis in, 122, 123t seizures in, 23, 24f Nerve conduction study in carpal tunnel syndrome, 383 in entrapment neuropathy, 383 in peripheral nerve injury, 245, 247, 248 in ulnar neuropathy, 385 Nerve graft, in peripheral nerve injury, 250t Nerve transfer, in peripheral nerve injury, 250t Neuralgia glossopharyngeal, 8183, 82f postherpetic, 8386, 85f trigeminal, 8183, 82f Neuritis, optic, 185189, 187f, 188f Neuroborreliosis. See Lyme disease Neurofibroma, 99, 99t Neurofibromatosis, 98103 type 1 (von Recklinghuasens disease), 98103, 99t diagnosis of, 98, 99t differential diagnosis of, 99t genetic counseling in, 102 MRI in, 102
441
Neurofibromatosis (Continued) neurologic complications in, 100 ophthalmic lesions in, 100 optic pathway glioma in, 100101 plexiform neuromas in, 100 skeletal lesions in, 101 skin lesions in, 99100, 99t vasculopathy in, 101 type 2, 102, 102t Neurogenic bladder in multiple sclerosis, 193, 193t, 197198, 198f in spinal cord injury, 243 Neurogenic hyperventilation, 4 Neurogenic orthostatic hypotension, 813 acetylcholinesterase inhibitors in, 11t, 12 blood pressure measurement in, 9 chronic anemia and, 12 diet in, 910 patient education in, 9 pharmacologic therapy in, 1112, 11t physical measures in, 1011 postprandial, 12 supine hypertension and, 12 sympathomimetics in, 1112, 11t volume-expanding agents in, 11, 11t Neuroleptics, orthostatic hypotension with, 10t Neurolysis in peripheral nerve injury, 250t in trigeminal neuralgia, 8283 Neuroma, 247, 250t, 252 in neurofibromatosis 1, 99t, 100 in neurofibromatosis 2, 109 Neuromodulating agents in diabetic polyneuropathy, 371, 371t in painful neuropathy, 365366, 367t Neuromyotonia, paraneoplastic, 278, 278t Neuropathy. See also specific disorders diabetic, 368373. See also Diabetes mellitus drug-related, 371372, 372t, 373, 375t376t entrapment, 382386, 383t, 384f, 386t familial, 377382, 378t379t, 380t in HIV infection, 149150 painful, 363368. See also Painful neuropathy paraneoplastic, 278, 278t sarcoid, 202t, 204 toxic, 373376, 374t375t Neuropathy, ataxia, retinitis pigmentosa (NARP), 298t, 299, 338t, 339 Neuropraxia, 246f, 247, 247t, 251 Neuroprotection in Huntingtons disease, 294 in Parkinsons disease, 282 Neuropsychological testing, in psychogenic nonepileptic seizures, 52 Neuroretinitis, 186 Neurorrhaphy, in peripheral nerve injury, 250t Neurosarcoidosis, 201206 chronic, 206 clinical manifestations of, 201202, 202t, 204 corticosteroids in, 419t diagnosis of, 201202, 203f encephalitic, 202t, 204 hydrocephalus in, 206 meningeal, 202, 202t, 204 myelopathic, 202t, 204 myopathic, 202t, 204 neuropathic, 202t, 204 refractory, 206
442
Index Oculomotor apraxia type 1, ataxia and, 297 Oculomotor (3rd cranial nerve) palsy, in diabetes, 373 Oligodendroglioma, 264 allelic loss of heterozygosity and, 261, 264 On-off phenomenon, in Parkinsons disease, 285 Onapristone, in Charcot-Marie-Tooth disease, 379 Opiates abuse of, 347348 in complex regional pain syndromes, 65 in failed back syndrome, 61 in familial neuropathy, 382 in migraine, 68t in painful neuropathy, 367368, 367t in postherpetic neuralgia, 86 Optic glioma, in neurofibromatosis 1, 99t, 100101 Optic nerve sheath fenestration, in idiopathic intracranial hypertension, 333, 334 Optic neuritis, 185189 clinical features of, 185186 corticosteroids in, 419t diagnosis of, 186 monosymptomatic, 185, 188f retrobulbar, 186 treatment of, 186189, 188f Optic neuropathy, in giant cell arteritis, 233 Organophosphate exposure, 375t Orthostatic hypotension definition of, 8 drug-related, 9, 10t in Parkinsons disease, 286t, 287 neurogenic, 813. See also Neurogenic orthostatic hypotension Osteoporosis, corticosteroid use and, 417418, 417t Overdose benzodiazepine, 350 cocaine, 349350 flunitrazepam, 350 gamma-hydroxybutryic acid, 351 methamphetamine, 348 methylenedioxymethamphetamine, 349 opiate, 347348 phencyclidine, 351 Overeating, in frontotemporal degeneration, 315 Oxaliplatin, toxicity of, 375t Oxcarbazepine in complex partial seizures, 35t, 37, 37t in familial neuropathy, 381 in glossopharyngeal neuralgia, 81 in trigeminal neuralgia, 81 Oxybutynin, in multiple sclerosis, 198 Oxycodone abuse of, 347348 in painful neuropathy, 367t in postherpetic neuralgia, 86 in restless legs syndrome, 411t Oxygen therapy in cluster headache, 70, 72 in ischemic stroke, 216 in malaria, 182, 183t in subarachnoid hemorrhage, 227 P Pachymeningitis, sarcoid, 202, 202t, 204 Paclitaxel, toxicity of, 375t Pain. See also Painful neuropathy after acute transverse myelitis, 196t after peripheral nerve injury, 252 avulsion, after peripheral nerve injury, 252 Pain (Continued) back. See also Failed back syndrome in epidural spinal cord compression, 268 chronic, 5558 assessment of, 56 definition of, 55 psychosocial factors in, 55 treatment of, 5657 in carpal tunnel syndrome, 383 in cervical spondylosis, 62 in Charcot-Marie-Tooth disease, 379381 in diabetic polyneuropathy, 370371, 371t in epidural spinal cord compression, 268 in Guillain-Barr` syndrome, 360 e in multiple sclerosis, 193t, 194 leg, restless legs syndrome vs., 409 neck, in cervical spondylosis, 63 neuropathic, 5556. See also Complex regional pain syndromes; Neuralgia, postherpetic after peripheral nerve injury, 252 nociceptive, 55 ocular, in optic neuritis, 185 sympathetically mediated, 368 Painful neuropathy, 363368 causes of, 364, 364t differential diagnosis of, 365, 366f laboratory studies in, 365 pain characteristics in, 364365 patient history in, 364365 physical examination in, 365 treatment of, 365368, 367t Pallidotomy, in Parkinsons disease, 288 Papilledema, in idiopathic intracranial hypertension, 331332, 334 Papillitis, 186 Paraldehyde, in malaria-related seizures, 184 Paralysis in arboviral infection, 136 in enteroviral infection, 141 in polio virus infection, 141 periodic hyperkalemic, 403404, 404f hypokalemic, 404405, 405f in Andersen-Tawil syndrome, 406407, 406f thyrotoxic, 406f, 407 sleep, 19, 22 tick, 355t, 358, 374t Paramyotonia, in hyperkalemic periodic paralysis, 403404, 404f Paraneoplastic neurologic syndromes, 274279, 275t, 298t, 299 antibody-associated, 274276, 275t, 277 diagnosis of, 276277, 276t treatment of, 277278, 278t, 279f tumor identification in, 277 Parasomnias, 1318 arousal, 1314, 13t, 15t, 17 evaluation of, 17 REM sleeprelated, 14, 15t, 1617 treatment of, 17 Parkinsonism, 281 Parkinsons disease, 281292 amantadine in, 283f, 284 anticholinergics in, 284285 apomorphine in, 285 bladder disorders in, 286t, 287 carbidopa/levodopa in, 282284, 283f, 283t, 285 clinical manifestations of, 281 COMT inhibitors in, 283f, 284 deep brain stimulation in, 288 dementia in, 286t, 287
Neurosarcoidosis (Continued) relapsing-remitting, 206 treatment of, 204206, 205f Neurosyphilis, 172176 clinical features of, 173174, 173t diagnosis of, 174, 174f, 175f early, 172173, 173t in HIV infection, 154 late, 173t retreatment of, 176, 176t treatment of, 174176, 175t, 176t Neurotization, in peripheral nerve injury, 250t Neurotmesis, 246f, 247, 247t Nevirapine, in HIV infection, 147t New daily persistent headache, 72f, 76 Nicardipine, in intracerebral hemorrhage, 223t Niemann-Pick disease, 297, 298t Nightmares, 15t, 1617 Nimodipine in essential tremor, 291 in subarachnoid hemorrhage, 226 Nitrates, orthostatic hypotension with, 10t Nitroglycerin, orthostatic hypotension with, 10t Nitroprusside, in intracerebral hemorrhage, 223t NMDA blockers, in frontotemporal degeneration, 317 Nocturnal leg cramps, restless legs syndrome vs., 409 Noncardiogenic pulmonary edema, in opiate overdose, 347 Nonepileptic seizures, 4953, 49t. See also Psychogenic nonepileptic seizures Nonsteroidal anti-inflammatory drugs, in childhood headache, 79 Norepinephrine, in intracerebral hemorrhage, 223t Normal-pressure hydrocephalus, 299, 335337, 335f Nortriptyline in attention deficit hyperactivity disorder, 117t in childhood headache prevention, 79, 80t in depression, 428t in painful neuropathy, 367t in vestibular migraine, 6 Nucleoside analogues, mitochondrial disorders with, 339 Nutrition in amyotrophic lateral sclerosis, 326 in Guillain-Barr` syndrome, 359 e in ischemic stroke, 215216 in subarachnoid hemorrhage, 227 Nystagmus, in altered states of consciousness, 3 O Obesity, intracranial hypertension and, 331, 332 Obsessive-compulsive disorder, Tourettes syndrome and, 307308 Obtundation, 2t Occipital nerve stimulation, in cluster headache, 73 Occupational therapy in amyotrophic lateral sclerosis, 324 in complex regional pain syndromes, 6465 Octreotide, in neurogenic orthostatic hypotension, 11t Ocular pneumoplethysmography, in giant cell arteritis, 234
Index Parkinsons disease (Continued) depression in, 286287, 286t diet in, 285 differential diagnosis of, 281 dopamine agonists in, 283f, 283t, 284 drug-induced dyskinesias in, 285 hallucinations in, 286t, 287 neuroprotective therapy in, 282 on-off phenomenon in, 285 orthostatic hypotension in, 286t, 287 pallidotomy in, 288 sexual dysfunction in, 286t, 287 sleep disorders in, 285286, 286t thalamotomy in, 287288 wearing off phenomenon in, 285 Paroxetine, in depression, 428t Paroxysmal atrial fibrillation, transient ischemic attack and, 210, 212 Patent foramen ovale, cardioembolism and, 221 Pavor nocturnes, 14 PCP (phencyclidine) abuse, 350351 Pearsons syndrome, 339, 340 Penciclovir, in herpes virus infection, 121 D-Penicillamine, in lead poisoning, 353354, 353t, 354t Penicillin in bacterial meningitis, 157158, 157t in HIV-associated neurosyphilis, 154 in Lyme disease, 179 in neurosyphilis, 174176, 175t Penis, prosthetic, in erectile dysfunction, 200 Pentobarbital, in status epilepticus, 48 Pentobarbital coma, in status epilepticus, 48 Percutaneous balloon ganglion compression, in trigeminal neuralgia, 83 Percutaneous transluminal angioplasty, in subarachnoid hemorrhage, 227 Pergolide in Parkinsons disease, 283f, 283t, 284 in restless legs syndrome, 411412, 411t in Tourettes syndrome, 308t Perhexiline, toxicity of, 376t Perimetry, in idiopathic intracranial hypertension, 332333 Periodic limb movements, 410, 411412, 411t. See also Restless legs syndrome in Parkinsons disease, 286t Periodic paralysis, 403407 hyperkalemic, 403404, 404f hypokalemic, 404405, 405f in Andersen-Tawil syndrome, 406407, 406f thyrotoxic, 406f, 407 Peripheral nerve injury, 244253 avulsion pain in, 252 axonotmesis in, 246f, 247, 247t, 251 bone changes with, 252 complete, 250251, 251f complex regional pain syndrome after, 252 complications of, 252253 compression and, 249t, 250 contusion and, 248, 249t denervation pain in, 252 depression after, 253 electrical, 250 electrophysiologic assessment of, 245, 246f iatrogenic, 248, 249t, 250 in motor nerves, 245 in sensory nerves, 245, 247 incomplete, 250251, 251f intraoperative monitoring for, 251252 irradiation, 250 ischemic, 249t, 250 joint changes with, 252 laceration and, 248, 249t Peripheral nerve injury (Continued) mechanism of, 248250, 249t neuroma in, 252 neuropathic pain in, 252 neuropraxia in, 246f, 247, 247t, 251 neurotmesis in, 246f, 247, 247t pain after, 252 phases of, 248 recovery from, 244245, 252 regeneration pain in, 252 severity of, 247248, 247t site of, 244247, 245t, 249t skin changes with, 253 stretch and, 248, 249t subcutaneous tissue changes with, 253 sympathetic dysfunction and, 247 thermal, 250 traction and, 248, 249t treatment of, 250252, 251f Peripheral neuropathy. See Neuropathy Peroneal neuropathy, 385386 Persistent vegetative state, 2t Pfiesteria, 355t, 356 Phencyclidine abuse, 350351 Phenobarbital drug interactions of, 166t in complex partial seizures, 35t, 37, 37t in febrile seizures, 28, 29 in neonatal encephalopathy, 91 in neonatal seizures, 23 side effects of, 29 Phenylephrine, in intracerebral hemorrhage, 223t Phenylpropanolamine, in neurogenic orthostatic hypotension, 12 Phenytoin in complex partial seizures, 35t, 37, 37t in intracerebral hemorrhagerelated seizures, 224, 224t in malaria-related seizures, 184 in neonatal encephalopathy, 91 in neonatal seizures, 23 in status epilepticus, 46, 48 in subarachnoid hemorrhagerelated seizures, 226 topical, in diabetic polyneuropathy, 371 Pheochromocytoma, in neurofibromatosis 1, 101 Physical therapy in amyotrophic lateral sclerosis, 324 in complex regional pain syndromes, 6465 in failed back syndrome, 60 in Guillain-Barr syndrome, 359 in inflammatory myopathy, 402 in spinal cord injury, 243 Pick bodies, 316 Pimozide drug interactions of, 166t in Tourettes syndrome, 308t Piriformis syndrome, 386t Plasma exchange, 422423 complications of, 423 contraindications to, 425 in chronic inflammatory demyelinating polyneuritis, 361f, 362 in Guillain-Barr syndrome, 360 in multiple sclerosis, 192 in myasthenia gravis, 389, 391 in transverse myelitis, 196 indications for, 423425, 423t, 425f Plasmodium falciparum infection, 181184, 182t, 183t Poisoning, lead, 352354 Poliomyelitis, 141 West Nile, 130
443
Polymerase chain reaction (PCR) in leptomeningeal metastases, 271 in Lyme disease, 177 in tuberculous meningitis, 159 Polymyalgia rheumatica, 232 Polymyositis, 396397 corticosteroid-induced muscle atrophy vs., 418 corticosteroids in, 419t cytokines in, 402 immunopathology of, 397 immunosuppressants in, 399400 intravenous immunoglobulin in, 400 prognosis for, 400 treatment of, 397402, 401f, 424, 425f Polyneuritis, demyelinating, inflammatory, 361363, 361f Polyneuropathy. See also Neuropathy diabetic, 369370 sensory, distal, in HIV infection, 149, 149f, 150t Polyradiculopathy, progressive, in HIV infection, 150 Porphyria, variegate, 380t Port-wine stain, 109110 Posterior fossa Chiari malformation I of, 94, 94t decompression of, 9596, 96t Postherpetic neuralgia, 8386, 85f Posturing extensor (decerebrate), 4 flexor (decorticate), 4 Potassium in Chiari malformation I, 95 in hypokalemic periodic paralysis, 405, 405f Powassan virus infection, 132t Pramipexole in Parkinsons disease, 283f, 283t, 284 in restless legs syndrome, 411412, 411t Prednisone in Bells palsy, 207208, 208f in cluster headache, 72, 73t in Duchennes muscular dystrophy, 393 in myasthenia gravis, 389390 in neurosarcoidosis, 205206, 205f in optic neuritis, 186187 in tuberculous meningitis, 160f, 161 Pregabalin, in postherpetic neuralgia, 86 Pregnancy antiepileptic drugs in, 38 idiopathic intracranial hypertension in, 333 Pressure ulcers ischemic stroke and, 217 spinal cord injury and, 243 Primary leptomeningeal lymphoma, 271 Primidone in complex partial seizures, 37, 37t in essential tremor, 290291, 290t Prion diseases, 319321 biosafety for, 321 diagnosis of, 320321 treatment of, 321 Prion protein (PrP), 319 Prochlorperazine, in migraine, 68t Progressive external ophthalmoplegia, 338t, 339 Progressive multifocal leukoencephalopathy, in HIV infection, 153 Progressive nonfluent aphasia, 315, 318t Progressive polyradiculopathy, in HIV infection, 150
444
Index Q Qinghaosu, in malaria, 183 Quadriplegic myopathy, 418 Quetiapine, in Huntingtons disease, 294 Quinidine, drug interactions of, 166t Quinine in amyotrophic lateral sclerosis, 327t in Guillain-Barr syndrome, 360 in malaria, 182183, 183t R Rabies virus infection, 142144 clinical manifestations of, 142 diagnosis of, 142143 prevention of, 143144, 143f treatment of, 143 Radial neuropathy, 385386 Radiation therapy in brain tumor, 255, 262264, 263f, 265267 in epidural spinal cord compression, 270 in leptomeningeal metastases, 272 nerve injury with, 250 Radiculitis, cytomegalovirus, 153154 Radiculomyelitis, herpes simplex virus, 123t Radiculopathy, spondylitic, cervical, 6162, 63 Radiofrequency thermocoagulation, in trigeminal neuralgia, 8283 Radiography. See also Computed tomography; Magnetic resonance imaging in failed back syndrome, 59 Radiosurgery, in brain metastases, 267 Ramsay Hunt syndrome, 84, 127 Rasagiline, in Parkinsons disease, 282, 285 Rebound headache, 7476, 75t, 76t in children, 80 Recombinant tissue plasminogen activator, in ischemic stroke, 213214, 216f Rectiva, in inflammatory myopathy, 402 Reflex sympathetic dystrophy. See Complex regional pain syndromes Refsums disease, 297, 298t, 380t Rehabilitation in failed back syndrome, 60 in spinal cord injury, 243244 REM sleep behavior disorder, 14, 15t, 1617, 286t Renal artery stenosis, in neurofibromatosis 1, 101 Reoviridae infection, 129, 134t135t diagnosis of, 130, 136 management of, 136137 Repetitive nerve stimulation, in myasthenia gravis, 387388 Respiration depression of in gamma-hydroxybutryic acid overdose, 351 in opiate overdose, 347 in altered states of consciousness, 4 in spinal cord injury, 241, 243 Respiratory system in amyotrophic lateral sclerosis, 326 in Duchennes muscular dystrophy, 394 in frontotemporal degeneration, 318319 Restless legs syndrome, 407412 assessment of, 409410 diagnosis of, 407, 408t, 409410, 409t differential diagnosis of, 409, 409t epidemiology of, 407408, 408f pathophysiology of, 408 treatment of, 410412, 410f, 411t Retina astrocytoma of, 104 hamartomata of, 104 Retinitis, cytomegalovirus, 124t125t, 128, 154 Rhabdomyolysis, in opiate overdose, 347 Rhabdomyomata, cardiac, 104 Ribavirin, in arboviral infection, 136 Ribufutin, drug interactions of, 166t Rifabutin, drug interactions of, 166t Rifampin drug interactions of, 166t in tuberculous meningitis, 159160, 160f Riluzole in amyotrophic lateral sclerosis, 327t in Friedreichs ataxia, 391 Risperidone in autism, 113, 113f in Tourettes syndrome, 308t Ritonavir drug interactions with, 148t in HIV infection, 147t Rituximab, in inflammatory myopathy, 399 Rivastigmine, in Alzheimers disease, 311312, 312t Rizatriptan in childhood headache, 79 in migraine, 67, 69t Ropinirole in Parkinsons disease, 283f, 283t, 284 in restless legs syndrome, 411412, 411t Rotorest bed, 241 S St. Louis encephalitis, 131t Salt tablets, in neurogenic orthostatic hypertension, 9 Saquinavir drug interactions with, 148t in HIV infection, 147t Sarcoidosis, 201206. See also Neurosarcoidosis Saxitoxin, 356 Schwannoma, in neurofibromatosis 2, 109 Schwannomin, 109 Sciatic neuropathy, 386t Scoliosis in Duchennes muscular dystrophy, 394 in neurofibromatosis 1, 101 Scombroid, 355t, 356 Scopolamine patch, in amyotrophic lateral sclerosis, 327t Sea snake, 355t, 357 Seizures. See also Anticonvulsants absence, 3033, 32t33t brain tumors and, 256 complex partial, 3339. See also Complex partial seizures febrile, 2529. See also Febrile seizures generalized, 3942, 41f in arboviral infection, 136 in brain metastases, 265 in fungal infection, 168 in glioma, 261262 in intracerebral hemorrhage, 224, 224t in ischemic stroke, 217 in malaria, 182, 183184 in mitochondrial encephalopathy, 339 in neonatal encephalopathy, 9091 in opiate overdose, 347 in Sturge-Weber syndrome, 108, 109110, 109f in subarachnoid hemorrhage, 226 in tuberous sclerosis complex, 104105, 106 neonatal, 23, 24f, 9091
Progressive supranuclear palsy, Parkinsons disease vs., 281 Prolonged QT interval, in Andersen-Tawil syndrome, 406 Promethazine in migraine, 68t in vertigo, 8 Propofol, in status epilepticus, 48 Propoxyphene abuse of, 347348 in restless legs syndrome, 411t Propranolol in cerebellar ataxia, 300 in childhood headache prevention, 79, 80t in essential tremor, 290, 290t in migraine, 69, 70t Prosthetic heart valves, cardioembolism and, 219, 220 Protein, CSF, in tuberculous meningitis, 158159 Proteus infection, 158 Proximal diabetic neuropathy, 372 Pruritus, in neurofibromatosis 1, 99t Pseudoephedrine, in neurogenic orthostatic hypotension, 12 Psilocybin, 355t Psychogenic nonepileptic seizures, 4953 classification of, 4950, 49t clinical features of, 5051, 50t diagnosis of, 5052, 50t, 51t EEG in, 51, 51t epilepsy and, 53 epileptic seizures vs., 50t, 5152, 51t neuropsychological testing in, 52 prognosis for, 53 prolactin levels in, 51 provocation procedures in, 51 sexual abuse and, 53 SPECT in, 5152 treatment of, 5253, 52t Psychosis in Alzheimers disease, 313314 in frontotemporal degeneration, 316 in Huntingtons disease, 294 Korsakoffs, 345346 Psychotherapy, in failed back syndrome, 5859 Ptosis, eyelid, in mitochondrial disorders, 339340 Pulmonary edema, in opiate overdose, 347 Pulmonary embolism ischemic stroke and, 217 subarachnoid hemorrhage and, 227 Pupils afferent defect of, in optic neuritis, 185 examination of in idiopathic intracranial hypertension, 333 in unconsciousness, 3 Purkinje cells, in ataxia, 300 Pyrazinamide, in tuberculous meningitis, 160, 160f Pyridostigmine in myasthenia gravis, 388 in neurogenic orthostatic hypotension, 11t, 12 Pyridoxine deficiency of, 91 in infantile spasms, 25 toxicity of, 376t Pyrimethamine, in cerebral toxoplasmosis, 151, 151t
Index Seizures (Continued) nocturnal, REM sleep behavior disorder vs., 16 nonepileptic, psychogenic, 4953. See also Psychogenic nonepileptic seizures Selective serotonin reuptake inhibitors in autism, 112113, 113f in depression, 428429, 428t in frontotemporal degeneration, 317, 317t in Huntingtons disease, 293 in painful neuropathy, 368 Selegiline, in Parkinsons disease, 285 Sensory evaluation, in peripheral nerve injury, 245, 247 Sertraline in amyotrophic lateral sclerosis, 327t in depression, 428t in Huntingtons disease, 293 Sexual abuse, psychogenic nonepileptic seizures and, 53 Sexual function after spinal cord injury, 244 in multiple sclerosis, 193, 198200, 199t in Parkinsons disease, 286t Shagreen patch, 104 Shellfish toxins, 356 Shingles, 8386, 85f, 123t124t, 126127 Short-lasting unilateral neuralgiform headache, 72f, 72t, 74 Short stature, in neurofibromatosis 1, 101 Shunt in Chiari malformation I, 95 in cryptococcal meningitis, 152 in idiopathic intracranial hypertension, 334 in leptomeningeal metastases, 274 in normal-pressure hydrocephalus, 336337 Sialorrhea, in Parkinsons disease, 286t Silberstein-Lipton criteria, 74, 74t Sildenafil, in erectile dysfunction, 199200, 199t Single proton emission computed tomography, in psychogenic nonepileptic seizures, 5152 Sirolimus drug interactions of, 166t in inflammatory myopathy, 399400 Skin biopsy of, in painful neuropathy, 365 disorders of, after peripheral nerve injury, 253 Sleep disorders of. See also Parasomnias in Alzheimers disease, 312313 in Parkinsons disease, 285286, 286t in autism, 113, 113f in Chiari malformation I, 95 REM, parasomnias with, 14, 15t, 1617 Sleep attacks, 19 Sleep paralysis, 19, 22 Sleep terrors, 14, 15t Sleepiness, in narcolepsy, 19 Sleepwalking, 14, 15t Snake bites, 355t, 357 Snowshoe hare virus infection, 133t SOD1 gene, in amyotrophic lateral sclerosis, 322323 Sodium chloride, in subarachnoid hemorrhage, 228 Sodium intake, in neurogenic orthostatic hypertension, 9 Sodium oxybate, in narcolepsy, 21t, 22 Solvent abuse, 374t Somnambulism, 14, 15t Spasms cervical, in Chiari malformation I, 95 in multiple sclerosis, 193t, 194 infantile, 2325, 24f in tuberous sclerosis complex, 105106 Spasticity after acute transverse myelitis, 196t in multiple sclerosis, 193, 193t Speech dysarthric, 328 in Parkinsons disease, 286t Speech therapy, in amyotrophic lateral sclerosis, 325326 Sphenoid bone, in neurofibromatosis 1, 99t, 100, 101 Spinal cord. See also Spinal cord injury acute inflammation of. See Transverse myelitis compression of, 268270, 269f neuroma of, 101 Spinal cord injury, 241244 autonomic dysreflexia in, 244, 244t bladder dysfunction in, 243 bowel dysfunction in, 243 cardiovascular complications of, 243 corticosteroids in, 420t deep vein thrombosis in, 243 immobilization in, 241 methylprednisolone in, 241 mobilization after, 243 neurologic assessment in, 241, 242f pressure ulcers in, 243 pulmonary embolus in, 243 rehabilitation after, 243244 respiratory dysfunction in, 241, 243 sexual dysfunction in, 244 urologic dysfunction in, 244 Spinal cord stimulation in complex regional pain syndromes, 65 in failed back syndrome, 6061 Spine, metastases to, 268270, 269f Spinocerebellar ataxia, 295296, 296t, 297t Spirometry, in myasthenia gravis, 388 Spondylosis, cervical, 6164. See also Cervical spondylosis Sporothrix schenckii infection, 164t Staphylococcus infection, 155158, 157t Statins, in stroke prevention, 212 Status epilepticus, 4549, 47f absence, 4546 assessment of, 46 complex partial, 45 evaluation of, 4849 myoclonic, 46 psychogenic, 46 simple partial, 45 tonic-clonic, 45 treatment of, 4648, 47f Stavudine in HIV infection, 147t toxicity of, 376t Stereotactic gamma knife radiosurgery, in trigeminal neuralgia, 83 Steroid myopathy, 398 Stiff person syndrome, 425, 425f Stimulants abuse of, 348350 in attention deficit hyperactivity disorder, 116118, 117t Streptococcus pneumoniae infection, 155158, 157t Streptomycin, in tuberculous meningitis, 160, 160f Stress, nightmares and, 17
445
Stroke cardioembolic, 218219, 220 in mitochondrial encephalopathy, 339 ischemic, 213218 aspiration in, 215216, 217 blood pressure in, 215 deep vein thrombosis in, 217 diagnosis of, 213, 214t dysphagia in, 215216, 217, 329331, 331f hyperglycemia in, 215 hyperthermia in, 215 intracranial pressure elevation in, 216217 investigational interventions for, 214215, 215t nutrition in, 215216 oxygen therapy in, 216 pathophysiology of, 213 pressure sores in, 217 prevention of, 217 pulmonary embolus in, 217 recombinant tissue plasminogen activator in, 213214, 216f recurrent, 217 seizures in, 217 urinary tract infection in, 217 transient ischemic attack vs., 209 Strokelike episodes, in Sturge-Weber syndrome, 110 Stupor, 2t in CNS fungal infection, 168 Sturge-Weber syndrome, 108111 diagnosis of, 108109, 109f glaucoma in, 108, 110 headache in, 110 laser therapy in, 110 learning disability in, 110 psychological disorders in, 110 seizures in, 108, 109110, 109f strokelike episodes in, 110 Subarachnoid hemorrhage, 224228, 225t, 226t Subcutaneous tissue disorders, after peripheral nerve injury, 253 Subdural empyema, 171 Subependymal giant cell astrocytoma, 104, 105, 106t Subependymal glial nodules, 104, 105, 106t Suboccipital microvascular nerve decompression, in trigeminal neuralgia, 83 Succimer, 353354, 353t, 354t Sudden death, in myotonic muscular dystrophy, 395 Sulfadiazine, in cerebral toxoplasmosis, 151, 151t Sumatriptan in childhood headache, 79 in cluster headache, 7172 in migraine, 67, 69t SUNCT (short-lasting unilateral neuralgiform headache), 72f, 72t, 74 Suprascapular neuropathy, 386t Surgery in brain metastases, 266267 in carpal tunnel syndrome, 384 in cervical spondylosis, 63 in dystonia, 305306 in epidural spinal cord compression, 269270 in essential tremor, 291292 in failed back syndrome, 5960 in idiopathic intracranial hypertension, 334 in leptomeningeal metastases, 274 in Parkinsons disease, 287288
446
Index Tick paralysis, 355t, 358, 374t Timolol, in migraine, 69, 70t Tissue plasminogen activator, recombinant, in ischemic stroke, 213214, 216f Tizanidine, in amyotrophic lateral sclerosis, 327t Togaviridae infection, 129, 133t134t diagnosis of, 130, 136 management of, 136137 Tolcapone, in Parkinsons disease, 283f, 284 Topiramate in childhood headache prevention, 79, 80t in cluster headache, 73t in complex partial seizures, 36t, 37, 37t in diabetic polyneuropathy, 371 in essential tremor, 291 in familial neuropathy, 381382 in glossopharyngeal neuralgia, 82 in migraine, 68, 69t in trigeminal neuralgia, 82 Tourettes syndrome, 306309 clinical evaluation of, 307 diagnosis of, 306307 treatment of, 307309, 308t Toxic-metabolic encephalopathy, 427 Toxic neuropathy, 373376 Toxoplasmosis, in HIV infection, 151, 151t, 152f Tracheostomy in amyotrophic lateral sclerosis, 326 in Guillain-Barr syndrome, 359 Tramadol in diabetic polyneuropathy, 371, 371t in painful neuropathy, 367t, 368 in restless legs syndrome, 411t Transcranial Doppler ultrasound, in subarachnoid hemorrhage, 227 Transesophageal echocardiography, in transient ischemic attack, 210 Transient ischemic attack, 209212 anterior, 209 atrial fibrillation and, 220 evaluation of, 209210, 210t, 211f large-vessel, 210, 212 limb-shaking, 210 posterior, 209 postural, 210 small-vessel, 210, 211 treatment of, 210212 vertigo and, 5t, 7 Transthoracic echocardiography, in transient ischemic attack, 210 Transverse myelitis, 194197 diagnosis of, 195 relapse of, 197 treatment of, 195196, 196t, 425, 425f Trauma. See Injury Travel history, in Lyme disease, 177 Tremor essential, 288292, 290f alprazolam in, 291 botulinum toxin injection in, 291 diagnosis of, 288289, 289t ethanol in, 291 gabapentin in, 291 genetics of, 289 nonpharmacologic treatment of, 289 primidone in, 290291, 290t propranolol in, 290, 290t surgery in, 291292 topiramate in, 291 in multiple sclerosis, 194 Triazolam, in restless legs syndrome, 411t Tricyclic antidepressants, 428429, 428t in complex regional pain syndromes, 65 in diabetic polyneuropathy, 371, 371t in familial neuropathy, 380381 in painful neuropathy, 367t, 368 in postherpetic neuralgia, 86 orthostatic hypotension with, 10t Trigeminal neuralgia, 8183, 82f Trihexyphenidyl in dystonia, 305 in Parkinsons disease, 284285 Trimethobenzamide, in migraine, 68t Triple flexion, 4 Triple-H therapy, in subarachnoid hemorrhage, 227 Triptans in childhood headache, 79 in migraine, 67, 69t Truncal radiculoneuropathy, 372373 TSC genes, 103, 107, 107t Tuberculosis, 158161, 159f, 160f Tuberous sclerosis complex, 103107 cardiac aspects of, 104 dermatologic aspects of, 103104 evaluation of, 105107, 105t, 106t genetic testing in, 103, 103t neurologic aspects of, 104105 ophthalmologic aspects of, 104 pulmonary aspects of, 104 renal aspects of, 104 Tyrosinemia, 380t U Ubiquitin inclusion, 316 Ulcers pressure, 217, 243 in spinal cord injury, 243 ischemic stroke and, 217 Ulnar neuropathy, 384385, 384f Ultrasonography, in subarachnoid hemorrhage, 227 Unconsciousness, 14, 2t, 3t classification of, 3t cranial nerve examination in, 3 diagnosis of, 12 motor examination in, 34 neurologic examination in, 24 respiratory pattern in, 4 resuscitation in, 4 vital signs in, 1 Unverrich-Lundborg disease, 297 Urinary incontinence in Alzheimers disease, 314 in multiple sclerosis, 193, 193t, 197198, 198f Urinary retention, in spinal cord injury, 243 Urinary tract infection, ischemic stroke and, 217 Urinary urgency, after acute transverse myelitis, 196t Urine, postvoid residual volume of, in multiple sclerosis, 197, 198f V Vaccine, rabies, 143144, 143f Vacuolar myelopathy, in HIV infection, 148149 Vacuum constriction devices, in erectile dysfunction, 200 Vagus nerve stimulator, in pharmacoresistant epilepsy, 45 Valacyclovir, in Bells palsy, 208 Valganciclovir, in herpes virus infection, 121
Surgery (Continued) in thoracic outlet syndrome, 385 in ulnar neuropathy, 385 Swallowing anatomy of, 328329 clinical examination of, 329331, 330f, 331f disorders of. See Dysphagia in ischemic stroke, 215216 phases of, 329 videofluoroscopic studies in, 330331, 331f Sympathectomy, in complex regional pain syndromes, 65 Sympathetically mediated pain, 368 Syndrome of inappropriate antidiuretic hormone secretion in CNS fungal infection, 168 in subarachnoid hemorrhage, 228 Syphilis, 172176. See also Neurosyphilis in HIV infection, 154 Syringomyelia, 9297, 92t management of, 9597, 97f Systemic lupus erythematosus, 419t Systremma, restless legs syndrome vs., 409 T Tachycardia, in unconsciousness, 1 Tacrolimus, in inflammatory myopathy, 399 Tadalafil, in erectile dysfunction, 199200, 199t Tangiers disease, 380t Tardive dyskinesia, 305 Tardive dystonia, 305 Tarsal tunnel syndrome, 386t Tau inclusions, 316 Temazepam, in restless legs syndrome, 411t Temperature, in ischemic stroke, 215 Temporal artery, biopsy of, 234 Temporal lobe epilepsy (complex partial epilepsy), 28 Tensilon test, 388 Tension-type headache, 76 Terfenadine, drug interactions of, 166t Tetrodotoxin, 355t, 356, 374t Thalamotomy in essential tremor, 291 in Parkinsons disease, 287288 Thalidomide, toxicity of, 376t Thallium ingestion, 375t Thiamine in unconsciousness, 2 in Wernickes disease, 345346 Thiotepa, in leptomeningeal metastases, 272 Thoracic outlet syndrome, 385 Thoracoabdominal neuropathy, diabetic, 372373 3,4-DL-Threodihydroxyphenylserine (DL-DOPS), in neurogenic orthostatic hypotension, 12 Thromboembolism, intravenous immunoglobulin administration and, 362 Thrombus, atrial, 219 Thymectomy, in myasthenia gravis, 388389 Thymomectomy, in myasthenia gravis, 388389 Thyrotoxic periodic paralysis, 406f, 407 Tiagabine, in complex partial seizures, 36t, 37, 37t Tibia, in neurofibromatosis 1, 101 Tic disorders, 306309 clinical evaluation of, 307 diagnosis of, 306308 stimulant-induced, 118 treatment of, 307309, 308t
Index Valproate sodium, 67 in complex partial seizures, 36t, 37, 37t in Huntingtons disease, 294 in intracerebral hemorrhagerelated seizures, 224, 224t in subarachnoid hemorrhagerelated seizures, 226 Valproic acid in absence seizures, 31, 32t in childhood headache prevention, 79, 80t in cluster headache, 73t Vancomycin, in bacterial meningitis, 157t, 158 Vardenafil, in erectile dysfunction, 199200, 199t Varicella zoster virus infection, 8386, 85f, 123t124t, 126127 Vascular malformation. See also Aneurysm arteriovenous, 231, 231f cavernous, 232 Vasculitis, 235239 corticosteroids in, 419t epidemiology of, 236 paraneoplastic, 278t primary, 235236 clinical features of, 236237, 237t diagnosis of, 237238, 237t treatment of, 238239, 238t secondary, 236, 236t varicella zoster virus, 124t, 127 Vasculopathy, in neurofibromatosis 1, 101 Vasodilators, orthostatic hypotension with, 10t Vasospasm, in subarachnoid hemorrhage, 227, 230 Vasovagal episodes, in spinal cord injury, 243 Vena cava filter, in brain tumorrelated thromboembolism, 262 Venereal Disease Research Laboratory (VDRL) test, 154, 172173, 174, 174f, 175f Venlafaxine in attention deficit hyperactivity disorder, 117t in cataplexy, 22 in depression, 428t in vestibular migraine, 6 Ventilation in amyotrophic lateral sclerosis, 326 in Guillain-Barr syndrome, 359 in spinal cord injury, 241 Ventriculitis, varicella zoster virus, 124t, 127 Ventriculoencephalitis, cytomegalovirus, 125t, 128 Ventriculoperitoneal shunt in Chiari malformation I, 95 in cryptococcal meningitis, 152 Ventriculoperitoneal shunt (Continued) in idiopathic intracranial hypertension, 334 in leptomeningeal metastases, 274 Ventriculostomy, in intracerebral hemorrhage, 223 Verapamil in childhood headache prevention, 79, 80t in cluster headache, 73, 73t in migraine, 69, 70t Vertigo, 48, 5t definition of, 5 Epley maneuver in, 7, 7f prolonged, acute, 56, 5t Vestibular migraine, 5t, 6 Vestibular neuritis, 56, 5t, 420t Vestibular suppressants, 8 Videofluoroscopic studies, of swallowing, 330331, 331f Vinblastine, toxicity of, 375t Vincristine, toxicity of, 375t Viper bite, 355t Viral infection. See specific viral infections Vision examination of, in idiopathic intracranial hypertension, 332333 loss of in giant cell arteritis, 232233, 234 in idiopathic intracranial hypertension, 333, 334 in optic neuritis, 185 Visual evoked potentials, in idiopathic intracranial hypertension, 333 Vital signs, in unconsciousness, 1 Vitamin(s) in mitochondrial disorders, 340341, 340t in Wernickes disease, 345 Vitamin B6, toxicity of, 372 Vitamin B1 deficiency, 299 Vitamin B12 deficiency, 299 Vitamin C in Charcot-Marie-Tooth disease, 379 in mitochondrial disorders, 340 Vitamin E deficiency of, 299 in cerebellar ataxia, 301 in frontotemporal degeneration, 316 Vomiting, in CNS fungal infection, 168 Voriconazole, 164t, 166, 166t W Waldenstrms macroglobulinemia, paraneoplastic, 278t Warfarin in brain tumorrelated thromboembolism, 262 in transient ischemic attack, 210212, 212t Wasting syndrome, in frailty, 413, 414f
447
Weakness in epidural spinal cord compression, 268 in myotonic muscular dystrophy, 395, 396 Wearing off phenomenon, in Parkinsons disease, 285 Wernickes disease, 345346 Weschler Adult Intelligence Scale, in psychogenic nonepileptic seizures, 52 West Nile virus infection, 130, 131t diagnosis of, 130, 136 management of, 136137 Western equine encephalitis, 134t Wests syndrome (infantile spasms), 2325, 24f Wilsons disease, 298t Withdrawal cocaine, 350 ethanol, 343344, 344t gamma-hydroxybutryic acid, 351 methamphetamine, 348349 methylenedioxymethamphetamine, 349 opiate, 347348 X Xanthogranuloma, in neurofibromatosis 1, 99 Xanthoma, in neurofibromatosis 1, 99 Y Yohimbine, in neurogenic orthostatic hypotension, 12 Z Zalcitabine in HIV infection, 147t mitochondrial disorders with, 339 toxicity of, 376t Zaleplon, in restless legs syndrome, 411t Zidovudine in HIV infection, 147t mitochondrial disorders with, 339 Ziprasidone, in Tourettes syndrome, 308t Zolmitriptan in childhood headache, 79 in migraine, 69t Zolpidem in amyotrophic lateral sclerosis, 327t in restless legs syndrome, 411t Zonisamide in childhood headache prevention, 79, 80t in complex partial seizures, 36t, 37, 37t in migraine, 69t Zoster sine herpete, 83, 124t, 127 Zygomycetes infection, 162, 162t, 164t

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1600 John F. Kennedy Blvd.

Ste 1800 Philadelphia, PA 19103-2899

CURRENT THERAPY IN NEUROLOGIC DISEASE Copyright 2006, Mosby Inc.

ISBN 13: 978-0-323-03432-6 ISBN 10: 0-323-03432-2

ISBN-13: 978-0-323-03432-6 ISBN-10: 0-323-03432-2

Printed in United States of America. Last digit is the print number: 9 8 7 6 5 4 3 2

Anish Bhardwaj, M.D., F.A.H.A., F.C.C.M.

Charles E. Argoff, Ph.D.

Kevin M. Biglan, M.D., M.P.H. Allen J. Askamit, Jr., M.D.

Tom J. Blanchard, M.R.C.P., DTM&H, Ph.D.

Alon Y. Avidan, M.D., M.P.H.

John B. Bodensteiner, M.D.

Laura J. Balcer, M.D., M.S.C.E.

Tallie Z. Baram, M.D., Ph.D.

Devin L. Brown, M.D.

Allan J. Belzberg, M.D.

John C. M. Brust, M.D.

Sara E. Benjamin, M.D.

Arthur L. Burnett, M.D.

Anthony S. Burns, M.D.

Peter Calabresi, M.D.

Ricardo Cruciani, M.D., Ph.D.

Grant L. Campbell, M.D., Ph.D.

Marinos C. Dalakas, M.D.

Vinay Chaudhry, M.D., F.R.C.P.

Josep Dalmau, M.D., Ph.D.

William P. Cheshire, Jr., M.D., M.A.

Stephanie K. Daniels, Ph.D.

Kenneth Cohen, M.D., M.B.A.

Larry E. Davis, M.D., F.A.A.N., F.A.C.P.

Andrew J. Cole, M.D., F.R.C.P.C.

David W. Dodick, M.D.

Anne Comi, M.D.

Heinrich Elinzano, M.D.

James J. Corbett, M.D.

Robert D. Fealey, M.D.

Andrea M. Corse, M.D.

Anne L. Foundas, M.D.

Nathan E. Crone, M.D.

Jacqueline A. French, M.D.

Linda P. Fried, M.D., M.P.H.

Benjamin M. Greenberg, M.D., M.H.S.

Adam L. Hartman, M.D. Scott Fromherz, M.D.

Fellow, Department of Pediatric Neurology, Johns Hopkins Hospital, Baltimore, Maryland

Susan T. Herman, M.D. Bhuwan P. Garg, M.B., B.S.

Donald L. Gilbert, M.D., M.S.

Argye E. Hillis, M.D., M.A.

Michio Hirano, M.D.

Mark R. Gilbert, M.D.

David Irani, M.D. Donald H. Gilden, M.D.

Sallu Jabati, M.D.

Frank G. Gilliam, M.D., M.P.H.

Alan C. Jackson, M.D., F.R.C.P.C.

Jonathan P. Gladstone, B.Sc., M.D.

Jee-Hyang Jeong, M.D.

Jonathan D. Glass, M.D.

H. A. Jinnah, M.D., Ph.D.

David S. Goldstein, M.D., Ph.D.

S. Claiborne Johnston, M.D., Ph.D.

Joao A. Gomes, M.D.

Burk Jubelt, M.D.

Robert Laureno, M.D.

Rafael H. Llins, M.D., F.A.H.A. Douglas Kerr, M.D., Ph.D.

Richard M. Kimball, M.S.