You are on page 1of 17

NEUROLOGIC MANIFESTATIONS OF SYSTEMIC DISEASE

07338619/02 $15.00 + .00

NEUROLOGIC MANIFESTATIONS OF HEMATOLOGIC DISORDERS


Deborah T. Blumenthal, MD, and Martha J. Glenn, MD

ANEMIA Fatigue, headaches, and nondescript symptoms are found in patients with a variety of anemic disorders. These symptoms do not always correlate with hemoglobin levels.27 Several specic anemic conditions with particular neurologic complications and relevant symptoms are described in this article. Megaloblastic Anemia Caused by Cobalamin Deciency Megaloblastic anemias are macrocytic anemias caused by either folate or cobalamin deciency. Those caused by vitamin B12 deciency can be associated with dramatic or subtle neurologic manifestations. Autoimmune chronic atrophic gastritis is the most common cause of vitamin B12 deciency (pernicious anemia), and may go undiagnosed in 1.9% of people older than 60 years of age.21, 92 Less common causes of vitamin B12 deciency include insufcient intake in strict vegetarians or inadequate absorption after total gastrectomy or ileectomy. The primary neurologic damage involves the white matter of the spinal cord with loss of myelin in the posterior and lateral columns. Neurologic presentation consists of paresthesias in the feet, which ascend to the legs and upper extremities; loss of vibratory and position senses in the legs and resultant sensory ataxia; polyneuropathy; and extensor plantar responses. Visual impairment and optic atrophy, mental changes, and dementia (megaloblastic mania) can appear with severe disease.
From the Divisions of Neuro-oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah

NEUROLOGIC CLINICS
VOLUME 20 NUMBER 1 FEBRUARY 2002

265

266

BLUMENTHAL & GLENN

Usually the anemia is manifest before the neurologic syndrome appears, but, rarely, neurologic symptoms may precede the hematologic disorder. Treatment with intramuscular injections of vitamin B12 results in dramatic and almost immediate improvement of the anemia, but neurologic improvement is usually slower, taking place within 2 months of therapy. Because the underlying defect causing vitamin B12 deciency is irreversible, lifelong replacement is required.71 Sickle-Cell Disease Sickle-cell disease is a hemoglobinopathy that stems from the inheritance of two mutated alleles encoding the beta chain of adult hemoglobin, which generates abnormal hemoglobin, typically HbS or sickle hemoglobin. When deoxygenated, sickle hemoglobin tends to irreversibly polymerize, and the normally pliant red blood cell becomes sickle shaped and rigid. This leads to vaso-occlusion and ischemia and infarction of end organs, including the neurologic system, and causes the severe and often intractable pain associated with sickle-cell disease. Other complications result from moderate-to-severe anemia caused by the continuous hemolysis of the abnormal red blood cells, thrombosis, and infection, all of which contribute to the neurologic manifestations of the disease.89 Twenty-ve percent of patients with sickle-cell disease have neurologic complications, including transient ischemic attack (TIAs), cerebrovascular accident (CVAs), intracerebral hemorrhage (ICH), seizures, coma, spinal cord infarction, central nervous system (CNS) infections, and sensorineural hearing loss.52, 65, 81 Patients with more severe anemia are at higher risk for CVA, as are older patients and those with high reticulocyte and white blood cell counts.4, 103 CVAs recur within 3 years in approximately 70% of this population and are fatal in 20% of presenting cases. Seventy percent to 80% of CVAs in sickle-cell disease are thrombotic. The recommended treatment for thrombotic CVA is immediate partial exchange transfusion, followed by chronic transfusions to prevent recurrence.78 Another cerebrovascular phenomenon seen in the setting of sicklecell disease is Moya-Moya (Japanese for puff of smoke), which can result from stenosis of major intracranial vessels, with formation of fragile collaterals. These small vessels are vulnerable to thrombosis and hemorrhage.83 Clinically silent infarcts in sickle-cell disease result in abnormal neurodevelopment and poor scholastic performance.96 Positron emission tomography scans may be useful in identifying otherwise silent areas of ischemia and in evaluating metabolic responses to interventions/ transfusions;64 however, positron emission tomography may not be sensitive enough to detect small vessel ischemic disease, for which conventional magnetic resonance imaging and detailed neuropsychological testing seem more sensitive.69 Both Streptococcus pneumoniae and Haemophilus inuenza type b, the most common causes of bacteremia in children with sickle-cell disease,

NEUROLOGIC MANIFESTATIONS OF HEMATOLOGIC DISORDERS

267

can lead to meningitis. Rapid initiation of antibiotics and immunization with the conjugate vaccine for H. inuenza has lessened the incidence of these potentially fatal CNS infections.58, 102 THROMBOCYTOPENIA Decreased platelet counts occur in many settings and are caused by either decreased production or increased destruction. Bone marrow suppression caused by medications, immune-mediated thrombocytopenia, heparin-induced thrombocytopenia, and myelophthisic processes, and increased destruction from hypersplenism and consumption are common causes of acquired thrombocytopenia. Whatever the underlying cause, a serious complication of thrombocytopenia is spontaneous intracranial bleeding, with an increased likelihood as the platelet count drops below 10,000/L. Prompt supportive measures with treatment of the primary disorder and platelet transfusion are required, except in the case of thrombotic thrombocytopenia/hemolytic uremic syndrome (TTP/HUS) (see subsequent section). Correction of any accompanying coagulation dysfunction is also important. Antibrinolytic therapy may benet some patients as long as no evidence for disseminated intravascular coagulation exists.8, 23 Heparin-Induced Thrombocytopenia Heparin-induced thrombocytopenia deserves special mention because it may be encountered by neurologists when treating cerebrovascular events. A mild thrombocytopenia can be associated with heparin use within 2 days to weeks of starting therapy, through platelet aggregation triggered by heparin. Therapy can usually be continued if the platelet count remains above 100,000/mm.21, 75 Treatment with heparin can also induce a severe immune-mediated thrombocytopenia 1 to 2 weeks after initial treatment. This can be paradoxically associated with arterial thrombosis, which may manifest as stroke.44 In these circumstances, heparin therapy should be discontinued and alternative treatments considered. There may be cross-reactivity with low molecular weight heparin.32 Thrombotic Microangiopathy Thrombotic microangiopathies or microangiopathic hemolytic anemias (MAHA) often have neurologic consequences. The underlying pathogenesis is widespread microvascular thrombosis and hemolytic anemia. TTP/HUS and disseminated intravascular coagulation (DIC) are examples of MAHA. The most common MAHA is DIC, which is seen in association with many systemic illnesses. Large brain hemorrhage from DIC is relatively rare, but petechial hemorrhages in the white matter are commonly

268

BLUMENTHAL & GLENN

seen at autopsy.24 Treatment of DIC addresses the underlying cause of systemic disease/disorder, replacement of depleted clotting factors, and anticoagulation. Heparin therapy (but not warfarin) may be benecial in some cases.38 Thrombotic Thrombocytopenia/Hemolytic Uremic Syndrome The classic description of TTP includes a pentad of diagnostic criteria: thrombocytopenia, hemolytic anemia, renal insufciency, neurologic symptoms, and fever.1 Less strict criteria used require only unexplained thrombocytopenia and hemolytic anemia.31 Hemolytic uremic syndrome (HUS) occurs more commonly in children, with a higher incidence of renal insufciency and less likely incidence of neurologic consequences. The inciting event of both processes is believed to be endothelial injury with an abnormal propagation of thrombosis.32, 77 TTP is caused by either immunologically mediated inhibition of von Willebrand factor cleavage or deciency of the cleaving protease, whereas the underlying pathogenesis of HUS remains obscure.29, 93 Neurologic impairment is seen in more than 80% of patients with TTP. Gray matter is affected more than white matter by platelet thrombi, manifesting in headache, cognitive changes, paresis, aphasia, visual disturbances, seizures, cranial nerve palsies, paresthesias, vertigo, and coma.53 Prompt treatment of patients with TTP with plasma exchange is remarkably effective, transforming an almost universally fatal disease to one with a 90% response rate.7, 72 Platelet transfusions should be avoided because they may exacerbate the disease; therefore, rapid recognition and diagnosis are crucial. HYPERCOAGULABLE STATES Hypercoagulability that leads to neurologic thrombotic complications (stroke) can be hereditary, acquired, or associated with certain risk factors. Some of the more common acquired causes include malignancy or disease-related hypercoagulability; treatment-related states (L-asparaginaseinduced antithrombin III deciency, heparin-induced thrombocytopenia); estrogen administration; homocystinuria; and postoperative and immobile states. Both proteins C and S deciencies have been described in families with reduced levels of the respective circulating protein and associated recurrent thromboses. Events can occur spontaneously or be precipitated by risk factors, usually after the patients early 20s. Both of these hereditary deciencies should be considered in screening for hypercoagulable abnormalities when thrombotic arterial stroke occurs in a young person. Treatment with oral anticoagulation or heparin can prevent recurrent thrombotic events.20, 25, 37, 61, 84 Antiphospholipid syndrome manifests as arterial or venous thromboses, recurrent fetal loss, and thrombocytopenia. Signicantly elevated

NEUROLOGIC MANIFESTATIONS OF HEMATOLOGIC DISORDERS

269

anticardiolipin antibodies and positive lupus anticoagulant states are diagnostic for this syndrome in the proper clinical setting. Systemic lupus erythematosus may be associated with this syndrome; but more often than not, antiphospholipid syndrome occurs alone, unrelated to connective tissue disease.35 Pregnancy Pregnancy and puerperium are associated with a hypercoagulable state that can lead to central venous thrombosis. Central sinus thrombosis may present clinically with headache, papilledema, change in level of consciousness, seizures, or focal motor, sensory, or visual decits. The placenta produces a specic plasminogen activator inhibitor, which may explain the higher incidence of sinus occlusion seen during pregnancy.67 Additionally, cases of sinus thrombosis in the puerperal period are associated with states of dysfunctional or decreased proteins C and S.74 Treatment with heparinization is recommended.94 Cancer Cancer is often associated with a hypercoagulable state caused by tumor-cell procoagulants and chemotherapy-induced disruption of normal coagulation.28 Cancer-associated nonbacterial thrombotic endocarditis can cause multiple strokes from arterial occlusion and should be suspected in patients with malignancy and CNS symptoms.10, 85 Neurologic symptoms from nonbacterial thrombotic endocarditis can precede the diagnosis of an occult malignancy.73 HEMATOLOGIC MALIGNANCIES In general, malignant disorders of the bone marrow cause decreased production of normal blood cells, leading to bleeding from thrombocytopenia, infections caused by leukopenia and impaired immunity, and neurologic complications such as fatigue and dizziness from severe anemia. Increased numbers of abnormal clonal cells also cause neurologic sequelae, typically caused by endothelial inltration with leukemic cells, hyperviscosity, and thrombosis. Production of large amounts of monoclonal antibodies in some lymphoproliferative disorders such as multiple myeloma is another common cause of neurologic symptoms in these patients. MYELOPROLIFERATIVE DISORDERS The myeloproliferative disorders are characterized by often massive production of normal-appearing blood cells. These are more indolent diseases than the acute leukemias and require management over long

270

BLUMENTHAL & GLENN

periods of time. Therapy is focused initially on control of this abnormal production. In time, however, patients develop problems because of decreased production of normal blood cells and transformation to acute leukemia, with a dismal prognosis. Polycythemia vera (PCV) and essential thrombocytosis are examples of myeloproliferative disorders with unique neurologic complications. Polycythemia Vera PCV is a chronic hematologic malignancy resulting in splenomegaly and increased numbers of erythrocytes, leukocytes, and platelets. Untreated PCV may have a prognosis as short as 18 months. The disease is believed to be a result of increased responsiveness of hematopoietic progenitor cells to regulatory molecules, which then go on to form malignant clones. Individuals with PCV can survive for extended periods of time, more than 10 years, if their red blood cells and platelets can be controlled, but they are often at risk for later developing myelobrosis or acute leukemia.97 Commonly used treatments include periodic phlebotomy to maintain a near normal hematocrit, hydroxyurea or P32 .34, 90 Phlebotomy may increase the risk of thrombosis in some patients.9, 99, 104 Patients may present with nonfocal neurologic complaints, such as headache, dizziness, paresthesias, and vision changes. Gastrointestinal symptoms from massive splenomegaly, weight loss, and gout are other common presenting complaints. Sixty percent to 80% of poorly controlled PCV patients will have neurologic events, including TIAs, CVAs, cerebral hemorrhage, confusion, or movement disorders. These are most commonly caused by vascular thrombosis from increased erythrocytes, and thrombosis may be the cause of death in 30% to 40% of patients with PCV.54, 60 Small penetrating end arteries (to the basal ganglia) seem particularly vulnerable to thrombosis.59 Pre-existing atherosclerotic disease and smoking may further heighten the risk for thrombotic events in this population. Several cases of cavernous sinus thrombosis have been reported.51 Hemorrhagic events are also relatively common in PCV. Anti-inammatory drugs that inhibit platelet function are associated with increased bleeding risk and should not be routinely prescribed for these patients.5 Other symptoms such as tinnitus, dizziness, paresthesias, and headaches may be caused by hyperviscosity, and peripheral ischemia, despite palpable pulses, may cause erythromelalgia or burning pain in the extremities.87 Essential Thrombocytosis Essential thrombocythemia is a related disorder of markedly increased numbers (> 600,000/L) of normal-appearing platelets. Like PCV and other myeloproliferative disorders, splenomegaly is a frequent

NEUROLOGIC MANIFESTATIONS OF HEMATOLOGIC DISORDERS

271

presenting physical nding, and thrombotic and hemorrhagic complications are common. Neurologic complaints in these patients are common, including headaches, paresthesias, and TIAs, and are typically caused by thrombosis.87 Smoking clearly increases this risk.98 Therapy is directed to lowering the platelet count. Emergency platelet pheresis can transiently lower the counts, whereas hydroxyurea, anagrelide, or other chemotherapy agents can control them more denitively. Therapy with anti-platelet drugs is controversial in these patients because it may increase bleeding risks, as in PCV.46, 79 Chronic Myelogenous Leukemia Chronic myelogenous leukemia is another example of a myeloproliferative disorder, characterized primarily by increased numbers of myeloid cells, typically 100,000300,000/L at diagnosis. Three phases of the disease are recognized: chronic phase, accelerated, and blast crisis. Blast crisis refers to the transformation to acute leukemia, again with a dismal outcome. Neurologic complications typically stem from hyperviscosity and intracerebral leukostasis. Interestingly, this is not seen in chronic phase chronic myelogenous leukemia despite exceedingly high white blood cells; however, once the transformation to acute leukemia has occurred, leukostasis can occur at much lower white blood cells (e.g., 100,000/L or even lower).49 Acute Leukemia The acute leukemias are distinctive disorders characterized by massive and rapid proliferation of clonal, immature white blood cells called blasts. Underlying chromosomal abnormalities are typically seen, and many are nonrandom and characteristic of morphologic subtypes of acute leukemia.101 Cloning of the involved genes has led to heightened understanding of the molecular underpinnings of malignancy and normal cell cycle control.17, 67, 76 Complications from acute leukemia, including neurologic ones, stem from anemia, thrombocytopenia, immunodeciency, and leukostasis. Iatrogenic complications also occur from the very intensive treatments used for acute leukemia. Acute Myelogenous Leukemia Acute myelogenous leukemia (AML) is a disease typically of the elderly. Myeloid leukemic blasts are identied by morphology, immunohistochemistry, and immunophenotyping. Patients present with fatigue, bleeding, or infection. CNS complications are caused by hemorrhage, leukostasis, or leukemic inltration of the CNS. Risk for hemorrhage is increased in patients with both thrombocytopenia and coagulation disorders such as disseminated intravascular coagulation (DIC). DIC is

272

BLUMENTHAL & GLENN

most common disorder in acute promyelocytic leukemia (APL), in which the leukemic blasts appear arrested at the promyelocytic stage of differentiation. It occurs in up to 60% of APL patients on presentation or during initial therapy. Risk of fatal hemorrhage, often intracerebral, is increased by thrombocytopenia, older age, anemia, and high blast counts. Low-dose heparin is sometimes used in this setting, although it is controversial and not routinely recommended. Symptoms of CNS leukostasis may occur at blast counts of greater than 50,000100,000/L and require immediate attempts to lower the blast count. This is most effectively achieved by prompt treatment with aggressive chemotherapy. Leukopheresis is often employed initially concomitantly to lower the white blood cells acutely. Prognosis is poor in this setting. Approximately 5% to 7% of patients have cerebrospinal involvement with leukemic blasts at presentation. High blast counts, monocytic morphology, and high leukocyte dehydrogenase (LDH) predispose to CNS involvement. Patients may be asymptomatic, complain of headaches, or have cranial neuropathies (typically facial weakness, facial paresthesias, or optic nerve inltration and acute blindness). Individuals with CNS involvement who have > 50,000/L circulating blasts are at risk for serious events related to hyperviscosity and leukemic small vessel emboli, which may manifest in intracerebral leukostatic hemorrhage. Radiation therapy to the involved nerve root symptoms can reverse neurologic decits if started quickly time after presenting symptoms. Median survival time after diagnosis of CNS involvement in AML is 6 months, with death related to bone marrow failure from hematologic relapse.19 Therapy for AML consists of supportive treatment with blood product support and aggressive treatment of infection. Prompt initiation of cytotoxic therapy is essential, with measures to prevent tumor lysis syndrome and hyperuricemia. The goal of induction therapy is remission. Further cycles of chemotherapy are required to ensure long-term remission, although overall survival rates for most AML patients remain low. Cytarabine remains a mainstay of therapy for AML, and high-dose schedules are more commonly employed. Cytarabine is associated with neurotoxicity, primarily cerebellar dysfunction, in up to 12% of treated patients.3 High-dose chemotherapy and stem cell rescue are often recommended for select patients. Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia (ALL) is a disease typically seen in children. In fact, of the 3000 cases of ALL diagnosed annually, two thirds are in children. Children typically present with pallor, fatigue, bleeding, and fever. Bone pain can be a common presentation. Children with specic genetic syndromes, such as Down syndrome and ataxiatelangiectasia, are at increased risk of developing ALL. Before modern treatment regimens were developed, ALL was a fatal disease with a 2 to 3 month survival rate. Now the disease is curable in up to 80% of cases.36, 66

NEUROLOGIC MANIFESTATIONS OF HEMATOLOGIC DISORDERS

273

Although the CNS is rarely involved at presentation (less than 5% in children and 15% in adults), without prophylactic treatment, unlike AML, most patients will develop CNS disease, with associated increased mortality risks.13 Therefore, CSF is examined early in the course of the disease to rule out subclinical involvement, and prophylactic intrathecal treatment during and after induction chemotherapy is routine. This has contributed greatly to the improved survival rates of these patients. There has been much debate regarding prophylactic cranial irradiation in children with ALL. Radiation can put children at later risk for developmental delays, as well as neurocognitive disorders and second malignancies.57, 70 Unfortunately, CNS relapse is high when cranial irradiation is withheld, and radiation is routinely given as part of the initial treatment regimen. Risk stratication strategies are now employed to spare those children at low risk from CNS relapse the toxicity from unnecessary prophylactic treatments.12, 30 Infants diagnosed with ALL are at particularly high risks for CNS disease, and so are treated with high-dose systemic methotrexate and intrathecal methotrexate and cytarabine. Studies of neurodevelopmental outcomes in these infants show that they seem to do well with this chemotherapy approach, withholding radiation, and have reduced CNS relapse rates.42 Other studies suggest neurotoxicity of both acute/subacute and permanent, debilitating nature associated with methotrexate in the context of ALL treatment protocols.86 Involvement of the CNS is believed to occur through hematogenous seeding of the meninges.91 Neurologic involvement may manifest with signs of increased intracranial pressure, such as headache, nausea and vomiting, mental status change, depressed level of consciousness, or papilledema. Cranial neuropathy may also be present. Diagnosis is determined by the nding of leukemic cells on cytology. Median survival rate after diagnosis of CNS leukemia in ALL is 8 months.19 Treatment recommendations for children presenting with CNS involvement include intensive intrathecal cytarabine treatments until no leukemic blasts are detected on cytology, followed by cranial irradiation and continued intrathecal drugs.14 Bone pain in ALL is a common presenting complaint. Rarely, patients may present with vertebral collapse from spinal involvement as a presenting symptom, even with normal peripheral blood cell counts.43, 50 The back pain associated with fracture is typically relieved after chemotherapy.80 Chronic Lymphocytic Leukemia Chronic lymphocytic leukemia (CLL) deserves mention as the most common type of leukemia in the United States, with 10,000 new cases diagnosed annually. The leukemic cell of CLL is a mature-appearing B-lymphocyte that accumulates gradually without evidence of active proliferation, with sustained peripheral counts of 5 109 /L (usually > 20 109 /L), and > 30% lymphocytes in bone marrow. Again, this is a disease of the elderly, with a mean age at diagnosis of about 55. CLL is often

274

BLUMENTHAL & GLENN

discovered incidentally when a routine complete blood count (cbc) is obtained. Occasionally, patients present with systemic symptoms such as fatigue, night sweats, and fever. Lymphadenopathy, splenomegaly, and hepatomegaly are often found on examination. Immune suppression is a common feature of CLL, and patients are susceptible to frequent bacterial and viral infections. Prognosis varies from an aggressive course with 2 to 3 years of survival, to more indolent disease, with a life span of 10 to 20 years. Therapy is initially withheld until prompted by signicant progression of disease or symptoms. CLL is typically quite responsive to initial cytotoxic therapies, including alkylators or purine analogues, such as udarabine. Neurologic symptoms from CLL are rare. Leukocytosis and hyperviscosity are not typical syndromes. Although CNS inltration in CLL may be frequent (as high as 50% in one autopsy study of a small number of CLL patients), it is rarely symptomatic.16 Although CNS infection must be ruled out, meningeal leukemia should be suspected in patients with CLL who have neurologic symptoms, such as confusion, cranial neuropathy, optic nerve involvement with visual disturbances, and cerebellar symptoms.41, 88 Cerebrospinal uid (CSF) examination by cytology and ow cytometry reveals a clonal population of CSF lymphocytes. These patients can have durable response to intrathecal chemotherapy and cranial irradiation but often dies of infection related to underlying disease.26, 95 Monoclonal Gammopathies Monoclonal gammopathies are a group of plasma cell disorders characterized by the secretion of abnormal, monoclonal immunoglobulins, detected as an M spike on serum or urine electrophoresis. Monoclonal gammopathy of uncertain signicance, multiple myeloma, Waldenstroms macroglobulinemia, and amyloidosis are examples. Neurologic symptoms can be caused by immunoglobulin deposition in peripheral nerves causing peripheral neuropathy, spinal cord compression from plasmacytomas of the vertebral bodies or vertebral collapse, and nonspecic symptoms from anemia or treatment-related toxicities. Multiple Myeloma Multiple myeloma is also a disease of the elderly, with peak incidence in the seventh decade of life. The diagnosis is made by demonstration of a signicant level of monoclonal immunoglobulin production, inltration of the bone marrow with plasma cells or biopsy-proven plasmacytoma, and osteolytic lesions on radiologic examination. The myeloma protein is typically IgG or, less commonly, IgA. Kappa light chains are more common than lambda light chains. Patients commonly present with bone pain or even vertebral compression fracture. Pallor, weakness, fatigue, and anemia are also common at presentation.

NEUROLOGIC MANIFESTATIONS OF HEMATOLOGIC DISORDERS

275

The most common neurologic symptom in multiple myeloma is radiculopathy secondary to vertebral bone collapse. A small percentage of patients may have spinal cord compression (myelopathy) from myeloma extending from the vertebral marrow into the epidural space. Immediate treatment of spinal cord compression with high-dose corticosteroids and local radiotherapy is imperative. Surgical decompression is typically used for radiotherapy failure, but occasionally used as initial therapy. Unlike Waldenstroms macroglobulinemia, peripheral neuropathy is un common. When present, it is often associated with amyloidosis. Leptomeningeal inltration has been described rarely.18, 48 Atypical plasma cells of a monoclonal population can be identied in the cerebrospinal uid. Treatment with intrathecal chemotherapy and/or craniospinal irradiation can be successful, but overall prognosis is often poor, with a survival rate of approximately 6 months.22 Median survival rate in multiple myeloma is 2.5 to 3 years. Treatment is recommended for clinically symptomatic disease, and studies show no advantage to early treatment.39 Cure is not possible with current standard treatments, but signicant responses of greater than 50% are seen with commonly used regimens. Treatment includes cytotoxic chemotherapy and corticosteroids such as melphalan and prednisone. More aggressive combination regimens have been employed, such as infusional vincristine, doxorubicin, and high-dose dexamethasone. Highdose chemotherapy and stem cell rescue, from either autologous or allogeneic sources, are being explored. Radiation is useful for treatment of painful bony lesions that have failed chemotherapy treatment. Interestingly, recent studies show as high as a 30% response rate to therapy with thalidomide for relapsed myeloma, even in cases relapsing after transplantation. The mechanism of action is unclear, but may be through anti-angiogenesis.68 Studies exploring the use of thalidomide for initial treatment are underway. Neurologic toxicity from thalidomide, including peripheral neuropathy and somnolence, is common. Waldenstroms Macroglobulinemia Waldenstroms macroglobulinemia is characterized by uncontrolled growth of lymphoplasmacytoid lymphocytes with a circulating monoclonal IgM serum protein. The disease is rare, 2.5 per million annually, and much less common than multiple myeloma.33 Patients can present with weakness, fatigue, and bleeding, and most patients have moderate to severe normocytic normochromic anemia. Several neurologic sequelae are reported in Waldenstroms macroglobulinemia, and most are related to hyperviscosity caused by the tendency of the multivalent IgM to aggregate. Sensorimotor peripheral neuropathy is common also, with myelin-associated glycoprotein antibodies found in 50% of cases.56 Hyperviscosity syndrome related to high levels of the IgM monoclonal protein may cause papilledema and visual disturbances. Dizziness,

276

BLUMENTHAL & GLENN

headache, vertigo, ataxia, paresthesias, and depressed levels of consciousness leading to coma may also manifest from hyperviscosity.15 Plasma exchange, with rapid relief of symptoms, is the therapy of choice for hyperviscosity syndrome associated with macroglobulinemia and myeloma.45 The Bing-Neel syndrome has been used to describe the CNS symptoms seen in macroglobulinemia, now known largely to be related to hyperviscosity.11 Neurologic symptoms reported include acute deafness, progressive spinal muscular atrophy, and leukoencephalopathy.63 In addition to causing hyperviscosity, paraproteins may inltrate the cerebral vessels and white matter, causing inammation and demyelination.82 Inltration of neoplastic macroglobulins in the brain parenchyma may respond to focal irradiation.40 POEMS POEMS is an acronym describing a multisystem disorder characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes. Thrombocytosis or polycythemia may also accompany these symptoms. POEMS is typically associated with either osteosclerotic myeloma, or, in 50% of the cases, with Castlemans disease (also known as angiofollicular lymph node hyperplasia), which is believed to be a condition of reactive chronic lymphoid hyperplasia. The diagnosis of POEMS requires recognition of the clinical syndrome. Circulation of a lambda light chain monoclonal protein is seen, usually in small amounts. Bone marrow plasmacytosis is usually less than 15%. Five-year survival rate is approximately 60%.6 The associated polyneuropathy is a severe sensory-motor mixed type. No standard therapy exists, but the disease may respond to treatments similar to those for multiple myeloma. Plasma exchange and immunosuppressive therapy have shown varied responses.55 Therapy with radiation for neuropathy associated with solitary bone lesions in POEMS of osteosclerotic myeloma can be effective for symptom relief.100 Amyloidosis Amyloidosis is a condition characterized by accumulation of monoclonal light chains of amyloid brils. There are several different categories of amyloidosis, distinguished by association with other conditions. The primary form of amyloidosis may be associated with multiple myeloma. Type I familial amyloidosis is seen in families from Japan, Sweden, and Portugal, and is characterized by a sensorimotor neuropathy predominant in the lower extremities, affecting young adults, and autonomic/ gastrointestinal dysfunction.2 Type II disease, described in a family from Indiana, manifests with carpal tunnel syndrome and later sensorimotor neuropathy, occurring in middle to late ages.

NEUROLOGIC MANIFESTATIONS OF HEMATOLOGIC DISORDERS

277

ACKNOWLEDGMENT
The authors thank Susan Schulman for her invaluable assistance in the preparation and editing of this manuscript.

References
1. Amorosi E, Ultmann J: Thrombotic thrombocytopenic purpura: Report of 16 cases and review of the literature. Medicine 45:139159, 1966 2. Andrade C: A peculiar form of peripheral neuropathy: Familiar atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain 75:408427, 1952 3. Baker WJ, Royer GL, Weiss RB: Cytarabine and neurologic toxicity. J Clin Oncol 9:679 693, 1991 4. Balkaran B, Char G, Morris JS, et al: Stroke in a cohort of patients with homozygous sickle-cell disease. J Pediatr 120:360366, 1992 5. Barbui S, Buelli M, Cortellazzo S, et al: Aspirin and risk of bleeding in patients with thrombocythemia. Am J Med 83:265268, 1987 6. Bardwick PA, Zvaier NJ, Resnick DL, et al: Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes: The POEMS syndrome. Report on two cases and a review of the literature. Medicine 59:311322, 1980 7. Bell WR, Braine HG, Ness PM, Kickler TS: Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. N Engl J Med 325:398403, 1991 8. Benson K, Fields K, Hiemenz J, et al: The platelet-refractory bone marrow transplant patient: Prophylaxis and treatment of bleeding. Semin Oncol 20:102109, 1993 9. Berk PD, Goldberg JN, Donovan PB, et al: Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Semin Hematol 23:132143, 1986 10. Biller J, Challa VR, Toole JF, Howard VJ: Nonbacterial thrombotic endocarditis. A neurologic perspective of clinicopathologic correlations of 99 patients. Arch Neurol 39:95 98, 1982 11. Bing J, Neel AV: Two cases of hyperglobulinemia with affection of the central nervous system on a toxic-infectious basis. Acta Med Scand 88:492506, 1936 12. Biondi A, Cimino G, Pieters R, Pui CH: Biological and therapeutic aspects of infant leukemia. Blood 96:2433, 2000 13. Bleyer WA: Central nervous system leukemia. Pediatr Clin North Am 35:789814, 1988 14. Bleyer WA, Poplack DG: Prophylaxis and treatment of leukemia in the central nervous system and other sanctuaries. Semin Oncol 12:131148, 1985 15. Bloch KJ, Maki DG: Hyperviscosity syndromes associated with immunoglobulin abnormalities. Semin Hematol 10:113124, 1973 16. Bojsen-Moller M, Nielsen JL: CNS involvement in leukaemia. An autopsy study of 100 consecutive patients. Acta Pathol Microbiol Immunol Scand 91:209216, 1983 17. Boxer LM: The role of oncogenes in hematologic malignancies. Annu Rev Med 45:1 11, 1994 18. Brenner B, Nagler A, Viener A, et al: Partial response of meningeal myeloma to craniospinal radiotherapy. Scand J Haematol 37:360362, 1986 19. Brinch L, Evensen SA, Stavem P: Leukemia in the central nervous system. J Intern Med 224:173178, 1988 20. Camerlingo M, Finazzi G, Casto L, et al: Inherited protein C deciency and nonhemorrhagic arterial stroke in young adults. Neurology 41:13711373, 1991 21. Carmel R: Prevalence of undiagnosed pernicious anemia in the elderly. Arch Intern Med 156:10971100, 1996 22. Cavanna L, Invernizzi R, Buscarini L, et al: Meningeal involvement in multiple myeloma: Report of a case with cytologic and immunocytochemical diagnosis. Acta Cytol 40:571575, 1996

278

BLUMENTHAL & GLENN

23. Chakrabarti S, Varma S, Singh S, Kumari S: Low dose bolus aminocaproic acid: An alternative to platelet transfusion in thrombocytopenia? Eur J Haematol 60:313314, 1998 24. Collins RC, Al-Mondhiry H, Chernik NL, et al: Neurologic manifestation of intravascular coagulation in patients with cancer. A clinicopathologic analysis of 12 cases. Neurology 25:795806, 1975 25. Comp PC, Esmon CT: Recurrent venous thromboembolism in patients with a partial deciency of protein S. N Engl J Med 311:15251528, 1984 26. Cramer SC, Glaspy JA, Louis DN, et al: Chronic lymphocytic leukemia and the central nervous system: A clinical and pathological study. Neurology 46:1925, 1996 27. Elwood PC, Waters WE, Greene WJW, et al: Symptoms and circulating haemoglobin level. J Chron Dis 21:615628, 1969 28. Falanga A, Donati MB: Pathogenesis of thrombosis in patients with malignancy. Int J Hematol 73:137144, 2001 29. Furlan M, et al: von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 339:15781584, 1998 30. Friedmann AM, Weinstein HJ: The role of prognostic features in the treatment of childhood acute lymphoblastic leukemia. Oncologist 5:321328, 2000 31. George JN: How I treat patients with thrombotic thrombocytopenic purpurahemolytic uremic syndrome. Blood 96:12231229, 2000 32. Gerhard-Herman M: Heparin-induced thrombocytopenia: Current treatment options in cardiovascular medicine 3:215224, 2001 33. Gertz MA, Fonseca R, Rajkumar SV: Waldenstroms macroglobulinemia. Oncologist 5:6367, 2000 34. Gilbert HS: Current management in polycythemia vera. Semin Hematol 38:2528, 2001 35. Greaves M: Antiphospholipid syndrome: State of the art with emphasis on laboratory evaluation. Haemostasis 2:1625, 2000 36. Greaves M: Molecular genetics, natural history and the demise of childhood leukaemia. Eur J Cancer 35:19411953, 1999 37. Grifn JH, Evatt B, Zimmerman TS, et al: Deciency of protein C in congenital thrombotic disease. J Clin Invest 68:13701373, 1981 38. Gurewich V, Lipinski B: Low-dose heparin in the treatment of disseminated intravascular coagulation. Am J Med Sci 274:8386, 1977 39. Hjorth M, Hellquist L, Holmberg E, et al: Initial versus deferred melphalanprednisone therapy for asymptomatic multiple myeloma stage Ia randomized study. Eur J Haematol 50:95102, 1993 40. Imai F, Fujisawa K, Kanno T, et al: Intracerebral inltration by monoclonal plasmacytoid cells in Waldenstroms macroglobulinemiaCase report. Neurol Med Chir 35: 575579, 1995 41. Jego P, Le Strat A, Leblay R, et al: Cryptococcal meningitis associated with chronic lymphocytic leukemia: A case report. Review of the literature. Rev Med Interne 21:83 85, 2000 42. Kaleita TA, Reaman GH, Whitt JK, et al: Neurodevelopmental outcome of infants with acute lymphoblastic leukemia: A Childrens Cancer Group report. Cancer 85:1859 1865, 1999 43. Kayser R, Mahlfeld K, Nebelung W, Grasshoff H: Vertebral collapse and normal peripheral blood cell count at the onset of acute lymphatic leukemia in childhood. J Pediatr Orthop 9:5557, 2000 44. Kelton JG, Sheridan D, Santos A, et al: Heparin-induced thrombocytopenia: Laboratory studies. Blood 72:925930, 1988 45. Kes P, Pecanic Z, Getaldic B, Ratkovic-Gusic I: Treatment of hyperviscosity syndrome in the patients with plasma cell dyscrasias. Acta Med Croatica 50:173177, 1996 46. Kessler CM, Klein HG, Havlik RJ: Uncontrolled thrombocytosis in chronic myeloproliferative disorders. Br J Haematol 50:157167, 1982 47. Lecander I, Astedt B: Isolation of a new specic plasminogen activator from pregnancy plasma. Br J Haematol 62:221228, 1986 48. Leifer D, Grabowski T, Simonian N, Demirjian ZN: Leptomeningeal myelomatosis

NEUROLOGIC MANIFESTATIONS OF HEMATOLOGIC DISORDERS

279

49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74.

presenting with mental status changes and other neurologic ndings. Cancer 70:1899 1904, 1992 McKee LC Jr, Collins RD: Intravascular leukocyte thrombi and aggregates as a cause of morbidity and mortality in leukemia. Medicine: 53:463478, 1974 Meehan PL, Viroslav S, Schmitt EW Jr: Vertebral collapse in childhood leukemia. J Pediatr Orthop 15:592595, 1995 Melamed E, Rachmilewitz EA, Reches A, Lavy S: Aseptic cavernous sinus thrombosis after internal carotid arterial occlusion in polycythemia vera. J Neurol Neurosurg Psychiatry 39:320324, 1976 Merkel KH, Ginsberg PL, Parker JC, et al: Cerebrovascular disease in sickle-cell anemia: A clinical, pathological and radiological correlation. Stroke 9:4552, 1978 Moschcowitz E: An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries: An undescribed disease. Arch Intern Med 35:8993, 1975 Najean Y, Mugnier P, Dresch C, Didier Rain J: Polycythemia vera in young people: An analysis of 58 cases diagnosed before 40 years. Br J Haemotol 67:285291, 1987 Nishimoto N, Sasai M, Yoshizaki K, et al: Improvement in Castlemens disease by humanized anti-interleukin-6 receptor antibody therapy. Blood 95:5661, 2000 Nobile-Orazio E, Marmiroli P, Baldini L, et al: Peripheral neuropathy in macroglobulinemia: Incidence and antigen-specicity of M proteins. Neurology 37:1506 1514, 1987 Ochs J, Mulhern RK: Late effects of antileukemic treatment. Pediatr Clin North Am 35:815833, 1988 Overturf GD, Powars D, Baraff LJ: Bacterial meningitis and septicemia in sickle-cell disease. Am J Dis Child 131:784787, 1977 Pearch JMS, Chandrasekera CP, Ladusans EJ: Lacunar infarcts in polycythemia with raised packed cell volumes. Br Med J 287:935, 1983 Pearson TC, Wetherly-Mein G: Vascular occlusive episodes and venous haematocrit in primary proliferative polycythemia. Lancet 2:12191222, 1978 Pescatore SL: Clinical management of protein C deciency. Expert Opin Pharmacother 2:431439, 2001 Pisoni R, Remuzzi G. Thrombotic microangiopathy. Eur J Intern Med 11:135139, 2000 Platia EV, Saral R: Deafness and Waldenstroms macroglobulinemia. South Med J 72:14951496, 1979 Powars DR, Conti PS, Chan LS, et al: Cerebral vasculopathy in sickle-cell anemia: Diagnostic contribution of positron emission tomography. Blood 93:7179, 1999 Powars DR, Wilson B, Imbus C, et al: The natural history of stroke in sickle-cell disease. Am J Med 65:461471, 1978 Pui CH: Acute lymphoblastic leukemia in children. Curr Opin Oncol 12:312, 2000 Rabbitts TH: Chromosomal translocations in human cancer. Nature 372:143149, 1994 Rajkumar SV: Thalidomide in multiple myeloma. Oncology 14:1116, 2000 Reed W, Jagust W, Al-Mateen M, Vichinsky E: Role of positron emission tomography in determining the extent of CNS ischemia in patients with sickle-cell disease. Am J Hematol 60:268272, 1999 Rimm IJ, Li FP, Tarbell NJ, et al: Brain tumors after cranial irradiation for childhood acute lymphoblastic leukemia. Cancer 59:15061508, 1987 Robertson DM, Dinsdale HB, Campbell RJ: Subacute combined degeneration of the spinal cord. Arch Neurol 24:203209, 1971 Rock GA, Shumak KH, Buskard NA, et al: Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med 325:393397, 1991 Rogers LR, Cho ES, Kempin S, Posner JB: Cerebral infarction from non-bacterial thrombotic endocarditis. Clinical and pathological study including the effects of anticoagulation. Am J Med 83:746756, 1987 Roos KL, Pascuzzi RM, Manco-Johnson MJ: Postpartum intracranial venous thrombosis associated with dysfunctional protein C and deciency of protein S. Obstet Gynecol 76:492494, 1990

280

BLUMENTHAL & GLENN

75. Rothrock JF, Hart RG: Antithrombotic therapy in cerebrovascular disease. Ann Intern Med 115:885895, 1991 76. Rowley JD: The critical role of chromosome translocations in human leukemias. Annu Rev Genet 32:495519, 1998 77. Ruggenenti P, Remuzzi G: Pathophysiology and management of thrombotic microangiopathies. J Nephrol 11:300310, 1998 78. Russell MO, Goldberg HI, Reis L, et al: Effect of transfusion on the arteriographic abnormalities and on the recurrence of stroke in sickle-cell disease. Blood 63:162169, 1984 79. Salem HH, van Der Weyden MB, Kouts J, Firkin BG: Leg pain and platelet aggregates in thrombocythemia myeloproliferative disease. JAMA 244:11221123, 1980 80. Santangelo JR, Thomson JD: Childhood leukemia presenting with back pain and vertebral compression fractures. Am J Orthop 28:257260, 1999 81. Sarnaik AS, Lusher JM: Neurologic complications of sickle-cell anemia. Am J Pediatr Hematol Oncol 4:386394, 1982 82. Scheithauer BW, Rubinstein LJ, Herman MM: Leukoencephalopathy in Waldenstroms macroglobulinemia. Immunohistochemical and electron microscopic observations. J Neuropathol Exp Neurol 43:408425, 1984 83. Schmugge M, Frischknecht H, Humbert J, et al: Stroke in hemoglobin (SD) sicklecell disease with moya moya: Successful hydroxyurea treatment after cerebrovascular bypass surgery. Blood 97:21652177, 2001 84. Schwarz HP, Fischer M, Hopmeier P, et al: Plasma protein S deciency in familial thrombotic disease. Blood 64:12971300, 1984 85. Schwartzman RJ, Hill JB: Neurologic complications of disseminated intravascular coagulation. Neurology 32:791797, 1982 86. Shuper A, Stark B, Yaniv I, et al: Methotrexate treatment protocols and the central nervous system: Signicant cure with signicant neurotoxicity. J Child Neurol 15:573580, 2000 87. Silverstein A, Gilbert H, Wasserman LR: Neurologic complications of polycythemia. Ann Intern Med 57:909916, 1962 88. Solal-Celigny P, Schuller E, Boivin P, et al: Cerebromeningeal location of chronic lymphoid leukemia. Rapid immunochemical diagnosis and complete remission by intrathecal chemotherapy. Presse Med 12:23232325, 1983 89. Steinberg MH: Management of sickle-cell disease. N Engl J Med 340:10211030, 1999 90. Tefferi A, Solberg LA, Silverstein MN: A clinical update in polycythemia vera and essential thrombocythemia. Am J Med 109:141149, 2000 91. Thomas L, Chirigos M, Humphreys S, Golden A: Pathology of the spread of L1210 leukemia in the central nervous system of mice and effect of treatment with cytoxan. J Natl Cancer Inst 28:13551368, 1962 92. Toh BH, van Driel IR, Gleeson PA: Pernicious anemia. N Engl J Med 337:14411448, 1997 93. Tsai H, Lian E: Antibodies to von Willebrand Factor-Cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 339:15851594, 1998 94. Villringer A, Garner C, Meister W, et al: High dose heparin treatment in cerebral sinus venous thrombosis. Stroke 19:135, 1988 95. Wang ML, Shih LY, Dunn P, Kuo MC: Meningeal involvement in B-cell chronic lymphocytic leukemia: Report of two cases. J Formos Med Assoc 99:775778, 2000 96. Wasserman AL, Williams JA, Fairclough DL, et al: Subtle neuropsychological defects in children with sickle-cell disease. Am J Pediatr Hematol Oncol 3:1420, 1991 97. Wasserman LR: Polycythemia veraIts course and treatment: Relation to myeloid metaplasia and leukemia. Bull NY Acad Med 3:343375, 1954 98. Watson KV, Key N: Vascular complications of essential thrombocythemia: A link to cardiovascular risk factors. Br J Haematol 83:198203, 1993 99. West W: Hydroxyurea in the treatment of polycythemia vera: A prospective study of 100 patients over a 20-year period. South Med J 80:323327, 1987 100. Wicklund MP, Kissel JT: Paraproteinemic neuropathy. Curr Treat Options Neurol 3:147156, 2001 101. Williams DL, Look AT, Melvin SL, et al: New chromosomal translocations correlate

NEUROLOGIC MANIFESTATIONS OF HEMATOLOGIC DISORDERS

281

with specic immunophenotypes of childhood acute lymphoblastic leukemia. Cell 36:101109, 1984 102. Wong W-Y, Powars DR, Chan L, et al: Polysaccharide encapsulated bacterial infection in sickle-cell anemia: A thirty year epidemiologic experience. Am J Hematol 39:176 182, 1992 103. Wood DH: Cerebrovascular complications of sickle-cell anemia. Stroke 12:7375, 1977 104. Zittoun R, EORTC Leukemia and Haematosarcoma Cooperative Group: Busulfan versus 32 P in polycythemia vera. Drugs Exp Clin Res 12:283285, 1986 Address reprint requests to Deborah T. Blumenthal, MD Neuro-oncology Huntsman Cancer Institute/University of Utah 2000 Circle of Hope, Suite 2152 Salt Lake City, UT 84112 email: deborah.blumenthal@hsc.utah.edu