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Opinion

VIEWPOINT
Management of Parkinson Disease in 2017
Personalized Approaches for Patient-Specific Needs
Michael S. Okun, MD Parkinson disease (PD) has been described as one of particularly in the absence of stringent monitoring. Fre-
Departments of the most complex syndromes encountered in clinical quent adjustment of drug dose and delivery interval are
Neurology and medicine. Long-term treatment with dopaminergic needed to address motor fluctuations and dyskinesia.
Neurosurgery,
agents, the mainstay of therapy, necessitates constant Two common clinical questions are what medication
University of Florida
Center for Movement recalibration and possibly additional pharmacological, toinitiateinearlyPDtreatmentandwhetheranytherapies
Disorders and behavioral, and surgical therapy. Numerous motor and may slow disease progression. In a study of 800 patients
Neurorestoration, nonmotor PD symptoms may complicate the diagnosis with PD, the monoamine oxidase type B (MAO-B) inhibi-
Gainesville.
and present therapeutic challenges (Figure). torselegilinedidnotslowdiseaseprogressionbutdidhave
a small symptomatic effect on medication wearing off and
Diagnosis and Multidisciplinary Care
PD motor symptoms.4 Rasagiline, a newer MAO-B formu-
ThediagnosticcriteriaforPDhavebeenrecentlybroadened
lation, was recently tested in a delayed-start trial of 1176
to consider premotor disease features. Symptoms such as
patients to test the possibility of disease modification.
anosmia, constipation, and rapid eye movement sleep be-
The results were controversial, with the 1-mg dose but not
havioral disorder commonly predate the occurrence of
the2-mgdosemeetingtheprimarymotorscoreendpoint;
the typical and recognizable motor features of tremor,
thus, this drug failed to achieve criteria for slowing disease
rigidity, bradykinesia, and shuffling gait. Depression, anxi-
progression.5 The Movement Disorders Society evidence-
ety,apathy,sleepdisorders,bladderdysfunction,andother
basedmedicinereviewrecommendsusingoneofmanyge-
nonmotorfeatureshavenowbeenrecognizedaspartofthe
neric or brand formulations of MAO inhibitors in patients
PD symptom complex. Although dopamine transporter
with early PD to address symptoms of primary PD and of
imaging has been approved by the US Food and Drug Ad-
wearingoffofthedrug.6 MAO-Binhibitorsinlowdosescan
ministration (FDA) to separate PD from essential tremor,
usually be combined safely with antidepressants.
this technique is expensive and rarely necessary.
Levodopa is a short-acting medication (half-life of 1-2
A multidisciplinary approach to PD treatment includ-
hours) when administered in combination with carbidopa.
ing physical, occupational, and speech and swallowing
Levodopa-induced dyskinesias are associated more with
therapy;neuropsychology;counselingpsychology;andso-
total levodopa dose and disease duration rather than by
cialworktherapyislikelybeneficial.PatientswithPDrequire
timingoflevodopainitiation.Within5years,halfofpatients
ongoing management of comorbidities such as hyperten-
treated with levodopa develop motor fluctuations and
sion, hypotension, diabetes, and heart failure, particularly
possibly dyskinesia. These issues can be addressed by
because many patients die of diseases other than PD. Pa-
changing drug dose, adjusting medication intervals, and
tients with PD have a substantial risk of falls and increased
possiblybyaddinganMAO-Boracatechol-O-methyltrans-
risk of osteoporosis; therefore, both men and women
ferase inhibitor, although the latter may increase dyskine-
shouldhavebonemineraldensityscreeningbasedongen-
sia.Severalrandomizedtrialshaveshownthatamantadine
eral geriatric guidelines. Patients with PD also have in-
can suppress PD-related dyskinesia, and recent evidence-
creasedriskofmelanomaunrelatedtodopaminetherapies,
based guidelines suggest it is likely efficacious.
andyearlyskinexaminationsarealsorecommended.There
Dopamine agonists such as pramipexole and ropiner-
isanexpandingpalliativecaremovementtobetterhelppa-
ole are longer acting than levodopa (6- to 8-hour half-life)
tientsinadvancedstagesofPDandtoassisttheircaregivers.
and have less dyskinesia but are not as potent for treat-
A substantial shift in the management of patients
ing motor symptoms. Based on evidence published in the
with PD has been the introduction of widespread use of
last 3 years, it is now common to use combinations of low-
exercise therapy, with recent studies suggesting a ben-
dose levodopa and dopamine agonists early in the disease
efit. Aerobic exercise, resistance strength training, and
to capitalize on synergistic effects and to delay dose-
tai chi are a few approaches with positive outcome data.
Corresponding dependent adverse effects of both medications. Ergot-
Author: Michael S. Pharmacologic Therapy based dopamine agonists, such as bromocriptine and per-
Okun, MD,
Two decades of debate on the early use of levodopa cre- golide, are no longer used because of associated heart
Departments of
Neurology and ated significant treatment uncertainty. However, 2 trials valve and pulmonary fibrosis. Apomorphine subcutane-
Neurosurgery, suggest there is no reason to withhold early levodopa ous injections can be used to address delay or difficulty
University of Florida therapy.1,2 Levodopa is considered the safest and most ef- in absorption of oral dopaminergic medications.
Center for Movement
Disorders and
ficacious medication for treatment of PD, and its use early Collectiveevidencehasrevealedthatnonmotorsymp-
Neurorestoration, following diagnosis should be considered. Dopamine toms and nonmotor fluctuations can be as disabling and
PO Box 100236, agonists,suchasropineroleandpramipexole,arealsocon- affect quality of life as much as PD motor symptoms. The
Room L3-100, sidered safe; however, there is a 2- to 3-fold increase in mostrecentMovementDisordersSocietyevidence-based
Gainesville, FL 32610
(okun@neurology.ufl the odds of emergence of impulse control disorders,3 re- recommendations suggested that it is likely efficacious to
.edu). ducing previous enthusiasm for early agonist initiation, treat depression, dementia, psychosis, constipation, and

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Opinion Viewpoint

Figure. Symptom Progression and Proposed Treatment of Parkinson Disease


Sequence of symptoms in progression of Parkinson disease
Early Late
Early symptoms Motor fluctuations Dyskinesias Emerging medication- Disabling medication-
resistant symptomsa resistant symptomsb
Pharmacologic treatment
Treatment of motor symptoms Monotherapy
MAO-B inhibitor
Levodopa
Dopamine agonist
COMT inhibitors
Amantadine
c
Pump-delivered therapy
Levodopa intestinal gel
Subcutaneous apomorphine
Treatment of nonmotor symptoms
Antidepressants
Antipsychotics
Cholinesterase inhibitors
Nonpharmacologic treatment c
Deep brain stimulation
Exercise
Physical and occupational therapy
Speech and swallow therapy
Psychosocial care
Bars indicate approximate periods of initiation and duration of each treatment except where Medication-resistant symptoms refer to symptoms resistant to medications for the
noted. COMT indicates catechol-O-methyl transferase. treatment of motor symptoms.
For the treatment of motor symptoms, drugs are usually added sequentially. Monoamine a Gait dysfunction, soft speech (hypophonia), and memory and cognitive problems.
oxidase type B (MAO-B) inhibitor monotherapy may be started in the early symptom period b Dysphagia, falls, and memory and cognitive problems.
followed by the addition of levodopa or a dopamine agonist. As symptoms progress, other drugs c Beyond this point, pump-delivered therapy and deep brain stimulation should not be
may be added and then discontinued as medication-resistant symptoms and adverse effects initiated but may be continued if already prescribed.
emerge. Levodopa may be continued through late stages of the disease as monotherapy.

sialorrhea. Although there is less current evidence for treatments of or- an externally worn medication pump, providing another option for
thostatic hypotension, sexual symptoms, urinary symptoms, and apa- patients with severe medication-resistant motor fluctuations.
thy, these are also important. Clozapine, quetiapine, and pimavanserin
canbeusedtoaddresspsychosiswithoutworseningmotorPDfeatures. Personalizing Therapy
The 2017 approach to the treatment of patients with PD requires per-
Deep Brain Stimulation and Infusion Therapy sonalization of therapy and attention to the varied and changing symp-
The introduction of deep brain stimulation (DBS) for severe motor toms.Cliniciansmustbeadeptatdiagnosingclustersofmotorandnon-
symptoms is an another advance in the treatment of PD. Clinical trials motor symptoms and mapping a comprehensive symptom-specific
have demonstrated that DBS is useful for addressing tremor, dys- strategy that may necessitate involvement of a multidisciplinary team,
kinesia, motor fluctuations, and off-dopaminergic time. Subtha- including neurology, neuropsychology, psychiatry, neurosurgery,
lamic nucleus and globus pallidus internus DBS are both FDA ap- and rehabilitative services. Clinicians must also be aware that PD is
proved, and a randomized trial involving 251 patients revealed dynamic and treatment strategies may need to shift abruptly as the
potential benefits to applying DBS earlier and in younger patients, disease progresses and the symptom clusters shift. The combination
especially those with motor fluctuations.7 In 2015, the FDA ap- of medical therapy with exercise and in some cases surgical interven-
proved use of a gel formulation of carbidopa/levodopa enteral sus- tions can improve quality of life for most patients with PD and can
pension that can be infused directly into the small intestine using transform a potentially debilitating disease into a livable condition.

ARTICLE INFORMATION from the New England Journal of Medicine 4. Parkinson Study Group. Effects of tocopherol and
Published Online: August 21, 2017. Journal Watch. He is the national medical director deprenyl on the progression of disability in early
doi:10.1001/jama.2017.7914 for the National Parkinson Foundation and Parkinsons disease. N Engl J Med. 1993;328(3):176-183.
Conflict of Interest Disclosures: The author has oversees the foundations question-and-answer 5. Olanow CW, Rascol O, Hauser R, et al. A double-
completed and submitted the ICMJE Form for website and blog. blind, delayed-start trial of rasagiline in Parkinsons
Disclosure of Potential Conflicts of Interest. REFERENCES disease. N Engl J Med. 2009;361(13):1268-1278.
Dr Okun reports receipt of grants from the National 6. Fox SH, Katzenschlager R, Lim S-Y, et al.
1. Fahn S, Oakes D, Shoulson I, et al. Levodopa and
Institutes of Health, the Michael J. Fox Foundation, Update on Treatments for Motor Symptoms
the progression of Parkinsons disease. N Engl J Med.
the Tourette Association of America, the Bachmann of PD. February 9, 2015. http://www
2004;351(24):2498-2508.
Strauss Foundation, and the National Parkinson .movementdisorders.org/mds-files1/pdfs/ebm
Foundation; publication royalties from 2. Gray R, Ives N, Rick C, et al. Long-term
-papers/updateforwebsitemotortreatmentforpd
Books4Patients, Demos, Manson, Cambridge effectiveness of dopamine agonists and
_text_9feb2015_finaltext.pdf. Accessed
University Press, Smashwords, and Amazon/KDP; monoamine oxidase B inhibitors compared with
August 16, 2017.
continuing medical education honoraria from levodopa as initial treatment for Parkinsons disease
WebMD-Medscape, QuantiaMD, the American (PD MED). Lancet. 2014;384(9949):1196-1205. 7. Schuepbach WM, Rau J, Knudsen K, et al.
Academy of Neurology, the Movement Disorders Neurostimulation for Parkinsons disease with early
3. Weintraub D, Koester J, Potenza MN, et al.
Society, and Mededicus; honoraria for a Vanderbilt motor complications. N Engl J Med. 2013;368(7):
Impulse control disorders in Parkinson disease. Arch
University teaching course; and personal fees 610-622.
Neurol. 2010;67(5):589-595.

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