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The new england journal of medicine John G. Nutt, M.D., and G. Frederick Wooten, M.D.
This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors’ clinical recommendations. A 62-year-old man presents with an intermittent tremor in his left hand and some
vague discomfort in the left arm. Physical examination shows a minimal rest tremor
in the left hand that disappears with use of the limb, mild rigidity at the left wrist and
elbow, slowness of finger tapping with the left hand, and decreased arm swing on the
left while walking. How should he be evaluated and treated?

Parkinsonism, the syndrome, is a common movement disorder, and Parkinson’s dis- From the Department of Neurology, Ore- ease, the most common cause of parkinsonism, is the second most prevalent neurode- land (J.G.N.); and the Department of generative disease after Alzheimer’s disease. Parkinson’s disease is estimated to afflict Neurology, University of Virginia, Char-about 1 million Americans, or about 1 percent of the population over 60 years of age.1,2 lottesville (G.F.W.). Address reprint re- As the U.S. population ages, this number is likely to double in the next 15 to 20 years.
The disease is uncommon before the age of 40; both the prevalence and the incidence University, 3181 S.W. Sam Jackson Parkincrease steadily thereafter.3,4 The incidence is higher among men than among wom- Rd., Portland, OR 97239, or at nuttj@ohsu.
en. All races and ethnic groups are affected. Although therapy can ameliorate thesymptoms of Parkinson’s disease and improve both the quality of life and life expect- N Engl J Med 2005;353:1021-7.
ancy, Parkinson’s disease continues to be associated with progressive disability and in- Copyright 2005 Massachusetts Medical Society.
creased mortality.6,7 Parkinson’s disease is caused by the disruption of dopaminergic neurotransmission in the basal ganglia. On pathological examination, the dopaminergic neurons in thesubstantia nigra are markedly reduced, and Lewy bodies (cytoplasmic inclusions) arepresent in the residual dopaminergic neurons.
More than 10 autosomal dominant and recessive genes or gene loci have been linked to Parkinson’s disease, but mutation in a single gene is an uncommon cause.8 Never-theless, 10 to 15 percent of people with Parkinson’s disease will have an affected first-degree or second-degree relative.9 No clear environmental determinants of Parkinson’sdisease have been identified.2 s t r a t e g i e s a n d e v i d e n c e d i a g n o s i s
The diagnosis of Parkinson’s disease is based on the presence of the core features ofslowness and paucity of movement (bradykinesia and akinesia) and tremor when thelimb is at rest or resistance to passive movement of the joints (rigidity), or both.10,11 Pos-tural abnormalities are often included in the definition but generally occur later in thecourse of the disorder and are nonspecific, making them of little clinical usefulness inearly disease.11 There are four common presentations of Parkinson’s disease: tremor, Downloaded from www.nejm.org at HARVARD UNIVERSITY on October 2, 2006 . Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine a weak and clumsy limb, a stiff and aching limb, and movement (see video clip in the Supplementary Ap-a gait disorder (Table 1).
pendix). Fine movements are affected more than The classic tremor of Parkinson’s disease is a large movements, so that the patient first notices resting tremor in a limb, most commonly one hand, difficulty using small tools and fastening buttons.
that disappears with voluntary movement. It fre- Repetitive movements also suffer; for example,quently emerges in a hand while the person is walk- brushing the teeth may be difficult.
ing. (A video clip can be viewed in the Supplemen- The rigidity of Parkinson’s disease may be expe- tary Appendix, available with the full text of this rienced as stiffness associated with vague achingarticle at www.nejm.org.) Rest tremor is virtually pa- and discomfort of a limb suggesting musculoskele-thognomonic of Parkinson’s disease. However, the tal syndromes, particularly bursitis and tendinitis.
diagnosis may be complicated by nonclassic find- In the arm, this rigidity may progress to a frozenings, such as tremor when the person is holding the shoulder.14arms out or using the hands in voluntary movement Early Parkinson’s disease may cause slowing of or the absence of a tremor (about 20 percent of gait, dragging of the foot, and decreased arm swingcases).12 on the affected side that can suggest a mild hemipa- Essential tremor is the entity that is most com- resis (see video clip in the Supplementary Appen- monly confused with early Parkinson’s disease.13 dix). Patients may notice difficulty getting out ofPatients with essential tremor frequently report dif- cars, rising from deep chairs, and rolling over inficulty drinking from a cup because of their tremu- bed. However, a shuffling gait, freezing, and fallslous hands. Essential tremor generally causes a sym- are rare in early disease. The separation of the feetmetric tremor in the hands, often accompanied by in Parkinson’s disease is normal or even narrow;head and voice tremor. If the tremor of Parkinson’s a wide-based gait suggests other diagnoses. Shuf-disease affects the cranial musculature, it is gener- fling gait disorders with other causes were the sec-ally as tongue, jaw, and chin tremor, not as head ond most common misdiagnosis of Parkinson’stremor. Handwriting may differentiate the two con- disease in general practice.13ditions: in essential tremor, the handwriting is large The diagnosis of Parkinson’s disease is based on and tremulous; in Parkinson’s disease, it is small a careful history taking and physical examination.
and irregular. Rigidity and bradykinesia are not as- There are no laboratory tests or imaging studies thatsociated with essential tremor.
confirm the diagnosis. Magnetic resonance imag- The bradykinesia of Parkinson’s disease begins ing of the brain or other tests may be appropriate in asymmetrically in about 75 percent of patients.11 It some patients, particularly those with prominentis often described by the patient as a weakness of a gait abnormalities, to exclude other conditions, buthand or leg, but strength testing reveals no abnor- are seldom necessary in a typical case. Ligands thatmalities. However, assessment of dexterity by finger bind the dopamine transporter and are visible ontapping and toe tapping shows slowing, reduced single-photon-emission computed tomographyamplitude of movement, and irregular cadence that provide a measure of the density of dopamine nervebecome more apparent as the patient continues the terminals; such ligands are available in Europe and Table 1. Common Presentations of Parkinson’s Disease.
Presentation
Parkinsonism
Differential Diagnosis
Distinguishing Signs
Downloaded from www.nejm.org at HARVARD UNIVERSITY on October 2, 2006 . Copyright 2005 Massachusetts Medical Society. All rights reserved. are undergoing testing in the United States. nonpharmacologic management
Dopamine-transporter imaging may provide use- Support and education of patients are critical when
ful diagnostic information for treatment when giving a diagnosis of Parkinson’s disease. Patients
clinical findings are subtle or equivocal.15,16 The should understand that Parkinson’s disease often
patient’s response to a trial of levodopa has been has a course over decades, the rate of progression
suggested as a diagnostic test for Parkinson’s dis- varies greatly from one person to another, and many
ease but is of questionable value, particularly if the approaches are available to reduce symptoms. Sup-
severity of symptoms does not justify long-term port groups that include patients with more ad-
therapy with levodopa.17
vanced disease may be alarming rather than help-ful to persons with newly diagnosed disease.
d i f f e r e n t i a l d i a g n o s i s
Patients should be counseled about exercise, includ- There is a long list of causes of parkinsonism that ing stretching, strengthening, cardiovascular fit-
includes toxins, infections of the central nervous ness, and balance training, although only small,
system, structural lesions of the brain, metabolic short-term studies suggest that these may improve
disorders, and other neurologic disorders. Most of activities of daily living, gait speed, and balance.18,19
these causes are rare and are generally suggested
by atypical features in the history or examination. pharmacologic therapy
In practice, the clinician routinely needs to consider The diagnosis of Parkinson’s disease is not neces-
two alternative diagnoses: drug-induced parkinson- sarily cause to begin drug therapy. Drug therapy is
ism and “parkinsonism-plus” syndromes.
warranted when the patient is sufficiently bothered Drug-induced parkinsonism is important to by symptoms to desire treatment or when the dis- recognize because it is reversible, although reversal ease is producing disability; patients’ preferencesmay require weeks or months after the offending are critical to making this decision.
medication is stopped. Drug-induced parkinson- If the patient needs treatment for motor symp- ism accounted for 20 percent of cases of parkin- toms, efficacious agents for initial therapy includesonism in a population-based study.4 Dopamine levodopa, dopamine agonists, anticholinergicantagonists, including neuroleptic agents, atypical agents, amantadine, and selective monoamine ox-neuroleptic agents, antiemetic drugs, and calcium- idase B (MAO-B) inhibitors (Table 2).21,22 Exceptchannel antagonists (flunarizine and cinnarizine), for comparisons of individual dopamine agonistscan induce parkinsonism. Other drugs, such as with levodopa, there are no robust comparisons ofamiodarone, valproic acid, and lithium, may also efficacy among these agents, but clinical experiencecause parkinsonism, but uncommonly and by un- suggests that the dopaminergic agents are more po-certain mechanisms. Dopamine antagonists also tent than the anticholinergic agents, amantadine,exacerbate Parkinson’s disease and should be avoid- and selective MAO-B inhibitors. For this reason, do-ed, if possible, in the treatment of patients with the paminergic drugs are often the initial therapy rec-disease.
ommended for patients with troublesome symp- Approximately 25 percent of patients who re- toms. Guidelines from the American Academy of ceived an initial clinical diagnosis of Parkinson’s Neurology23 and the evidence-based review of thedisease are found to have parkinsonism as part of Movement Disorder Society21 indicate that initiat-another disorder, such as one of the so-called par- ing therapy with levodopa or a dopamine agonist iskinsonism-plus syndromes.12 Features suggesting reasonable.
other conditions include falls or dementia early inthe course of the disease, symmetric parkinsonism, Levodopawide-based gait, abnormal eye movements, Babin- Levodopa, a dopamine precursor, is considered theski signs, marked orthostatic hypotension, urinary most effective antiparkinsonian agent. In random-retention, and the development of marked disability ized trials comparing levodopa and a dopaminewithin five years after the onset of the symptoms. agonist, activities of daily living and motor featuresThe parkinsonism-plus syndromes respond poorly of Parkinson’s disease improved with levodopa byto antiparkinsonian medications and have a worse about 40 to 50 percent (as compared with approxi-prognosis than does idiopathic Parkinson’s disease. mately 30 percent with dopamine agonists).6,24,25Neurologic consultation is warranted if the clinical Levodopa, combined with a peripheral decarboxyl-features suggest these other diagnoses.
ase inhibitor such as carbidopa to reduce the decar- Downloaded from www.nejm.org at HARVARD UNIVERSITY on October 2, 2006 . Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Table 2. Initial Therapy for Symptoms in Parkinson’s Disease.*
Drug Class
Initial Dosage
Usual Dosage
Side Effects
First-line dopaminergic agents
At initiation: anorexia, nausea, vomiting, carbidopa:levodopa reduces gastroin-testinal symptoms), long-term therapy: motor fluctuations, dyskinesias, confu-sion, hallucinations Nausea, vomiting, hypotension, ankle ede- pulsive behavior, confusion, and hallu-cinations Same as for nonergot drugs plus retroperi- Second-line alternatives
Impaired memory, confusion, constipation, blurred vision, urinary retention, xeros-tomia, and angle-closure glaucoma 1 mg twice daily Same as for trihexyphenidyl 5 mg twice daily Insomnia, nausea, anorexia, hallucina- tions, potential for interactions with SSRIs and meperidine Dizziness, insomnia, nervousness, livedo * All antiparkinsonian drugs are started at low doses and increased slowly to reduce adverse effects. Likewise, slow withdrawal of these drugs af- ter long-term treatment is prudent to avoid a marked worsening of parkinsonism or even the neuroleptic malignant syndrome (discussed by Keyser and Rodnitzky20). MAO-B denotes monoamine oxidase B, SSRI selective serotonin-reuptake inhibitor, and NMDA N-methyl-d-aspartate.
Downloaded from www.nejm.org at HARVARD UNIVERSITY on October 2, 2006 . Copyright 2005 Massachusetts Medical Society. All rights reserved. boxylation of levodopa before it reaches the brain, brosis.28 In addition, an association has recentlyis available as immediate-release and controlled- been reported between pergolide treatment andrelease formulations. Carbidopa plus levodopa com- thickening and dysfunction of cardiac valves.29bined with a catechol O-methyltransferase inhibitor, Echocardiography in patients receiving long-termentacapone, is another preparation designed to treatment with pergolide suggests that restrictiveprolong the action of levodopa by preventing its valvular disease may be two to four times more com-O-methylation. Randomized trials have not found mon among these patients than among patientscontrolled-release preparations to be superior to im- with Parkinson’s disease who are not receiving per-mediate-release preparations as initial therapy.23,26 golide.30,31 Given this concern, agonists not derivedTrials with entacapone preparations are under way. from ergot, such as pramipexole and ropinirole, are There are many causes of failure to respond to currently preferred.
levodopa, including the use of an inappropriate in-dex of response such as tremor, inadequate doses, Other Pharmacologic Agentsinadequate duration of treatment, and drug inter- In general, anticholinergic agents are not used foractions (e.g., concomitant treatment with meto- Parkinson’s disease because of associated adverseclopramide or risperidone). A trial of levodopa effects. However, they are sometimes added if trem-should be given for three months with gradual ti- or is particularly bothersome and unresponsive totration upward to at least 1000 mg per day (imme- other drugs, although evidence is lacking to supportdiate-release form) or until the appearance of dose- a particular efficacy of these agents in treatinglimiting adverse effects before concluding that a tremor.21 Anticholinergic agents are contraindicat-patient does not have a response to levodopa. Be- ed for patients with dementia and are usually avoid-cause failure to have a response to an adequate trial ed in the treatment of patients older than 70 years.
of levodopa occurs in less than 10 percent of pa- MAO-B inhibitors and amantadine have fewer ad-tients with pathologically proved Parkinson’s dis- verse effects and require little titration to reach ther-ease,27 failure suggests the possibility of another apeutic doses, but because the effects tend to bedisorder and indicates that no pharmacologic or moderate, these agents generally provide inade-surgical therapy is likely to be beneficial.
quate symptomatic therapy when used alone (Ta-ble 2).
Dopamine Agonists
Although dopamine agonists are slightly less effec- surgical therapy
tive than levodopa, they are alternative first-line Thalamotomy and thalamic stimulation — deep-
agents for Parkinson’s disease. The various dopa- brain stimulation with the use of implanted elec-
mine agonists have similar efficacy. One potential trodes — can be efficacious in treating the tremor
advantage of these agents is that, as compared with of Parkinson’s disease when it is severe and unre-
levodopa, their use is associated with a lower risk sponsive to medication. Pallidotomy, pallidal deep-
by a factor of two or three of dyskinesia and motor brain stimulation, and subthalamic deep-brain
fluctuations in the first four to five years of treat- stimulation can improve all features of Parkinson’s
ment, particularly among patients receiving dopa- disease in patients in whom the response to anti-
mine-agonist monotherapy.6,24,25 However, it is parkinsonian medications is complicated by severe
common for levodopa to be needed in addition to motor fluctuations and dyskinesia. Because this in-
dopamine-agonist therapy within a few years after dication is absent in the early stage of the disease,
diagnosis to control advancing symptoms; it is un- and because of the risks and expense, surgical ther-
known how long the risk of motor complications apy has no role in early Parkinson’s disease.
remains lower when levodopa is added to a dopa-
mine agonist.6 Dopamine agonists are avoided in
the treatment of patients with dementia because ofthe drugs’ propensity to produce hallucinations.
p o s s i b l e n e u r o p r o t e c t i v e t h e r a p i e s
The older dopamine agonists, bromocriptine At present, there are no proven neuroprotective and pergolide, are ergot derivatives that can rarely therapies. There are, however, clinical trials sug-induce retroperitoneal, pleural, and pericardial fi- gesting that selective MAO-B inhibitors,32,33 do- Downloaded from www.nejm.org at HARVARD UNIVERSITY on October 2, 2006 . Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine pamine agonists,34,35 and coenzyme Q1036 may trolled-release preparations of levodopa decreaseslow the progression of Parkinson’s disease. Data this risk.26,42 Ongoing studies are examining theare needed to clarify the neuroprotective effects of effects of carbidopa, levodopa, and entacapone inthese agents as well as of other putative neuropro- combined preparations as initial therapy.
tective therapies.37 t i m i n g o f t h e i n i t i a t i o n o f l e v o d o p a
The optimal time for initiating levodopa therapy is The American Academy of Neurology has issueduncertain. Limited in vitro data have aroused con- clinical-practice guidelines for initial therapy in Par-cern that levodopa may be toxic to dopamine neu- kinson’s disease,22,23 and the Movement Disorderrons and may actually accelerate the disease pro- Society has published evidence-based recommen-cess,38 suggesting that its use should be delayed as dations for Parkinson’s disease therapy.21,43 Thelong as possible. However, there is little evidence recommendations in the present review are consis-of in vivo toxicity in animals and none in humans.39 tent with these guidelines.
In a randomized trial involving patients with earlyParkinson’s disease, those studied after 40 weeks s u m m a r y a n d r e c o m m e n d a t i o n s of levodopa therapy (followed by 2 weeks of with-drawal), as compared with those treated with pla- The presence of an asymmetric rest tremor, rigidity,cebo, had better motor function, suggesting that and bradykinesia, as in the patient in the vignette,levodopa was not toxic.40 Neuroimaging, however, are classic features of early Parkinson’s disease. Ifshowed a reduction in dopamine transporters in there are no other neurologic signs inconsistentthe patients treated with levodopa; these results with the diagnosis, and if the patient is not takingsuggest the possibility of some toxic effect but al- drugs that may cause parkinsonism, the diagnosisternatively, may reflect pharmacologic down-regu- of Parkinson’s disease can be made with confidencelation of the transporters.40 without further testing. We would educate the pa-tient about the disease, suggest useful Web sites c h o i c e o f i n i t i a l t h e r a p y
(e.g., www.apdaparkinson.org, www.michaeljfox.
It is uncertain whether levodopa therapy or dopa- org, and www.parkinson.org), and encourage reg-mine-agonist therapy is the better choice for initial ular exercise (although its efficacy in slowing dis-treatment for Parkinson’s disease. The trade-off ease progression is unclear). His mild symptomsfor reduced motor complications with the use of do not necessarily require treatment. Patients whodopamine agonists is that the agonists are less effi- do not require pharmacologic therapy might be en-cacious antiparkinsonian agents and have a differ- couraged to enter trials of neuroprotective thera-ent spectrum of adverse events — namely, an in- pies. Were his symptoms interfering with function,crease in the rate of somnolence, hallucinations, we would discuss the pros and cons of various ther-freezing of gait, and ankle edema.6,24,25 Measures apies. If the patient had no preference, and givenof the quality of life do not differentiate between that he is younger than 70 years and his cognitivepatients treated with dopamine agonists as initial ability is intact, we would start therapy with a non-therapy and those treated with levodopa as initial ergot dopamine agonist because of the low risk oftherapy.25 Guidelines from the American Academy motor complications during the first five years ofof Neurology suggest that initiating dopaminergic treatment. Levodopa would be a reasonable, andtherapy with either levodopa or dopamine agonists more potent, alternative. If there were an inade-is reasonable.23 quate response to the agonist at the maximal toler- It is also uncertain whether reducing pulsatile ated dose, levodopa could be added to the regimen.
dopaminergic stimulation, as occurs with imme- Dr. Nutt reports having received consulting fees from Amgen, diate-release oral preparations of levodopa, will Novartis, and Pfizer and grant support from Pfizer and Amgen. Dr.
Wooten reports having received consulting fees from Amgen, lec- decrease the risk of motor fluctuations and dyski- ture fees from Pfizer and Embryon, and grant support from Amgen,nesia.41 There is currently no evidence that con- Guilford, and Cephalon.
Downloaded from www.nejm.org at HARVARD UNIVERSITY on October 2, 2006 . Copyright 2005 Massachusetts Medical Society. All rights reserved. r e f e r e n c e s
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RB Jr. Pergolide use in Parkinson disease is D.C.: U.S. Census Bureau, 2004. (Accessed associated with cardiac valve regurgitation.
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