Documente Academic
Documente Profesional
Documente Cultură
clinical practice
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?
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 Parkinsons 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 Parkinsons disease may be expe-
tary Appendix, available with the full text of this rienced as stiffness associated with vague aching
article at www.nejm.org.) Rest tremor is virtually pa- and discomfort of a limb suggesting musculoskele-
thognomonic of Parkinsons 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 frozen
ings, such as tremor when the person is holding the shoulder.14
arms out or using the hands in voluntary movement Early Parkinsons disease may cause slowing of
or the absence of a tremor (about 20 percent of gait, dragging of the foot, and decreased arm swing
cases).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 Parkinsons disease.13 dix). Patients may notice difficulty getting out of
Patients with essential tremor frequently report dif- cars, rising from deep chairs, and rolling over in
ficulty drinking from a cup because of their tremu- bed. However, a shuffling gait, freezing, and falls
lous hands. Essential tremor generally causes a sym- are rare in early disease. The separation of the feet
metric tremor in the hands, often accompanied by in Parkinsons disease is normal or even narrow;
head and voice tremor. If the tremor of Parkinsons 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 Parkinsons
tremor. Handwriting may differentiate the two con- disease in general practice.13
ditions: in essential tremor, the handwriting is large The diagnosis of Parkinsons disease is based on
and tremulous; in Parkinsons 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 that
sociated with essential tremor. confirm the diagnosis. Magnetic resonance imag-
The bradykinesia of Parkinsons 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 prominent
is often described by the patient as a weakness of a gait abnormalities, to exclude other conditions, but
hand or leg, but strength testing reveals no abnor- are seldom necessary in a typical case. Ligands that
malities. However, assessment of dexterity by finger bind the dopamine transporter and are visible on
tapping and toe tapping shows slowing, reduced single-photon-emission computed tomography
amplitude of movement, and irregular cadence that provide a measure of the density of dopamine nerve
become more apparent as the patient continues the terminals; such ligands are available in Europe and
* 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.
boxylation of levodopa before it reaches the brain, brosis.28 In addition, an association has recently
is available as immediate-release and controlled- been reported between pergolide treatment and
release formulations. Carbidopa plus levodopa com- thickening and dysfunction of cardiac valves.29
bined with a catechol O-methyltransferase inhibitor, Echocardiography in patients receiving long-term
entacapone, is another preparation designed to treatment with pergolide suggests that restrictive
prolong 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 patients
controlled-release preparations to be superior to im- with Parkinsons disease who are not receiving per-
mediate-release preparations as initial therapy.23,26 golide.30,31 Given this concern, agonists not derived
Trials 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 Agents
inadequate duration of treatment, and drug inter- In general, anticholinergic agents are not used for
actions (e.g., concomitant treatment with meto- Parkinsons disease because of associated adverse
clopramide 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 to
tration upward to at least 1000 mg per day (imme- other drugs, although evidence is lacking to support
diate-release form) or until the appearance of dose- a particular efficacy of these agents in treating
limiting 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 Parkinsons 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 be
disorder 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 Parkinsons 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 Parkinsons 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 Parkinsons
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 Parkinsons disease.
remains lower when levodopa is added to a dopa-
mine agonist.6 Dopamine agonists are avoided in areas of uncertainty
the treatment of patients with dementia because of
the drugs propensity to produce hallucinations. possible neuroprotective therapies
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-
pamine agonists,34,35 and coenzyme Q1036 may trolled-release preparations of levodopa decrease
slow the progression of Parkinsons disease. Data this risk.26,42 Ongoing studies are examining the
are needed to clarify the neuroprotective effects of effects of carbidopa, levodopa, and entacapone in
these agents as well as of other putative neuropro- combined preparations as initial therapy.
tective therapies.37
guidelines
timing of the initiation of levodopa
The optimal time for initiating levodopa therapy is The American Academy of Neurology has issued
uncertain. Limited in vitro data have aroused con- clinical-practice guidelines for initial therapy in Par-
cern that levodopa may be toxic to dopamine neu- kinsons disease,22,23 and the Movement Disorder
rons 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 Parkinsons disease therapy.21,43 The
long 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 early
Parkinsons disease, those studied after 40 weeks summary and recommendation 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 Parkinsons disease. If
showed a reduction in dopamine transporters in there are no other neurologic signs inconsistent
the patients treated with levodopa; these results with the diagnosis, and if the patient is not taking
suggest the possibility of some toxic effect but al- drugs that may cause parkinsonism, the diagnosis
ternatively, may reflect pharmacologic down-regu- of Parkinsons disease can be made with confidence
lation of the transporters.40 without further testing. We would educate the pa-
tient about the disease, suggest useful Web sites
choice of initial therapy (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 Parkinsons disease. The trade-off ease progression is unclear). His mild symptoms
for reduced motor complications with the use of do not necessarily require treatment. Patients who
dopamine 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 given
of the quality of life do not differentiate between that he is younger than 70 years and his cognitive
patients 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 of
therapy.25 Guidelines from the American Academy motor complications during the first five years of
of Neurology suggest that initiating dopaminergic treatment. Levodopa would be a reasonable, and
therapy 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.
references
1. de Rijk MC, Breteler MM, Graveland S, Murphy J, Marek K. (123I) beta-CIT and 29. Pritchett AM, Morrison JF, Edwards
GA, et al. Prevalence of Parkinsons disease single-photon emission computed tomo- WD, Schaff HV, Connolly HM, Espinosa RE.
in the elderly: the Rotterdam Study. Neurol- graphic imaging vs clinical evaluation in Valvular heart disease in patients taking per-
ogy 1995;45:2143-6. Parkinsonian syndrome: unmasking an ear- golide. Mayo Clin Proc 2002;77:1280-6.
2. Marras C, Tanner CM. Epidemiology of ly diagnosis. Arch Neurol 2004;61:1224-9. 30. Van Camp G, Flamez A, Cosyns B, et al.
Parkinsons disease. In: Watts RL, Koller 17. Clarke CE, Davies P. Systematic review Treatment of Parkinsons disease with per-
WC, eds. Movement disorders: neurologic of acute levodopa and apomorphine chal- golide and relation to restrictive valvular
principles & practice. 2nd ed. New York: lenge tests in the diagnosis of idiopathic heart disease. Lancet 2004;363:1179-83.
McGraw-Hill, 2004:177-95. Parkinsons disease. J Neurol Neurosurg 31. Baseman DG, OSuilleabhain PE, Re-
3. U.S. interim projections by age, sex, Psychiatry 2000;69:590-4. imold SC, Laskar SR, Baseman JG, Dewey
race, and Hispanic origin. Washington, 18. Hirsch MA, Toole T, Maitland CG, Rider RB Jr. Pergolide use in Parkinson disease is
D.C.: U.S. Census Bureau, 2004. (Accessed RA. The effects of balance training and associated with cardiac valve regurgitation.
August 11, 2005, at http://www.census.gov/ high-intensity resistance training on per- Neurology 2004;63:301-4.
ipc/www/usinterimproj/.) sons with idiopathic Parkinsons disease. 32. Shoulson I, Oakes D, Fahn S, et al. Im-
4. Bower JH, Maraganore DM, McDonnell Arch Phys Med Rehabil 2003;84:1109-17. pact of sustained deprenyl (selegiline) in le-
SK, Rocca WA. Incidence and distribution of 19. Ellis T, de Goede CJ, Feldman RG, vodopa-treated Parkinsons disease: a ran-
parkinsonism in Olmsted County, Minneso- Wolters EC, Kwakkel G, Wagenaar RC. Effi- domized placebo-controlled extension of
ta, 1976-1990. Neurology 1999;52:1214-20. cacy of a physical therapy program in pa- the Deprenyl and Tocopherol Antioxidative
5. Wooten GF, Currie LJ, Bovbjerg VE, Lee tients with Parkinsons disease: a random- Therapy of Parkinsonism trial. Ann Neurol
JK, Patrie J. Are men at greater risk for Par- ized controlled trial. Arch Phys Med Rehabil 2002;51:604-12.
kinsons disease than women? J Neurol 2005;86:626-32. 33. Parkinson Study Group. A controlled,
Neurosurg Psychiatry 2004;75:637-9. 20. Keyser DL, Rodnitzky RL. Neuroleptic randomized, delayed-start study of rasa-
6. Lees AJ, Katzenschlager R, Head J, Ben malignant syndrome in Parkinsons disease giline in early Parkinson disease. Arch Neu-
Shlomo Y. Ten-year follow-up of three dif- after withdrawal or alteration of dopaminer- rol 2004;61:561-6.
ferent initial treatments in de-novo PD: gic therapy. Arch Intern Med 1991;151:794- 34. Idem. Dopamine transporter brain im-
a randomized trial. Neurology 2001;57: 6. aging to assess the effects of pramipexole vs
1687-94. 21. Goetz CG, Koller WC, Poewe W, Rascol levodopa on Parkinson disease progression.
7. Fall PA, Saleh A, Fredrickson M, Olsson O, Sampaio C. Management of Parkinsons JAMA 2002;287:1653-61.
JE, Granerus AK. Survival time, mortality, disease: an evidence-based review. Mov Dis- 35. Whone AL, Watts RL, Stoessl AJ, et al.
and cause of death in elderly patients with ord 2002;17:Suppl 4:S1-S166. Slower progression of Parkinsons disease
Parkinsons disease: a 9-year follow-up. 22. Quality Standards Subcommittee of the with ropinirole versus levodopa: the REAL-
Mov Disord 2003;18:1312-6. American Academy of Neurology. Practice PET study. Ann Neurol 2003;54:93-101.
8. Healy DG, Abou-Sleiman PM, Wood parameters: initial therapy of Parkinsons 36. Shults CW, Oakes D, Kieburtz K, et al.
NW. PINK, PANK, or PARK? A clinicians disease. Neurology 1993;43:1296-7. Effects of coenzyme Q10 in early Parkinson
guide to familial parkinsonism. Lancet Neu- 23. Miyasaki JM, Martin W, Suchowersky O, disease: evidence of slowing of the function-
rol 2004;3:652-62. Weiner WJ, Lang AE. Practice parameter: al decline. Arch Neurol 2002;59:1541-50.
9. Payami H, Larsen K, Bernard S, Nutt J. initiation of treatment for Parkinsons dis- 37. Ravina BM, Fagan SC, Hart RG, et al.
Increased risk of Parkinsons disease in par- ease: an evidence-based review: report of the Neuroprotective agents for clinical trials in
ents and siblings of patients. Ann Neurol Quality Standards Subcommittee of the Parkinsons disease: a systematic assess-
1994;36:659-61. American Academy of Neurology. Neurolo- ment. Neurology 2003;60:1234-40.
10. Gibb WRG, Lees AJ. The relevance of gy 2002;58:11-7. 38. Fahn S. Is levodopa toxic? Neurology
the Lewy body to the pathogenesis of idio- 24. Rascol O, Brooks DJ, Korczyn AD, 1996;47:Suppl 3:S184-S195.
pathic Parkinsons disease. J Neurol Neuro- De Deyn PP, Clarke CE, Lang AE. A five-year 39. Agid Y, Chase TN, Marsden CD. Ad-
surg Psychiatry 1988;51:745-52. study of the incidence of dyskinesia in pa- verse reactions to levodopa: drug toxicity or
11. Gelb DJ, Oliver G, Gilman S. Diagnostic tients with early Parkinsons disease who progression of disease? Lancet 1998;351:
criteria for Parkinsons disease. Arch Neurol were treated with ropinirole or levodopa. 851-2.
1999;56:33-9. N Engl J Med 2000;342:1484-91. 40. Fahn S, Oakes D, Shoulson I, et al. Le-
12. Hughes AJ, Daniel SE, Kilford L, Lees 25. Holloway RG, Shoulson I, Fahn S, et al. vodopa and the progression of Parkinsons
AJ. Accuracy of clinical diagnosis of Parkin- Pramipexole vs levodopa as initial treatment disease. N Engl J Med 2004;351:2498-508.
sons disease: a clinico-pathological study for Parkinson disease: a 4-year randomized 41. Olanow CW, Agid Y, Mizuno Y, et al. Le-
of 100 cases. J Neurol Neurosurg Psychiatry controlled trial. Arch Neurol 2004;61:1044- vodopa in the treatment of Parkinsons dis-
1992;55:181-4. 53. [Erratum, Arch Neurol 2005;62:430.] ease: current controversies. Mov Disord
13. Meara J, Bhowmick BK, Hobson P. Ac- 26. Koller WC, Hutton JT, Tolosa E, 2004;19:997-1005.
curacy of diagnosis in patients with pre- Capilldeo R. Immediate-release and con- 42. Dupont E, Andersen A, Boas J, et al. Sus-
sumed Parkinsons disease. Age Ageing trolled-release carbidopa/levodopa in PD: tained-release Madopar HBS compared
1999;28:99-102. a 5-year randomized multicenter study. with standard Madopar in the long-term
14. Riley D, Lang AE, Blair RD, Birnbaum A, Neurology 1999;53:1012-9. treatment of de novo parkinsonian patients.
Reid B. Frozen shoulder and other shoulder 27. Hughes AJ, Daniel SE, Blankson S, Lees Acta Neurol Scand 1996;93:14-20.
disturbances in Parkinsons disease. J Neu- AJ. A clinicopathologic study of 100 cases of 43. Goetz CG, Poewe W, Rascol O, Sampaio
rol Neurosurg Psychiatry 1989;52:63-6. Parkinsons disease. Arch Neurol 1993;50: C. Evidence-based medical review update:
15. Marshall V, Grosset D. Role of dopa- 140-8. pharmacological and surgical treatments of
mine transporter imaging in routine clinical 28. Agarwal P, Fahn S, Frucht SJ. Diagnosis Parkinsons disease: 2001 to 2004. Mov Dis-
practice. Mov Disord 2003;18:1415-23. and management of pergolide-induced fi- ord 2005;20:523-39.
16. Jennings DL, Seibyl JP, Oakes D, Eberly brosis. Mov Disord 2004;19:699-704. Copyright 2005 Massachusetts Medical Society.