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Although the fine tuning of treatment for Parkinsons disease is largely in the province of the neurologist, the primary care physician is in the best position to make the diagnosis, institute therapy, and monitor the often substantial side effects associated with antiparkinsonian agents.
Genetic Contributions
Gene mutations appear to be most i mportant in hereditary forms of the disease, which typically have onset before the age of 50 years. Several gene mutations have been identified as contributory, including mutations of the parkin gene on chromosome 6 and the -synuclein gene on chromosome 4 . The products of these genes are likely to be important in pathogenesis, with -synuclein being a major component of presynaptic terminals and Lewy bodies and the product of the parkin gene being involved in protein degradation and clearance. In persons w ith the more common idiopathic form of Parkinsons disease, gene mutations probably do not play as large a role, but some evidence suggests a susceptibility function for mutations of the tau gene , which codes for the tau protein, a component of microtubules.
Environmental Contributions
In sporadic idiopathic Parkinsons disease with onset older than the age of 50 years, environmental factors are believed to be possibly important. The substantia nigra of patients with Parkinsons disease seems particularly vulnerable to oxidative insults. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an analogue of meperidine injected by intravenous -drug abusers) and the pesticide rotenone (used in animal models of the disease) both inhibit mitochondrial complex I, imp airing mitochondrial function and leading to findings nearly identical to those of idiopathic disease. The demonstration that mitochondrial toxins can produce parkinsonism has stimulated an ongoing search for causative environmental precipitants. It is sus pected that long-term, low-
level exposures may be important and predate the onset of symptoms by years. Of note, being from a rural area is a risk factor for parkinsonism, as is not smoking. Separately, high caffeine intake is associated with a decreased r isk of Parkinsons disease, suggesting a role for the adenosine receptor, which it antagonizes.
Clinical Presentation
Parkinsons disease is an affliction of middle to late adult life, although 30% of patients report recognizable symptoms before the age of 50 years. In another 40%, the disease develops between the ages of 50 and 60 years, and the remainder are older than 60 years old at the time of diagnosis. The classic syndrome of parkinsonism includes tremor at rest, rigidity, bradykinesia, masked face, stooped posture , and a shuffling gait . Although tremor is the most obvious initial finding, it is absent in 20% of pat ients. Parkinsons disease may begin insidiously with vague, aching pain in the limbs, neck, or back and with decreased axial dexterity before tremor is noted. Dysarthria may be an early feature; dysphagia usually occurs later. The onset of Parkinsons disease, whether primarily with tremor, rigidity, or bradykinesia, is usually asymmetric. Subtler symptoms may also be noted, sometimes early. Orthostatic hypotension suggests cardiac sympathetic denervation, which can be found in many patients and may cause neurocirculatory failure. Micrographia (decrease in the caliber of handwriting), decrease in volume of the voice, and anosmia are other subtle but characteristic manifestations. Depression may be a feature of early disease. The estimated frequency of dementia (which usually develops late) varies widely, but cognitive
impairment, including hallucinations and psychosis, develops in at least 15% to 20% of patients (some of whom are likely to have Lewy body disease; see Chapter 169). However, dementia and psychosis are not inevitable, and remediable causes of changes in mental status always need to be sought.
Clinical Course
Before the introduction of levodopa, Parkinsons disease had a fairly predictable course. At 5 years after onset, 60% of patients were severely disabled, and at 10 years, nearly 80% were. The rate of progression varied widely. Death rarely was a direct consequence of parkinsonism; rather, it was a consequence of immobility (aspiration pneumonia, urinary tract infections) or of trauma. Patients with Parkinsons disease comprise several different subgroups manifesting specific clinical patterns. It is believed that patients who present primarily with tremor have a slower course than do those for whom bradykinesia is the primary symptom. Patients who present with significant instability of posture and gait are largely an older group who are more likely to have cognitive impairment and a more rapid progression of disease. The advent of dopaminergic agents has changed the natural history of the disease significantly. The initial benefit of levodopa therapy is one of the diagnostic criteria for the disease. Althoug h patients with idiopathic Parkinsons disease usually respond to levodopa, the initial benefits of therapy decline for as many as one half of all treated patients after 2 or more years. Delay in onset of disability has been enhanced by the use of the monoamine oxidase B inhibitor deprenyl (see later discussion). P.1223
Diagnosis (6,7)
The classic presentation of Parkinsons disease usually poses few diagnostic problems. However, several other presentations may be more problematic. These include isolated tremor at presentation, symptoms confined to half of the body (hemiparkinsonism), and the presence of these symptoms in younger patients. Symptomatic parkinsonism can be seen in several other disorders, such as progressive supranuclear palsy and multisystem atrophy, or as a side effect of numerous medications ( Table 174.1). An extrapyramidal syndrome resembling that of parkinsonism also occurs in Lewy body disease and may be mistaken for Alzheimers disease because of the prominent dementia that ensues (see Chapters 169 and 173). Table 174.1 Differential Diagnosis of Parkins onism
Idiopathic Parkinsonism (Parkinsons Disease) Infectious and postinfectious Postencephalitic parkinsonism (von Economos disease) Other viral encephalitides Toxins Manganese Carbon monoxide Carbon disulfide Cyanide
Methanol MPTP a Drugs Neuroleptics Reserpine Metoclopramide Lithium Amiodarone -Methyldopa Multisystem Degeneration Striatonigral degeneration Progressive supranuclear palsy Olivopontocerebellar degeneration Shy Drager syndrome Primary Dementing and Other Degenerative Disorders Alzheimers disease Lewy body disease Creutzfeldt Jakob disease Other Central Nervous System Disorders Multiple cerebral infarction s (lacunar state, Binswangers disease) Hydrocephalus (normal-pressure or high-pressure) Posttraumatic encephalopathy (pugilistic parkinsonism) Metabolic Conditions Hypoparathyroidism Chronic hepatocerebral degeneration Idiopathic calcification of basal ga nglia
This list is not meant to be all -inclusive. Rather, it highlights the more common disorders that may have parkinsonism as a prominent feature.
a
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a meperidine
analogue used by intravenous -drug abusers. Adapted from Koller WC. How accurately can Parkinsons disease be diagnosed? Neurology 1992;42(Suppl 1):6, with permission.
The clinical diagnosis of Parkinsons disease is based on a careful examination in which the clinician looks for physical signs other than those associated with the basal ganglia, elicits a careful drug and family history, and most likely performs at least one neuroimaging study, probably magnetic resonance imaging, to exclude significant small -vessel vascular disease, which may produce a parkinsonian -like state. Table 174.2 provides a summary of inclusion and exclusion criteria, which should help the physician in this clinical diagnosis. Among the inclusion criteria is a sustained responsiveness to levodopa therapy, with improvement lasting for 1 year or more. Many parkinsonian syndromes with other causes may show a transient response to dopaminergic agents. There are no confirmatory laboratory tests or imaging studies, but ligands that bind the dopamine transporter
and are visible on single phot on emission computed tomography can be helpful in the investigational setting. The list of causes of parkinsonism includes toxins, central nervous system infections, structural lesions of the brain, and drugs. Dopamine antagonists, including neuroleptic agents and atypical neuroleptics, antiemetic drugs, valproate, and lithium all have been reported to cause parkinso nism.
If the degeneration of dopaminergic neurons in the substantia nigra and striatum is a consequence of oxidative injury, then might it be possible to interrupt the degenerative process and slow or halt disease progression with agents that inhibit oxidative activity in the central nervous system? This hypothesis has led to the study of the monoamine oxidase B inhibitors.
Selegiline (Deprenyl)
Although not universally accepted, evidence from several double blinded, placebo-controlled studies of this monoamine oxidase B inhibitor indicates that monotherapy early in the P.1224 course of disease delays the onset of disability and the need to initiate levodopa therapy. It is suspected that the mechanism of benefit is protection of striatal tissue from oxidative injury, but this has yet to be proved, and the major benefit may be some direct effect of relieving symptoms. Table 174.2 Criteria for the Diagnosis of Parkinsons Disease
Inclusion Criteria Presence for 1 yr or more of two of the three cardinal motor signs:
Neuroleptic therapy
within 1 yr
Bradykinesia
Rigidity
History of encephalitis
Responsiveness to levodopa therapy with moderate to marked improvement and duration of improvement for 1 yr or more
Oculogyric crises Supranuclear downward or lateral gaze palsy Cerebellar signs Unexplained upper motor neuron or lower motor neuron signs More than one affected relative Dementia from the onset of disease Severe autonomic symptoms
Adapted from Reich SG, DeLong M. Parkinsons disease. In: Johnson R, ed. Current therapy in neurologic disease, 3rd ed. St. Louis: Mosby, 1990, with permission.
Nonetheless, it seems reasonable to recommend this drug as initial treatment when Parkinsons disease is first diagnosed because it delays the requirement for levodopa therapy. It may also increase the time during which patients remain functional on levodopa, and, for some patients, it may decrease the levodopa requirement. This drug is given in the standard dose found to inhibit monoamine oxidase B in most patients: 5 mg given in the morning and 5 mg at noon. Side effects of tremor and dyskinesia are common when deprenyl is used in conjunction with levodopa. These are attributable to increased dopaminergic activity, which can be controlled by lowering the levodopa dose.
Other Antioxidants
In the largest and best -designed of the deprenyl studies, tocopherol, a vitamin E analogue with antioxidant properties, was tested. Tocopherol showed no benefit, either alone or as an enhancer of deprenyl activity. Further study of antioxidants and their prolonged effects is ongoing.
Symptomatic Relief
Whereas anticholinergic therapy was the mainstay of treatment before the advent of levodopa (see later discussion), today the most important choice of initial therapy involves a decision between levodopa/dopa decarboxylase preparations and a direct dopamine agonist . The choice may influence the chance of future motor compilations, such as drug - induced dyskinesias and on off motor fluctuations. Levodopa provides superior motor benefit but is associated with a higher risk of dyskinesia.
Anticholinergic Therapy
Anticholinergic agents were the mainstay of parkinsonian therapy for more than a century, and they have remained important. Commonly used drugs are trihexyphenidyl (Artane) and benztropine (Cogentin). These agents may be particularly beneficial for patients with tremor as a prominent symptom. Both are muscarinic blocking agents with typical anticholinergic side effects of urine retention, dry mouth, increased intraocular pressure in patients with glaucoma, and confusion ( Table 174.3).
Dopamine Agonists
Treatment with one of the dopamine agonists bromocriptine, pergolide , and more recently pramipexole (Mirapex) and ropinirole ( Requip ) is increasingly recommended as first-line therapy for patients with mild to moderate parkinsonian symptoms. These medicines may suffice to control symptoms and delay for several years the need to pres cribe levodopa. Their side effects are similar to those of levodopa but with less risk of dyskinesias and motor fluctuations. Recently a dopamine agonist patch with rotigotine, a nonergoline dopamine agonist, has been developed. Whether continuous rather t han pulsatile dopamine delivery protects against long-term motor complications is unknown, but the U.S. Food and Drug Administration approval of the transdermal patch allows a new and well -tolerated form of drug delivery. Since its introduction to the U.S. market, pramipexole has become the most widely prescribed drug for early parkinsonism. Recent reports of several motor vehicle accidents in patients on pramipexole or ropinirole, as a consequence of paroxysmal attacks of sleep, have led to the recommendat ion that patients taking these medicines refrain from driving. A possibly unique
complication of pergolide is tricuspid insufficiency, resembling that associated with fenfluramine/phentermine use. In view of these findings, dopamine -agonist therapy should be initiated with a nonergot agonist.
Levodopa
Eventually, most patients experience a worsening of symptoms that requires the introduction of levodopa (in combination with a peripheral dopa decarboxylase inhibitor). Levodopa is recommended for patients who become too symptomatic to function satisfactorily despite anticholinergic therapy with deprenyl plus a dopamine agonist. By prescribing levodopa, the physician is able to offer most parkinsonian patients much benefit, P.1225 although the drug has a number of important limitations and side effects. Table 174.3 Drugs Used for the Treatment of Parkinsons Disease
Starti Prepara Drug Anticholiner gic Agents (representati ve examples) tion Dose Sched ule ng Dose
2, 5 mg 2 mg/ 5 mL
tid qid
2 mg
2 10 mg
Timedrelease capsule
5 mg
qd
(Timed-release capsule may be substituted for regular Artane after maintenance dose is determined)
Tablets
0.5, 1, 2 mg
qd or bid
1 mg
0.5 6 mg
Dopaminerg ic Agents
bid qid
50/2 00 mg
mg 25/100 mg 25/250 mg
Sinemet CR
50/200 mg
bid
50/2 00 mg bid
Variable
Bromocriptin e (Parlodel)
Scored tablets
2.5 mg
bid tid
1.25 mg qd
7.5 30 mg
Capsule s
5.0 mg
Scored tablets
tid
0.05 mg qd
1 3 mg
Tablets
5.0 mg
bid
5 mg qd
10 mg
Amantadine (Symmetrel)
Capsule s
100 mg
bid
100 mg qd
200 mg
Pramipexole (Mirapex)
Tablets
tid
0.25 mg tid
Variable
Ropinirole (Requip)
Tablets
0.2 5, 0.5, 1, 2 mg
tid
0.25 mg tid
Variable
COMT
Inhibitor
Tolcapone (Tasmar)
Tablets
100 , 200 mg
tid
100 mg tid
100 mg tid
bid, twice daily; COMT, catechol - O -methyltransferase; qd, daily; qid, four times daily; tid, thrice daily. Adapted from Reich SG, DeLong M. Parkinsons disease. In: Johnson R, ed. Current therapy in neurologic disease, 3rd ed. St Louis: Mosby, 1990; and Lang AE, Lozano AM, Medical progress: Parkinsons disease. N Engl J Med 1998;339:1044, 1130; with permission.
Timing of Initiation
The limited duration of levodopa efficacy makes it necessary to consider carefully when to begin therapy. Weighing against early initiation of levodopa treatment is the phenomenon of a decline in its effectiveness in as many as 50% of patients after 2 years of use. This observation is the basis for the traditional view that onset of therapy should be delayed as long as possible. However, some data indicate a reduction in mortality when levodopa is started within 1 to 3 years of onse t of symptoms rather than after 4 years. Clinical judgment that takes into account both of these findings is required.
Levodopa is the naturally occurring precursor of dopamine. It crosses the blood brain barrier and enhance s dopaminergic activity. However, because much of the drug is converted peripherally by a decarboxylase into dopamine (which cannot cross the blood brain barrier), levodopa is best given in combination with a peripheral decarboxylase inhibitor, such as carbidopa . Combination preparations containing both agents in various strengths are commonly used. In a typical starting program, the combination preparation of 25 mg of carbidopa and 100 mg of levodopa is given (e.g., Sinemet 25 to 100 mg two or three times daily; see Table 174.3). Levodopa is rapidly absorbed after oral administration, reaches its peak effect after 30 minutes to 2 hours, and has a half-life of 1 to 3 hours. The rate of absorption is decreased by the ingestion of a protein -rich meal.
Adverse Effects
Significant adverse reactions develop in many patients; nausea, vomiting, anorexia, hypertension, dyskinesias , and hallucinations can be disturbing. The nausea can be partly overcome by taking the drug with small meals. Dyskinesias include chorea, athetosis, and dystonia. They usually occur simultaneously with peak concentrations of levodopa and are best managed by having the patient take small doses of medication at frequent intervals.
therapy appear to wear off more quickly, producing marked fluctuations in symptoms. Wearing off is the recurrence of severe symptoms hours after the most recent dose of medication and is often followed by a recurrence of rigidity and bradykinesia. A controlled-release preparation (e.g., Sinemet CR ) relieves this problem for some patients. The development of a sustained -release preparation of levodopa/carbidopa (e.g., Sinemet CR, 50 mg/200 mg) has been a therapeutic advance for patients afflicted with motor fluctua tions. The controlled-release form can almost double the duration of effect to 5 to 6 hours. To match the effects of conventional levodopa preparations, a program of up to 25% more daily levodopa in the controlled -release form may be required. Doses administered after 6:00 p.m. can be given in the rapidly absorbed form to eliminate nocturnal side effects of the medication. Other ways to manage wearing -off symptoms include administering drugs that reduce the metabolism of dopamine or levodopa. The catechol-O-methyltransferase (COMT) inhibitors (e.g., tolcapone [ Tasmar ] and entacapone [ Comtan ]) have been introduced for this purpose. Tolcapone must be used with caution because cases of fulminant hepatic failure have been reported. The physician should refer a p atient requiring this therapy to a neurologist with expertise in the treatment of late -stage Parkinsons disease. As drug efficacy declines, patients may experience the on off phenomenon, with a severe fluctuation of dose response relations and rapid onset and termination of therapeutic and adverse effects. Impairment of levodopa absorption and transport into the
brain by dietary amino acids contributes to the problem. Treatment entails scheduling levodopa 1 hour before meals, reducing protein intake, and a dding an ergot preparation (see later discussion). Use of a controlled -release formulation may also help, but the development of the on off state represents an advanced form of disease and a difficult one to treat. Drug holidays have been proposed to r estore sensitivity to levodopa, but results are not impressive.
facilitated by the observations of the primary physician closely monitoring the patient.
Supportive Measures
Because maintaining function is a central goal of therapy, one should not forget the value of such important adjunctive measures as physical therapy and psychological support . Physical therapy can improve functioning by helping t o preserve muscle strength and flexibility. Although a central component of the supportive psychological effort involves close follow -up and detailed patient education (see later discussion), one must also be watchful for the development of depression and the need to treat it promptly and effectively (see Chapter 227).
disappointing, but work on fetal tissue and stem cell transplantation continues; results are promising.
After other potential causes of parkinsonism have been excluded, it is appropriate to start selegiline in the early stages of disease. The daily dose is 10 mg (5 mg in the
morning and 5 mg at noon). This drug may also be started in patients already taking levodopa/carbidopa in an attempt to lower the amount of levodopa needed.
If symptoms progress to impair daily functioning despite the use of deprenyl, then start one of the dopamine agonists (e.g., pramipexole, starting at 0.125 mg three times daily); double the dose at weekly intervals until a maintenance dose of about 1 mg three times daily is reached. As symptoms progress, begin levodopa/carbidopa, starting at a dose of 25 mg/100 mg three times dai ly; adjust the dose according to the patients response. There is no advantage to starting with a sustained -release preparation. Add amantadine or an anticholinergic if tremor is problematic. Consider a sustained-release levodopa/carbidopa preparation for dealing with on off symptoms; prescribe the taking of medication 1 hour before meals and restrict protein intake. Obtain neurologic consultation at this stage of disease. Similarly, consider a COMT inhibitor (e.g., tolcapone or entacapone ) for late-stage wearing-off phenomenon; again, obtain neurologic consultation. A trial of gabapentin therapy might be considered for late -stage disease but only with consultation. Do not overlook the important roles of physical therapy, psychological support, and recognit ion and treatment of depression. Refer patients to one of the excellent websites available, including http://www.apdaparkinson.org , http://www.michaeljfox.org , and http://www.parkinson.org .
In patients with advanced, incapacitating disease, consider referral for interventional or investigational therapy, but only to a nationally recognized center with expertise in these measures.
Annotated Bibliography
1. Goldstein DS, Holmes C, Li ST, et al. Cardiac sympathetic denervation in Parkinson disease. Ann I ntern Med 2000;133:338. ( Evidence that cardiac sympathetic denervation is common. ) 2. Lang AE, Lozano AM. Medical progress: Parkinsons disease (two parts). N Engl J Med 1998;339:1044, 1130. ( A superb twopart review covering pathophysiology and treatment. ) 3. Marin ER, Scott WK, Nance MA, et al. Association of single nucleotide polymorphisms of the tau gene with late -onset Parkinson disease. JAMA 2001;286:2245. ( Evidence for a genetic contribution to idiopathic disease. ) 4. Ross GW, Abbott RD, Petrovitch H , et al. Association of coffee and caffeine intake with risk of Parkinson disease. JAMA 2000;283:2674. ( Data from the Honolulu Heart Study population showing that caffeine intake is associated with reduced risk. ) 5. Siderowf A, Stern M. Update on Parkinson disease. Ann Intern Med 2003;138:651. ( A review that includes an excellent summary of the evidence for genetic and environmental contributions to clinical disease. ) 6. Koller WC. How accurately can Parkinsons disease be diagnosed? Neurology 1992;42(Suppl 1):6. ( A particularly lucid description of the clinical diagnosis. )
7. Nutt JG, Wooten GF. Diagnosis and initial management of Parkinsons disease. N Engl J Med 2005;353:1021. ( A comprehensive review for the generalist read er. ). 8. Deuschl G, Schade -Brittinger C, Krack P, et al. for the German Parkinson Study Group Neurostimulation Section. A randomized trial of deep- brain stimulation for Parkinsons disease. N Engl J Med 2006;355:896. ( The approach was found to be more effe ctive than medical therapy alone. ) 9. Diamond SG, Markham CH, Hoehn MM, et al. Multi -center study of Parkinson mortality with early versus later dopa treatment. Ann Neurol 1987;22:8. ( Mortality was less in patients treated earlier than in those treated lat er. ) 10. Fine J, Chen R, Hutchinson W, et al. Long -term follow-up of unilateral pallidotomy in advanced Parkinsons disease. N Engl J Med 2000;342:1708. ( Sustained improvement was found in off period contralateral signs. ) 11. Freed CRT, Greene PE, Breeze R E, et al. Transplantation of embryonic dopamine neurons for severe Parkinsons disease. N Engl J Med 2001;344:710. ( The results were largely negative, except for an improvement in motor performance in patients <60 years of age. ) 12. Krack P, Patir A, Van B iercom N, et al. Five -year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinsons disease. N Engl J Med 2003;349:1925. ( An uncontrolled trial; improvements were found in motor function and dyskinesia. ) 13. Jankovic J. New and emerging therapies for Parkinsons disease. Arch Neurol 1999;56:785. ( A good review of catechol -Omethyltransferase inhibitors and research on surgical therapies. )
14. Miyasaki JM, Martin W, Sujchowersky O, et al. Practice parameter: initiation of treatme nt for Parkinsons disease: an evidence-based review. Neurology 2002;58:11. ( Includes evidence for a neuroprotective effect for selegiline and a recommendation for its early use. ) 15. Olson WL, Gruenthal M, Mueller ME, et al. Gabapentin for parkinsonism: a double-blind, placebo-controlled, crossover trial. Am J Med 1997;102:60. ( A small-scale, short-term study, but it shows very encouraging results in patients with advanced disease. ) 16. Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. JAMA 2000;284:1931. ( A lower incidence of any motor complication was found in patients receiving pramipexole. ) 17. Parkinson Study Group. Low -dose clozapine for the treatment of drug-induced psychosis in Parkinsons disease. N Engl J Med 1999;340:757. ( Very few side effects and excellent efficacy were found, whereas virtually all other antipsychotic agents exacerbated symptoms. ) 18. Parkinson Study Group. Effects of tocopherol and deprenyl on the progressi on to disability in early Parkinsons disease. N Engl J Med 1993;328:176. ( Deprenyl, but not tocopherol, was effective in delaying the onset of disability and the need for levodopa therapy. ) 19. Rascol O, Brooks DJ, Korczyn AD, et al. A five -year study of the incidence of dyskinesia in patients with early Parkinsons disease who were treated with ropinirole or levodopa. N Engl J Med 2000;342:1484. ( A 5-year trial in Europe, Canada, and
Israel, showing that patients receiving ropinirole had a lower risk of dyskinesias. ) 20. Watts RL, Jankovic J, Waters C, et al. Randomized blind controlled trial of transdermal rotigotine in early Parkinson disease. Neurology 2007;68:171. ( The patients on rotigotine improved primarily in their motor scores; oral ropinirole in a prolonged-release preparation is also on the horizon. ) 21. Duvoisin RC. Parkinsons disease: a guide for patient and family, 4th ed. New York: Raven Press, 1996. ( A sensible, very useful guide for the patient and family embarking on a course of treatment for Parkinsons disease .)