Primary Care Medicine: Office Evaluation and Management of the Adult Patient6th Edition

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Chapter 174Approach to the Patient with Parkinson’s DiseaseAmy A. PruittParkinson’s disease is the second-most-common neurodegenerative disease in older Americans, affecting more than 1 million people in North America. It is characterized by tremor at rest, rigidity, and bradykinesia. The refinement of drug therapy for Parkinson’s disease has brought relief to thousands of patients with this immobilizing condition. The recent development of therapy that may slow disease progression makes the early diagnosis and treatment of Parkinson’s disease particularly critical. Proper treatment requires careful timing and skillful utilization of drugs because important difficulties are associated with pharmacologic therapy. Moreover, drug efficacy declines with time, and the therapeutic response may be blunted by improper timing or inappropriate selection of antiparkinsonian agents.P.1222

Although the fine tuning of treatment for Parkinson’s 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.

Pathophysiology, Clinical Presentation, and Course (1 ,2 ,3 ,4 ,5)PathophysiologyParkinson’s disease is a neurodegenerative condition. Its most characteristic pathologic feature is a loss of dopamine-containing neurons; the nuclei of these neurons reside in the pars compacta of the substantia nigra, and the axons terminate in the caudate nucleus and putamen (the striatum). Other pigmented and nonpigmented nuclei in the brainstem and elsewhere are also affected. Associated with neuronal loss is the development of concentric hyalin inclusions in the cytoplasm of affected neurons, called Lewy bodies. Symptoms are believed to be related to the imbalance between dopaminergic and cholinergic influences on striatal tissue created by the loss of dopamine-containing neurons. Proper striatal function depends on this balance. Loss of sympathetic innervation can occur in the nigrostriatal system in the brain and in the sympathetic nervous system of the heart, leading to neurocirculatory failure.Both genetic and environmental factors have been implicated in the development of Parkinson’s disease. Their relative contributions differ for early-onset and late-onset disease.

Genetic ContributionsGene mutations appear to be most important 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 α-synuclein gene on chromosome 4. The products of these genes are likely to be important in pathogenesis, with α-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 with the more common idiopathic form of Parkinson’s 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 ContributionsIn sporadic idiopathic Parkinson’s disease with onset older than the age of 50 years, environmental factors are believed to be possibly important. The substantia nigra of patients with Parkinson’s 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, impairing 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 suspected 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 risk of Parkinson’s

disease, suggesting a role for the adenosine receptor, which it antagonizes.

Clinical PresentationParkinson’s 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 patients. Parkinson’s 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 Parkinson’s 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 CourseBefore the introduction of levodopa, Parkinson’s 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 Parkinson’s 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. Although patients with idiopathic Parkinson’s 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 Parkinson’s 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 Alzheimer’s disease because of the prominent dementia that ensues (see Chapters 169 and 173 ).

Table 174.1 Differential Diagnosis of Parkinsonism

Idiopathic Parkinsonism (Parkinson’s Disease)Infectious and postinfectiousPostencephalitic parkinsonism (von Economo’s disease)Other viral encephalitidesToxinsManganeseCarbon monoxideCarbon disulfideCyanideMethanolMPTPa

DrugsNeurolepticsReserpineMetoclopramideLithiumAmiodaroneα-Methyldopa

Multisystem DegenerationStriatonigral degenerationProgressive supranuclear palsyOlivopontocerebellar degenerationShy–Drager syndromePrimary Dementing and Other Degenerative DisordersAlzheimer’s diseaseLewy body diseaseCreutzfeldt–Jakob diseaseOther Central Nervous System DisordersMultiple cerebral infarctions (lacunar state, Binswanger’s disease)Hydrocephalus (normal-pressure or high-pressure)Posttraumatic encephalopathy (pugilistic parkinsonism)Metabolic ConditionsHypoparathyroidismChronic hepatocerebral degenerationIdiopathic calcification of basal gangliaHereditary DisordersWilson’s diseaseJuvenile Huntington’s disease (rigid variant)

This list is not meant to be all-inclusive. Rather, it highlights the more common disorders that may have parkinsonism as a prominent feature.a1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a meperidine analogue used by intravenous-drug abusers.Adapted from Koller WC. How accurately can Parkinson’s

disease be diagnosed? Neurology 1992;42(Suppl 1):6, with permission.

The clinical diagnosis of Parkinson’s 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 photon 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 parkinsonism.

Principles of Management (7 ,8 ,9 ,10 ,11 ,12 ,13 ,14 ,15 ,16 ,17 ,18 ,19 ,20)Parkinson’s disease cannot be cured, but advances in treatment have improved prospects for patients.

Goals and Overall StrategyThe goals of therapy are (a) to delay disease progression, (b) to relieve symptoms, and (c) to preserve functional capacity. Restoring the striatal balance between dopaminergic and cholinergic activity is at the core of efforts to achieve symptomatic relief. Inhibiting oxidative injury appears to be helpful in retarding disease progression. The patient may be able to tolerate many of the early signs of parkinsonism, which are sufficient to prompt medical consultation but, aside from provoking psychological discomfort, are not disabling. The goal of therapy is to maintain the patient at maximum function with minimal medication.The three categories of management strategies are preventive treatment, symptomatic relief, and regenerative therapy.

Delay of Disease Progression: Preventive TreatmentIf 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 Parkinson’s Disease

Inclusion Criteria Exclusion Criteria

Presence for 1 yr or more of two of the three cardinal motor signs:

Abrupt onset of symptoms Remitting or stepwise progression

Resting or postural tremor Neuroleptic therapy within 1 yr

Bradykinesia Exposure to drugs or toxins associated with parkinsonism

Rigidity History of encephalitis

Responsiveness to levodopa therapy with moderate to marked improvement and duration of improvement for 1 yr or more

Oculogyric crisesSupranuclear downward or lateral gaze palsyCerebellar signsUnexplained upper motor neuron or lower motor neuron signsMore than one affected

relativeDementia from the onset of diseaseSevere autonomic symptoms

Adapted from Reich SG, DeLong M. Parkinson’s 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 Parkinson’s 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 AntioxidantsIn 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 TherapyAnticholinergic 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 AgonistsTreatment 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 prescribe 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 than 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 recommendation 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.

LevodopaEventually, 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 Parkinson’s Disease

Drug Preparation

Dose Schedule

Starting

Maintenance

Dose Dose

Anticholinergic Agents (representative examples)

Trihexyphenidyl hydrochloride (Artane)

Scored tabletsElixir

2, 5 mg2 mg/5 mL

tid–qid

2 mg 2–10 mg

Timed-release capsule

5 mg

qd (Timed-release capsule may be substituted for regular Artane after maintenance dose is determined)

Benztropine mesylate (Cogentin)

Tablets 0.5, 1, 2 mg

qd or bid

1 mg 0.5–6 mg

Dopaminergi

c Agents

Carbidopa/levodopa (Sinemet)

Scored tablets10/100 mg25/100 mg25/250 mg

bid–qid

50/200 mg in two divided doses

400–500 mglevodopa

Sinemet CR 50/200 mg

bid 50/200 mg bid

Variable

Bromocriptine (Parlodel)

Scored tablets

2.5 mg

bid–tid

1.25 mg qd

7.5–30 mg

Capsules

5.0 mg

Pergolide mesylate (Permax)

Scored tablets

0.05, 0.25, 1.0 mg

tid 0.05 mg qd

1–3 mg

Deprenyl (Eldepryl, selegiline hydrochloride)

Tablets 5.0 mg

bid 5 mg qd

10 mg

Amantadine (Symmetrel)

Capsules

100 mg

bid 100 mg qd

200 mg

Pramipexole (Mirapex)

Tablets 0.125, 0.25, 0.5, 1, 1.5 mg

tid 0.25 mg tid

Variable

Ropinirole (Requip)

Tablets 0.25, 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. Parkinson’s disease. In: Johnson R, ed. Current therapy in neurologic disease, 3rd ed. St Louis: Mosby, 1990; and Lang AE, Lozano AM, Medical progress: Parkinson’s disease. N Engl J Med 1998;339:1044, 1130; with permission.

Timing of InitiationThe 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 onset of symptoms rather than after 4 years. Clinical judgment that takes into account both of these findings is required.

Preparations and Initial DosingLevodopa is the naturally occurring precursor of dopamine. It crosses the blood–brain barrier and enhances 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 EffectsSignificant 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.

Problems in Late-Stage Therapy—Wearing Off and On–Off PhenomenaWith disease progression, the benefits of levodopa P.1226

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 fluctuations. 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 patient requiring this therapy to a neurologist with expertise in the treatment of late-stage Parkinson’s 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 adding 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 restore sensitivity to levodopa, but results are not impressive.

Other Dopaminergic Agents in Late-Stage Disease

Bromocriptine and pergolide are direct dopamine-receptor agonists. These agents are used to enhance the therapeutic effects of levodopa and may be particularly helpful in late stages of the disease, when the conversion of levodopa to dopamine is inefficient in the degenerating substantia nigra. They are less likely than levodopa to cause dyskinesias and the on–off phenomenon. In addition, they may allow the use of lower doses of levodopa when given early on with levodopa as combined therapy.Gabapentin (Neurontin) has shown some efficacy for patients with advanced disease and is well tolerated except for drowsiness at high doses. Small-scale, short-term study of gabapentin, which stimulates the striatal release of γ-aminobutyric acid (GABA), has produced promising results in patients with advanced disease. It is theorized that GABA stimulation may help overcome the loss of dopaminergic stimulation.Both the direct dopamine agonists and the levodopa controlled-release preparations are likely to be prescribed by neurologists, but recognition of the necessity to move to such therapies is facilitated by the observations of the primary physician closely monitoring the patient.

Treatment of Psychiatric SymptomsNightmares, hallucinations, and increased sexual drive are disturbing psychiatric features of late-stage disease. Hallucinations and psychosis are best treated with the atypical neuroleptic clozapine. Use of phenothiazines such as haloperidol should be avoided, especially if there is frank Lewy body disease (see Chapters 169 and 173 ). Severe depression is managed with the same medications given to patients without Parkinson’s disease. However, because most of these patients are elderly, the physician must be careful of side effects of the tricyclic

antidepressants (see Chapter 227 ). Theoretically, the combination of selegiline and a selective serotonin reuptake inhibitor is problematic, and indications for this class of drug should be carefully weighed against the possibility of inducing the serotonin syndrome (hypertension, tachycardia, other autonomic dysfunction, and hallucinations). Electroconvulsive therapy may be used in depressed patients who are not confused.

Supportive MeasuresBecause 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 to 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 ).

Interventional and Investigational TherapiesSurgery and Deep-Brain StimulationAs the pathophysiology of parkinsonism has become better understood, the role of functional neurosurgical procedures has grown. Surgery is reserved for disabling, medically refractory disease. When the problem is severe dyskinesia and on–off fluctuations, unilateral pallidotomy has been demonstrated to be effective.Deep-brain stimulation of the globus pallidus and subthalamic nucleus is a less invasive interventional option. In randomized study, deep brain stimulation in patients younger than the age of

75 years with severe motor complications provided significantly better relief of symptoms (especially improved mobility and relief of dyskinesia) than medical therapy alone, allowing patients to achieve independent mobility after being previously in need of daily assistance; however, risk of a serious adverse event was 13% versus 4%, including one death from cerebral hemorrhage. These procedures are not as effective for bradykinesia.

Transplantation of Fetal Tissue and Stem CellsThis investigational method involves transplantation of fetal substantia nigra tissue into the striatum, which relieves the signs of parkinsonism in animals with experimental lesions of the substantia nigra. Early attempts to treat humans who had Parkinson’s disease with grafts of human fetal tissue were disappointing, but work on fetal tissue and stem cell transplantation continues; results are promising.

Other Methods under DevelopmentThese include new drugs for inhibiting dopamine breakdown, synthesis of new dopamine-receptor agonists, and blockade of excitotoxic neurotransmitter receptors in the subthalamic P.1227

nucleus. Finally, jejunal infusion of levodopa and carbidopa has been tried in an attempt to improve levodopa absorption.

Patient Education (19)Patient and family education is essential to the success of therapy. The need for trial and error to obtain maximal benefit with minimal side effects must be explained. Frequent visits are needed in the initiation period and later in the course of the disease. Although

therapy can be proposed optimistically, the inevitable diminution in the efficacy of therapy must be anticipated and discussed with patient and family so that they can be adequately prepared, both psychologically and practically. Patients are obviously concerned about their prognosis, and a frank discussion of what is known is usually appreciated. A number of helpful guidebooks are available for patients and their families.

Therapeutic Recommendations (7 ,14)

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 daily; adjust the dose according to the patient’s 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 recognition 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 Bibliography1. Goldstein DS, Holmes C, Li ST, et al. Cardiac sympathetic denervation in Parkinson disease. Ann Intern Med 2000;133:338. (Evidence that cardiac sympathetic denervation is common. )2. Lang AE, Lozano AM. Medical progress: Parkinson’s disease (two parts). N Engl J Med 1998;339:1044, 1130. (A superb two-part 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 Parkinson’s 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 Parkinson’s disease. N Engl J Med 2005;353:1021. (A comprehensive review for the generalist reader. ).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 Parkinson’s disease. N Engl J Med 2006;355:896. (The approach was found to be more effective 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 later.)10. Fine J, Chen R, Hutchinson W, et al. Long-term follow-up of unilateral pallidotomy in advanced Parkinson’s disease. N Engl J Med 2000;342:1708. (Sustained improvement was found in off-period contralateral signs.)11. Freed CRT, Greene PE, Breeze RE, et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s 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 Biercom N, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced

Parkinson’s 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 Parkinson’s disease. Arch Neurol 1999;56:785. (A good review of catechol-O-methyltransferase inhibitors and research on surgical therapies. )14. Miyasaki JM, Martin W, Sujchowersky O, et al. Practice parameter: initiation of treatment for Parkinson’s 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 Parkinson’s 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 progression to disability in early Parkinson’s 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 Parkinson’s 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. Parkinson’s 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 Parkinson’s disease .)

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