Parkinson Disease and Other Movement Disorders Part 2

Clinical Features

The cardinal clinical features of PD are bradykinesia, muscular rigidity, and a rest tremor of 4 to 6 cycles per second (hertz [Hz]). The presence of two of the three cardinal signs and a robust clinical response to levodopa, the amino acid precursor of dopamine, are sufficient to make a probable diagnosis of PD.9 Onset of symptoms on one side of the body and the presence of rest tremor further support a diagnosis of PD. Masklike facies [see Figure 4], decreased blinking, stooped posture, decreased arm swing when walking, and micrographia are often present early in the disease.

Diagnosis of PD in its early stages may be difficult unless the characteristic rest tremor is present. In the absence of tremor, the most common complaints are nonspecific; patients note weakness, fatigue, and muscle aches.

Parkinsonian tremor typically begins as a so-called pill-rolling motion of the fingers of one hand. The tremor usually spreads proximally in the arm and sometimes to the leg before crossing to the other side of the body over the next 1 to 2 years. The face, tongue, and jaw may be involved, but typically, the patient does not have voice tremor (lingual titubation). In contrast to essential and cerebellar tremors, parkinsonian tremor is usually present at rest and attenuates or disappears during movement. It may reappear after the movement is completed, even when a posture is sustained. However, postural or essential tremor may sometimes precede and coexist with parkinsonian rest tremor.

Bradykinesia (slowness of movement) and akinesia (paucity of movement) are among the most disabling features of PD cause they interfere with all aspects of daily living, especially ambulation. Fine motor control is also affected, as manifested by impaired finger dexterity and micrographia. Hypophonia and monotonic speech are manifestations of bradykinesia affecting the cranial musculature.be

Figure 3 Proposed cascade of pathogenic events leading to the death of neurons in Parkinson disease. Note the possible interaction between genetic and environmental factors.

Rigidity in PD represents a uniform increase in resistance to passive movement throughout the full range of motion of all muscle groups acting around a joint. Brief, regular interruptions of resistance during passive movement, corresponding to sub-clinical tremor, may give rise to a cogwheeling sensation. Combinations of rigidity and dystonia typically result in neck flexion, stooping, and a tendency to hold the arms in a flexed, adducted position.

Parkinsonian gait is usually associated with shuffling, short steps and a tendency to turn en bloc. In advanced stages of disease, gait initiation and turning become increasingly difficult. Advanced PD may be marked by festinating gait, which is characterized by stiff flexion at the knees and hips, an absence of arm swinging, and short steps (often on tiptoe) that accelerate in an apparent effort to catch up with the body’s center of gravity. Postural instability is one of the most disabling and refractory features of parkinsonism and a major contributor to falls. Although decreased postural reflexes may be noted early in PD, significant postural instability is rarely a problem until the disease progresses to more advanced stages. Indeed, significant postural instability early in the course of the illness suggests a diagnosis other than PD.

Freezing, a feature of more advanced PD, occurs most commonly at the initiation of locomotion (start hesitation), when attempting to change direction, or upon entering a crowded or narrow space (e.g., a doorway). Freezing is most commonly a manifestation of inadequate dosing or wearing off of medication but may occasionally occur in well-medicated patients (so-called on freezing). The presence of an ataxic or otherwise atypical gait, however, suggests an alternative diagnosis, such as normal-pressure hydrocephalus, multiple system atrophy with cerebellar involvement, or spinal stenosis.

Figure 4 Face of a patient with Parkinson disease. Note the lack of expressivity and poor definition of the nasolabial fold. Scaling seborrhea is also common.

Nonmotor disturbances In addition to motor symptoms, many patients with PD experience disturbances of cognition, mood, sensation, sleep, and autonomic function. Changes in cognition, behavior, and mood may result in part from involvement of nuclei in the brain stem and elsewhere, as well as disruption of the nonmotor circuits of the basal ganglia [see Figure 1].

Dementia is not a presenting or early feature of idiopathic PD, but dementia occurs in up to 30% of patients in advanced stages of disease.35,36 It is more common in patients with the akinetic-rigid subtype of parkinsonism. Dementia is frequently preceded by depression or drug-induced hallucinations. Patients with parkinsonism and dementia typically have mixed pathologies, including senile dementia of the Alzheimer type and diffuse cortical Lewy bodies (i.e., Lewy body dementia).36

Depression affects as many as 50% of patients with PD and may develop at any stage of the illness, irrespective of disease severity.37 Depression may be difficult to recognize because overt emotionality may be lacking and the psychomotor retardation of depression may closely resemble the hypokinetic aspects of par-kinsonism. Anxiety often accompanies depression. Anxiety and dysphoria can occur episodically in relation to the wearing off of levodopa. Depression can be induced or aggravated iatrogeni-cally by polypharmacy and poorly managed motor symptoms. Conversely, emerging depression may adversely affect motor symptoms. Personality changes in the form of apathy, lack of asser-tiveness, and indecisiveness are also common. It is important to rule out hypothyroidism and hypogonadism with low testosterone levels in men, which may not only contribute to the negative symptoms of PD but may make depression resistant to treatment.

Sleep disorders are common in PD.38 A variety of problems, including insomnia and sleep fragmentation, can interfere with both the duration and quality of sleep. In addition, rapid eye movement sleep-related behavioral disorders (e.g., nocturnal vocalizations and bursts of motor activity) and restless legs syndrome contribute to sleep disruption. Nighttime reemergence of parkinsonian motor signs and involuntary movements (e.g., my-oclonic jerks and periodic leg movements) may also disrupt sleep.38 Vivid dreams and hallucinations, which may be side effects of antiparkinsonian therapy, may also contribute to sleep disruption.39 In addition, sleep apnea and other sleep disturbances often occur in older PD patients. Daytime drowsiness and frequent napping may be typical signs of sleep disruption or an adverse effect of dopaminomimetic therapy, particularly dopamine agonists.

Other nonmotor disturbances in PD include orthostatic hypotension, constipation, sexual and urinary dysfunction, and se-borrhea. All of these result from autonomic dysfunction.

Treatment

The goals of treatment in PD are to maintain function by controlling primary disability with symptomatic therapy and to minimize secondary disability (e.g., deconditioning, contrac-tures, accelerated arthritis) with a consistent program of physical exercise.40 Other goals include maintaining drug efficacy, avoiding drug-induced dyskinesias, preventing psychiatric complications, and slowing the progression of the disease. Goals still on the horizon include addressing currently unresponsive symptoms such as speech, balance disturbances, and autonomic dysfunction and eliminating common side effects such as nausea, orthostatic hypotension, and daytime sedation.

Levodopa Since 1969, when Cotzias demonstrated that oral administration of the dopamine precursor levodopa could alleviate parkinsonism,41 levodopa therapy has been the mainstay of treatment. It greatly improves the quality of life and the lifespan of patients with PD. Although levodopa is toxic to dopamine neurons in vitro, it has not been shown to be toxic in vivo.42 In a randomized, double-blind, placebo-controlled study of car-bidopa-levodopa in early PD, clinical data suggested that treatment with levodopa for 40 weeks either slows the progression of PD or at least has a prolonged effect on disease symptoms; whereas neuroimaging studies suggested that either levodopa accelerates the loss of nigrostriatal dopamine nerve terminals or its pharmacologic effects modify the dopamine transporter.43 Long-term levodopa administration clearly can kindle motor fluctuations and dyskinesias in PD.44,45

Dopamine agonists Concerns about side effects with long-term levodopa use have spurred interest in treating PD with dopamine agonists (see below). Several double-blind placebo-controlled studies have now established that compared with carbidopa-levodopa treatment, starting PD treatment with dopamine-agonist monotherapy will delay the onset and reduce the severity of motor fluctuations.4"8 A randomized, controlled comparison of initial PD treatment with pramipexole or lev-odopa found that initial treatment with pramipexole resulted in lower incidences of dyskinesias and wearing-off (i.e., shortened duration of therapeutic effect of individual drug doses), whereas initial treatment with levodopa resulted in lower incidences of freezing, somnolence, and edema and provided for better symptomatic control.49 Of interest, a comparison of controlled-release carbidopa-levodopa (e.g., Sinemet CR) with regular (immediate-release) carbidopa-levodopa found that the incidence of dyski-nesia was not significantly lower with the controlled-release formulation, which suggests that there are fundamental differences in the long-term consequences of dopamine receptor stimulation between levodopa and dopamine agonists.

Table 2 Carbidopa-Levodopa Preparations

Preparation	Levodopa Dose Equivalency	Available Strengths (mg)	Initial Dosage	Comments
Carbidopa-levodopa IR	100 mg (anchor dose)	10/100 25/100 25/250	25/100; 0.5-1 tablet t.i.d.	—
Carbidopa-levodopa CR	150 mg	25/100 50/200	50/200; one tablet b.i.d or t.i.d	Increased bioavailability with food; splitting the tablet negates the CR properties
Carbidopa-levodopa-entacapone	120 mg	12.5/50/200 25/100/200 37.5/150/200	25/100/200; one tablet b.i.d or t.i.d.	Do not split tablets

CR—controlled release

IR—immediate release

Initiating treatment The major determinants in the choice of initial therapy in PD are age of onset, the presence of dementia, the level of existing polypharmacy, and cost.45,51 In cognitively intact patients with no significant medical problems, we favor initiation of dopamine-agonist monotherapy in sufficient doses to adequately control motor symptoms. This typically means giving higher doses than when dopamine agonists are used in combination with levodopa. Although symptoms such as or-thostasis, dizziness, and nausea are more common with dopa-mine agonists than with levodopa, these can be avoided in most cases by slow titration. A common mistake with dopamine-ago-nist monotherapy is the failure to push the dose high enough to maintain adequate symptom control, leading to the premature addition of levodopa.

Most, if not all, patients with PD will need levodopa therapy at some point. When to introduce levodopa depends on the patient’s ability to maintain function on dopamine-agonist mono-therapy. Some patients resist starting levodopa for fear of its side effects. These patients should be advised against compromising their quality of life for the sake of avoiding levodopa therapy. In addition, they should be reassured that when levodopa is added, its dose is limited to that necessary to complement the effect of the dopamine-agonist, which remains the dominant component of therapy.

Still controversial is whether dopamine agonists provide a neuroprotective effect.45 This hypothesis is currently being tested in a number of clinical trials in Europe and the United States.

Demented patients and those on multiple other medications are particularly prone to developing sedation, orthostasis, and drug-induced psychiatric symptoms. Initiation of therapy in this setting is aimed at reducing the incidence of central nervous system symptoms. To this end, in these patients we favor starting treatment with levodopa, with or without levodopa augmentation strategies (see below). Dopamine-agonist augmentation is introduced later as needed. In demented patients, anticholiner-gics and amantadine are to be avoided as much as possible to minimize CNS side effects. In cognitively intact patients, these agents may be given to minimize the use of levodopa and to control tremor and dystonic symptoms.

Levodopa formulations Levodopa is customarily given in combination with carbidopa, a peripheral dopa decarboxylase (DDC) inhibitor that blocks peripheral breakdown of levodopa, thus augmenting the bioavailability of levodopa while minimizing the side effects associated with peripheral conversion of lev-odopa to dopamine (notably, nausea). Carbidopa-levodopa is available in immediate-release formulations (10 mg car-bidopa/100 mg levodopa, 25 mg/100 mg, and 25 mg/250 mg) and in controlled-release formulations (25 mg/100 mg, 50 mg/200 mg) [see Table 2]. Immediate-release carbidopa-lev-odopa is also available in an orally disintegrating form (Parcopa) that can be taken without water.

Carbidopa supplements (25 to 200 mg/day) are occasionally used to pretreat selected patients who have persistent nausea, presumably in response to inadequate plasma and carbidopa levels. For patients with persistent nausea, antiemetics such as trimethobenzamide and domperidone (available in Canada and Europe) may be well-tolerated and effective temporary measures. Because of its high cost, ondansetron is not a practical choice for long-term outpatient management. Other antiemetics, such as the dopamine receptor antagonists prochlorperazine and metoclopramide, should be avoided because they may significantly worsen parkinsonian symptoms.

Initiating treatment with either a regular or a controlled-re-lease formulation of carbidopa-levodopa is acceptable. Although regular carbidopa-levodopa is better absorbed on an empty stomach, many experts recommend that early in treatment it be taken with meals to minimize nausea. In contrast, the absorption and bioavailability of the controlled-release formulations are increased when taken with meals.52 The side effects of carbidopa-levodopa can be controlled by starting with a small dose (e.g., one-half tablet of carbidopa-levodopa, 25 mg/100 mg b.i.d.) and then increasing the dose as tolerance to the nausea develops. Dose adjustments should be made slowly because the full response to each increase in dose evolves over weeks. In the early stages of the disease, a typical daily dose should not exceed 300 to 400 mg/day of levodopa (as carbidopa-levodopa). Higher and more frequent doses may be necessary in patients with more advanced disease who experience wearing-off and other motor fluctuations.

Compared with immediate-release carbidopa-levodopa, con-trolled-release carbidopa-levodopa provides the convenience of one or two fewer daily doses and smaller oscillations in plasma levodopa levels, which results in a decrease in motor fluctuations in patients who experience mild to moderate wearing-off.50,52 The bioavailability of levodopa in the controlled-release formulations is about 70% of that in the immediate-release formulations. The bioavailability of carbidopa in controlled-release formulations is about 50% that of immediate-release formulations. If controlled-release carbidopa-levodopa is selected as initial therapy, the initial dose is half of a 50 mg/200 mg tablet taken twice daily. Splitting the tablet negates the controlled-release properties; we do not recommend initiating therapy with con-trolled-release 25 mg/100 mg formulations because of the high incidence of nausea compared with immediate-release therapy. We prefer that patients start taking doses at breakfast and lunch only, maintaining 5- to 6-hour intervals between doses, rather than adopt a strict twice-daily schedule. The goal is to build a plateau of plasma levodopa levels early in the day and let the patient "ride" this plateau the rest of the day. Eventually, the patient will need late-afternoon and evening doses. Typical schedules of the various formulations of carbidopa-levodopa vary at different stages of disease and with different types of motor response abnormalities [see Table 3]. As the disease progresses and the level of motor-response abnormality increases, we rely less on controlled-release carbidopa-levodopa formulations and more on immediate-release formulations or on dopamine-ago-nist-dominant treatment.

Table 3 Strategies for the Use of Carbidopa-Levodopa Formulations

	Dosage (Tablets)
	Monotherapy (CR 50 mg/200 mg)	Early Fluctuations		Late Fluctuations
Time		CR 50 mg/200 mg	IR 25 mg/100 mg*	CR 50 mg/200 mg	IR 25 mg/100 mg
0700 hr	1	1	1	1	1
1100 hr	—	1	—	1	1
1200 hr	1	—	—	—	—
1500 hr	—	1
1900 hr			—	—	1
2300 hr	—	1	—	—	1

*Booster doses.

CR—controlled release

IR—immediate release

Levodopa augmentation One strategy for levodopa augmentation is the use of monoamine oxidase (MAO) inhibitors. MAO-B enzyme activity is one of the major catabolic pathways for dopamine in the CNS. Blocking its activity increases the in-trasynaptic half-life of dopamine, leading to reduced motor fluctuations and tremor. Selegiline is a selective and irreversible MAO-B inhibitor that has a weak antiparkinsonian effect when used alone and a moderate effect when used as an adjunct to car-bidopa-levodopa.53 Selegiline is available as a 5 mg capsule or tablet. The usual dose is 5 mg with breakfast and lunch. In contrast to the nonselective MAO inhibitors (MAO-AB) and the MAO-A inhibitors, dietary tyramine restrictions are not necessary with selegiline. Insomnia is a significant side effect of selegi-line, particularly when the drug is taken after midday. Older persons and those with significant but stable cardiac disease may benefit from daily doses as low as 2.5 mg. The dose should be reduced or the drug withdrawn if refractory hyperdopaminergic side effects occur (e.g., worsening dyskinesias, hallucinosis, confusion). A single European report citing increased mortality in elderly patients using selegiline54 is inconsistent with all previous studies and with the long-term experience with selegiline in the Parkinson Study Group in North America.

Another levodopa augmentation strategy consists of blocking the activity of the enzyme catechol-O-methyltransferase (COMT). Together, COMT and DDC activity account for approximately 85% (10% and 75%, respectively) of the peripheral breakdown of levodopa.55 Inhibition of COMT activity with tolcapone or enta-capone can decrease oscillations in plasma levodopa levels. Both short-term and long-term administration of these agents slow the elimination of carbidopa-levodopa, thus increasing the area under the curve of plasma levodopa by 10% to 15% without changing the peak plasma level or the time to reach this peak.

A number of double-blind, placebo-controlled studies have shown that this leads to a clinically important reduction in motor fluctuations and an increase in the time that the medication dose is effective ("on" time) of 1 to 2 hours a day.56 In patients treated with tolcapone, the daily dose of carbidopa-levodopa may need to be decreased by 10% to 30% to avoid dyskinesias or other hyperdopaminergic side effects. In patients treated with entacapone, we generally wait until after the first few weeks of treatment to see whether any reduction in the dose of carbidopa-levodopa becomes necessary. Tolcapone is available in 100 and 200 mg tablets and is taken three times a day. Entacapone is available in 200 mg tablets and is administered as a single tablet with each dose of carbidopa-levodopa. Entacapone is now available in combination with carbidopa-levodopa (Stalevo 50 mg/100 mg/150 mg), which offers some convenience in reducing the number of pills taken.

COMT inhibitors can worsen levodopa-induced dyskinesias and cause nausea and diarrhea. Tolcapone carries a small risk of hepatotoxicity (including fatal hepatic necrosis) that has prompted a black-box warning from the Food and Drug Administration; for that reason, it is necessary to obtain informed consent before initiating therapy and to monitor liver function during therapy.57 Rare cases of rhabdomyolysis associated with tolcapone use have also been described. Entacapone causes orange urine discoloration. Both agents can cause piloerection. Although the clinical antiparkinsonian effect of tolcapone appears to be more robust than that of entacapone, we favor initiating treatment with entacapone because of its greater safety.

There is little information comparing COMT inhibitors with dopamine agonists. Trials comparing tolcapone with the dopa-mine agonists bromocriptine and pergolide have been conducted, but those trials did not have sufficient power to detect clinically relevant differences between the agents.58 Unlike dopamine agonists, COMT inhibitors are not effective for monotherapy, nor have they been shown to decrease the incidence of dyskine-sias when introduced early in the course of treatment.

Dopamine agonists Dopamine agonists require neither transformation nor facilitated transport across the blood-brain barrier; they act directly on postsynaptic dopamine receptors. The available agents are the ergot alkaloids bromocriptine and pergolide and the newer nonergot alkaloids pramipexole and ropinirole [see Table 4].’46,48 The nonergot alkaloids are approved for early PD monotherapy and as adjuncts to carbidopa-lev-odopa in patients with advancing disease. Accumulating data indicate that pergolide may also be an effective monotherapeu-tic agent in PD.48 However, pergolide has been associated with rare cases of cardiac valve dysfunction, most commonly tricus-pid regurgitation.59

In a few head-to-head comparisons, the newer agents proved to be slightly superior to bromocriptine. There is no obvious advantage among the other three agents. Nonergot alkaloids are thought to cause less nausea and orthostatic hypotension than the ergots, but this difference appears to be clinically marginal. The newer agents offer no advantage over the old agents in terms of CNS side effects (e.g., confusion, hallucinations, and sleep disturbances). In fact, pramipexole has been associated with episodes of somnolence during the daytime—so-called sleep attacks—that have led to automobile accidents in patients.60 This has led to the FDA’s issuing a warning. There have been a few similar reports with ropinirole. Although the ergot alkaloids appear to be less likely to cause such episodes, we warn all our patients about this potential danger.

Amantadine and anticholinergics Some physicians prefer to treat early, mild PD with less potent agents, such as amanta-dine or anticholinergic agents, to delay the introduction of lev-odopa. There are no data to indicate that this levodopa-sparing maneuver prevents the emergence of dyskinesias.

Amantadine is particularly helpful in the treatment of drug-induced dyskinesias and thus may be especially valuable in later stages of the disease. Amantadine is available in 100 mg tablets and capsules and in 50 mg/5 ml syrup; the usual dosage is 200 to 400 mg/day in two or three divided doses. The mechanism of action of amantadine is unclear. In vitro, it can enhance dopamine transmission, it has anticholinergic effects, and it acts as a weak glutamate antagonist.61 The side effects of amantadine are edema, erythema, and livedo reticularis. In older patients, it may aggravate confusion and psychosis. Amantadine needs to be used with caution and in smaller doses in patients with renal insufficiency.

Anticholinergics have long been used in PD, particularly for their effects on tremor, rigidity, and dystonia. They have limited effects on akinesia, bradykinesia, posture, and gait. Their major drawbacks, particularly in elderly patients, are memory impairment, hallucinations, visual blurring, aggravation of glaucoma, constipation, urinary hesitancy, and dry mouth. The last side effect can be exploited as a treatment for the drooling (sialorrhea) that affects many patients with PD. Specifically, patients with significant sialorrhea may benefit from glycopyrrolate (1 to 2 mg b.i.d.), which is an anticholinergic with low CNS penetrability. Other available anticholinergic agents include ethopropazine (50 to 200 mg/day), trihexyphenidyl (1 to 10 mg/day) and benz-tropine (1 to 4 mg/day). Tolerance of these agents decreases with advancing age. Of these agents, ethopropazine is a less potent antiparkinsonian agent but is more likely to be tolerated by elderly patients. In the United States, ethopropazine can be obtained through compounding pharmacies.

Treatment of advanced disease and its complications Clinical management of PD becomes increasingly complex as the disease advances and patients experience worsening gait and postural instability, increased freezing, falls, and the emergence of motor fluctuations and dyskinesias. Equally disabling are drug-induced confusional spells, hallucinations, and psychosis. Referral to a movement-disorder specialist is indicated when disease progresses to this point.62

Motor fluctuations Wearing off of levodopa’s clinical antiparkinsonian benefit after 3 to 4 hours is the earliest sign of motor fluctuations. Giving antiparkinsonian drugs before rather than with meals or in a slurry (liquid levodopa) helps to bypass the erratic and partial drug absorption that contributes to this problem. Similarly, first-pass metabolism is avoided through the use of the orally disintegrating formulation of carbidopa-lev-odopa. Immediate-release carbidopa-levodopa can be combined with the controlled-release formulation to provide a better balance between prompt and sustained antiparkinsonian responses [see Table 2]. Dopamine agonists and selegiline have a longer half-life than carbidopa-levodopa, and combination therapy that includes one of these agents produces a smoother clinical response than carbidopa-levodopa alone in patients who experience motor fluctuations.

Table 4 Dopamine Agonists for Parkinson Disease

Class	Agent	Dose Equivalent to Levodopa Anchor Dose*	Starting Dosage	Titration Schedulef	Typical Maintenance Dosage for Single-Agent Therapy	Typical Maintenance Dosage As Adjunct to Levodopa	Comments
	Pramipexole	1 mg	0.125 mgt.i.d.	Increase to 0.25 mg t.i.d. after 1 wk, then increase weekly in increments of 0.25 mg t.i.d.	Maximum dosage 1.5 mg t.i.d.	Maximum dosage 1.5 mg t.i.d.	Renal metabolism; dose adjustments needed in renal insufficiency; occasionally associated with sleep attacks
Nonergot alkaloids	Ropinirole	5mg	0.25 mg t.i.d.	Weeks 1-4, increase weekly in increments of 0.25 mg t.i.d. to a dosage of 1 mg t.i.d.; after week 4, increase in weekly increments of 1.5 mg/day to a dosage of 9 mg/day, then of 3 mg/day to maximum dosage of 24 mg/day	12-24 mg/day	3-16 mg/day	Hepatic metabolism; potential drug-drug interactions; occasionally associated with sleep attacks
Ergot alkaloids	Bromocriptine	2mg	1.25 mg b.i.d. or t.i.d.	Increase by 2.5 mg/day every 2-4 wk	7.5-15 mg/day	3.75-7.5 mg/day	Rare reports of pulmonary and retroperitoneal fibrosis; relative incidence of sleep attacks not well studied
	Pergolide	1 mg	0.05 mg/day, t.i.d. at mealtimes	Every 2-5 days	3-4.5 mg/day	1.5-3 mg/day	Rare reports of valvular heart disease; fewer reports of sleep attacks compared with noner-got agents

*100 mg immediate-release levodopa; see Table 2.

^ Because of lower tolerance, some patients will require slower titration.

Another strategy involves shortening the dosing intervals. However, regimens that involve dosing more frequently than every 4 hours are difficult to manage clinically; such regimens should probably be undertaken in specialty movement-disorder clinics.

Neuropsychiatric symptoms Depression in patients with PD typically responds well to conventional antidepressants (e.g., tricyclics, selective serotonin reuptake inhibitors [SSRIs], ven-lafaxine, and bupropion). Short-acting rather than long-acting SSRIs are preferred, because there are reports that fluoxetine, a long-acting SSRI, may produce extrapyramidal symptoms (EPS). Although all SSRIs are probably effective in PD, we find that citalopram (10 to 30 mg/day), sertraline (50 to 150 mg/day), and paroxetine (10 to 30 mg/day) are particularly well tolerated. Limited experience with bupropion (50 to 200 mg/day) and sustained-release venlafaxine (37.5 to 150 mg/day) suggests that these agents are also well tolerated and may be less sedating. Concerns about the potential for hyperserotoninergic reaction (delirium with myoclonus and hyperpyrexia) stemming from the combination of selegiline and SSRIs in PD appear to have been grossly exaggerated.

In patients who fail to respond to antidepressant medication, it is important to rule out other causes of refractory depression, such as hypothyroidism. Patients with PD who suffer from refractory depression or are intolerant of oral antidepressants are candidates for electroconvulsive therapy (ECT). In addition to alleviating depression, ECT may also improve parkinsonian motor symptoms.

Patients with PD may undergo slow but profound drug-induced personality changes, which may be expressed as erratic, temperamental, unreasonable, and demanding behaviors; self-centeredness; and apparent disregard for the needs of others. These may be a prelude to depression or psychotic symptoms that are either drug induced or secondary to emerging dementia. Drug-induced psychosis is typified by visual hallucinations with retention of insight. Auditory hallucinations suggest coexisting psychotic depression or dementia, but they may be a side effect of anticholinergic medications.64 In many instances, disturbing cognitive and psychiatric symptoms will cease with elimination of anticholinergics or amantadine. Some patients, however, require reduction in doses or elimination of drugs, typically in the following order: selegiline, nocturnal doses of dopamine agonists or controlled-release carbidopa-levodopa, and regular car-bidopa-levodopa. If the patient improves after only a modest adjustment in polypharmacy, the impact on the parkinsonian motor symptoms will range from negligible to positive. If the patient requires a drastic reduction in antiparkinsonian therapy, the resulting aggravation of motor symptoms is likely to be in-tolerable.64 Levodopa drug holidays are no longer recommended, because several reports indicate that they are potentially dangerous and provide no significant long-term benefit.

When the reduction in antiparkinsonian polypharmacy has intolerable consequences, an antipsychotic drug may be necessary. Conventional antipsychotics are poorly tolerated because of associated EPS and worsening of parkinsonism. Atypical antipsychotics have a higher ratio of serotonin 5-HT2a to dopamine D2 blockade and, compared with conventional antipsychotics, a lower incidence of EPS. Of the atypical antipsychotics, clozapine has been shown to be more effective than placebo in the treatment of drug-induced hallucinations in PD in two double-blind, placebo-controlled studies.65 Clozapine may have additional beneficial effects on tremor, dystonia, and dyskinesias. Associated side effects include dizziness, orthostatic hypotension, sialorrhea, and confusion. Although most PD patients tolerate small doses of clozapine (12.5 to 75 mg in the evening), its use has been tempered by the 1% risk of agranulocytosis, which requires frequent monitoring of the leukocyte count.

The atypical antipsychotic quetiapine appears to be the first-line drug for the treatment of all psychotic symptoms in PD. It is not associated with hematologic or other serious toxicity and has a low incidence of EPS across the therapeutic spectrum. In a series of open-label studies, it was shown to be effective and well tolerated in PD.65 The median range of effective doses is 50 to 75 mg/day, with most of the dose administered at night. This dose is significantly less than that typically used in schizophrenia (400 to 600 mg/day). The side effects are similar to those of clozapine except for the lack of hematologic toxicity or sialorrhea. If neu-ropsychiatric symptoms are not well controlled with quetiapine, the patient is switched to clozapine.

Risperidone is the second oldest atypical antipsychotic. In small doses (0.25 to 1 mg/day), it is an effective antipsychotic in PD patients who have drug-induced hallucinations. In a few open-label studies, however, it appeared to aggravate motor symptoms in many patients over a period of weeks to months.65 This worsening was typified by increasing akinesia, decreased walking, and other signs of EPS. Olanzapine is not well tolerated by patients with PD.66 AH atypical antipsychotics carry warnings of potential hyperglycemia; monitoring of blood glucose levels is recommended.

Treatment of dementia in PD with the dual cholinesterase inhibitor rivastigmine has been studied. In a 24-week, placebo-controlled study, rivastigmine use was associated with moderate improvements in PD-associated dementia; however, it was also associated with higher rates of nausea, vomiting, and tremor.

Neuroprotective therapy Slowing the progression of PD through neuroprotective therapy is a major focus of current re-search.68 Epidemiologic studies suggest that the long-term use of cyclooxygenase inhibitors or of estrogen replacement in post-menopausal women may delay or prevent the onset of PD through yet unclear mechanisms. Coffee drinking has also been associated with a reduced incidence of PD, as has cigarette smoking. Current treatment strategies involve interrupting the cascade of biochemical events that leads to death of dopaminer-gic cells [see Table 5]. The first such clinical trial in PD was the large multicenter Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) study, in which selegiline monotherapy delayed the need for levodopa therapy by 9 to 12 months in newly diagnosed patients.69 Most evidence indicates that this delay resulted from a mild symptomatic effect of selegi-line. Long-term follow-up of the DATATOP cohort revealed that patients who remained on selegiline for 7 years experienced slower motor decline compared with those who were changed to placebo after 5 years. Interestingly, patients in the 7-year patient group were more likely to develop dyskinesias but less likely to develop freezing gait. A metabolite of selegiline, desmethyl-selegiline, has been shown in laboratory studies to have powerful neuroprotective effects. Clinical trials to test this agent are now in progress.

Table 5 Selected Neuroprotective Treatments for Parkinson Disease

Pathogenetic Factor	Intervention	Specific Agents
Oxidative stress	Antioxidants	Vitamin E, vitamin C, iron chelators
	MAO-B inhibitors	Selegiline, rasagiline
Mitochondrial dysfunction	Bioenergetic agents	Coenzyme Q10
Excitotoxicity	Antiglutamatergic agents	NMDA receptor antagonists
Inflammation	Anti-inflammatory agents	COX-2 inhibitors
Neuronal dysfunction	Trophic factors	Glial cell line-derived neurotrophic factor
Apoptosis	Antiapoptotic agents	Dopamine agonists, caspase inhibitors, minocycline, propargylamines

COX—cyclooxygenase

MAO—monoamine oxidase

NMDA—N-methyl-D-aspartate

In another pilot study, coenzyme Q10, an antioxidant and a cofactor of complex I of the mitochondrial oxidative chain, appeared to delay progression of early disability in PD.70 A large multicenter trial is now under way. Other potentially neuropro-tective agents under investigation are acetyl-levo-carnitine and creatine monohydrate. A large controlled study of the antigluta-matergic agent riluzole was prematurely discontinued after a futility analysis revealed little effect on progression of symptoms.71 As noted, dopamine agonists are also being studied for a neuro-protective role, based on their ability in vitro to decrease dopa-mine turnover, scavenge free radicals, and interfere with pro-apoptotic cell signals. Other promising agents include nitric oxide synthase inhibitors, antiapoptotic agents such as Jun N-terminal kinase inhibitors, and the antibiotic minocycline.71 Minocycline can inhibit microglial activation in vitro and interrupt apoptosis by inhibiting caspase 1 and 3, which are involved in the enzymatic processing of a-synuclein.

Surgical treatment The past decade has witnessed a renaissance in the surgical treatment of PD and other movement disorders. This has been motivated first by the fact that after 5 or more years of pharmacologic treatment, many patients develop significant drug-induced motor fluctuations and dyskinesias. Second, major advances in understanding the pathophysiologic basis of parkinsonism have provided a clearer rationale for the effectiveness of surgical procedures and guidance for targeting specific structures, such as the GPi and the STN [see Figure 2].

The selection of suitable patients for surgery is critical, because in general, patients with atypical PD do not benefit from surgery. Candidates for surgery must have the following: (1) a clear diagnosis of idiopathic PD, (2) a good initial response to levodopa, and (3) significant intractable symptoms of PD or (4) drug-induced dyskinesias and wearing-off. The major contraindications to surgery are atypical PD, dementia, major psychiatric illness, and substantial medical comorbidities. Age is not a contraindication, but older patients derive less benefit from surgery. Patients with clinical manifestations such as unresponsive features, postural instability and falling, hypophonia, micro-graphia, drooling, and autonomic dysfunction are unlikely to benefit from surgery. In general, the benefits of surgery are unlikely to exceed the best benefits of antiparkinson medication. The major benefit of surgery is the elimination of dyskinesias and "off" periods (i.e., periods when medication is ineffective) and production of a stable "on" state. The decision for surgery should be made by a movement disorder neurologist who is part of a team that includes a neurosurgeon with fellowship training in functional neurosurgery, a psychiatrist, a neuropsy-chologist, and trained technicians.

Use of procedures that involve the creation of surgical lesions (e.g., pallidotomy or thalamotomy) has decreased greatly since the introduction of deep brain stimulation. In deep brain stimulation, a lead wire is surgically implanted in the GPi or STN and connected to a pulse generator that is implanted subcutaneously, generally on the chest wall near the clavicle. The patient can activate the system by passing a small handheld magnet over the generator. This system was approved by the FDA in August 2004 for patients with PD.

The major advantages of deep brain stimulation are that it is less invasive than the creation of surgical lesions and that the system may be adjusted to best effect after implantation. Although the choice between STN and GPi as targets for deep brain stimulation has shifted toward the STN, the available evidence suggests that both sites are effective for all the cardinal features of PD, as well as for dyskinesias and motor fluctuations. Several clinical trials are now under way to compare these two targets. Although bilateral surgery is generally necessary for patients with advanced disease and those with significant bilateral manifestations, unilateral stimulation is appropriate for patients with asymmetrical disease. Postoperative reductions in drug dosages appear to be easier with STN than GPi approaches.

The mechanism of action of deep brain stimulation remains controversial. Because both ablation and stimulation of a given target have a similar clinical effect, it was assumed that stimulation caused a functional blockade. With both approaches, it is probable that the remaining motor systems in the brain stem, thalamus, and cortex are able to compensate more effectively for the abnormal activity associated with the parkinsonian state. Whatever the mechanism, it is clear that these approaches can offer impressive results in properly selected patients with PD, as well as in patients with other movement disorders.

Although deep brain stimulation can be very effective, serious complications occur in 1% to 2% of patients who receive the device.72 Even in the best hands, approximately 15% of patients require a second operation to treat complications or improve efficacy.

Although neurotransplantation of dopamine-producing fetal cells once seemed promising, the results from two large controlled clinical trials have proved considerably disappointing.73 The first study showed only modest benefit in patients younger than 60 years, and it showed no benefit in those older than 60 years. Moreover, a number of patients developed dyskinesias, which occurred when the patients were off medication. The second study showed similar findings with regard to benefit and the development of dyskinesias. Because of this, as well as the considerable obstacles to obtaining sufficient fetal tissue and the opposition to the use of fetal tissue on ethical grounds, this approach is now viewed as purely investigational. Conceivably, other sources of replacement dopaminergic cells (e.g., carotid body cells, stem cells, or encapsulated, genetically engineered cells capable of producing levodopa, dopamine, or trophic factors) may prove more successful. An open-label trial of direct infusion of glial cell-derived neurotrophic factor (GDNF) to the putamen in a small number of patients with PD raised hopes for this approach; however, in a subsequent randomized, double-blind trial of GDNF administered through an implanted intra-cerebroventricular catheter, patients showed no improvements in parkinsonism.