INTRODUCTION — The array of pharmacologic and surgical treatments available for the treatment of idiopathic (or Lewy body) Parkinson's disease (PD) is broader than for any other degenerative disease of the central nervous system. Management of individual patients requires careful consideration of a number of factors including the patient's symptoms and signs, age, stage of disease, degree of functional disability, and level of physical activity and productivity. Treatment can be divided into nonpharmacologic, pharmacologic, and surgical therapy.

Nonpharmacologic management of Parkinson's disease:

Parkinson's disease (PD) is a chronic disorder that requires broad-based management including patient and family education, support group services, general wellness maintenance, exercise, and nutrition.

EDUCATION — The prospect of having a chronic and progressive neurologic disease is frightening. Many individuals are familiar with Parkinson's Disease (PD) and may even have had first-hand acquaintance with its disabling effects in an affected family member or friend. Education is essential in order to provide the patient and family with some understanding and control over the disorder.

However, caution should be exercised in newly diagnosed patients with mild symptoms and an uncertain future with regard to progression; early overexposure to potentially disturbing material may be counterproductive. Focused education surrounding particular symptoms may be more effective and is available through books written for the lay audience; national and regional Parkinson's disease organizations, which publish educational pamphlets and organize symposia for patients and families; and the Internet. A useful central information resource is the "We Move" Foundation at www.wemove.org .

SUPPORT — The emotional and psychologic needs of the patient and family should be addressed. Normal reactions of anger, depression, anxiety, and social and economic concerns often begin with the onset of the disease and evolve as it progresses. Support for the caregiver is particularly important as he or she learns to cope with the increasing needs of the spouse or parent, or more rarely, a son or daughter. Support groups are especially valuable for allowing interactions with other patients or families with similar experiences and for providing access to useful educational information.

For patients with early Parkinson's disease (PD), referral to another affected patient or family may be less overwhelming than a large support group composed of patients with advanced disease. Young-onset PD groups also have been formed in some locales, and a young-onset PD handbook is available. There are also some national support organizations. Referral of the patient and/or family to a psychologist or psychiatric social worker experienced in dealing with chronic illness may be appropriate in some cases. In other instances, referral for legal, financial, or occupational counseling is indicated.

EXERCISE AND PHYSICAL THERAPY — Regular exercise promotes a feeling of physical and mental well-being; it is especially valuable due to the chronic nature of Parkinson's disease (PD) and its associated progressive motor limitations. Exercise will not slow the progression of akinesia, rigidity, or gait disturbance, but it can prevent or alleviate some secondary orthopedic effects of rigidity and flexed posture such as shoulder, hip, and back pain, and it may also improve function in some motor tasks.

Stretching and strengthening exercises to improve flexibility and strength should be emphasized. Strengthening of extensor muscles can help counteract the flexed posture of PD. Brisk walks, swimming, and water aerobic exercises are particularly useful. Referral to a physical therapist or exercise group may be a good way to get patients started in such activities.

A practice parameter from the American Academy of Neurology (AAN) issued in 2006 concluded that various physical therapy modalities are probably effective in improving functional outcome for patients with PD. These modalities include: Multidisciplinary rehabilitation with standard physical and occupational therapy components. Treadmill training with body weight support. Balance training and high-intensity resistance training. Cued exercises with visual (mirror), auditory (metronome), and tactile feedback. Active music therapy.

The AAN review found that the magnitude of the observed functional improvement with these interventions is small and not sustained after therapy is discontinued. Nevertheless, many patients gain lasting confidence and a sense of control over one aspect of the disease, especially if they have never engaged in physical activity in the past.

SPEECH THERAPY — Dysarthria and hypophonia are common manifestations of Parkinson's disease (PD). The practice parameter from the American Academy of Neurology (AAN) issued in 2006 concluded that speech therapy for patients with PD may be helpful in improving speech volume.

This conclusion was based on two small studies that compared speech therapy with no therapy. One employed speech therapy emphasizing prosodic features of pitch and volume reinforced with visual feedback, while the other employed therapy aimed solely at maximizing phonatory effort. Both of these methods were found to be possibly effective by the AAN.

NUTRITION — Elderly patients with chronic illness are at risk for poor nutrition and weight loss. Prompt recognition and management of this problem is important to avoid loss of bone and muscle mass. No specific diet influences the course of Parkinson's disease (PD), although certain recommendations can be made. A high fiber diet and adequate hydration help manage the constipation of PD. Large, high-fat meals that slow gastric emptying and interfere with medication absorption should be avoided. Dietary protein restriction is not necessary except in some patients with advanced disease and motor fluctuations in whom competition with other amino acids interferes with L-dopa absorption. There is no evidence at this time that large doses of vitamin E or other antioxidants are useful in PD.

DIAGNOSIS OF PD — Correct diagnosis is fundamental to the appropriate therapy of Parkinson's disease (PD), although the same menu of antiparkinson drugs is used to treat all of the various parkinsonian syndromes. The four cardinal signs of parkinsonism are rest tremor, rigidity, akinesia, and gait disturbance. Usual criteria for a clinical diagnosis of PD require the presence of at least two of these four features; diagnostic certainty increases in proportion to the predominance of rest tremor as a finding, especially if it is unilateral.

Postmortem and magnetic resonance imaging (MRI) studies indicate a substantial diagnostic error rate based upon the use of these criteria. In some studies, up to 25 percent of patients with a diagnosis of PD during life were found to have other causes of parkinsonian symptoms at autopsy, such as cerebrovascular disease involving the basal ganglia or other neurodegenerative disorders, such as multiple system atrophy and progressive supranuclear palsy. On the other hand, the clinical diagnostic accuracy of PD and the other parkinsonian syndromes, confirmed by neuropathology, increases substantially if patients are evaluated and observed throughout the long course of their illness by specialists at movement disorders centers.

The clinical features most suggestive of idiopathic PD include asymmetric or unilateral onset, the presence of rest tremor, and a clear cut response to treatment with levodopa. Clues to the diagnosis of the other parkinsonian syndromes include a history of exposure to dopamine receptor blocking drugs such as antipsychotic agents or metoclopramide, hyperactive tendon reflexes, Babinski signs, cerebellar signs, prominent abnormalities of ocular motility, the early development of dementia, significant postural instability, and major autonomic manifestations (orthostatic hypotension, atonic bladder, sexual impotence, and gastrointestinal dysmotility).

A practice parameter from the American Academy of Neurology (AAN) concluded that features probably useful for distinguishing other parkinsonian syndromes from PD include early falls, poor response to levodopa, symmetry of motor manifestations, lack of tremor, and early autonomic dysfunction.

NEUROPROTECTIVE THERAPY — The pharmacologic treatment of Parkinson's disease (PD) can be divided into neuroprotective and symptomatic therapy. In practice, however, nearly all of the available treatments are symptomatic in nature and do not appear to slow or reverse the natural course of the disease.
Neuroprotective therapy of PD is still theoretical, but it is based on the concept that the three to four hundred thousand at-risk dopaminergic neurons in the human substantia nigra can somehow be protected from the complex degenerative process that causes premature cell death and depletion of dopamine. Once identified and shown to be effective, neuroprotective drugs could be used in patients with early clinical signs of disease or potentially even prior to the appearance of disease in those shown to be at genetic risk.

Several potential neuroprotective agents for PD have shown some promise in animals and/or humans and are undergoing further investigation. Selegiline and rasagiline (both monoamine oxidase inhibitors), dopamine agonists, and the complex I mitochondrial fortifier coenzyme Q10 have been evaluated in clinical trials and are receiving the most attention as possible neuroprotective agents.

MAO B INHIBITORS — Monoamine oxidase (MAO B) inhibitors such as selegiline and rasagiline have been studied as neuroprotective agents due to their ability to block free radical formation from the oxidative metabolism of dopamine; these agents may also inhibit apoptosis (programmed cell death). In addition to a possible neuroprotective effect, selegiline has a mild symptomatic benefit.
Selegiline — The possibility of long-term neuroprotection with selegiline has neither been confirmed nor disproven: A large prospective, double-blind, placebo-controlled multicenter study (the DATATOP study) found that selegiline (deprenyl) 10 mg daily delayed the progression of parkinsonian signs in previously untreated patients by nine months. However, a small but measurable reduction of parkinsonian symptoms attributable to selegiline confounded the findings of this study, thereby casting doubt on the likelihood that the delayed progression of symptoms was due to a true neuroprotective effect. A subsequent trial that took this symptomatic effect into account noted a mild neuroprotective effect. Selegiline treatment of patients with early Parkinson's disease (PD) in the absence of levodopa was associated with a decreased risk for developing later freezing of gait, suggesting a possible neuroprotective effect.

Prior treatment with selegiline in the DATATOP cohort did not reduce the occurrence of subsequent levodopa-associated motor fluctuations in this population; no persistent, long-term benefit in slowing the progression of PD was demonstrated with selegiline.

This lack of long-term benefit in part accounted for the conclusion issued in a 2002 report of the Quality Standards Subcommittee of the American Academy of Neurology (AAN) that there is insufficient evidence to recommend the use of selegiline for a neuroprotective effect. A practice parameter from the AAN issued in 2006 found no interim studies that would alter this conclusion.

Rasagiline — The selective MAO B inhibitor rasagiline has neuroprotective properties in animal models. Results from a short term randomized controlled trial of rasagiline monotherapy versus placebo, using a delayed start design, suggested that it might slow progression of parkinsonian disability; patients treated with rasagiline had a smaller increase in mean adjusted total Unified Parkinson's Disease Rating Scale (UPDRS) score compared with those who were treated with placebo. However, the symptomatic benefit of rasagiline, rather than a neuroprotective effect, may have been responsible for this result. Further trials with a greater number of patients are planned to test the hypothesis that rasagiline slows the progression of PD. The AAN practice parameter concluded that there is insufficient evidence to support or refute the use rasagiline for neuroprotection in patients with PD.

DOPAMINE AGONISTS — Dopamine agonists are neuroprotective in the laboratory because they are antioxidants and free radical scavengers and because of feedback reduction of endogenous dopamine turnover. These findings have led to the hypothesis that the use of agonists early in the clinical course of PD may slow progression of the underlying neurodegeneration. Later studies employing radiographic markers of basal ganglia function, although highly controversial, have provided further, tentative support for a possible neuroprotective effect of dopamine agonists.

One potential biologic marker uses single photon emission computed tomography (SPECT) with the dopamine transporter ligand [123I]beta-CIT (B-CIT) as an anatomic measure of nigrostriatal integrity and as a surrogate marker of PD progression. Earlier investigations of the natural history of PD had shown a 5 to 10 percent reduction of B-CIT uptake per year in a heterogeneous mix of patients with PD.

Pramipexole — The CALM-PD study evaluated 82 patients with early PD, using SPECT B-CIT scans as a surrogate marker of neuroprotection, and found that the patients who were randomly assigned to receive pramipexole (0.5 mg three times per day) demonstrated less of a decline in striatal B-CIT uptake over four years compared with those treated with carbidopa/levodopa (25/100 mg three times per day). There was no difference between the two treatment groups for the change in the UPDRS scores from baseline.

Ropinirole — A randomized trial studied 162 patients eligible for analysis who were assigned to ropinirole or levodopa treatment, using positron emission tomography (PET) scanning and the dopa decarboxylase ligand 18F-fluorodopa ((18)F-dopa) as a measure of nigrostriatal integrity. There was significantly less decline in (18)F-dopa uptake in patients assigned to ropinirole compared with those assigned to levodopa. Another randomized trial employing (18)F-dopa PET as a surrogate marker of neuroprotection studied 45 patients who were assigned to ropinirole or levodopa. At two years, the ropinirole treatment group showed a smaller reduction in the primary endpoint of putaminal (18)F-dopa uptake compared with placebo, but the difference was not statistically significant (13 versus 18 percent, respectively).

Interpretation — It is uncertain whether these imaging studies reflect changes in the underlying pathology of PD or differential pharmacologic "regulatory" changes directly attributable to the drugs themselves. Therefore, these findings raise the possibility that dopamine agonists may be neuroprotective, but confirmation is required in additional clinical studies, including prospective data in untreated patients.

The AAN practice parameter noted that significance of the studies evaluating pramipexole and ropinirole is uncertain, given the lack of validation for the surrogate measures of neuroprotection employed (i.e, SPECT B-CIT and (18)F-dopa PET scans) and the absence of placebo control groups. The AAN statement concluded that there is insufficient evidence to support or refute the use of pramipexole or ropinirole for neuroprotection in patients with PD.

LEVODOPA — Accumulating clinical trial data suggest that levodopa either slows the progression of PD or has a prolonged benefit even after the drug has been stopped. These data are presented separately. The AAN practice parameter concluded that levodopa is possibly neuroprotective for at least nine months and does not accelerate disease progression.

OTHER AGENTS

Coenzyme Q10 — Interest in coenzyme Q10 has been stimulated by evidence that mitochondrial dysfunction may play a role in the pathogenesis of PD. In a small clinical trial, 80 subjects with early untreated PD were randomly assigned to three dosage groups of coenzyme Q10 or to placebo, and were followed for progression of disease as measured by the Unified Parkinson's Disease Rating Scale (UPDRS). Treatment with coenzyme Q10 at the highest dosage (1200 mg daily) was associated with a lower rate of disability progression over 16 months compared with placebo. Although the results did not achieve statistical significance, they did meet the prespecified criteria for a positive trend for the trial. However, the study was underpowered to detect a neuroprotective effect. As with selegiline, it is not entirely clear whether the benefit of coenzyme Q10 was due to neuroprotection or to symptomatic improvement; the study investigators considered the symptomatic effect of coenzyme Q10 to be negligible. These promising results regarding coenzyme Q10 require confirmation in clinical trials with larger samples of patients. A practice parameter from the AAN concluded that there is insufficient evidence to support or refute the use of coenzyme Q10 for neuroprotection in patients with PD.

Vitamin E — In the randomized controlled DATATOP trial of patients with early PD, Vitamin E (tocopherol) was included as a treatment arm. There was no beneficial effect of vitamin E compared with placebo for the primary end point of average time to onset of disability requiring levodopa use. Given these data, the AAN practice parameter concluded that vitamin E should not be considered for neuroprotection [10].

Riluzole — A randomized controlled trial of patients with early PD found no beneficial effect of riluzole compared with placebo as measured by change in the UPDRS. However, this study was not sufficiently powered to exclude a modest neuroprotective effect of riluzole.

SUMMARY AND CONCLUSIONS — Neuroprotective therapy of Parkinson's disease (PD) is still theoretical, but it is based on the concept that dopaminergic neurons in the substantia nigra can be protected from the degenerative process that causes premature cell death and depletion of dopamine, leading to the development of PD. Monoamine oxidase (MAO B) inhibitors such as selegiline and rasagiline have been studied as neuroprotective agents due to their ability to block free radical formation from the oxidative metabolism of dopamine; these agents may also inhibit apoptosis. Dopamine agonists are neuroprotective in the laboratory because they are antioxidants and free radical scavengers and because of feedback reduction of endogenous dopamine turnover. Interest in coenzyme Q10 has been stimulated by evidence that mitochondrial dysfunction may play a role in the pathogenesis of PD. No treatment for PD has been proven to be neuroprotective. However, levodopa is possibly neuroprotective and does not accelerate disease progression. Existing clinical trial evidence in patients with PD is insufficient to support or refute the possibility of neuroprotection for selegiline, rasagiline, pramipexole, ropinirole, coenzyme Q10, and riluzole. There is no evidence that Vitamin E is neuroprotective.

SYMPTOMATIC THERAPY — The decision to initiate symptomatic medical therapy in patients with Parkinson's disease (PD) is determined by the degree to which the patient is functionally impaired. The timing of this decision varies greatly among patients but is influenced by a number of factors, including [1]: The effect of disease on the dominant hand The degree to which the disease interferes with work, activities of daily living, or social and leisure function The presence of significant bradykinesia or gait disturbance Personal philosophy regarding the use of drugs

The major drugs available for symptomatic therapy include: Levodopa MAO B inhibitors Dopamine agonists COMT inhibitors Anticholinergic agents Amantadine. In addition to these agents, low-dose estrogen may be helpful as adjunctive therapy in postmenopausal women.

Levodopa — Levodopa (L-dopa) is well established as the most effective drug for the symptomatic treatment of idiopathic or Lewy body PD. It is particularly effective for the management of akinetic symptoms and should be introduced when these become disabling and are uncontrolled by other antiparkinsonian drugs. Tremor and rigidity can also respond to levodopa therapy, but postural instability is less likely to do so.

Levodopa is combined with a peripheral decarboxylase inhibitor to block its conversion to dopamine in the systemic circulation and liver (before it crosses the blood-brain barrier) in order to prevent nausea, vomiting, and orthostatic hypotension. The decarboxylase inhibitor is carbidopa. The combination drug carbidopa/levodopa (immediate-release Sinemet) is available in tablets of 10/100, 25/100, and 25/250 mg, with the numerator referring to carbidopa and the denominator referring to the levodopa dose. An immediate-release formulation of carbidopa/levodopa (Parcopa) is available that dissolves on the tongue and can be taken without water, but there are no published studies of this formulation, and its onset of action is no different from Sinemet.

In Europe and Canada, benserazide is the peripheral decarboxylase inhibitor. The combination drug benserazide/levodopa (Madopar or Prolopa) is available in 25/100 and 50/200 mg tablets.

Controlled-release formulations of carbidopa/levodopa and benserazide/levodopa are available as Sinemet CR and Madopar HBS, respectively.

Dosing — Treatment should be initiated with small doses such as one-half tablet of carbidopa/levodopa (Sinemet) 25/100 mg three times daily with meals, titrated upward over several weeks to 25/100 mg three times daily as tolerated and according to the response. See table 1. Elderly patients or those with dementia should begin with smaller doses and titrate more slowly because of their increased susceptibility to psychiatric side effects. The usual practice is to use the lowest dose that produces a useful clinical response. This varies from patient to patient, but at the start typically is in the vicinity of 300 to 600 mg of levodopa daily.

The vast majority of patients with idiopathic PD will enjoy a significant therapeutic response to moderate doses of levodopa (400 to 600 mg daily); complete absence of response to a dose of 1000 to 1500 mg/day strongly suggests that the original diagnosis of PD was incorrect and that the diagnosis should be revised to one of the other parkinsonian syndromes, such as multiple system atrophy or progressive supranuclear palsy.

Controlled release levodopa preparations are less completely absorbed and require a dose up to 30 percent higher to achieve an equivalent clinical effect. The clinical effect of each tablet is typically less dramatic than for immediate release preparations, since controlled release formulations reach the brain more slowly. This presents a disadvantage in assessing the response of patients just beginning therapy. As a result, it is recommended that therapy be initiated with an immediate release preparation with a subsequent switch to controlled release if desired. Both the immediate and the controlled release formulations appear to maintain a similar level of symptom control after several years of use.

Patients taking levodopa for the first time should take each dose with a meal or snack to avoid nausea, a common early side effect. Patients with more advanced disease, especially those with motor fluctuations, often notice that a dose of levodopa is more effective if taken on an empty stomach one hour before or after meals due to reduced competition with other amino acids for gastrointestinal absorption.

Small starting doses of levodopa combined with a decarboxylase inhibitor (eg, Sinemet, Madopar, or Prolopa) are more likely to cause nausea because of inadequate amounts of carbidopa; this can be managed by administering supplemental doses of carbidopa (Lodosyn) or by use of antiemetics such as trimethobenzamide (Tigan) or domperidone taken prior to Sinemet. Phenothiazine antiemetics and metoclopramide should be avoided because they are dopamine receptor blockers that can aggravate the parkinsonian symptoms.

Adverse effects — Nausea, somnolence, dizziness, and headache are among the more common side effects that may accompany treatment with levodopa, but they are not likely to be serious in most patients. More serious adverse reactions to levodopa (mainly in older patients) may include confusion, hallucinations, delusions, agitation, and psychosis. Levodopa may also induce a mild to moderate elevation in serum homocysteine levels, which in turn may be associated with an increased risk of hip fractures in elderly patients.

Compulsive dopaminergic drug use has been reported in patients taking dopamine agonists, typically in conjunction with levodopa therapy. However, it is unclear if these behavioral issues arise with levodopa monotherapy. The "higher doses of dopaminergic medications than necessary to effectively control parkinsonian symptoms should be avoided," but noted that some patients with worse (ie, more rapidly progressive) disease may require high doses of dopaminergic medications to manage symptoms and therefore may be at greater risk for the development of motor complications. However, motor complications do not necessarily cause clinically significant functional impairment and can potentially be managed.

Given these data, practitioners should always try to find the lowest but still effective dose of dopaminergic medication, either singly or in combination, for patients with PD, each of whom must be evaluated and managed according to his or her individual needs. The increase in motor fluctuations over time is most likely due to the progressive degeneration of nigrostriatal dopamine terminals, which increasingly limits the normal physiologic uptake and release of dopamine, thereby leading to reduced buffering of the natural fluctuations in plasma levodopa levels that occur due to levodopa's 90-minute pharmacologic half-life. Controlled release preparations are useful for management of these fluctuations, although, in one report, the use of Sinemet CR from the start of therapy, in an effort to provide more continuous stimulation of dopamine receptors, was not associated with fewer motor complications than immediate release Sinemet.

There has been longstanding concern among some clinicians that levodopa causes motor fluctuations and dyskinesia by its potential to promote oxidative stress and accelerated neurodegeneration, rather than by the change in levodopa pharmacodynamics that occurs with natural progression of the underlying disease. Therefore, it is commonly proposed that the initiation of levodopa be delayed until symptoms significantly interfere with function. Others contend, however, that there is no strong evidence that levodopa is responsible for late motor complications, and that delay of treatment unnecessarily deprives patients of therapeutic benefit early in the disease, when the potential for sustained improvement is greatest. A sudden exacerbation of Parkinson's disease (PD) characterized by an akinetic state that lasts for several days and does not respond to treatment with antiparkinson medication is called acute akinesia. This phenomenon is very different from the more common wearing "off" effects.

Motor fluctuations — A substantial number of patients develop levodopa-induced complications within several years of starting levodopa. These include motor fluctuations (the wearing-off phenomenon), involuntary movements known as dyskinesia, abnormal postures of the extremities and trunk known as dystonia, and a variety of complex fluctuations in motor function. As many as 50 percent of patients on levodopa for five years experience motor fluctuations (MF) and dyskinesia. These symptoms are especially common in patients with young-onset (eg, under the age of 50) Parkinson's disease (PD); they are unique to levodopa and are not produced by the other antiparkinson drugs. Such motor complications occur in at least 50 percent of patients after 5 to 10 years of treatment. In the large group of patients with early PD studied in the DATATOP study, motor complications occurred in 30 percent after only two years of treatment with levodopa. However, in a study of early PD, the prevalence of motor complications was only 20 percent after five years of treatment with levodopa.

Retrospective data from a study of the effect of pramipexole and levodopa on early PD (the CALM-PD study) suggest that the earlier occurrence of motor fluctuations in the course of PD is associated with higher cumulative levodopa doses and higher cumulative levodopa-equivalent doses (ie, levodopa plus the dopamine agonist pramipexole). In contrast, prospective data from the same study suggest that a later onset of motor fluctuations in PD is associated with initial treatment with pramipexole rather than levodopa.

Patients typically experience a smooth and even response to the early stages of levodopa treatment. As the disease advances, however, the effect of levodopa begins to wear off approximately four hours after each dose, leaving patients anticipating the need for their next dose. This phenomenon may be explained by the observation that dopamine nerve terminals are able to store and release dopamine early in the course of disease but, with more advanced disease and increasing degeneration of dopamine terminals, the concentration of dopamine in the basal ganglia is much more dependent upon plasma levodopa levels. Plasma levels may fluctuate erratically because of the 90 minute half-life of levodopa and the frequently unpredictable intestinal absorption of this medication.

Motor fluctuations (MF) are alterations between periods of being "on," during which the patient enjoys a good response to medication, and being "off" during which the patient experiences symptoms of their underlying parkinsonism.

Dyskinesia consists of abnormal involuntary movements that are usually choreic or dystonic but, when more severe, may be ballistic or myoclonic. Dyskinesia usually appears when the patient is "on." It may occasionally occur in the form of painful dystonia when the patient is "off," especially in the morning on awakening, when dystonic intorsion of a foot (usually on the side of greater parkinsonian involvement) occurs as a withdrawal reaction because of the long interval without medication overnight.

Surgery for advanced PD is another therapeutic option, as bilateral deep brain stimulation of the subthalamic nucleus or globus pallidus appears to improve motor function in selected patients with advanced typical PD and MF, whose condition cannot be further improved by medical therapy.

WEARING-OFF PHENOMENON — Patients with advanced Parkinson's disease (PD) begin to be aware of a wearing "off" or end-of-dose effect less than four hours following a dose of levodopa.

Alteration of levodopa dosing — Wearing "off" can initially be managed by increasing the dose of levodopa, if the patient is not having side effects and is taking a relatively low dose. However, increasing the dose often increases side effects without effectively increasing the dose duration.

Shortening the interdose interval while administering lower doses is usually a more effective approach. However, it is often difficult to titrate the dose precisely, and some patients begin to exhibit an "all or none" response whereby individual lower doses produce no evident clinical response. This occurs because the pharmacologic response threshold is higher in advanced disease than it is in earlier disease.

Liquid Sinemet (carbidopa/levodopa) is occasionally used for patients when titration of the dose and dose interval using tablets is difficult. However, this approach is not typically practical since Sinemet is insoluble in water and no commercial preparation of liquid Sinemet is available. Instructions for preparation of a daily supply of liquid Sinemet are available, but use of this approach is best left to the specialist.

The sustained-release forms of levodopa preparations (eg, Sinemet CR) may be useful in the early stages of the wearing "off" phenomenon and may add up to 90 additional minutes throughout the day to levodopa's duration of effect. However, Sinemet CR is less well absorbed than immediate release Sinemet; thus, an individual dose increase of approximately 30 percent may be required to achieve the same clinical response. Sustained-release carbidopa/levodopa does not decrease "off" time compared with immediate release formulations.

Addition of a second drug — Addition of a second drug is indicated if the adjustments cited above are not successful (table 1).

Dopamine agonists — Dopamine agonists are commonly used to reduce the amount of "off" time in patients with advanced PD and may also allow for the dose of levodopa to be reduced. The drugs currently approved by the United States Food and Drug Administration (FDA) include bromocriptine (Parlodel), pergolide (Permax), pramipexole (Mirapex), ropinirole (Requip), and apomorphine (Apokyn). Cabergoline is approved by the FDA only for the treatment of hyperprolactinemic disorders, and its use for advanced PD is off label. Studies comparing the efficacy of various dopamine agonists have found either no significant difference or only mild superiority of one agent over another.

The dopamine agonist apomorphine administered subcutaneously can be used for rapid onset (usually within 10 minutes) rescue therapy when patients suddenly turn "off". In a randomized, double-blind, placebo-controlled study of 29 patients with advanced PD and two hours or more of "off" time despite aggressive oral therapy, administration of subcutaneous apomorphine (2 to 10 mg) resulted in successful amelioration of "off" state events following 95 percent of injections compared with 23 percent receiving placebo injection.

One review concluded that the magnitude and pattern of the motor response to a single subcutaneous dose of apomorphine is qualitatively comparable to that of oral levodopa; a 4 mg dose achieved a clinically significant improvement in 75 percent of patients.

Cabergoline may have some utility for reduction of "off" time in patients with advanced PD, but data are limited. In a single center, 24-week study of 37 patients (19 active, 18 placebo), treatment with cabergoline (mean dose 5.4 mg/day) was associated with a significant decrease in daily "off" time compared with placebo (2 versus 0.7 hours [40 versus 18 percent]). However, these results are limited by a potentially confounding baseline difference in "off" time duration between the treatment groups. In another single center, 24-week study of 27 patients (17 active, 10 placebo), patients treated with cabergoline (mean dose 4.9 mg/day) had an increase in "on" time (2.7 hours [30 percent]) and a decrease in "off" time (3.3 hours [59 percent]), but no information was provided for the placebo group about these parameters.

Cabergoline treatment was not associated with increased dyskinesia in these trials. However, a retrospective case control study of 210 patients with PD found that high cumulative dose and long-term treatment with cabergoline was associated with an increased risk of cardiac valvulopathy detected on transthoracic echocardiography.

In a randomized controlled trial, bromocriptine decreased "off" time compared with placebo (8 versus 3 percent, respectively), but the difference was not statistically significant.

COMT inhibitors — Catechol-O-methyl transferase (COMT) inhibitors such as tolcapone (Tasmar) and entacapone (Comtan) may prolong and potentiate the levodopa effect and reduce the "off" time when given with a dose of levodopa. The net result is an increased levodopa effect in fluctuating patients. These medications may allow a reduction in the total daily levodopa dose by as much as 30 percent. The starting dose of tolcapone is 100 mg three times daily; the clinical effect is evident immediately. The dose of entacapone is one 200 mg tablet with each dose of levodopa, up to a maximum of eight doses per day.  The most common side effects of these drugs are due to increased dopaminergic stimulation and include dyskinesia, psychiatric effects (mainly visual hallucinations), nausea, diarrhea, and orthostatic hypotension. The adverse effects are managed by lowering the dose of levodopa either before or after the addition of tolcapone or entacapone. Both drugs may also cause a brown-orange urine discoloration. In clinical trials, tolcapone was associated with transient, asymptomatic elevations of transaminases (AST and ALT) in 1 to 3 percent of subjects exposed to the drug. Three reported deaths from hepatotoxicity in patients using tolcapone prompted its removal from the market in Canada and Europe, although it is still available in the United States with the recommendation that it be used for treatment of motor fluctuations only after other methods have been exhausted and with monitoring of ALT and AST levels for the first six months of therapy. Entacapone has thus far not been associated with hepatotoxicity. Monitoring of liver enzymes with liver function tests (LFTs) must be done at baseline and then every two weeks for the first year of tolcapone therapy, then every four weeks for the next six months, then every eight weeks thereafter. Monitoring of LFTs should be resumed at the previous frequency if the tolcapone dose is increased to 200 mg three times a day. Tolcapone should be discontinued if the ALT or AST exceeds the upper limit of normal or if the clinical signs and symptoms suggest the onset of liver failure.

MAO B inhibitors — Rasagiline is a selective monoamine oxidase (MAO) B inhibitor. It has potential long-term effects on dopamine transmission because it acts irreversibly on MAO B receptors.

Rasagiline appears to be effective for motor complications in PD as demonstrated in randomized clinical trials. One of these, the 18-week multicenter LARGO trial, evaluated 687 patients with PD who had motor fluctuations (MF) for at least one hour every day despite optimum levodopa/dopa decarboxylase therapy. Patients were randomly assigned to adjunct therapy with either rasagiline 1 mg daily, entacapone 200 mg with every levodopa dose, or placebo. Both rasagiline and entacapone reduced mean daily "off" time (the primary outcome measure) by about one hour compared with placebo, and both increased daily "on" time without troublesome dyskinesia compared with placebo. The beneficial effect of rasagiline was independent of age (<70 versus 70 years) and of adjunct use of dopamine agonists.
Rasagiline was well tolerated in these studies. The frequency of dopaminergic adverse events in the LARGO trial was similar to that seen in the entacapone and placebo groups.
Rasagiline is approved by the European Commission as initial monotherapy in patients with early PD and as adjunct treatment in moderate to advanced PD. It received similar approval by the United States Food and Drug Administration in May 2006.

Selegiline is another selective MAO B inhibitor. Unlike rasagiline, selegiline is metabolized to amphetamine derivatives. Although selegiline may extend the levodopa effect, the clinical benefit this produces is usually relatively mild. Results from a small randomized controlled trial suggest that orally disintegrating selegiline may also be beneficial, although the study did not report change in levodopa dose.

Other strategies — Anticholinergic drugs and amantadine are not very effective in managing the wearing "off" effect and are rarely indicated for this purpose, given the other more effective options. Early studies of adenosine A2A antagonists as adjunctive therapy in PD have yielded promising results, and clinical trials are ongoing.

Preliminary studies suggest that eradication of Helicobacter colonization, which is present in about half of the population, may be a useful method for improving levodopa absorption and reducing motor fluctuations in patients with PD. These require confirmation in larger clinical trials before routine testing for H. pylori and antibiotic eradication can be recommended.

Guideline recommendations for treating "off" time — An evidenced-based practice parameter from the AAN issued in 2006 made the following recommendations for the treatment of "off" time in patients with PD and motor fluctuations: Entacapone and rasagiline are established as effective and should be offered to reduce "off" time Pergolide, pramipexole, ropinirole, and tolcapone are probably effective and should be considered to reduce "off" time, with the stipulation that the adverse effects of tolcapone (hepatotoxicity) and pergolide (valvular fibrosis) require that they be used with caution and monitoring Apomorphine, cabergoline, and selegiline are possibly effective and may be considered to reduce "off" time Sustained release carbidopa/levodopa does not decrease "off" time compared with immediate release carbidopa/levodopa; bromocriptine does not reduce "off" time compared with placebo; both may be disregarded to reduce "off" time.

UNPREDICTABLE OFF PERIODS — Transitions from being "on" to being "off" can be sudden and unpredictable in some patients. Unlike the wearing "off" phenomenon at the end of a levodopa dose cycle, there is sometimes no obvious relationship between the time of levodopa administration and the appearance of "off" episodes in patients with unpredictable "off" periods. These periods typically occur in patients with advanced Parkinson's disease (PD) who are also experiencing motor fluctuations (MF) and severe dyskinesia.

Management of these individuals is similar to that for patients who are having problems with wearing "off," although it typically is much more difficult. Direct observation of the patient during a prolonged outpatient visit as he or she cycles through such episodes is useful to determine the relationship of levodopa doses to "off" episodes. In some cases, these episodes occur at times of peak levodopa effect due to excessive rather than insufficient dopaminergic stimulation; such patients are best treated by reducing rather than raising the levodopa dose.

Addition of a COMT inhibitor or a dopamine agonist can be helpful; marked reduction of the levodopa dose together with the addition of high doses of a dopamine agonist may be required. Controlled release levodopa preparations (eg, Sinemet CR) are usually not helpful and occasionally exacerbate the situation.

Competition with neutral amino acids for transport across the gut and into the brain may be responsible for "offs" that appear following meals. A protein redistribution diet in which most protein intake is reserved for the evening was useful in approximately two-thirds of such patients in small studies, although this type of diet tends to be impractical for long-term use.

Episodic freezing is a special form of unpredictable "off" in which patients suddenly become immobilized for seconds to minutes at a time. This complication usually occurs while walking when it may cause falls; it is often not medication related and is very resistant to treatment. When freezing is more prolonged and accompanied by the emergence of other parkinsonian signs, treatment is similar to patients with other forms of the wearing "off" effect.

ACUTE AKINESIA — Acute akinesia is a sudden exacerbation of Parkinson's disease (PD) characterized by an akinetic state that lasts for several days and does not respond to treatment with antiparkinson medication. This phenomenon is different from wearing "off" effects and may occur in patients not previously treated with levodopa.

Acute akinesia should prompt a search for systemic infection or other intercurrent medical problems that are capable of causing a sudden worsening of parkinsonism. In a review of this problem in 26 patients, acute akinesia appeared after a flu-like syndrome in six patients, hip joint surgery or bone fractures in eight patients, gastrointestinal disturbances in three patients, and various medication manipulations in the remaining patients. Four patients died in spite of treatment. Episodes of acute akinesia may therefore have serious consequences and usually warrant acute hospitalization in order to identify and correct the underlying cause.

FAILURE OF ON-RESPONSE — Patients with motor fluctuations (MF) sometimes fail to turn "on" following a dose of levodopa. This has been called the "no-on" response. In some cases, this is due to delayed gastric motility, which results in inadequate plasma concentrations in advanced patients who have a narrow therapeutic window. A common reason for the "no-on" phenomenon is an excessively prolonged or severe "off" period occurring before the "no-on." This is best managed by avoiding "offs."

The prokinetic agent cisapride increases gastrointestinal motility and may be helpful in such patients, but the drug has been associated with a number of drug interactions and fatal cardiac arrhythmias, prompting the manufacturer to severely restrict its availability in the United States. The prokinetic drug metoclopramide is a dopamine receptor blocker that should be avoided. Patients should be encouraged to take levodopa on an empty stomach and avoid protein at the time of drug administration.

Domperidone is a D2-blocker with selective peripheral activity in the upper gastrointestinal tract; it does not cross the blood-brain barrier and therefore lacks the neurologic side effects of metoclopramide. It is currently not available in the United States but is available in Canada and other countries. Although data are limited, domperidone (starting at 20 mg four times daily) may be useful as a prokinetic agent to treat delayed gastric emptying in patients with PD. However, animal studies suggest that, like cisapride, domperidone may increase the risk of cardiac arrhythmias.

DYSKINESIA — Dyskinesia refers to a variety of involuntary movements, which occur as a direct effect of levodopa. Other antiparkinson drugs are much less likely to produce these motor abnormalities but may exacerbate them once they have appeared following treatment with levodopa. Dyskinesia is sometimes mistaken for manifestations of progressive Parkinson's disease (PD) or confused with tremor by patients and their families, rather than recognized as reversible consequences of treatment. Dyskinesia occurs in 30 to 40 percent of patients treated with levodopa by five years and nearly 60 percent by ten years, but not all dyskinesia requires treatment. A retrospective study suggests that the rate of dyskinesia requiring medication adjustment at five and ten years after levodopa treatment is 17 and 43 percent, respectively. Dyskinesia is usually choreiform in type, manifested by continuous, restless appearing movements of the extremities, head, face, trunk, and respiratory muscles. These dyskinetic movements are remarkably well tolerated by most patients since patients feel entirely relieved of their parkinsonism while dyskinesia is present. However, severe dyskinesia may take the form of large amplitude, ballistic movements that interfere with function and become very disturbing to patients and their families.

Levodopa was given in relatively high doses when it was first used as therapy for PD. As a result, dyskinesia was often seen early in treatment, especially in those with advanced disease who were being treated for the first time. The subsequent use of more modest doses resulted in its later appearance, months to years after initiating levodopa. Dyskinesia is especially common in patients with young-onset PD.

Peak-dose dyskinesia is most common. It occurs 60 to 90 minutes following a dose of levodopa. Early in the disease, this complication can be managed by lowering the medication dose, switching to a controlled release preparation, or reducing adjunctive drugs such as dopamine agonists, selegiline, or anticholinergic drugs. However, in more advanced patients with brittle responses, reducing the dose of levodopa may result in complete failure to generate an "on" response. In this situation, the dose of dopamine agonist should be greatly increased and the levodopa dose reduced, since dopamine agonists are much less likely to induce dyskinesia than levodopa.

An unusual pattern sometimes evolves in which dyskinesia peaks twice after each dose (diphasic dyskinesia) - when patients turn "on" and again as they begin to turn "off". In the second phase, dyskinesia in one body part may coexist with the emergence elsewhere of parkinsonian signs such as tremor and dyskinesia. This pattern is often unrecognized and may only be appreciated if the patient is observed during a prolonged outpatient visit.

The diphasic pattern is notoriously difficult to manage and usually requires more frequent levodopa dosing to prevent wearing "off" prior to each dose. However, this strategy often leads to progressively increasing dyskinesia as the day goes on. Addition of a dopamine agonist and a marked reduction in the levodopa dose should be tried in such patients.

Sustained release levodopa is best avoided in patients with severe or complex patterns of dyskinesia since absorption may be delayed and dyskinesia tends to progressively increase into the afternoon and evening.

Amantadine — Amantadine may be useful for treating dyskinesia in advanced PD. Several studies have shown short-term benefit. As an example, a single-center randomized controlled trial found that amantadine administration compared with placebo was associated with a 24 percent reduction in the total dyskinesia score. In addition, a placebo-controlled study involving 17 patients showed that the beneficial effects of amantadine on motor response fluctuations were maintained for at least one year; initial and one-year reductions in dyskinesia scores were 60 and 56 percent, respectively.

In another placebo-controlled study in 40 patients with dyskinesia, amantadine treatment for 15 days resulted in a 45 percent reduction in dyskinesia scores compared with placebo. However, the benefit in this study lasted less than eight months, and amantadine withdrawal resulted in a rebound with increase of dyskinesia in 11 patients. Amantadine was not associated with worsening of parkinsonism symptoms in these studies. The dose of amantadine for dyskinesia is one tablet (100 mg) one to three times a day. Side effects may include peripheral edema, psychosis, and livedo reticularis.

Clozapine — Low doses of the antipsychotic clozapine (30 to 50 mg/day) reduced dyskinesia in several open-label studies, and low dose clozapine (12.5 to 75 mg/day) was significantly more effective than placebo in treating levodopa-induced dyskinesia in a double-blind, randomized controlled trial of 50 patients. The usefulness of clozapine is limited by its potential for inducing bone marrow suppression, but this risk may be acceptably low with monitoring. Clozapine treatment requires obtaining the white blood cell count (WBC) and absolute neutrophil count (ANC) at baseline and weekly for the first six months of continuous treatment, followed by biweekly monitoring thereafter.

The dibenzodiazepine derivative olanzapine has similar properties to clozapine. In a randomized controlled trial of 10 patients with PD, low-dose olanzapine was effective in reducing dyskinesia, but was associated with unacceptable increases in parkinsonism and "off" time.

Guideline recommendations for reducing dyskinesia — An evidenced-based practice parameter from the AAN issued in 2006 made the following recommendations for the treatment of dyskinesia in patients with PD and motor fluctuations: Amantadine is possibly effective and may be considered for reducing dyskinesia.  There is insufficient evidence to support or refute the effectiveness of clozapine in reducing dyskinesia.

DYSTONIA — Dystonia is a more sustained abnormal posture than dyskinesia. Dystonic postures usually involve the limbs but can affect the face, neck, or trunk. Dystonia can be a manifestation of early untreated Parkinson's disease (PD) or may appear as a complication of levodopa treatment. A careful history is required since, when due to levodopa, dystonia can occur either as a peak levodopa effect or during "off" periods due to levodopa withdrawal. Withdrawal dystonia most commonly occurs in the early morning when it produces painful flexion and inversion postures of the feet and toes.

Peak dystonia is managed similarly to peak dyskinesia. "Off" period dystonia that occurs early in the morning is managed either by taking sustained release levodopa before retiring or by taking levodopa or a dopamine agonist during the night or first thing in the morning before arising. "Off" period dystonia during the day is managed similarly to other forms of the wearing "off" effect.

Another form of levodopa withdrawal is akathisia (motor restlessness) or restless legs, which usually occurs at night, several hours after the last dose of levodopa. This is managed by providing levodopa or a dopamine agonist before retiring.

RECOMMENDATIONS — The following treatment suggestions represent my approach to some difficult management issues that occur in advanced Parkinson's disease (PD). Wearing "off" phenomenon Document the pattern of motor fluctuations (MF). Obtain a careful and accurate history, and observe the patient directly in an outpatient setting. Examine the effect of diet, and avoid taking levodopa with high protein meals. A sustained-release levodopa formulation may be beneficial, but only in the early stages of wearing "off" in patients with less advanced PD. In patients with more advanced PD, reduce the levodopa dose interval by 30 to 60 minutes. This may require the addition of an extra levodopa dose at the end of the day. In most cases, individual levodopa doses should be left unchanged. Consider adding the COMT inhibitors entacapone (Comtan) or tolcapone (Tasmar). Entacapone should be given first because of the small risk that tolcapone can cause an elevation of liver enzymes. Be prepared to lower the levodopa dose by up to 30 percent because of the increased peak levodopa effect if tolcapone is used.Consider adding an oral dopamine agonist such as pramipexole or ropinirole. Watch for dopaminergic toxicity such as visual hallucinations and confusion, and be prepared to lower the levodopa dose. Consider parenteral apomorphine in patients with sudden and severe wearing "off" effects. This rescue therapy is very effective, but it has the disadvantage of requiring a prophylactic antiemetic such as trimethobenzamide. In addition, the effective dose of parenteral apomorphine must be established for each patient by administration during a prolonged outpatient evaluation prior to initiating therapy. Consider the MAO B inhibitors rasagiline and selegiline. Be aware that selegiline exerts only a mild effect on the wearing "off" phenomenon, while rasagiline has an effect comparable to entacapone. Rasagiline is now approved in the United States and in the European Union.

Unpredictable "off" periods Document that "off" periods are unpredictable and long lasting. In many cases, they are sudden wearing "off" effects or transient freezing episodes. Avoid taking levodopa with high protein meals Evaluate and treat the possible effects of anxiety, which may precipitate sudden "off" episodes Consider raising the levodopa dose. Plasma levodopa levels may be falling below the therapeutic threshold Alternatively, consider lowering the levodopa dose. In rare cases, sudden "off" episodes may be due to excessive levodopa effects. Failure or delay of the "on" response- Avoid taking levodopa with high protein meals- Examine gastrointestinal absorption -Avoid wearing "off" effects. Failure or delay of the "on" responses often occur after prolonged wearing "off" episodes

Dyskinesia and dystonia: Lower the levodopa dose when possible. Replace a portion of the levodopa dose with a dopamine agonist, if necessary Replace sustained-release levodopa with regular levodopa, if dyskinesia is occurring in the late afternoon and evening. Add amantadine to counteract dyskinesia. Manage diphasic dyskinesia with more frequent levodopa dosing. Use middle-of-the-night levodopa or a dopamine agonist to treat early morning "off" period dystonia. Reduce the levodopa dose intervals or add a dopamine agonist to treat "off" period dystonia during the day.

Neurotoxic versus neuroprotective effects — The concern that prolonged use of levodopa may directly hasten the degeneration of dopamine neurons in the substantia nigra by promoting the generation of free radicals and oxidative stress is the basis for delaying the use of levodopa in the treatment of PD. However, the evidence is not strong enough to justify a definitive conclusion regarding levodopa toxicity to dopamine neurons. In vitro, levodopa is toxic to cultured dopamine neurons, although it does not damage dopamine neurons in normal humans (who do not have PD) or intact animals. Nevertheless, it remains possible that levodopa is toxic in patients with PD. In one study in rodents, for example, levodopa increased neuronal damage in animals with partial injury to dopaminergic neurons. However, this was not confirmed in subsequent reports.

A consensus conference convened to discuss the issue of levodopa toxicity reached the following conclusions: There is no evidence that levodopa causes neuronal death in animal models of parkinsonism The relevance of in vitro studies of levodopa toxicity to clinical use of levodopa is highly uncertain There is no evidence that chronic administration of levodopa exacerbates the degenerative process in PD Late motor complications arise due to the combination of progressive degeneration of dopamine neurons and the reversible effects of levodopa administration

Accumulating clinical trial data suggest that levodopa, rather than being neurotoxic, either slows the progression of PD or has a prolonged benefit even after the drug has been stopped. To address the continuing uncertainty surrounding the long term effect of levodopa, the Earlier versus Later Levodopa Therapy in Parkinson Disease (ELLDOPA) study examined 361 patients with newly diagnosed PD and randomly assigned them to one of three carbidopa/levodopa doses (37.5 mg/150 mg; 75 mg/300 mg; 150 mg /600 mg) three times daily or placebo for 40 weeks, followed by withdrawal of treatment for two weeks. At 42 weeks, when the underlying native disease would be theoretically revealed as a result of the two week washout, all groups assigned to levodopa showed significantly less worsening in the symptoms of parkinsonism (as measured by the UPDRS) than did the placebo group. Patients receiving the highest levodopa dose schedule (600 mg/day) had the lowest (better) UPDRS score but also had significantly more dyskinesia. Hypertonia, infection, headache, and nausea were also more common than in the placebo group. Therefore, the clinical data suggested, surprisingly, that the use of levodopa for 40 weeks was neuroprotective.

On the other hand, imaging data from a substudy of 116 patients supported the observations from two previous studies that levodopa treatment is associated with a greater decline in basal ganglia uptake of dopamine. The substudy used single photon emission computed tomography (SPECT) to assess striatal dopamine by measuring [123I]beta-CIT uptake, and showed greater reduction in nigrostriatal dopamine transport in patients taking levodopa compared with those on placebo. Once again, the question of levodopa toxicity versus levodopa-related down regulation of the dopamine transporter receptors could not be resolved. Therefore, the question of potential neuroprotective versus neurotoxic effects of levodopa can not yet be answered.

Further clinical trials are underway to study the effects of levodopa on the progression of PD. In the meantime, levodopa remains the most effective therapy for PD, and should be introduced if there is sufficient compromise of quality of life or functional ability to warrant treatment.

MAO B inhibitors — Selegiline (Eldepryl), a selective monoamine oxidase (MAO) type B inhibitor, is modestly effective as symptomatic treatment for PD and may have neuroprotective properties. In many individuals, however, selegiline monotherapy does not produce a functionally significant benefit, thereby leaving patients disappointed. However, the use of selegiline in early PD is a reasonable option as long as the patient understands its limitations. The selective MAO B inhibitor rasagiline has neuroprotective properties in animal models and appears modestly effective as symptomatic treatment for PD in human clinical trials. Rasagiline is approved by the European Commission as initial monotherapy in patients with early PD and as adjunct treatment in moderate to advanced PD. It received similar approval by the United States Food and Drug Administration in May 2006.

Effectiveness — Evidence supporting the symptomatic effect of MAO B inhibitors for PD has been bolstered by the findings of a meta-analysis that examined data from 17 randomized trials involving 3525 patients. These individual trials compared MAO B inhibitors (predominately selegiline) with either levodopa or placebo (predominately placebo) in the treatment of early PD. Many of these trials were limited by short-term follow-up, poor reporting of results, and absence of quality of life data. With these limitations in mind, the following observations were made: Data for clinical rating scales were available from six trials of selegiline; treatment with MAO B inhibitors was associated with significantly better total scores, motor scores, and activities of daily living scores on the Unified Parkinson's Disease Rating Scale (UPDRS) at three months compared with controls. Data on the need for levodopa were available from eight studies with a median follow-up of 13 months; treatment with MAO B inhibitors was associated with a reduction in the need for additional levodopa compared with controls. Data on motor complications were available from five trials; treatment with MAO B inhibitors was associated with a modest reduction in the development of motor fluctuations compared with controls. However, MAO B treatment was not associated with a significant difference in the incidence of dyskinesia. Data on mortality were available from 10 trials, nine of which involved selegiline. MAO B inhibitor treatment was not associated with increased mortality compared with controls, in contrast to one observational study from the United Kingdom that showed increased mortality in patients using selegiline. The results of the UK study have not been confirmed by subsequent reports, including an earlier meta-analysis.

Additional evidence supporting the long-term symptomatic benefit of selegiline for PD comes from the continuation phase of a randomized controlled trial involving 157 patients with PD, in which patients who were initially assigned to selegiline in the earlier phase of the study were treated with combined selegiline and levodopa, while those initially assigned to placebo were treated with combined placebo and levodopa. At seven years, treatment with the combination of selegiline and levodopa was associated with significantly better symptom control than treatment with placebo and levodopa. Uncertainty remains about the relative risks and benefits of MAO B inhibitors, as few trials compared them with other antiparkinson medications. Comparative data are particularly lacking for the dopamine agonists.

  Dosing — The dose of selegiline used in DATATOP was 5 mg twice daily, with the second dose given at noon to avoid insomnia. However, lower doses are sufficient to induce MAO B inhibition, and 5 mg once a day in the morning is currently recommended. Doses higher than 10 mg daily are of no additional benefit and may result in nonselective MAO inhibition, thereby placing the patient at risk of hypertensive crisis in the absence of dietary restrictions.

  Adverse effects — Nausea and headache are associated with the use of MAO B inhibitors, and the amphetamine metabolites of selegiline can cause insomnia. Selegiline often causes confusion in the elderly, thereby limiting its use in patients with late-onset of disease. As previously mentioned, selegiline enhances the effect of levodopa by slowing its oxidative metabolism. Thus, it may increase levodopa-induced side effects such as dyskinesia and psychiatric toxicity. However, the need for continued selegiline is debatable once patients have reached the point of requiring levodopa.

Serious adverse reactions have rarely occurred following the concomitant use of selegiline with tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRIs). In practice, the vast majority of patients on these combinations are able to tolerate them for years without problems. However, the Physicians' Desk Reference (PDR) warns not to use selegiline with either tricyclics or SSRIs. The possible interaction of SSRI and MAO B inhibitor treatment in patients with PD is discussed in greater detail separately. Unlike nonselective MAO inhibitors, selegiline does not precipitate a hypertensive crisis in patients who concomitantly ingest tyramine-containing foods.

Dopamine agonists — The dopamine agonists (DAs) are a group of synthetic agents that directly stimulate dopamine receptors. The drugs currently approved by the United States Food and Drug Administration (FDA) include bromocriptine (Parlodel), pergolide (Permax), pramipexole (Mirapex), ropinirole (Requip), and injectable apomorphine.

Apomorphine and lisuride are additional DAs that can be administered parenterally for "rescue therapy" in patients experiencing sudden akinetic episodes. Lisuride is not currently approved in the United States, but it is available in Europe. Injectable apomorphine has been approved by the United States FDA for treatment of motor fluctuations in PD.

Unlike carbidopa/levodopa (Sinemet), these drugs are direct agonists that do not require metabolic conversion, do not compete with amino acids for transport across the gut or into the brain, and do not depend upon neuronal uptake and release. An additional advantage over immediate-release forms of levodopa is the longer duration of action of most of these agents.

Monotherapy — Dopamine agonists were initially introduced as adjunctive treatment for advanced PD complicated by reduced levodopa response, motor fluctuations, dyskinesia, and other adverse effects of levodopa. However, the hypothetical concern that free radicals generated by the oxidative metabolism of dopamine contribute further to the degeneration of dopaminergic neurons has prompted some investigators, despite lack of conclusive evidence, to advocate the early use of DAs as an levodopa sparing strategy.

With this approach, treatment with levodopa can be postponed and saved for a later time in the course of the disease, when disability worsens and the less effective agonists no longer provide adequate benefit. This strategy is based upon the unproven concept that the long-term duration of a given patient's responsiveness to levodopa is finite and that the drug, like money in a savings or retirement account, should be rationed. However, whether reduced responsiveness to levodopa over time is due to a decline in drug response or progression of underlying PD is currently uncertain.

Controlled trials have shown that bromocriptine, pergolide, pramipexole, and ropinirole are all effective in patients with advanced PD complicated by motor fluctuations and dyskinesia. However, these drugs are ineffective in patients who have shown no therapeutic response to levodopa.

Several studies have examined the use of DAs in patients with early PD; pramipexole, ropinirole, and pergolide were effective as monotherapy in patients with early disease. In relatively long-term studies, patients with early PD treated with DA monotherapy have a lower incidence of dyskinesia and motor fluctuations compared with those treated with levodopa.  As an example, one study found that the cumulative incidence of dyskinesia over five years was 20 percent in patients treated with ropinirole (plus or minus supplementation with levodopa) and 45 percent in patients treated with levodopa [55].

A second four-year trial found a similar 20 percent absolute reduction in the development of dyskinesia and a 15 percent reduction in wearing "off" with pramipexole compared with levodopa. On the other hand, initial treatment with levodopa resulted in lower incidences of freezing, somnolence, and leg edema (the latter two attributable to side effects of pramipexole) and provided for better symptomatic control. Both treatments resulted in similar quality of life.

In practice, while symptoms can be controlled initially with DAs, few patients with progressive disease can be satisfactorily maintained on DA monotherapy for more than a few years before levodopa is needed. Studies comparing the long-term effects of levodopa monotherapy versus early bromocriptine or ropinirole followed by the delayed addition of levodopa have produced mixed results, showing either fewer motor complications with combined therapy or no significant difference.

Thus, the hypothesis that early DA monotherapy reduces the future incidence of motor complications is supported by several clinical trials, but this benefit occurs at the expense of reduced efficacy when compared with levodopa. Furthermore, one comparative study found that while early treatment with bromocriptine was associated with a slightly lower incidence of motor complications compared with levodopa therapy, overall disability scores were worse in the bromocriptine group throughout the first years of therapy.

Effectiveness — The few studies that have compared the efficacy of various DAs with each other have found either no significant difference or only mild superiority of one agent over another.

The two classes of DAs, ergot (bromocriptine and pergolide) and nonergot (pramipexole and ropinirole), stimulate dopamine D2 receptors preferentially. Some stimulate D1 receptors. D1 and D2 are the most important of the five known dopamine receptors that relate to levodopa therapy. Differences in receptor selectivity are as follows: Pramipexole and ropinirole are nonergot compounds that also selectively stimulate D3 dopamine receptors in the ventral striatum, a non motor region of the basal ganglia. Since D3 receptors are not present in the dorsal or motor striatum, their role in drug responsiveness in PD is unclear. Ropinirole and pramipexole also differ from bromocriptine and pergolide in their ability to nonselectively stimulate serotonin or adrenergic receptors. Bromocriptine is a mixed D1 agonist and antagonist, and a D3 agonist. Pergolide stimulates D1 receptors. Apomorphine is a short-acting D1 and D2 receptor agonist.

Whether these differences will translate into greater efficacy and less toxicity of the newer DAs (pramipexole and ropinirole) over the older ergot compounds (bromocriptine and pergolide) remains to be seen. At the present time, however, there is probably no indication to switch from one agonist to another in a patient experiencing a satisfactory therapeutic benefit from one agent.

Dosing — The DAs generally require administration at least three times a day at maintenance doses: Bromocriptine (Parlodel) is usually started at 1.25 mg twice a day; the dose is increased at two to four week intervals by 2.5 mg a day. Most patients can be managed on 20 to 40 mg daily in three to four divided doses, although total daily doses as high as 90 mg can be used. Pramipexole (Mirapex) is usually started at 0.125 mg three times a day. The dose should be increased gradually by 0.125 mg per dose every five to seven days. Most patients can be managed on total daily doses of 1.5 to 4.5 mg. Ropinirole (Requip) is usually started at 0.25 mg three times a day. The dose should be increased gradually by 0.25 mg per dose each week for four weeks to a total daily dose of 3 mg. Most patients can be managed on this dose. After week four, the ropinirole dose may be increased weekly by 1.5 mg a day up to a maximum total daily dose of 24 mg. Benefit most commonly occurs in the dosage range of 12 to 16 mg per day. Pergolide (Permax) is best avoided because of the potential for cardiac valve problems (see "Valvular heart disease" below). If used, it is usually started at 0.05 mg a day for two days, then increased by 0.1 or 0.15 mg a day every three days for 12 days. After that, the dose may be increased by 0.25 mg a day every three days until the optimal therapeutic response is achieved. The usual total daily dose range is 1.5 to 3 mg in three divided doses. The maximum total daily dose is 5 mg. Apomorphine (Apokyn) may be administered either as intermittent rescue injections or as continuous infusions to treat "off" episodes or levodopa-induced motor fluctuations. A challenge test dose must precede routine use. This is usually done with a 2 mg subcutaneous injection under medical supervision and monitoring of standing and supine blood pressure before the injection, and repeated at 20, 40, and 60 minutes after.

Antiemetic therapy (eg, with trimethobenzamide) is initiated three days prior to starting apomorphine and is usually continued for two months before reassessing need. However, the use of apomorphine is contraindicated with ondansetron and other serotonin receptor agonists commonly used to treat nausea and vomiting, as the combination may cause severe hypotension and loss of consciousness. In addition, dopamine antagonists used to treat nausea and vomiting such as prochlorperazine and metoclopramide should be avoided, as they may reduce the effectiveness of apomorphine.

The usual starting dose for intermittent apomorphine use is 2 mg, if the patient tolerates and responds to the test dose. The dose may be increased by 1 mg per dose every two to four days to a maximum of 6 mg per dose. The average dosing frequency is three times daily and should not exceed five times a day dosing or a total daily dose of 20 mg.

Adverse effects of dopamine agonists — Adverse effects caused by dopamine agonists (DAs) are similar to those of levodopa, including nausea, vomiting, sleepiness, orthostatic hypotension, confusion, and hallucinations. Peripheral edema is common with the chronic use of DAs but is rare in patients using levodopa alone.

These adverse effects can usually be avoided by initiating treatment with very small doses and titrating to therapeutic levels slowly over several weeks. Patients intolerant of one agonist may tolerate another. As with all of the antiparkinsonian drugs, elderly and demented patients are much more susceptible to psychiatric side effects.

Accumulating evidence suggests that the use of DAs as a class may lead to compulsive use of dopaminergic drugs and/or impulse control disorders in a small percentage of patients taking these drugs. The use of ergotamine DAs is also associated with a risk of valvular heart disease.

Adverse events with apomorphine are usually mild and consist, predominantly of cutaneous reactions and neuropsychiatric problems. The incidence of these problems is higher in patients receiving continuous infusion than in those receiving intermittent subcutaneous injections. Chest pain, angina, and orthostatic hypotension are more serious problems; orthostasis peaks 20 minutes after dosing and lasts at least 90 minutes. A test dose of apomorphine to establish tolerance and responsiveness is essential prior to routine administration.

Ergot-related side effects such as Raynaud phenomenon, erythromelalgia, and retroperitoneal or pulmonary fibrosis are uncommon with bromocriptine and pergolide, and they do not occur at all with the nonergot agonists ropinirole and pramipexole. Dopamine receptor agonists decrease prolactin concentration. Thus, there is a potential for decreased milk production in postpartum women taking these agents, which are contraindicated in women who are breast feeding. The manufacturer of pramipexole has issued a warning regarding somnolence that can occur abruptly and without premonition, particularly at a dose above 1.5 mg/day. Patients with PD who drive are at particular risk of developing these "sleep attacks". They advise that patients be warned of this potential side effect and asked about factors that may increase the risk of drowsiness, such as concomitant sedating medications, sleep disorders, and medications that increase pramipexole levels (eg, cimetidine).

Valvular heart disease — Mounting evidence suggests that treatment with pergolide or cabergoline is associated with a clinically and statistically significant risk of valvular heart disease, with lesions similar to those associated with carcinoid, ergot, and fenfluramine-induced valvular disease. The risk of valvular heart disease appears to increase relative to the cumulative dose of pergolide or cabergoline, and the mechanism is probably related to pergolide and cabergoline activation of serotonin (5-HT 2B type) receptors expressed on heart valves, which in turn leads to valvular overgrowth. In a nested case-control study from the United Kingdom involving a cohort of 11,417 patients taking antiparkinsonian drugs, 31 patients with newly diagnosed cardiac valve regurgitation were compared with 664 controls. The risk of cardiac valve regurgitation was significantly increased with current use of pergolide (incidence-rate ratio [IRR] 7.1, 95% CI 2.3-22.3) and cabergoline (IRR 4.9, 95% CI 1.5-15.6) but not with other DAs. The risk of cardiac valve regurgitation was increased only for patients taking pergolide or cabergoline for six months or longer, and was particularly increased for both medications at doses higher than 3 mg daily. In a case-control study from Italy involving 155 patients taking DAs for PD and 90 control subjects, the frequency of clinically important valve regurgitation determined by echocardiography was significantly higher in patients taking pergolide or cabergoline compared with controls (23.4 and 28.6 versus 5.6 percent, respectively) but not in those taking nonergot DAs (0 percent).

Thus, pergolide and cabergoline should not be used as treatment for PD. For patients already taking these agents and doing well, we recommend discussing the risk of valvular heart disease with the patient and family, and switching to a non-ergot DA such as ropinirole or pramipexole whenever possible. Patients who choose to continue therapy with pergolide or cabergoline despite the risk should have periodic echocardiograms to evaluate the cardiac valves for deformity or regurgitation.

Dopaminergic dysregulation syndrome — Compulsive use of dopaminergic drugs develops in a small number of patients with PD and has been termed the dopaminergic dysregulation syndrome (DDS). DDS typically involves male patients with early onset PD who take increasing quantities of dopaminergic drugs despite increasingly severe drug-induced dyskinesia. DDS can be associated with a cyclical mood disorder characterized by hypomania or manic psychosis. Tolerance (or frank dysphoria) to the mood elevating effects of dopaminergic therapy develops, and a withdrawal state occurs with dose reduction or withdrawal. Impulse control disorders including hypersexuality and pathologic gambling may accompany DDS. A form of complex, prolonged, purposeless, and stereotyped behavior called punding may be also be associated with DDS.

DDS appears to be uncommon but not rare. In a series of 202 patients with PD, criteria for DDS were fulfilled in seven (3.4 percent). DDS may occur more frequently with dopaminergic agonists than with levodopa, but data are scarce. A small case-control study found that susceptibility factors for DDS included younger age at disease onset, higher novelty seeking personality traits, depressive symptoms, and alcohol intake.

Management of DDS is not well studied. Practitioners should limit dopaminergic dose increases when possible, particularly in patients who may have increased susceptibility to DDS. Continuous subcutaneous apomorphine infusions may be useful to suppress off-period dysphoria, and low doses of clozapine or quetiapine may be useful for some patients.

Impulse control disorders — Dopamine agonist therapy may be associated with an increased risk of impulse control disorders including pathologic gambling, compulsive sexual behavior, or compulsive buying, as illustrated by the following reports: In a Canadian case series of 297 patients with PD, the lifetime prevalence of pathologic gambling, hypersexuality, or compulsive shopping was 13.7 percent in patients on DAs. The lifetime prevalence of pathologic gambling for all patients and for those receiving any DA was 3.4 and 7.2 percent, respectively, compared with a lifetime prevalence of 1.0 percent in the Ontario population. There was a statistically significant association of pathologic gambling and hypersexuality with earlier PD onset and DA therapy. In line with earlier retrospective studies, pathologic gambling did not develop in patients receiving levodopa monotherapy. Another series of 272 patients with PD found that criteria for impulse control disorders, either anytime during the course of PD or currently active, were met by 6.6 and 4.0 percent of patients, respectively. The frequency of pathologic gambling, compulsive sexual behavior, and compulsive buying anytime during PD were 2.6, 2.6, and 1.5 percent, respectively. On multivariate analysis, significant predictors of an active impulse control disorder were use of a DA and a history of impulse control disorder symptoms before the onset of PD.

In a retrospective case series of 11 patients with PD who developed pathologic gambling linked to DA therapy, the pathologic gambling resolved with tapering or discontinuation of DA therapy in all patients available for follow-up (8 of 11). Only 1 of 11 patients in the series met criteria for the dopaminergic dysregulation syndrome described above, although six patients simultaneously developed other inappropriate behaviors such as hypersexuality.

COMT inhibitors — The catechol-O-methyl transferase (COMT) inhibitors tolcapone (Tasmar) and entacapone (Comtan) are useful as levodopa extenders. They are ineffective when given alone, but they may prolong and potentiate the levodopa effect when given with a dose of levodopa. These medications are mainly used to treat patients with motor fluctuations who are experiencing end-of-dose wearing "off" periods. When given to patients without motor fluctuations, entacapone did not improve UPDRS motor scores but was associated with several improved quality of life measures.

Inhibition of catechol-O-methyl transferase reduces the peripheral (entacapone) and central (tolcapone) methylation of levodopa and dopamine, which in turn increases the plasma half-life of levodopa, produces more stable plasma levodopa concentrations, and prolongs the therapeutic effect of each dose. Use of COMT inhibitors may allow a reduction in the total daily levodopa dose by as much as 30 percent. The net result is an increased levodopa effect.

Dosing — The starting dose of tolcapone is 100 mg three times daily; the clinical effect is evident immediately. The dose of entacapone is one 200 mg tablet with each dose of levodopa, up to a maximum of eight doses per day.

Adverse effects — The most common side effects of tolcapone are due to increased dopaminergic stimulation and include dyskinesia, hallucinations, confusion, nausea, and orthostatic hypotension. The adverse effects are managed by lowering the dose of levodopa either before or after the addition of tolcapone. Diarrhea poorly responsive to antidiarrheal medications appears in approximately 5 percent of patients. An orange discoloration of the urine is a common but benign adverse event. Elevations in liver enzymes may rarely occur.

Three reported deaths from hepatotoxicity in patients using tolcapone prompted its removal from the market in Canada and Europe, although it is still available in the United States with the recommendation that it be used for treatment of motor fluctuations only after other methods have been exhausted and with regular monitoring of ALT and AST levels.

Side effects of entacapone are similar to tolcapone, although entacapone has thus far not been associated with hepatotoxicity.

Anticholinergics — Dopamine and acetylcholine are normally in a state of electrochemical balance in the basal ganglia. In PD, dopamine depletion produces a state of cholinergic sensitivity so that cholinergic drugs exacerbate and anticholinergic drugs improve parkinsonian symptoms.

Centrally acting anticholinergic drugs such as trihexyphenidyl (Artane) and benztropine (Cogentin) have been used for many years in PD and continue to have a useful role. Other anticholinergic agents such as biperiden (Akineton), orphenadrine (Disipal), and procyclidine (Kemadrin) produce similar effects and are more commonly used in Europe than the United States. Benztropine also may increase the effect of dopamine by inhibiting its presynaptic reuptake, but it is not known whether this contributes to its mechanism of action.

Anticholinergic drugs are most useful as monotherapy in patients under age 70 with disturbing tremor who do not have significant akinesia or gait disturbance. They also may be useful in patients with more advanced disease who have persistent tremor despite treatment with levodopa or DAs.

Dosing — Trihexyphenidyl is the most widely prescribed anticholinergic agent, although there is little evidence to suggest that one drug in this class is superior to another. The starting dose of trihexyphenidyl is 0.5 to 1.0 mg twice daily, with a gradual increase to 2 mg three times daily. Benztropine traditionally is more commonly used by psychiatrists for the management of antipsychotic drug-induced parkinsonism; the usual dose is 0.5 to 2.0 mg twice daily.

Adverse effects — Adverse effects of anticholinergic drugs are common and often limit their use. Elderly and cognitively impaired patients are particularly susceptible to memory impairment, confusion, and hallucinations and should not receive these drugs. When an anticholinergic drug is used to treat sialorrhea or urinary frequency, peripherally acting agents such as propantheline (probanthine) should be used, although confusion and hallucinations are not infrequent adverse effects with these drugs as well. Younger patients usually tolerate these agents better than the elderly, although some experience dysphoric symptoms, sedation, or memory impairment.

Peripheral antimuscarinic side effects include dry mouth, blurred vision, constipation, nausea, urinary retention, impaired sweating, and tachycardia. Caution is advised in patients with known prostatic hypertrophy or closed-angle glaucoma. Discontinuation of anticholinergic drugs should be performed gradually to avoid withdrawal symptoms that may manifest as an acute exacerbation of parkinsonism, even in those in whom the clinical response has not seemed significant.

Amantadine — Amantadine is an antiviral agent that has mild antiparkinsonian activity. Its mechanism of action is uncertain; it is known to increase dopamine release, inhibit dopamine reuptake, stimulate dopamine receptors, and it may possibly exert central anticholinergic effects. Amantadine has N-methyl-D-aspartate (NMDA) receptor antagonist properties that may account for its therapeutic effect by interfering with excessive glutamate neurotransmission in the basal ganglia.

In early uncontrolled clinical trials, two-thirds of patients receiving amantadine monotherapy showed an improvement in akinesia, rigidity, and tremor. Subsequent controlled studies demonstrated that it was more effective than anticholinergic drugs for akinesia and rigidity. The benefit induced by amantadine appears to be transient in some patients; it is best used as short-term monotherapy in those with mild disease. Amantadine is of little benefit when added to levodopa, although the addition of levodopa to amantadine causes significant additive improvement.

Amantadine in divided doses of 200 to 400 mg a day may reduce the intensity of levodopa-induced dyskinesia and motor fluctuations in patients with PD. Although the published randomized trials on amantadine in advanced PD are limited by serious methodological flaws and small numbers of patients, experience has shown that individual patients with advanced PD who have motor fluctuations and dyskinesia can benefit dramatically, at least for a while, from the addition of amantadine to a regimen of levodopa.

Dosing — The dose of amantadine in early PD is 200 to 300 mg daily; there is no evidence that larger doses are of additional benefit. The main advantage of this agent is a low incidence of side effects. It is excreted unchanged in the urine and should be used with caution in the presence of renal failure.

Adverse effects — Peripheral side effects include livedo reticularis and ankle edema, which are rarely severe enough to limit treatment. Confusion, hallucinations, and nightmares occur infrequently, but unpredictably, even after long periods of use without side effects. These effects are more likely when amantadine is used together with other antiparkinsonian drugs in older patients.

Estrogen — Low-dose estrogen may be helpful as adjunctive therapy in postmenopausal women with motor fluctuations on antiparkinsonian medication. In one study, administration of Premarin 0.625 mg daily for eight weeks significantly improved "on" time and motor control in such women, although it did not result in global improvement on an activities of daily living rating scale. There is no evidence that estrogen has a specific effect on dopamine receptors; the benefit attributable to estrogen use may be related to an overall sense of well being. It is not clear if these results would be similar in women taking combined estrogen/progestin therapy (necessary in women with an intact uterus). Furthermore, concerns about adverse effects associated with long-term estrogen/progestin therapy may limit its use in PD.

SUMMARY AND RECOMMENDATIONS — Either levodopa or a dopamine agonist (DA) can be used initially for patients who require symptomatic therapy. Practitioners should always try to find the lowest but still effective dose of dopaminergic medication, either singly or in combination, for patients with PD, each of whom must be evaluated and managed in a highly individual way. Levodopa (combined with a peripheral decarboxylase inhibitor, ie, Sinemet, Madopar, or Prolopa) is the most effective symptomatic therapy for Parkinson's disease (PD) and should be introduced when the patient and physician jointly decide that quality of life, particularly related to job performance or self care, is substantially compromised. However, levodopa is associated with a higher risk of dyskinesia than the DAs. There does not appear to be a benefit of initiating treatment with controlled release levodopa compared with the immediate release preparation, and the former may limit the ability to follow the initial response to therapy. As a result, it is recommended that therapy be initiated with an immediate release preparation with a subsequent switch to controlled release if indicated. With the exception of pergolide and cabergoline, the dopamine agonists are a useful group of drugs that may be used either as monotherapy in early PD or in combination with other antiparkinsonian drugs for treatment of more advanced disease. They are ineffective in patients who show no response to levodopa. They possibly delay initiation of levodopa therapy and the subsequent appearance of levodopa dyskinesia and motor fluctuations, but at the risk of slightly less efficacy and increased adverse effects. Pergolide and cabergoline should not be used for PD because of the risk of valvular heart disease. It is reasonable to initiate therapy with a DA in younger patients (age <65) with PD, and with levodopa in elderly patients (age >65). However, there are exceptions to these general rules, and all treatments should be individualized. Levodopa is the drug of choice if symptoms seriously threaten the patient's lifestyle. Selegiline has mild symptomatic benefit, and it may be used in patients with early PD. Its use should be limited to patients with early disease since the symptomatic benefits are unlikely to be significant in those with more advanced PD. Nevertheless, patients should understand that there may not be much symptomatic improvement if selegiline is the initial treatment for early PD, and early follow-up and consideration of additional symptomatic therapy should be arranged. The value of selegiline for neuroprotection is unclear. Rasagiline is a newer MAO B inhibitor that produces significant benefit as monotherapy in PD, as demonstrated in randomized clinical trials. It therefore has a better defined role than selegiline in the symptomatic treatment of patients with early PD. Anticholinergic drugs should be reserved for younger patients in whom tremor is the predominant problem. Their use in older or demented individuals and those without tremor is strongly discouraged. Amantadine is a relatively weak antiparkinsonian drug with low toxicity that is most useful in treating patients with early or mild PD and perhaps later when dyskinesia becomes problematic.