Parkinson's Disease

Author: Dr Daniel Tarsy Harvard Medical School 2008-07-28

Background

Parkinson’s disease (PD) was described by Dr. James Parkinson in 1817 in “An Essay on the Shaking Palsy.” His description of a “relentlessly progressive disease” causing tremor, gait disturbance, slow movement, and disturbed sleep remains valid, although fortunately, modern treatments have done much to change this early description. Loss of dopamine producing cells in the midbrain was discovered in the middle of the last century, but the underlying cause of this continues to elude researchers. Despite modern technology, the diagnosis of PD continues to be based on the history and physical examination rather than brain imaging or laboratory tests.

Epidemiology of Parkinson’s disease

PD affects more than 1 million people in the US but it is likely it will become increasingly common as the population ages. General awareness concerning PD has been heightened by high profile patients such as Michael J. Fox, Muhammad Ali, and the late Pope John Paul II. Average age of onset is in the late 50s but prevalence continues to increase with age. PD is estimated to affect 0.3% of people age 55 to 64, 1.0% of those age 65 to 74, 3.1% of those age 75 to 84, and 4.3% of people above age 85. There is a 3:2 male to female predominance, but this difference is less evident in later life. There is no significant

 difference in prevalence among white, Afro-American, Hispanic, or Asian populations. PD occurs more frequently in individuals who grew up in rural areas. Early exposure to pesticides has been proposed as a possible risk factor due to the observed increased risk among farmers and people drinking well water but no specific pesticides have been incriminated. Researchers have been intrigued by consistent observations that patients with PD are less likely to smoke or drink caffeine beverages than the general population. It is unknown whether these agents are protective against PD or whether it is possible that early changes in dopamine-mediated reward systems in the brain of persons destined to develop PD make them less susceptible to the addictive qualities of nicotine and caffeine.

Pathology of Parkinson’s disease

Despite not knowing the underlying cause of PD, scientists have discovered much about the pathologic brain changes caused by the disease. In PD, dopamine-producing cells contained in the substantia nigra of the brainstem become gradually depleted. This leads to malfunction of dopamine-dependent pathways for the initiation and control of voluntary movements. However, PD is not only a disease of dopamine nerve cells, since cells utilizing other brain neurotransmitters such as serotonin, norepinephrine, and glutamate are also affected. There is interesting recent evidence that pathologic changes may actually begin in regions of the lower brainstem and olfactory system before ascending to involve the dopamine-containing substantia nigra and eventually the cerebral cortex.

The pathologic hallmark of PD is the Lewy body, an abnormal cellular inclusion which is found widespread in dying cells in the brain. These inclusions contain large concentrations of a protein called alpha-synuclein. This is a normal brain protein of uncertain function that accumulates to an abnormal degree in the brain cells of patients with PD. Scientists have hypothesized that the metabolism of this cellular building block may be disturbed in PD. Other recognized abnormalities include dysfunctional nerve cell mitochondria (the intracellular energy centers), which produce less cellular energy and more free radicals capable of causing oxidative damage.

Clinical features of Parkinson’s disease

In general, PD begins and progresses slowly, although the rate of progression is highly variable among different patients. Some patients recall possible early symptoms that may have existed years before they developed the disease. Certain symptoms are, indeed, now recognized to precede the motor signs of PD. These include decreased sense of smell, constipation, and a sleep disturbance known as REM sleep behavior disorder. In addition, many patients later diagnosed with PD suffer from depression or anxiety for several years prior to diagnosis. Some families have noticed a decrease in facial expression, a flatness of the voice, and a more passive personality before the diagnosis of PD was made.

The four major signs of PD are tremor, bradykinesia (slowness of movement), rigidity (resistance to passive manipulation of the extremity or trunk), and gait disturbance with postural instability (impaired balance). The diagnosis of PD requires that bradykinesia and at least one other of these cardinal features be present. The earliest motor signs may be subtle and are often first noticed by family members rather than the patient. These signs typically first affect only one side of the body and continue to be asymmetric in their distribution as the disease progresses. Tremor is the most common presenting symptom which, when it first appears, may be intermittent and exacerbated only during stressful situations. Decreased arm swing on one side while walking can lead to shoulder pain as an early symptom. In some cases, handwriting becomes smaller. Others notice difficulty with fine motor coordination and making quick movements. This can result, for example, in difficulty doing up buttons, brushing teeth, shaving, typing, and chopping vegetables. As the disease progresses the motor signs become more obvious. Tremor becomes more constant, although it may be absent in approximately 25% of patients. Parkinson tremor is usually present only with the extremities at rest and some patients are able to control it by gripping a pen or other object. Alternatively, some patients have a more disturbing action tremor while using their hands. As the disease advances, bradykinesia becomes increasingly prominent and eventually becomes the most disabling aspect of the disease, with slowing of activities of daily living. Facial masking with a staring expression, and a low volume and monotonous voice may appear. Subjectively, patients often describe bradykinetic slowness as a feeling of stiffness, weakness, or fatigue. One leg may drag and walking may become shuffling, sometimes associated with a stooped posture. Getting up from a deep chair or getting out of a car also becomes more difficult.

Differential diagnosis of Parkinson’s disease

Because the diagnosis of PD is largely based on history and examination of the patient with relatively limited brain imaging or laboratory support, there is an inaccuracy rate in diagnosis of PD of about 10-20%, depending on the expertise of the neurological consultant. Several neurological disorders may mimic PD. Essential tremor is a postural and action tremor which is often mistaken for PD by laypersons as well as physicians. Unlike PD, it is only slowly progressive and not accompanied by bradykinesia or rigidity. Hypertensive cerebrovascular disease may cause small strokes in deep motor regions of the brain which result in more symmetric bradykinesia and gait disturbance. Normal pressure hydrocephalus is an obstruction of spinal fluid circulation which occurs in older individuals and may present with bradykinesia and shuffling gait but is often accompanied by cognitive deficits, personality change, or urinary incontinence. Chronic treatment with antipsychotic drugs and anti-emetics such as metoclopramide or prochlorperazine, commonly cause drug-induced parkinsonism which is reversible with discontinuation of the offending medication.

Additionally, there are several less common degenerative diseases which cause parkinsonism. Collectively, these are referred to as “atypical parkinsonism” or “Parkinson’s plus.” The differentiation of these disorders from PD relies largely upon clinical examination with occasional assistance provided by brain imaging. There are several clues used to differentiate these disorders from PD. These include more symmetrical motor symptoms, absence of tremor, early balance disturbance with falls, more rapid progression to major disability and wheelchair status in five years, and the presence of other neurological abnormalities such as disturbed eye movements, ataxia, dementia, and autonomic nervous system signs such as low blood pressure, impotence, and bladder dysfunction. A typical hallmark of “atypical parkinsonism” is a poor or absent response to antiparkinson medications. More specifically, paralysis of vertical eye movements and early falls suggest progressive supranuclear palsy (PSP); cerebellar ataxia or prominent autonomic dysfunction suggest multiple system atrophy (MSA); early dementia, visual hallucinations, and fluctuations in alertness suggest diffuse Lewy body disease (DLBD). Corticobasal ganglionic degeneration (CBD) is a rare asymmetric disorder associated with difficulty performing learned motor tasks (apraxia) and prominent sensory deficits.

Treatment of Parkinson’s disease

The array of pharmacologic and surgical treatments available to treat PD is much broader than for any other neurodegenerative disease. Unfortunately, treatment options for atypical parkinsonism are very limited. The evaluation of when to initiate treatment and which drug to begin with is a major decision. Levodopa (L-dopa) (Sinemet) was the first major antiparkinson medication to be introduced and remains the “gold standard” of treatment. Next in efficacy are the dopamine agonists. A debate has raged concerning whether initial treatment should be with levodopa or dopamine agonists. Physicians have been concerned about forestalling the appearance of dyskinesias and motor fluctuations while many patients have incorrectly been led to believe that levodopa has a limited duration of usefulness of several years, making it important to defer treatment for as long as possible. This has created a “levodopa phobia” which sometimes stands in the way of useful treatment. In spite of this controversy, there is uniform agreement that the appropriate time to begin treatment is when symptoms are intrusive and the patient is beginning to be disabled. This varies from patient to patient and depends on age, employment status, nature of job, level of physical activity, concern about appearance, and other factors. The choice of a specific drug should be dictated by the patient’s specific symptoms. For example levodopa is preferable for severe akinesia, an anticholinergic drug may be more useful for tremor, and dopamine agonists may be indicated for patients with relatively mild symptoms. It is also important to manage non-motor symptoms in patients with early PD. Anxiety and depression are particularly common early in PD and sometimes are presenting symptoms of PD. Where appropriate, counseling and/or treatment with anxiolytics and antidepressants should be considered.

Education and support

PD is a high-profile disorder for which much public information is available on the internet, not all of which is accurate. A new diagnosis of PD is frightening. Patients may be familiar with its disabling effects in an affected family member, friend, or public figures. Proper education is essential to provide patient and family with understanding and therefore better control over the disorder. Rate of progression is variable and many treatment options exist. Focused education regarding specific symptoms can be effective and is available through books for the lay audience, regional and national PD organizations which publish useful educational materials and organize symposia for patients and their families, and carefully selected internet sites such as those listed below. When the diagnosis of PD has been made, there are important questions to ask of the neurologist or movement disorders expert. These include how the diagnosis was arrived at, what other motor or non-motor symptoms are likely to appear in the future, how rapidly will the disease progress, does it run in families, and when should treatment be initiated.

These are useful websites for information on PD: www.mdvu.org ( We Move); www.parkinson.org (National Parkinson Foundation), www.apdaparkinson.org (American Parkinson’s Disease Association), www.pdf.org (Parkinson’s Disease Foundation), www.yopa.org (Young Onset Parkinson’s Association)

The emotional and psychologic needs of the patient and family should be addressed. Anger, depression, anxiety, and social and economic concerns often occur early, and may evolve as it progresses. Support for the caregiver is essential. Support groups are valuable to foster interactions with patients or families with similar experiences and for providing access to education. Referral to a skilled psychiatric social worker experienced in dealing with chronic illness may be necessary. Referral for legal, financial, or occupational counseling may also be indicated.

Diet and lifestyle

• Newly diagnosed patients often inquire about the amount of protein they should consume after reading that protein may interfere with gastrointestinal absorption of levodopa. This is actually more important in patients with advanced PD who experience motor fluctuations in response to levodopa. Certain large amino acids derived from protein may reduce levodopa absorption in the intestine and transport from the blood into the brain, thereby potentially interfering with its clinical efficacy. In such cases, levodopa should not be taken less than 30 minutes before or 60 minutes after meals. A protein redistribution diet which limits most protein intake to an evening meal is only necessary in occasional patients.
• Nausea or vomiting after levodopa or dopamine agonists is alleviated by taking these medications during or following meals. In patients with early PD and a stable medication response this will not compromise therapeutic efficacy.
• Large, high fat meals which slow gastric emptying may interfere with medication absorption and should be avoided.
• Patients should consume sufficient fiber and fluid to prevent constipation, which is frequently associated with PD.
• Weight loss is sometimes associated with PD or treatment with levodopa. Elderly patients are at greater risk for poor nutrition and weight loss. Recognition and management of this problem is important to avoid loss of bone and muscle mass. Dietary calorie and vitamin supplements may be indicated. In postmenopausal women, calcium supplements and medications to prevent osteoporosis are recommended.
• Coenzyme Q10 enhances mitochondrial function. PD is associated with reduced platelet mitochondrial and serum coenzyme Q10 activity. In clinical trials in PD patients, coenzyme Q10 , 1200 mg/day has been proven safe and has been associated with slightly less progressive motor disability, compared with placebo.
• Large doses of vitamin E do not slow progression of PD.
• Large doses of vitamin B6 (pyridoxine) interfere with L-dopa metabolism and should be avoided in the currently very rare patient who takes L-dopa without carbidopa, a peripheral dopa decarboxylase inhibitor. This is not a practical concern when levodopa is combined with carbidopa.
• Patients should be encouraged to assume a positive attitude, remain professionally and socially active, and assume a generally healthy lifestyle with emphasis on regular exercise and good general nutrition.

Exercise and physical/speech therapy

• Regular exercise promotes a feeling of physical and mental well-being, important in the management of PD. Although exercise does not slow progression of PD symptoms it can prevent or alleviate orthopedic effects of akinesia, rigidity and flexed posture such as shoulder, hip, and back pain and has also been shown to improve some motor functions. Supervised training including cardiovascular fitness exercise, muscle stretching and strengthening, and balance training have been found to be useful in some short- and long-term studies. Occupational therapy to assess home safety, supervise use of walking aids, and provide instruction concerning sensory cuing plays a greater role in more advanced PD associated with gait and balance deficits. Tai Chi may be useful for balance training. Controlled trials have shown that acupuncture does not improve PD motor symptoms.
• Loss of voice volume often becomes a significant problem in more advanced PD. Patients should be encouraged to be more consciously aware of their voice output and concentrate on projecting more loudly than they think is necessary. Lee Silverman voice therapy is a special technique which emphasizes increased volume production and has been demonstrated to be helpful in PD. More information regarding this may be obtained at www.lsvt.org

Treatment with medications

• Treatment with medications is dictated by whether one is dealing with PD, atypical parkinsonism, or secondary parkinsonism. Antiparkinson medications are highly effective in PD but relatively ineffective in most patients with atypical parkinsonism. Secondary parkinsonism such as drug-induced parkinsonism, vascular parkinsonism, and normal pressure hydrocephalus are treated according to underlying causes. However, although there are established criteria for diagnosis of PD, they are not foolproof and a trial of antiparkinson medications is warranted in all patients with parkinsonism. However, patients with atypical parkinsonism are more liable to experience medication side effects.
• The first consideration is when to initiate medication. Currently available medications are given to improve symptoms; they have no proven ability to slow progression of the underlying disease. Therefore, drug treatment should be initiated only when symptoms begin to interfere with routine activities of daily living, employment, lifestyle, or physical appearance. Patient age and level of physical and professional productivity are also important considerations. The decision on when to begin treatment and which medications to use should be considered jointly by the physician, patient, and patient’s family. Active research is ongoing to identify disease modifying or neuroprotective drugs to slow disease progression. To date no proven agents have emerged from the many medications which have been screened. The following groups of medications are for treatment of only the motor symptoms of PD, which are tremor, bradykinesia (slowness), and rigidity and are listed in the table. They are listed approximately in the order in which they are often introduced into treatment but it should be realized that different patients may require different medications and that there is no firm or absolute rule for the order of using these medications. 

Monoamine oxidase inhibitors

This group of drugs are used early in PD for the treatment of relatively mild symptoms and also in more advanced PD, as adjuncts to other medications to smooth out responses in patients with fluctuating responses to their medications. Selegiline (Eldepryl) is a selective monoamine oxidase (MAO) type B inhibitor (MAOI) which is mildly effective for symptomatic treatment of PD but, contrary to initial expectations, does not have significant neuroprotective properties. Standard dose is 5 mg each morning. Contraindications to its use are confusion, sensitivity to MAOIs, and concomitant use of meperidine or other narcotics. Serious interactions with meperidine include cardiac instability, hyperoxia, and coma. The manufacturer has advised that selegiline not be used with tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRIs) in order to avoid causing a “serotonin syndrome” with severely disturbed mental, motor, and autonomic function. However, two studies have shown an extremely low occurrence of serious side effects among patients taking selegiline with an SSRI. Although this combination appears to be safe, appropriate caution is advisable.

Side effects are uncommon but include insomnia, confusion in elderly patients, nausea, and headache. Unlike nonselective MAO-A inhibitors used for treatment of depression, selegiline doesn’t precipitate acute and severe high blood pressure when used with tyramine-containing foods.

Rasagiline is a newly available MAO-B inhibitor with properties similar to selegiline but not metabolized to amphetamine-like metabolites. It has been established to be safe and effective both in early PD and in advanced PD with motor fluctuations.

Zydis selegiline is a selegiline formulation which is taken once daily as a tablet which dissolves in the mouth and is thereby absorbed directly into the blood stream

Amantadine

Amantadine is an antiviral agent with mild therapeutic effects in PD which was used originally in patients with early PD for relatively mild motor symptoms. Currently it is more commonly used in more advanced PD to suppress levodopa-induced dyskinesias. It increases dopamine release, inhibits dopamine reuptake, and may have central anticholinergic effects. However, these effects are modest and its N-methyl-D-aspartate (NMDA) receptor antagonist properties likely produce their effect by interfering with excessive glutamate transmission in the basal ganglia. Amantadine produces only temporary benefit for PD symptoms in most patients and is best used as short-term monotherapy in patients with mild symptoms. Standard dose is 100 mg 2-3 times daily. In older patients it is best to begin with 100 mg daily and increase to 100 mg twice daily after one week.

Side effects are uncommon but may include confusion, visual hallucinations, nightmares, insomnia, anxiety, peripheral edema, skin rash, and gastrointestinal symptoms. The central nervous system side effects are more common in elderly individuals. Contraindications to use of amantadine are confusion, ankle edema, allergy, and renal failure since it is excreted in the urine. Main drug interactions are anticholinergic symptoms and confusion if given together with other drugs with these effects. Other adverse drug interactions include trimethoprim, triamterene, and bupropion.

Anticholinergic drugs

In PD, dopamine depletion results in increased sensitivity to the effects of the neurotransmitter acetylcholine. Anticholinergic drugs therefore improve Parkinson symptoms. Centrally acting anticholinergic drugs such as trihexyphenidyl and benztropine have been used for many years in PD and continue to play a useful role in certain patients. Biperiden, orphenadrine, ethopropazine, and procyclidine are more commonly used in Europe. Anticholinergic drugs may be useful as monotherapy in patients under age 70 with disturbing tremor but without significant akinesia or gait disturbance for which they are much less effective. They may also be useful in patients with more advanced disease who have persistent tremor despite treatment with levodopa or dopamine agonists. They are also effective for dystonia in the foot or toes, which often accompanies early PD in younger patients.

Trihexyphenidyl is the most widely prescribed anticholinergic agent in PD. Starting dose is 0.5 to 1.0 mg twice daily, increasing gradually to 6 mg daily as tolerated. For benztropine the usual dose is 1-2 mg daily.

Most common side effects are dry mouth, constipation, urinary retention, memory impairment, confusion, mood changes, and visual hallucinations. Contraindications to its use are narrow angle glaucoma, prostatism, gastroparesis, confusion, and psychiatric symptoms. Main drug interactions are confusion or increased anticholinergic side effects if added to other drugs with these effects.

Dopamine agonists

Dopamine agonists are synthetic drugs which directly stimulate or activate dopamine receptors. They are commonly used early in PD in patients who fail to respond to the milder drugs described above or in patients whose symptoms are more advanced at the time of diagnosis. Currently available dopamine agonists in the US include bromocriptine, pramipexole, ropinirole, rotigotine (administered by skin patch), and injectable apomorphine. Bromocriptine was the first dopamine agonist to be used for PD but is a weaker agent with larger number of side effects. Apomorphine and lisuride (lisuride is not FDA approved in the US) are administered parenterally for "rescue therapy" in patients with advanced PD who experience sudden loss of medication effect. Dopamine agonists have a longer duration of action than does levodopa, do not require metabolic conversion to an active agent, do not compete with amino acids for gut or brain transport, and do not depend upon uptake and release from nerve cells. At one time there was a concern that treatment with levodopa would generate free radicals as a by-product of the metabolism of dopamine, which might cause further degeneration of dopamine neurons. This led to the suggestion that early use of dopamine agonists in place of levodopa might serve as a “levodopa sparing strategy.” Using this approach, levodopa therapy is postponed to later in the disease when dopamine agonists no longer provide adequate benefit. It has since been established that levodopa does not damage dopamine nerve cells and is safe to administer at any point in the course of PD. Contrary to popular belief, early treatment with levodopa in younger patients (under age 60) is not withheld because the duration of levodopa responsiveness is limited to a finite number of years. Instead, early treatment with levodopa is usually avoided in relatively younger patients because these patients appear to be more susceptible to levodopa side effects, such as severe dyskinesias and motor fluctuations.

Pramipexole, ropinirole, and the rotigotine patch are all effective as monotherapy in patients with early PD. In studies lasting 3-5 years, patients with early PD treated with dopamine agonists showed a lower incidence of dyskinesia and motor fluctuations compared with those treated with levodopa. On the other hand, initial treatment with levodopa resulted in better control of symptoms and fewer side effects of somnolence and ankle edema. In practice, relatively few patients with progressive disease can be maintained on dopamine agonists for more than a few years before levodopa becomes necessary. The various dopamine agonists appear to be equally effective so that there is no indication to switch from one to another in a patient experiencing therapeutic benefit without side effects.

Standard dose of the dopamine agonists is achieved by titrating gradually, according to clinical response, and as tolerated on a 3 times daily schedule. Bromocriptine is started at 1.25 mg twice daily and increased slowly to 20-60 mg daily. Pramipexole is started at 0.125 mg 3 times daily and increased slowly until reaching 1.5-4.5 mg daily. Ropinirole is started at 0.25 mg 3 times daily and increased slowly to a maximum of 24 mg daily.

Main side effects include nausea, vomiting, orthostatic hypotension, confusion, and visual hallucinations. Drowsiness, including sudden “sleep attacks,” may also occur, including while driving. Sensitivity to these side effects can be assessed by initiating treatment with small doses and titrating over several weeks. Patients intolerant of one agonist may sometimes tolerate another. Elderly and demented patients are more susceptible to psychiatric side effects. Pathologic gambling and other compulsive behaviors such as hypersexual preoccupations, compulsive eating, and compulsive shopping have been associated with all of the dopamine agonists and are much less common in patients treated with levodopa.

Ergotamine-related side effects such as Raynaud’s phenomenon, skin redness, retroperitoneal or pulmonary fibrosis, and peripheral constriction of blood vessels occur with the ergot dopamine agonist bromocriptine but not with ropinirole, pramipexole, or rotigotine. Pergolide is another ergot type dopamine agonist which was withdrawn from the market because it was associated with valvular heart disease. Contraindications for bromocriptine include sensitivity or prior adverse responses to ergot alkaloids, cardiovascular disease, peripheral vascular disease, pregnancy, postpartum nursing, and concomitant use of triptan or antihypertensive medications. For the nonergot compounds, the only contraindication is hypersensitivity to pramipexole or ropinirole.

Levodopa

Levodopa is currently most commonly used in patients who have been treated with dopamine agonists but who are losing their response because of progression of PD symptoms. It is currently common, but not universal practice, to withhold levodopa in the early treatment of PD, especially in relatively younger patients under age 60. This is because younger patients appear to be more susceptible to earlier and more severe motor complications such as wearing off effects and dyskinesias (See below: Special problems in the treatment of advanced Parkinson’s disease). In patients above age 60 and especially if bradykinesia (slowness) is the major feature of the disease, levodopa is often indicated as the first drug to be used. Contrary to common belief among many patients, levodopa is not withheld in younger patients because its effect will be lost after several years of treatment. Levodopa is the most effective drug for treatment of idiopathic PD and is therefore referred to as the “gold standard” of treatment. It is particularly effective for akinetic symptoms and should be introduced first in older patients and when these are uncontrolled by other antiparkinson drugs in younger patients. Levodopa is combined with a peripheral decarboxylase inhibitor (carbidopa in the US) to block conversion to dopamine outside the brain, which prevents side effects of nausea, vomiting, and lowered blood pressure when standing. The majority of patients with PD experience a significant therapeutic response to moderate doses of levodopa. A poor or completely absent response to high doses of levodopa suggests that the patient may have a form of atypical parkinsonism. For this reason, some physicians administer levodopa for a 3-week trial to confirm the diagnosis of PD as opposed to atypical parkinsonism. However, the validity of a levodopa trial has not been established as a method to support or refute the diagnosis of PD.

Carbidopa/levodopa (CD/LD) is available in combinations of 10/100, 25/100, and 25/250 mg. For patients with swallowing difficulty, there is an immediate-release formulation of CD/LD known as Parcopa that dissolves orally but does not reach the systemic circulation any faster than standard tablets. Sustained-release formulations of both preparations are available. Treatment is usually begun with 1/2 tablet of Sinemet 25/100 mg three times daily and increased after 1-2 weeks to 25/100 mg three times daily. Elderly or demented patients should begin with smaller doses, which are increased more slowly because of their increased susceptibility to confusion and psychiatric side effects.

Sustained release preparations are less completely absorbed and require a dose up to 30% higher than that of immediate release preparations, to achieve equivalent clinical effects. Therapeutic effect is typically less dramatic than for immediate release preparations. It is therefore recommended that therapy be initiated with an immediate release preparation to establish medication response, followed by a switch to sustained release CD/LD if desired.

CD/LD should be taken at least 30 minutes before or 60 minutes after meals because of competition with other amino acids for gastrointestinal absorption. This is more important in advanced disease when motor fluctuations are more likely to occur. Nausea is a side effect usually managed by taking CD/LD with a snack or meals. Small starting doses of CD/LD are more likely to cause nausea because of inadequate amounts of carbidopa. This is managed by administering supplemental doses of carbidopa or by taking an antiemetic such as trimethobenzamide or domperidone (not available in the US) prior to taking Sinemet. Phenothiazine antiemetics and metoclopramide should be avoided because they aggravate parkinsonism.

Lightheadedness, somnolence, insomnia, and headache are uncommon side effects. More serious side effects usually occur in patients with cognitive impairment and include confusion, visual hallucinations, delusions, agitation, anxiety, and psychosis.

Motor complications of levodopa include dyskinesia (jerky involuntary movements), dystonia (painful muscle spasms), myoclonus (muscle jerks), and a shortened response to levodopa doses known as the end-of-dose wearing-off effect. The frequency of these has been variable but occurs in 20-50% of patients after 5 to 10 years of levodopa treatment. Cautious use of relatively low doses of levodopa reduces the incidence of dyskinesia but has an uncertain effect on future occurrence of wearing-off effect. Increased wearing-off effect over time is most likely due to the progressive degeneration of dopamine neurons. This limits proper uptake and release of dopamine, leading to fluctuations in plasma levodopa levels. Sustained release CD/LD preparations are sometimes useful to manage early wearing-off effects but unpredictable absorption and delayed cumulative effects over the course of the day often cause increased afternoon and evening dyskinesia. There has been concern that levodopa motor fluctuations and dyskinesias may be due to a levodopa-induced acceleration of nigral degeneration by generation of free radicals and promotion of oxidative stress rather than a change in the ability of the fewer remaining nerve cells to handle levodopa due to disease progression. It is commonly recommended that initiation of levodopa should be delayed until symptoms significantly interfere with function. Others have contended 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. Accumulated data concerning this subject indicates that levodopa doesn’t accelerate the degenerative process in PD and that late motor complications probably occur due to a combination of progressive disease and the reversible effects of levodopa administration.

At the present time, levodopa remains the most effective therapy for PD and should be introduced when other medications have failed and the patient's social, occupational, or self-care functions are sufficiently compromised to warrant treatment with the best available drug for PD. The quality standards subcommittee of the American Academy of Neurology concluded that either L-dopa or a DA can be used for initiation of treatment in patients with early PD, and that L-dopa is more effective than the DA’s.

There are no absolute contraindications to levodopa. Caution should be exercised in patients with a history of malignant melanoma although there is no conclusive evidence that levodopa increases the risk of melanoma recurrence. Drug interactions mainly concern dopamine receptor blocking drugs such as antipsychotic medications and the antiemetics metoclopramide and prochlorperazine, which block levodopa effect. Phenytoin and papaverine also interfere with levodopa effects by uncertain mechanisms. Bupropion may increase incidence of L-dopa side effects. Pyridoxine increases peripheral metabolism of levodopa if given in the absence of carbidopa.

Catechol-O-methyl transferase inhibitors

Entacapone and tolcapone inhibit the enzyme catechol-O-methyl transferase (COMT) which slows the metabolism of levodopa. This increases the plasma half-life of levodopa, produces more stable blood levodopa concentrations, and prolongs the duration of benefit produced by each dose of levodopa. These drugs have no antiparkinson effects when given alone. They are used to treat patients in whom the duration of levodopa effects are becoming shorter, called the wearing-off effect. They are not necessary in patients with early PD without shortened responses to levodopa. A combination tablet containing CD/LD together with entacapone called Stalevo is available for convenience.

The standard dose of entacapone is 200 mg with each dose of levodopa, up to a maximum of eight doses daily. Tolcapone dose is 100-200 mg three times daily.

Side effects are limited to diarrhea in 5-10% of patients, and rare nausea, vomiting, or abdominal pain. Orange urine discoloration is common with entacapone but is harmless. Tolcapone was associated with 3 reported deaths from liver toxicity which prompted its removal from the market in Canada and Europe, although it has remained available in the US with the recommendation that it be used for motor fluctuations only after other treatment options have been exhausted and with monitoring of liver enzymes during the first 6 months of use. Further cases of severe hepatotoxicity have not been reported. Entacapone is not associated with hepatotoxicity. Because of slowing of dopamine metabolism, increased levodopa effects may occur such as dyskinesia, visual hallucinations, confusion, nausea, and orthostatic hypotension. This effect is more common after tolcapone than entacapone. Adverse effects are managed by lowering the levodopa dose either before or after be

ginning treatment with a COMT inhibitor.

Special problems in the treatment of advanced Parkinson’s disease

·         Motor fluctuations

Motor fluctuations refer to end of dose, wearing-off effects in which, after several years of treatment, patients with PD begin to experience gradually shorter duration improvement of motor symptoms following each dose of levodopa. This is believed to be due to a gradual decline in the number of dopamine neurons over time which causes less effective uptake and release of dopamine in the brain. This is nearly unique for the chronic use of levodopa and occurs much less frequently with chronic use of dopamine agonists. It begins with early morning bradykinesia causing slowness and stiffness on awakening in the morning after not taking levodopa since the previous evening and is later followed by a decline in duration of motor response from approximately 6-8 hours to 4 hours or less. In most cases, the decline in response occurs gradually over 15-30 minutes, sometimes accompanied by painful muscle cramps (off-period dystonia) and tingling feelings in the limbs (paresthesias). In patients with more advanced PD, the decline in response is more abrupt and causes a steeper decline in motor function. In some cases, more unpredictable “off periods” occur, which are less clearly linked to timing of medication dose and are often associated with freezing of motor function while walking.

There are several methods for treating such fluctuations. These include using sustained release formulations of levodopa, moving levodopa doses closer together, increasing the dose of levodopa, adding enzyme inhibitors to slow down dopamine metabolism such as COMT inhibitors or MAO-B inhibitors, or adding or increasing dopamine agonists. The diet should be examined to avoid taking levodopa with high protein meals which may interfere with intestinal absorption. Patients with severe wearing-off effects often go through a prolonged latency until they “turn on” after taking levodopa. This “delay to on” phenomenon can be avoided by not allowing wearing-off to occur through one or more of the medication adjustments listed above.

·         Involuntary movements

Excessive amounts of levodopa may cause involuntary movements called dyskinesias. As PD progresses dyskinesias may begin to appear at doses which initially did not cause this effect. Several types of involuntary movements are caused by levodopa, the most common of which are dyskinesias and dystonia. Dyskinesias are quick and jerky movements which involve the extremities, trunk, neck, and facial muscles. Dystonia is a slower, more prolonged and sometimes painful movement or muscle spasm involving the extremities, trunk or abdominal muscles, the neck, or face. Dopamine agonists only rarely cause involuntary movements when given alone but may potentiate the involuntary movements which are caused by levodopa.  The most common dyskinesias occur at the time of peak levodopa effect, about 30-90 minutes after a dose has been taken. When mild, they are often unnoticed by the patient but are usually evident to family members and caregivers. When more severe, they can become high velocity, large amplitude movements which are disturbing to patients and can have adverse effects on motor function, gait, and balance. They may be managed by lowering the levodopa dose, replacing a portion of the levodopa dose with a dopamine agonist, using immediate-release in place of sustained-release levodopa if dyskinesias are occurring mainly late in the day, or adding amantadine to directly reduces dyskinesia severity. Diphasic dyskinesias are more complex, occurring about 30 minutes after levodopa and again as levodopa is wearing off. The second dyskinesia phase often has a different appearance with bicycling movements of the legs which may be severe enough to force the patient to lie down. Dystonia usually occurs as levodopa is wearing off and less commonly at the time of peak levodopa effect. These are managed by avoiding wearing-off with the medication adjustments described above

Treatment of non-motor PD symptoms

In addition to the well known motor symptoms of PD, non-motor symptoms are currently attracting increased interest and concern.

• Sleep disorders are extremely common in PD; they affect 90% of patients. Poor night-time sleep and excessive daytime drowsiness are common. Possible causes include sedative effects of some antiparkinson medications such as the dopamine agonists, poor sleep hygiene, and poor sleep at night due to obstructive sleep apnea, restless legs syndrome, REM sleep behavior disorder, depression, anxiety, nocturnal stiffness, and fragmented sleep of unknown cause. Proper treatment relies on identifying the cause in a particular patient. REM sleep behavior disorder commonly precedes the onset of motor symptoms and is relieved by clonazepam taken before sleep. Sudden onset of sleep while driving (“sleep attacks”) have also been described, particularly in patients taking dopamine agonists although this is not necessarily associated with specific antiparkinson drugs.
• Fatigue is a related problem but more common in advanced PD. Treatable causes include poor sleep, depression, and bradykinesia but it may also be an independent symptom. Empiric treatment with methylphenidate, modafinil, or selegiline may be considered but the response to these is usually disappointing.
• Depression and anxiety often appear for the first time in early PD and may even be presenting symptoms. Treatment of these is important and will help patients to tolerate otherwise relatively mild motor symptoms. SSRI antidepressants are effective for both depression and anxiety and are usually well tolerated in patients with PD. Patients with PD may also exhibit apathy, with lack of motivation and emotional reactivity, in the absence of true depression. When severe enough to warrant pharmacologic intervention, this complaint may be responsive to methylphenidate.
• Psychosis and visual hallucinations occur in more advanced PD where they are usually side effects of antiparkinson drugs. They are managed by adjustment of medications or introduction of antipsychotic medications that do not exacerbate motor symptoms of PD, such as clozapine or quetiapine. Other antipsychotic drugs, all of which interfere with dopamine transmission, should be avoided in PD. This does not include antidepressants and anti-anxiety medications which may be safely used in PD and do not exacerbate parkinsonism.

 Cognitive impairment of varying severity occurs in up to one-third of patients with PD. More severe cognitive impairment or dementia must be distinguished from other causes of dementia in older patients such as Alzheimer’s disease, cerebrovascular disease, normal pressure hydrocephalus, hypothyroidism, and vitamin deficiency. When due to PD the pattern of deficits differs from Alzheimer’s disease in that frontal lobe functions such as multitasking, judgement, and personality are affected more than recent memory, language function, and spatial orientation. Treatment with cholinesterase inhibitors such as donepezil, galantamine, rivastigmine, or memantine is recommended, and are often more effective in PD than in Alzheimer’s disease. The presence of psychosis, visual hallucinations, or dementia in early PD raises the possibility of dementia with Lewy bodies.

Autonomic symptoms are not usually present in early PD, by contrast with multiple system atrophy, where they often appear before or together with onset of motor symptoms and are a major cause of difficulty. Nonetheless, proper attention should be paid to management of constipation, low blood pressure with standing (orthostatic hypotension), urinary frequency, and impotence. Constipation is managed with high fiber diet, stool softeners, and laxatives. Bladder symptoms usually require consultation with a urologist to identify the specific pattern of bladder dysfunction, to guide medication treatment, and to exclude other causes.  

·         Deep brain stimulation (DBS)

When patients fluctuate rapidly between too much levodopa effect (dyskinesias) or too little levodopa effect (the “off “ state), and this can no longer be managed with medication adjustments, deep brain stimulation (DBS) may become a consideration. DBS is contraindicated in patients who have had little or no response to levodopa. DBS is also not recommended for patients with mild symptoms and a good response to medications. Patients who have had the disease for a relatively short period of time are also not usually considered candidates for DBS. DBS has largely supplanted ablative procedures such as thalamotomy and pallidotomy which were previously done in this situation but were less effective and caused more side effects than DBS. Subthalamic nucleus or globus pallidus DBS are treatments in which electrodes are surgically implanted into the subthalamic nucleus or globus pallidus of the brain bilaterally.  Pulse generators are usually placed beneath the skin below the collar bone and are programmed externally.  The goal of surgery is to smooth the effect of medication throughout the day so that both dyskinesias and the depths of “off” time can be reduced.  After surgery, patients who have undergone subthalamic DBS are often able to reduce their levodopa dose and discontinue other antiparkinson medications.  As a result, side effects are reduced.  However, DBS is not an appropriate option for everyone with advanced PD. In order to qualify as a surgical candidate, except for tremor, patients should have been very responsive to levodopa but at a point in their disease when they are experiencing intrusive and difficult to control motor fluctuations and dyskinesias. It is not an option for patients who have never experienced a very good response to levodopa, such as patients with any form of atypical parkinsonism. Patients with cognitive deficits or patients who have experienced psychiatric symptoms in response to antiparkinson medications should be carefully evaluated with both neuropsychological testing and psychiatric evaluation before DBS is considered.

Certain motor symptoms associated with PD are poorly responsive to levodopa or other antiparkinson medications. These become much more prominent as the disease progresses and often gradually appear over several years following DBS surgery. The most common of these are motor freezing and postural instability with falls. Motor freezing refers to brief and sometimes more prolonged episodes in which, while walking, patients become unable to take another step and feel as if they are stuck to the floor. If these occur at a time when the patient is experiencing their response to levodopa (“on period freezing), they are especially difficult to correct with medications. Specially modified canes and walkers that project a red beam across their path for patients to step over, can be useful for breaking freezing episodes.  Postural instability may also worsen and resulting falls may become harder to prevent.  In this situation patients should be evaluated for walking aids and home modifications such as grab bars in the bathroom and other parts of the home.  Such interventions can help preserve a patient’s independence. 

Other surgical procedures have been used in the past and new ones are still being explored for treatment of advanced PD. Transplantation of fetal tissue containing dopamine-containing nerve cells into the motor centers of the brain in patients with advanced PD has been evaluated in two large-scale controlled trials. Unfortunately, both studies failed to demonstrate significant benefit compared to patients who underwent “sham” surgery as a control in which the skull was entered but no tissue was transplanted. In addition, some patients who received fetal tissue transplants experienced severe dyskinesias as a result of the procedure which could not be controlled by reducing their dose of levodopa. Stem cell research is currently being investigated in animal models of PD but is not undergoing clinical trials in PD patients at the present time. Implantation of growth factors and certain enzymes to enhance synthesis of brain neurotransmitters is currently undergoing early experimental investigation in patients with PD.

Table. Drug Treatments of Parkinson’s Disease

Generic Name	Trade Name	Usual Starting dose	Usual maintenance dose	Mechanism
Trihexyphenidyl	Artane	1 mg twice daily	2 mg 2-3 times daily	Anticholinergic
Benztropine	Cogentin	0.5 mg twice daily	1 to 2 mg twice daily	Anticholinergic
Amantadine	Symmetrel	100 mg twice daily	100 mg 2-3 times daily	Glutamate antagonist
Selegiline	Eldepryl	5 mg each morning	5 mg each morning	MAO B inhibitor
Zydis selegiline	Zelapar	1.25 mg daily	1.25 mg daily	MAO B inhibitor
Rasagiline	Azilect	0.5 mg each morning	1 mg each morning	MAO B inhibitor
Carbidopa/Levodopa	Sinemet	25/100 mg 3 times daily	50-200 mg to 25/250 mg 3 times daily	Dopamine precursor
Carbidopa/Levodopa sustained release	Sinemet CR	25/100 mg 3 times daily	50/200 mg 3 times daily	Dopamine precursor
Bromocriptine	Parlodel	2.5 mg daily	5 to 10 mg 4 times daily	Dopamine agonist
Pramipexole	Mirapex	0.125 mg 3 times daily	1.5 mg 3 times daily	Dopamine agonist
Ropinirole	Requip	0.25 mg 3 times daily	16-24 mg daily	Dopamine agonist
Rotigotine	Neupro	2 mg daily	2-6 mg daily	Dopamine agonist
Entacapone	Comtan	200 mg with each dose of levodopa	200 mg with each dose of levodopa	COMT inhibitor
Tolcapone	Tasmar	100 mg 3 times daily	100 to 200 mg 3 times daily	COMT inhibitor

 

 

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