Update on Parkinson’s Disease
June 5, 2000
Update on Parkinson’s Disease
Author: Jean P. Hubble, MD, Associate Professor, Clinical Neurology, Madden—National Parkinson Foundation Center of Excellence, Columbus, Ohio.
Peer Reviewer: Kenneth B. Pugar, MD, Chairman, Section of Neurology, Psychiatry, and Physical Medicine, Grandview/Southview Hospital; Division Head for Neurology, Wallace-Kettering Neuroscience Institute, Kettering Medical Center; Clinical Director, Comprehensive Stroke Management Team, Kettering Medical Center, Kettering, Ohio.
Editor’s Note—There is growing awareness and interest in Parkinson’s disease in the medical community and general public. This stems from remarkable achievements in our understanding of this illness and its treatments. Also playing a role is the media attention directed to Parkinson’s disease because of public figures who have disclosed their diagnosis. Finally, there is the growing realization that this and other age-related noncurable ailments will constitute a large socioeconomic burden for the foreseeable future.
Clinical Presentation and Diagnosis
Diagnosis
The term "parkinsonism" refers to a symptom complex consisting of two or more of the following: resting tremor, rigidity, or bradykinesia (slowed movement) (see Table 1). Whereas parkinsonism can occur as part of various disorders of the central nervous system (CNS), it most commonly takes the form of idiopathic Parkinson’s disease. Parkinson’s disease is a progressive disabling condition affecting approximately 1% of the U.S. population older than 60 years of age.
| Table 1. Clinical Features of Parkinsonism |
| • Resting (or postural) tremor |
| • Rigidity |
| • Bradykinesia (slowed movement) |
Many conditions can mimic Parkinson’s disease (see Table 2). A careful history and thorough neurological examination usually establish the diagnosis. Testing, including blood work and brain imaging, may be warranted in those instances when unusual signs or symptoms exist.
| Table 2. Differential Diagnosis of Parkinsonism and Tremor |
| Idiopathic Typical Parkinson's Disease |
| • Rest tremor is common |
| • Begins with asymmetric limb involvement |
| • Responds to levodopa (and related) drugs |
| Atypical Parkinsonism |
| • Example: progressive supranuclear palsy |
| • Advances more quickly |
| • Truncal rigidity, falling, and other neurological symptoms are common |
| • Fails to respond to levodopa (and related) drugs |
| Secondary Parkinsonism |
| • Symptoms are attributable to a specific cause |
| • A common cause is chronic exposure to dopamine-blocking drugs (e.g., haloperidol) |
| • Symptoms will usually resolve if the precipitating cause can be remedied (e.g., discontinuation of the offending drug) |
| Essential Tremor |
| • Most common form of tremor |
| • Muscle rigidity and bradykinesia are absent |
| • Family history is often positive |
| • Often responds to ethanol |
| • Tremor is usually accentuated with sustained posture (e.g., outstretched arms) |
Symptoms of Parkinson’s disease usually begin during the sixth decade of life or later. Motor signs and symptoms usually begin on one side of the body and progress to involve the opposite side. Although resting tremor is frequently considered the most obvious feature of Parkinson’s disease, its presence does not appear to be essential to the diagnosis. Thus, stiffness and discomfort in a single limb may be the initial presentation. Other early features of the disease may include small shaky handwriting (micrographia), voice changes (loss of volume, stuttering), decrease in facial expression, stooped posture, and slowed shuffling gait.
Nonmotor Features
Psychological disturbances are common in Parkinson’s disease and may include alteration in effect, personality, and cognition. Significant cognitive impairment (dementia) can occur, particularly in aged patients or in patients with advanced disease. Depression is also common. Other nonmotor features may include sensory disturbances, loss of the sense of smell, skin changes, and autonomic dysfunction (constipation, sweat abnormalities, and orthostatic hypotension).
Pharmacotherapy
Levodopa
Levodopa is often called the "gold standard" of the treatment of Parkinson’s disease because it typically produces a prompt and dramatic alleviation of motor signs and symptoms. A total absence of response to levodopa at high doses (e.g., 1000-2000 mg of levodopa per day given in conjunction with carbidopa) argues against the diagnosis of Parkinson’s disease. Not all the signs and symptoms of Parkinson’s disease respond equally to levodopa. Rigidity and bradykinesia tend to respond best. Tremor is variably affected. It is usually suggested that levodopa therapy be started when the illness is clearly resulting in disability or limitations in the individual’s day-to-day functioning. Most of the symptoms of Parkinson’s disease are due to the dopamine depletion within the striatum of the brain. Dopamine is not an effective oral remedy for Parkinson’s disease as it is not well absorbed in the gut and it does not readily enter the brain from the bloodstream. Levodopa is a precursor to dopamine. The therapeutic effect of levodopa depends upon its passage from the bloodstream into the brain, where it is decarboxylated into dopamine and exerts its symptomatic benefit in Parkinson’s disease.
Acute side effects from levodopa constituted a major problem when the drug was first introduced in the late 1960s (see Table 3). Large amounts of levodopa (6-8 g/d) were required to achieve a good response (i.e., improved mobility). These high doses were needed because more than 90% of orally administered levodopa is systemically metabolized before it can reach the brain. Metabolized levodopa is wasted and has no therapeutic benefit in Parkinson’s disease. The aromatic amino acid decarboxylase pathway is the major peripheral levodopa metabolic pathway, resulting in accumulation of systemically circulating dopamine. The systemic side effects of dopamine can include incapacitating nausea and vomiting and orthostatic hypotension. Decarboxylase inhibiting drugs are coadministered with levodopa in order to limit systemic metabolism and peripheral dopaminergic side effects. Carbidopa is the decarboxylase inhibitor available in the United States. The addition of carbidopa to each dose of levodopa permits more levodopa to enter the brain and usually prevents side effects such as nausea. Virtually all levodopa prescribed in the United States is given in a tablet form that contains levodopa and carbidopa. Various doses of carbidopa/levodopa are available in both brand name and generic products. Two common brand names for carbidopa/levodopa are Sinemet and Atamet.
| Table 3. Possible Side Effects of Levodopa |
| • Nausea/vomiting |
| • Sedation |
| • Hallucinations, psychosis |
| • Dyskinesia (involuntary wiggly movements) |
| • Nonsustained or unpredictable response (motor fluctuations) |
Other potential side effects of levodopa include hallucinations and psychosis. These reactions are more common in patients of advanced age and those with underlying cognitive impairment. Visual hallucinations are the most common form of levodopa-induced hallucinations. These hallucinations frequently consist of nonthreatening people or animals; insight initially may be retained. Such hallucinations may signal incipient psychosis. Lowering the dosage of levodopa can be tried but is often a problem because it results in a decline in motor function. Another approach to the treatment of levodopa-induced hallucinations is the use of antipsychotic medications. Because these antipsychotic agents block dopamine receptors in the brain, some will cause worsening of the motor features of Parkinson’s disease. More recently, the antipsychotic compound clozapine has been successfully used for levodopa-induced psychosis.1 This drug does not worsen Parkinson’s disease symptoms, but frequent blood counts are needed because of a rare blood disorder (agranulocytosis) associated with its use. Newer antipsychotic drugs (e.g., quetiapine) may also be used to safely control drug-induced psychosis in Parkinson’s disease.
The most frequent and troublesome problem associated with levodopa use is motor fluctuations. Response to levodopa is usually stable for the first several years. Thereafter, the length of benefit from a single dose tends to decline ("wearing off"), peak-dose dyskinesia (involuntary wiggly movements) may occur, and overall predictable efficacy lessens. Patients’ motor status may wax and wane throughout the day in relation to their levodopa dosing. Some patients may have random, abrupt motor fluctuations termed on-off phenomena. Levodopa can be given in multiple small doses in an attempt to alleviate fluctuations. However, smaller doses may not control symptoms, and larger total daily levodopa dose may result in side effects. Alternative strategies include switching to controlled-release carbidopa/levodopa or adding adjunctive drugs, as described below.
Carbidopa/Levodopa Preparations
To minimize peripheral side effects and enhance penetration into the brain, levodopa is usually administered with carbidopa, an enzyme decarboxylase inhibitor. Available formulations of carbidopa/levodopa denote the amount of carbidopa (mg) in the numerator and the amount of levodopa (mg) in the denominator as follows: standard formulation 10/100, 25/100, 25/250, and controlled release 25/100, 50/200. A reasonable starting dosage of standard formulation carbidopa/levodopa is one 25/100 tablet taken three times per day. The medicine is usually best given during the daytime, and it should be taken without food when possible (30 minutes before or 1 hour after meals). The drug dosage and timing of administration can be adjusted based on efficacy and side effects. Additional carbidopa (Lodosyn) can be given in conjunction with carbidopa/levodopa if nausea is a dose-limiting side effect.
Controlled-Release Carbidopa/Levodopa
Controlled-release carbidopa/levodopa can be used to attempt to control motor fluctuations.2 This formulation provides longer duration levodopa blood levels and may reduce motor fluctuations. Less frequent dosing of the controlled-release levodopa is needed, as compared with the conventional standard formulation (reduction in the number of doses by one-third to one-half). Because of altered bioavailability, a greater total amount of daily levodopa may need to be given in the form of controlled-release carbidopa/levodopa.
The slower onset of clinical effect of controlled-release carbidopa/levodopa may actually be experienced as disadvantageous by some individuals (i.e., patients may prefer the brisk and more pronounced effects of the standard formulation particularly when first arising in the morning). In these instances, additional standard formulation carbidopa/levodopa can be given along with the controlled-release tablets to provide a more rapid onset of therapeutic effect.
In addition to its role in treatment of advancing Parkinson’s disease, controlled-release carbidopa/levodopa can be used when levodopa therapy is first instituted—1-2 tablets daily may be sufficient. Early initiation of controlled-release carbidopa/levodopa does not seem to delay onset of motor fluctuations.3 As with all antiparkinsonian drugs, successful use of the controlled-release carbidopa/levodopa requires careful adjustment of dose depending on the patient’s clinical status and levodopa tolerance.
Dopamine Receptor Agonists
Dopamine agonists can provide symptomatic relief in Parkinson’s disease (see Table 4). The drugs act independently of levodopa by directly activating dopamine receptors.4 Bromocriptine (Parlodel) and pergolide (Permax) are ergoline compounds that have been available for use in Parkinson’s disease for several years.5 These two compounds have been most widely tested and used as adjunctive therapies along with levodopa in patients with more advanced disease and motor fluctuations.
| Table 4. Dopamine Agonists Used to Treat Parkinson's Disease |
| • Bromocriptine (Parlodel) |
| • Pergolide (Permax) |
| • Pramipexole (Mirapex) |
| • Ropinirole (Requip) |
Two newer dopamine agonists are now available in the United States.6-9 These compounds, pramipexole (Mirapex) and ropinirole (Requip), received approval from the Food & Drug Administration in the United States for use in both early and advanced Parkinson’s disease. In clinical trials, approximately 30-40% of patients with mild to moderate disease have received sufficient benefit from pramipexole or ropinirole so as to be able to postpone levodopa therapy for up to three or more years. The dopamine agonist ropinirole has been compared to carbidopa/levodopa in a five-year, double-blind study.10 By the end of the study, about two-thirds of the subjects assigned to the ropinirole group were also receiving open-label supplemental carbidopa/levodopa because of progression of motor symptoms. Dyskinesias (a form of motor fluctuations) developed in nearly half of those assigned to start with carbidopa/levodopa therapy but in only 20% of those initially assigned to the ropinirole group. Thus, the relative early use of dopamine agonists can postpone initiation of levodopa therapy and therefore may delay the onset of levodopa complications.
All the dopamine agonists currently available in the United States have been approved for use in more advanced Parkinson’s disease as adjunctive therapy used along with levodopa. Large-scale, controlled comparison studies of the dopamine agonists are lacking. There is no clear evidence to suggest that one drug is more effective or safer than the other drug. Potential side effects of dopamine agonists include: nausea, vomiting, hallucinations, sedation, insomnia, worsening of dyskinesia, and low blood pressure. Rarely has this class of drugs been associated with fibrosis or scarring of the membranous lining of internal organs or body cavities (e.g., pleural fibrosis).
Successful use of these drugs depends upon the introduction of a small dose, with incremental dose escalation every 4-7 days. Dose escalation schedules are provided by the drugs’ manufacturers. Based on clinical experience, target dosing ranges are provided: bromocriptine: 2.5-5.0 mg t.i.d. (or more frequently); pergolide 0.25-1.0 mg t.i.d.; pramipexole: 0.5-1.5 mg t.i.d.; ropinirole: 3-8 mg t.i.d. There is growing use of this class of drug as monotherapy in relatively early Parkinson’s disease in an effort to postpone the introduction of levodopa with the hope of postponing levodopa complications such as motor fluctuations.11
Selegiline
Selegiline blocks a brain chemical called monoamine oxidase type B. Selegiline when used at the recommended dose (10 mg daily) does not react with red wine and smoked meats and cheeses. No dietary restrictions are required with selegiline, which is in contrast to the older types of monoamine oxidase inhibitors used to treat depression. Selegiline’s effects in the brain are complex; thus, its potential effects in Parkinson’s disease may be multiple. Selegiline provides modest symptomatic relief and is approved as an adjunctive therapy with levodopa in patients with moderate to advanced disease.12 In addition, clinical trials with selegiline in early untreated Parkinson’s disease indicate that its use permits postponement of levodopa therapy; thus, it can be considered as monotherapy for early disease.13
For patients who are untreated or who are taking small doses of levodopa, selegiline therapy can usually begin at 5 mg twice daily at breakfast and lunch. Dosing late in the day is best avoided because it can produce or worsen insomnia. Other potential adverse effects include headache, confusion, hallucinations, dizziness, exacerbation of peptic ulcer disease, dyskinesia, nausea, and postural hypotension. Some of these side effects may be more common when given in conjunction with other antiparkinson medications. Similar to other monoamine oxidase inhibitors, selegiline can produce serious adverse reactions when taken with the pain reliever meperidine (Demerol). Selegiline should be used cautiously, if at all, with antidepressant drugs because of the potential for drug-drug interactions.
Other Therapies
Amantadine and anticholinergic drugs can also provide relief of symptoms for some patients with Parkinson’s disease.14 The efficacy of these drugs is usually modest compared with that of levodopa. The drugs typically may be given as adjunctive therapy with levodopa or as monotherapy to patients who are intolerant of other drugs or who have mild early disease. Anticholinergic drugs are reputed to be especially useful in reducing tremor while amantadine has recently been demonstrated to have antidyskinetic effects.15
Not all of the clinical problems associated with Parkinson’s disease can be remedied with antiparkinsonian medications. Urinary difficulties, constipation, hypotension, skin disorders, anxiety, and depression are examples of nonmotor manifestations that may occur. Medications directly targeting these symptoms can be used (e.g., antidepressants can be prescribed). No specific antidepressant has been demonstrated to be uniquely safe and effective for depression in Parkinson’s disease.16 Other nonpharmacologic therapies can often be of help, especially for more advanced cases. These include physical, occupational, and speech therapy. The home can be outfitted with safety equipment (e.g., handrails, elevated toilet seat) as needed.
The nonambulatory patient with advanced Parkinson’s disease is susceptible to all of the medical complications associated with immobility, including pneumonia, urosepsis, and venous thrombosis with pulmonary embolization. The ongoing care of such patients is complex and usually requires the assistance of a general medical practitioner. Availing the patient and family of social assistance may also be valuable in advanced cases. Lay support groups can serve as a remarkable resource throughout all stages of the illness. Such organizations are able to provide educational materials, plan social meetings, offer caregiver support and respite, develop exercise programs, and sponsor research activities.
COMT Inhibition
The catechol-O-methyl transferase (COMT) inhibitors comprise a novel class of drugs recently introduced for the treatment of Parkinson’s disease (see Table 5). These drugs reduce the systematic metabolism of levodopa, thereby extending the duration of benefit of orally administered carbidopa/levodopa. The COMT inhibitors are adjunctive drugs exerting no clinical effect when used alone. COMT inhibitor drugs can precipitate or worsen levodopa-related side effects such as dyskinesia or hallucinations. Such side effects can usually be managed by reducing the dose of levodopa. These compounds can cause a harmless reddish-brown urine discoloration.
| Table 5. COMT Inhibition as an Augment to Levodopa Therapy |
| • Extends the duration of action of each dose of levodopa |
| • May cause levodopa-related side effects |
| • May cause harmless urine discoloration |
| • Entacapone (Comtan): 200 mg with levodopa dose (maximum of 8 tablets per day) |
| • Tolcapone (Tasmar): see revised manufacturer's labeling due to potential hepatotoxicity |
Entacapone (Comtan) has recently been approved for use in the United States. Entacapone is indicated for the treatment of "wearing off" experienced at the end of carbidopa/levodopa dosing.17-18 Patients with "wearing off" may find that the therapeutic effects of a dose of carbidopa/levodopa lasts only 1-3 hours and then tremor, slowness, and poor mobility re-emerge. Studies have shown that the addition of entacapone can provide 1-1½ hours of improved mobility per day in such patients. Suggested dosing for entacapone is 200 mg tablets: one tablet with each dose of carbidopa/levodopa for a maximum of eight tablets per day.
Tolcapone (Tasmar) is also a COMT inhibitor.19 It has a longer half-life compared to entacapone. Tolcapone has been associated with diarrhea, elevated liver function tests, and potential hepatotoxicity (liver damage). Frequent liver function blood test monitoring is recommended with the use of tolcapone. Because of the risk of hepatotoxicity, tolcapone is now recommended only for patients with motor fluctuations who are not candidates for other therapies. Prescribing physicians need to be fully aware of these safety issues. Patients need to be informed of potential risks and a written consent document is recommended. Suggested dosing of tolcapone is 100 or 200 mg three times daily at approximate six-hour intervals.
Surgeries for Parkinson’s Disease
There are both conventional and investigational surgical treatment options for Parkinson’s disease. Pallidotomy is an established stereotactic neurosurgical procedure that involves selective destruction of a part of the globus pallidus of the brain.20-21 Although the surgery is not considered experimental, some issues regarding its use remain uncertain. Results published to date suggest that the procedure is most helpful in reducing levodopa-induced dyskinesia but its beneficial effects on other features of Parkinson’s disease may be less dramatic. Experience regarding the long-term effects of pallidotomy is limited. Proper patient selection appears important. Some patients, including the aged or those with dementia, may be at higher risk for poor outcome and complications.
Deep brain stimulation (DBS) is a novel therapy for the treatment of Parkinson’s disease. DBS involves the stereotactic implantation of an electrical lead within the brain; high-frequency stimulation is then delivered to the targeted brain region with the use of an implanted pulse generator analogous to a cardiac pacer device. The ventral intermediate nucleus of the thalamus is targeted to provide tremor control in Parkinson’s disease and other tremor disorders.22-23 Alternatively, the stimulator lead tip can be implanted in the globus pallidus or subthalamic nucleus to alleviate other features of Parkinson’s disease, including rigidity, bradykinesia, tremor, and drug-induced dyskinesia.24-25 Thus, thalamic DBS is analogous in its effect to the older lesion thalamotomy, whereas pallidal or subthalamic DBS is analogous to pallidotomy. The putative advantages of DBS over lesion surgery include its nondestructive nature and the capability to adjust stimulation parameters, thereby improving symptomatic benefit or lessening side effects postoperatively. Thalamic DBS for disabling parkinsonian tremor has been approved for use in the United States under the brand name Activa Tremor Control Therapy. Other uses of DBS are being developed.
Investigational Therapies
Other investigational therapies for Parkinson’s disease that require surgical intervention include brain cell transplantation and direct instillation of neurotrophic factor in the brain.26-27 Also under study are antiparkinsonian compounds that can be administered by skin patch, injection, or via rapidly dissolving tablets on or under the tongue. New types of drugs that differ from the mechanism of action of levodopa and related dopaminergic compounds are being tested. It is hoped that these new strategies may offer the means to halt or delay this degenerative disease.
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