Parkinson's Disease: Treatment

There is no cure for Parkinson's disease. Most drugs treat the symptoms of the disease only, although one drug, selegiline (Eldepryl), may slow degeneration of the substantia nigra.

Regular, moderate exercise has been shown to improve motor function without an increase in medication for a person with PD. Exercise helps maintain range of motion in stiff muscles, improve circulation, and stimulate appetite. An exercise program designed by a physical therapist has the best chance of meeting the specific needs of the person with PD. A physical therapist may also suggest strategies for balance compensation and techniques to stimulate movement during slowdowns or freezes.

Good nutrition is important to maintenance of general health. A person with PD may lose some interest in food, especially if depressed, and may have nausea from the disease or from medications, especially those known as dopamine agonists. Slow movements may make it difficult to eat quickly, and delayed gastric emptying may lead to a feeling of fullness without having eaten much. Increasing fiber in the diet can improve constipation, soft foods can reduce the amount of needed chewing, and a prokinetic drug such as cisapride (Propulsid) can increase the movement of food through the digestive system.

People with PD may need to limit the amount of protein in their diets. The main drug used to treat PD, L-dopa, is an amino acid, and is absorbed by the digestive system by the same transporters that pick up other amino acids broken down from proteins in the diet. Limiting protein, under the direction of the physician or a nutritionist, can improve the absorption of L-dopa.

No evidence indicates that vitamin or mineral supplements can have any effect on the disease other than in the improvement of the patient's general health. No antioxidants used to date have shown promise as a treatment except for selegiline, an MAO-B inhibitor which is discussed in the Drugs section. A large, carefully controlled study of vitamin E demonstrated that it could not halt disease progression.

The pharmacological treatment of Parkinson disease is complex. While there are a large number of drugs that can be effective, their effectiveness varies with the patient, disease progression, and the length of time the drug has been used. Dose-related side effects may preclude using the most effective dose, or require the introduction of a new drug to counteract them. There are five classes of drugs currently used to treat PD.

DRUGS THAT REPLACE DOPAMINE. One drug that helps replace dopamine, levodopa (L-dopa), is the single most effective treatment for the symptoms of PD. L-dopa is a derivative of dopamine, and is converted into dopamine by the brain. It may be started when symptoms begin, or when they become serious enough to interfere with work or daily living.

L-dopa therapy usually remains effective for five years or longer. Following this, many patients develop motor fluctuations, including peak-dose "dyskinesias" (abnormal movements such as tics, twisting, or restlessness), rapid loss of response after dosing (known as the "on-off" phenomenon), and unpredictable drug response. Higher doses are usually tried, but may lead to an increase in dyskinesias. In addition, side effects of L-dopa include nausea and vomiting, and low blood pressure upon standing (orthostatic hypotension), which can cause dizziness. These effects usually lessen after several weeks of therapy.

ENZYME INHIBITORS. Dopamine is broken down by several enzyme systems in the brain and elsewhere in the body, and blocking these enzymes is a key strategy to prolonging the effect of dopamine. The two most commonly prescribed forms of L-dopa contain a drug to inhibit the amino acid decarboxylase (an AADC inhibitor), one type of enzyme that breaks down dopamine. These combination drugs are Sinemet (L-dopa plus carbidopa) and Madopar (L-dopa plus benzaseride). Controlled-release formulations also aid in prolonging the effective interval of an L-dopa dose.

The enzyme monoamine oxidase B (MAO-B) inhibitor selegiline may be given as add-on therapy for L-dopa. Research indicates selegiline may have a neuroprotective effect, sparing nigral cells from damage by free radicals. Because of this, and the fact that it has few side effects, it is also frequently prescribed early in the disease before L-dopa is begun. Entacapone and tolcapone, two inhibitors of another enzyme system called catechol-O-methyltransferase (COMT), may soon reach the market as early studies suggest that they effectively treat PD symptoms with fewer motor fluctuations and decreased daily L-dopa requirements.

DOPAMINE AGONISTS. Dopamine works by stimulating receptors on the surface of corpus striatum cells. Drugs that also stimulate these cells are called dopamine agonists, or DAs. DAs may be used before L-dopa therapy, or added on to avoid requirements for higher L-dopa doses late in the disease. DAs available in the United States as of early 1998, include bromocriptine (Permax, Parlodel), pergolide (Permax), and pramipexole (Mirapex). Two more, cabergoline (Dostinex) and ropini-role (Requip), are expected to be approved soon. Other dopamine agonists in use elsewhere include lisuride (Dopergine) and apomorphine. Side effects of all the DAs are similar to those of dopamine, plus confusion and hallucinations at higher doses.

ANTICHOLINERGIC DRUGS. Anticholinergics maintain dopamine balance as levels decrease. However, the side effects of anticholinergics (dry mouth, constipation, confusion, and blurred vision) are usually too severe in older patients or in patients with dementia. In addition, anticholinergics rarely work for very long. They are often prescribed for younger patients who have predominant shaking. Trihexyphenidyl (Artane) is the drug most commonly prescribed.

DRUGS WHOSE MODE OF ACTION IS UNCERTAIN. Amantadine (Symmetrel) is sometimes used as an early therapy before L-dopa is begun, and as an add-on later in the disease. Its anti-parkinsonian effects are mild, and are not seen in many patients. Clozapine (Clozaril) is effective especially against psychiatric symptoms of late PD, including psychosis and hallucinations.

Two surgical procedures are used for treatment of PD that cannot be controlled adequately with drug therapy. In PD, a brain structure called the globus pallidus (GPi) receives excess stimulation from the corpus striatum. In a pallidotomy, the GPi is destroyed by heat, delivered by long thin needles inserted under anesthesia. Electrical stimulation of the GPi is another way to reduce its action. In this procedure, fine electrodes are inserted to deliver the stimulation, which may be adjusted or turned off as the response dictates. Other regions of the brain may also be stimulated by electrodes inserted elsewhere. In most patients, these procedures lead to significant improvement for some motor symptoms, including peak-dose dyskinesias. This allows the patient to receive more L-dopa, since these dyskinesias are usually what causes an upper limit on the L-dopa dose.

A third procedure, transplant of fetal nigral cells, is still highly experimental. Its benefits to date have been modest, although improvements in technique and patient selection are likely to change that.

— Laith Farid Gulli, MD