Tolcapone

Definition

Parkinson's disease (PD) is a progressive movement disorder marked by tremor, rigidity, slow movements (bradykinesia), and postural instability. It occurs when, for unknown reasons, cells in one of the movement-control centers of the brain begin to die.

Description

PD affects approximately 500,000 people in the United States, both men and women, with as many as fifty thousand new cases each year. Usually beginning in a person's late fifties or early sixties, it causes a progressive decline in movement control, affecting the ability to control initiation, speed, and smoothness of motion. Symptoms of PD are seen in up to 15% of those between the ages 65-74, and almost 30% of those between the ages 75-84.

Causes & symptoms

Causes

The immediate cause of PD is degeneration of brain cells in the area known as the substantia nigra, one of the movement control centers of the brain. Damage to this area leads to the cluster of symptoms known as "parkinsonism." In PD, degenerating brain cells contain Lewy bodies, which help identify the disease. The cell death leading to parkinsonism may be caused by a number of conditions, including infection, trauma, and poisoning. Some drugs given for psychosis, such as haloperidol (Haldol) or chlorpromazine (thorazine), may cause parkinsonism. When no cause for nigral cell degeneration can be found, the disorder is called idiopathic parkinsonism, or Parkinson's disease. Parkinsonism may be seen in other degenerative conditions, known as the "parkinsonism plus" syndromes, such as progressive supranuclear palsy.

The substantia nigra, or "black substance," is one of the principal movement control centers in the brain. By releasing the neurotransmitter known as dopamine, it helps to refine movement patterns throughout the body. The dopamine released by nerve cells of the substantia nigra stimulates another brain region, the corpus striatum. Without enough dopamine, the corpus striatum cannot control its targets, and so on down the line. Ultimately, the movement patterns of walking, writing, reaching for objects, and other basic programs cannot operate properly, and the symptoms of parkinsonism are the result.

Much research has gone into identifying the cause of PD, but to date no culprit has been found. While both genetic and environmental factors have been investigated, no clear candidate has emerged. There are some known toxins that can cause parkinsonism, most notoriously a chemical called MPTP, found as an impurity in some illegal drugs. Parkinsonian symptoms appear within hours of ingestion, and are permanent. MPTP may exert its effects through generation of toxic molecular fragments called free radicals, and reducing free radicals has been a target of several experimental treatments for PD using antioxidants.

It is possible that early exposure to some as-yet-unidentified environmental toxin or virus leads to undetected nigral cell death, and that PD then becomes manifest as normal age-related decline brings the number of functioning nigral cells below the threshold needed for normal movement. It is also possible that, for genetic reasons, some people are simply born with fewer cells in their substantia nigra than others, and they develop PD again as a consequence of normal decline. As of 1998, however, no gene or toxin had been identified to explain the large number of cases of Parkinson's disease seen each year.

Symptoms

The identifying symptoms of PD include:

• Tremors, usually beginning in the hands, often occuring on one side before the other. The classic tremor of PD is called a "pill-rolling tremor," because the movement resembles rolling a pill between the thumb and forefinger. This tremor occurs at a frequency of about three per second.
• Slow movements (bradykinesia) occur, which may involve slowing down or stopping in the middle of familiar tasks such as walking, eating, or shaving. This may include freezing in place during movements (akinesia).
• Muscle rigidity or stiffness, occuring with jerky movements replacing smooth motion.
• Postural instability or balance difficulty occurs. This may lead to a rapid, shuffling gait (festination) to prevent falling.
• In most cases, there is a "masked face," with little facial expression and decreased eye-blinking.

In addition, a wide range of other symptoms may often be seen, some beginning earlier than others:

• Depression
• Speech changes, including rapid speech without inflection changes
• Problems with sleep, including restlessness and nightmares
• Emotional changes, including fear, irritability, and insecurity
• Incontinence
• Constipation
• Handwriting changes, with letters becoming smaller across the page (micrographia)
• Progressive problems with intellectual function (dementia).

Diagnosis

The diagnosis of Parkinson's disease involves a careful medical history and a neurological exam to look for characteristic symptoms. There are no definitive tests for PD, although a variety of lab tests may be done to rule out other causes of symptoms, especially if only some of the identifying symptoms are present. Tests for other causes of parkinsonism may include brain scans, blood tests, lumbar puncture, and x rays.

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 the degeneration of the substantia nigra somewhat.

Exercise, nutrition, and physical therapy

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 (which are discussed further in the Drugs section). 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 their improvement of 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.

Drugs

The pharmacological treatment of Parkinson's 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 the use of 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.

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.

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 a dose 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 reach the market before the turn of the century, 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 which also stimulate these receptors 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 ropinirole (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.

Dopamine and acetylcholine normally counteract one another's effects in the brain. Anticholinergics maintain this balance as dopamine levels fall. 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 tremors. Trihexyphenidyl (Artane) is the drug most commonly prescribed.

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.

Surgery

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 places 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.

Alternative treatment

Currently, the best treatments for PD involve the use of conventional drugs such as levodopa. Alternative therapies, including acupuncture, massage and yoga, can help relieve some symptoms of the disease and loosen tight muscles. Alternative practitioners have also applied herbal and dietary therapies, including amino acid supplementation, antioxidant (vitamins A, C, E, selenium, and zinc) therapy, B vitamin supplementation, and calcium and magnesium supplementation, to the treatment of PD. Anyone using these therapies in conjunction with conventional drugs should check with their doctor to avoid the possibility of adverse interactions. For example, vitamin B₆ (either as a supplement or from foods such as whole grains, bananas, beef, fish, liver, potatoes) can interfere with the action of L-dopa when the drug is taken without carbidopa.

Prognosis

Despite medical treatment, the symptoms of Parkinson's disease worsen over time, and become less responsive to drug therapy. Late-stage psychiatric symptoms are often the most troubling, including difficulty sleeping, nightmares, intellectual impairment (dementia), hallucinations, and loss of contact with reality (psychosis).

Prevention

There is no known way to prevent Parkinson's disease.

Key Terms

AADC inhibitors

Drugs that block the amino acid decarboxylase; one type of enzyme that breaks down dopamine. Also called DC inhibitors, they include carbidopa and benserazide.

Akinesia

A loss of the ability to move; freezing in place.

Bradykinesia

Extremely slow movement.

COMT inhibitors

Drugs that block catechol-O-methyltransferase, an enzyme that breaks down dopamine. COMT inhibitors include entacapone and tolcapone.

Dopamine

A chemical in the brain (neurotransmitter) that helps send signals that control movement.

Dyskinesia

An abnormal involuntary movement. Dyskinesias are common late in PD as L-dopa therapy becomes less effective.

MAO-B inhibitors

Inhibitors of the enzyme monoamine oxidase B. MAO-B helps break down dopamine; inhibiting it prolongs the action of dopamine in the brain. Selegiline is an MAO-B inhibitor.

Orthostatic hypotension

A sudden decrease in blood pressure upon sitting up or standing. May be a side effect of several types of drugs.

Substantia nigra

One of the movement control centers of the brain.

Further Reading

For Your Information

Books

• Biziere, Kathleen, and Matthias Kurth. Living With Parkinson's Disease. New York: Demos Vermande, 1997.

  Periodicals

• An Algorithm for the Management of Parkinson's Disease. Neurology 44/supplement 10 (December 1994): 12. http://neuro-chief-e.mgh.harvard.edu/parkinsonsweb/Main/Drugs/ManPark1.html.

  Organizations

• National Parkinson Foundation. 1501 NW Ninth Ave., Bob Hope Road, Miami, FL 33136. http://www.parkinson.org.
• Parkinson's Disease Foundation. 710 West 168th St. New York, NY 10032. (800) 457-6676. http://www.apdaparkinson.com.
• Worldwide Education and Awareness for Movement Disorders (WE MOVE). Mt. Sinai Medical Center, 1 Gustave Levy Place New York, NY 10029. (800) 437-MOV2. http://www.wemove.org.

  Other

• AWAKENINGS. http://www.parkinsonsdisease.com.

Gale Encyclopedia of Medicine. Gale Research, 1999.