Tolcapone

Definition

Parkinson's disease (PD) is a progressive movement disorder marked by tremors, 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 50,000 new cases each year. Usually beginning in a person's late 50s or early 60s, 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 of 75 and 84.

Causes & symptoms

The immediate cause of PD is the 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 as of July 2000, no clear culprit has been found. Both genetic and environmental factors are suspected. In addition to these causes, 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 as a consequence of normal decline. As of early 2000, however, no gene or toxin had been identified to explain the large number of cases of Parkinson's disease seen each year.

The identifying symptoms of PD include:

• Tremors, usually beginning in the hands, often occurring 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, occurring 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. Currently, the best treatments for PD involve the use of conventional drugs such as dopamine antagonists and levodopa. However, therapies such as acupuncture, massage, and yoga can help relieve some symptoms of the disease and loosen tight muscles. Some healthcare professionals have used herbal and dietary therapies, including amino acid supplementation, essential fatty acids (omega-3, omega-6, fish oil , and flax oil), antioxidant (carotenoids, bioflavenoids, vitamins A, C, E, selenium, and zinc) therapy, B vitamin supplementation, and calcium and magnesium supplementation, to treat PD. Anyone using these therapies in conjunction with conventional drugs should check with their doctor to avoid possible 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.

Meditation and movement therapies such as Feldenkrais, t'ai chi , qigong, and yoga regain focus.

No evidence indicates that vitamin or mineral supplements can have an 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.

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.

Practitioners of Ayurveda, or traditional Indian medicine, have prescribed mucuna seeds (Mucuna pruriens) to treat Parkinson's disease (or Kampavata) for over 4,000 years. Mucuna contains a natural form of L-dopa, a powerful anti-parkinsons drug.

Allopathic treatment

Most drugs treat the symptoms of Parkinson's disease only, although one drug, selegiline (Eldepryl), may somewhat slow the degeneration of the substantia nigra.

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 is levodopa (L-dopa). 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.

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.

As of early 2000, L-dopa had been the front line medication of choice for treating Parkinson's disease for over 30 years. However, a study published in the May 2000 issue of the New England Journal of Medicine followed 300 Parkinson's patients in locations throughout the world and found that for young patients in the early stages of the disease, treatment was more effective with a class of drugs known as 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 have been found to be more effective in the treatment of early-stage Parkinson's than L-dopa. They can cost double what levodopa does, however, they may prevent or postpone the need for expensive neurosurgery later. DAs available in the United States include bromocriptine (Permax, Parlodel), pergolide (Permax), pramipexole (Mirapex), cabergoline (Dostinex), and ropinirole (Requip). Side effects of all the DAs are similar to those of dopamine, plus confusion and hallucinations at higher doses.

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. Studies on entacapone and tolcapone, two inhibitors of another enzyme system called catechol-O-methyltransferase (COMT) suggest that they effectively treat PD symptoms with fewer motor fluctuations and decreased daily L-dopa requirements.

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.

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.

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. 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.

Expected results

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

A May 2000 study of over 8,000 Japanese-American men published in the Journal of the American Medical Association found that drinking coffee may decrease the risk of getting Parkinson's disease. The study hypothesized that caffeine may have a protective effect against nerve damage.

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.

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.

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 Alternative Medicine. Gale Group, 2001.