Parkinson's disease (PD) is a progressive degenerative brain disorder marked by tremors, rigidity, slow movements (bradykinesia), and posture instability. It occurs when cells in one of the movement-control centers of the brain begin to die for unknown reasons. PD was first described by British physician James Parkinson in the early 1817.
About 1% of people over age 60 develop PD with an approximate prevalence of 120 cases per 100,000 population. The likelihood of developing PD increases with age with an estimated 15% of those ages 65–74, and almost 30% of those ages 75–84 showing symptoms. Because PD is difficult to diagnose accurately, these numbers are only estimates. PD is about 1.5 times more common in men than in women. Average age of onset is 60 years; the disease is uncommon in people under age 40.
Usually beginning in a person's late fifties or early sixties, Parkinson's disease causes a progressive decline in movement control, affecting the ability to control initiation, speed, and smoothness of motion. Many cases of PD are sporadic. This means that there is a spontaneous and permanent change in nucleotide sequences (the building blocks of genes). Sporadic mutations also involve unknown environmental factors in combination with genetic defects. The abnormal gene (mutated gene) will form an altered end product or protein. This will cause abnormalities in specific areas in the body where the protein is used. Some evidence suggests that there is also a genetic component that predisposes some people to develop the disease when exposed to certain (as yet undiscovered) environmental factors. Recent research has linked PD with a gene that codes for a protein called alpha-synuclein. Further research is attempting to fully understand the relationship with this protein and nerve cell degeneration.
Age is the greatest risk factor for developing PD. Gender also is a risk factor, as men are more likely to be diagnosed with the disease. Family history can increase risk; people with a first-degree relative (parent, sibling, child) with PD have double the chance of developing the disease compared to people without PD in the immediate family.
Smoking tobacco has consistently been shown to protect against the development of PD as has caffeine consumption. However, other health risks of smoking far outweigh the potential protective effect.
Causes and symptoms
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 are not found in healthy brain cells and which help to 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, Largactil), 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 dopamine, it helps to refine movement patterns throughout the body. The dopamine released by nerve cells of 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.
Some known toxins 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 Page 3921 | Top of Articlefragments 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-yetunidentified environmental toxin or virus leads to undetected nigral cell death, and PD then manifests 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.
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 (reported in about half of all individuals with PD)
- speech changes, including rapid speech without inflection changes
- problems with sleep, including restlessness and nightmares
- emotional changes, including fear, irritability, and insecurity
- handwriting changes, with letters becoming smaller across the page (micrographia)
- progressive problems with intellectual function (dementia)
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.
There is no cure for Parkinson's disease. Treatment can be complicated and is based on the individual's age, level of impairment, cognitive function and response to treatment.
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 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 Page 3922 | Top of Articlein 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 that is discussed below. A large, carefully controlled study of vitamin E demonstrated that it could not halt disease progression. However, in a preliminary study, the antioxidant co-enzyme Q10 appeared to slow the progression of PD. Co-enzyme Q10 remains under investigation.
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 using the most effective dose, or require the introduction of a new drug to counteract them. Response to drug therapy is monitored and drugs may be adjusted in an attempt to find a treatment regimen that provides the most benefits with the fewest side effects. Research is ongoing in an effort to find drugs to treat PD. Individuals should consult their doctor about advances in drug therapy and clinical trials underway to test new PD drugs. There are six 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 may be tried, but often 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 may 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 and Parcopa (Ldopa 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 (Eldepryl) may be given as add-on therapy for L-dopa. Selegiline appears to 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 frequently prescribed early in the disease before L-dopa is begun. Rasagiline (Azilect) is a secondgeneration MAO-B inhibitor with fewer potential side Page 3923 | Top of Articleeffects than selegiline. Entacapone (Comtan) and tolcapone (Tasmar), two inhibitors of another enzyme system called catechol-o-methyl transferase (COMT) are also available to treat PD symptoms with fewer motor fluctuations and decreased daily L-dopa requirements. When breakthrough symptoms appear, adding safinamide (Xadago) to the medication regime can reduce symptoms or lengthen the symptom-free timeframe.
CHOLINESTERASE INHIBITORS. The cholinesterase inhibitor Exelon (rivastigmine) both as a tablet an a transdermal patch is used to treat dementia in mild to moderate PD.
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 are often the first-line treatment for Parkinson's symptoms as they do not manifest the same long-term side effects of L-dopa unless higher doses are necessary. 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 include Apomorphine (Apokyn), a shortacting DA, bromocriptine (Parlodel), ropinirole (Requip), rotigotine (Neupro), and pramipexole (Mirapex).
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. Also, gene therapy is showing promise as a future treatment for PD. In one trial by Cornell University scientists involving 12 patients with PD, all had their symptoms improved by at least 25% for up to a year after gene therapy. Further research is being conducted.
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, and potatoes) can interfere with the action of L-dopa when the drug is taken without carbidopa.
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).
There is no known way to prevent Parkinson's disease.
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American Parkinson Disease Association, 135 Parkinson Ave., Staten Island, NY 10305, (718) 981-8001, (800) 223-2732, (718) 981-4399 email@example.com, http://www.apdaparkinson.org .
National Institute of Neurological Disorders and Stroke (NINDS), PO Box 5801, Bethesda, MD 20828, (301) 496-5751. TTY: (301) 468-5981, (800) 352-9424, http://www.ninds.nih.gov .
National Parkinson Foundation, 1501 N.W. 9th Avenue/Bob Hope Road, Miami, FL 33136-1494, (305) 243-6666, (800) 327-4545, (305) 243-5595 firstname.lastname@example.org, http://www.parkinson.org .
Parkinson's Disease Foundation, 1359 Broadway, Suite 1509, New York, NY 10018, (212) 923-4700, (800) 457-6676, (212) 923-4778 email@example.com, http://www.pdf.org .
The Parkinson's Institute and Clinical Center, 672 Almanor Ave, Sunnyvale, CA 94068, (408) 734-2800, (800) 655-2273 firstname.lastname@example.org, http://www.thepi.org .
Laith Farid Gulli, M.D.
Revised by Tish Davidson, AM