Parkinson's disease (PD) is a motor system disorder caused by the chronic, progressive degeneration of neurons (nerve cells) in regions of the brain that control movement. PD causes a decline in the initiation, speed, and smoothness of movement. Over time it may come to affect many bodily functions.
Description
Parkinson's Disease (PD) was first described in 1817 by James Parkinson. It affects more than one million people in the United States, including some 500,000 people who have yet to be diagnosed. About 50,000 new cases are diagnosed each year. The average age of PD onset is 60. Symptoms of PD are seen in as many as 15% of those between the ages 65 and 74 and almost 30% of those between the ages of 75 and 84. Only 5 to 10% of PD cases occur before the age of 50. Young-onset PD occurs in those under age 40. A parent or sibling with PD increases one's risk of developing the disease.
PD results from the degeneration and death of neurons in the substantia nigra, movement control centers on each side of the brain. These cells secrete dopamine, a neurotransmitter that attaches to receptors on cell surfaces in another part of the brain—the corpus striatum—that controls muscle action. When dopamine levels fall, the neurons of the corpus striatum begin to misfire. It is estimated that dopamine-producing cells begin dying about 13 years before PD symptoms become evident. The symptoms of PD begin when about 60% of the dopamine-producing cells have died.
Causes
Although the cause of Parkinson's Disease (PD) is unknown, it appears to result from a combination of environmental and hereditary factors as well as oxidative damage and aging. Factors for PD may include:
Early symptoms of PD often are quite subtle, developing on one or both sides of the body. The primary symptoms of PD are:
tremors (shaking) while at rest. (The classic PD tremor is the rubbing of the thumb and forefinger at a frequency of about three rubs per second. Tremors may spread to the hands, arms, legs, feet, jaw, and face. The tremors increase with stress. However, many people with PD do not experience tremors)
slow movement (bradykinesia) or freezing during movement (akinesia)
stiffness or rigidity of the limbs and trunk
poor balance leading to frequent falls
Other early symptoms of PD:
short, shuffling steps
stooped posture
masking (reduction) of facial expression and infrequent blinking
slow or rapid, soft, monotonic (without inflection) speech
other speech changes
insomnia, restlessness, and nightmares
depression
emotional changes, including fear, irritability, and insecurity
Medications for PD can also cause some of these symptoms.
Diagnosis
There is no definitive test for PD. Diagnosis is based on a careful medical history and complete neurological examination.
In addition to PD, anything that damages the substantia nigra can cause Parkinson's-like symptoms, called parkinsonism. Possible causes of parkinsonism:
A physical therapist can design an appropriate exercise program and suggest strategies and techniques for improving balance and stimulating movement during slowdowns or freezing.
For more than 4,000 years, practitioners of Ayurveda—traditional Indian medicine—have prescribed mucuna seeds (Mucuna pruriens) to treat Parkinson's disease. Mucuna contains a natural form of levodopa.
Drugs
The pharmacological treatment of Parkinson's disease is very complex. Although many drugs may relieve at least some symptoms of PD, their effectiveness varies with the patient and the progression of the disease. Side effects may preclude the use of the most effective dose or require another drug to counteract them.
LEVODOPA. Levodopa (L-dopa, L-3,4-dihydroxyphenylalanine) has been the standard treatment for PD since the 1960s and remains one of the best drugs for treating symptoms, particularly tremors and movement problems. Levodopa (Laradopa) is a naturally occurring derivative of dopamine that is converted into dopamine in the brain. However, unlike dopamine, levodopa can reach the brain from the bloodstream. Levodopa treatment may begin at the onset of PD symptoms or when the symptoms begin to interfere with daily life. At least 75% of patients are helped to some degree by levodopa and the drug enables many people with PD to live relatively normal lives for a number of years. Levodopa normally is prescribed only in combination with other drugs.
Side effects of levodopa:
nausea and vomiting
low blood pressure, particularly when standing up, resulting in dizziness and fainting
dyskinesias (abnormal movements including twisting and tics) in at least 50% of patients
These effects usually lessen after several weeks on levodopa.
After five or more years on levodopa, many patients develop:
motor fluctuations, including "peak-dose" dyskinesias when the drug is at its highest level in the brain
on-off phenomena—significant changes in response as the drug levels fluctuate
unpredictable responses to the drug
The levodopa dosage is usually increased when these changes occur. However, dyskinesias may increase with increasing dosages.
Levodopa is an amino acid that is absorbed from the digestive system by the same transporters that carry amino acids from dietary proteins. Therefore some healthcare practitioners may limit or redistribute protein intake to improve levodopa adsorption into the bloodstream.
ENZYME INHIBITORS. Since levodopa and dopamine are amino acids, they can be broken down by the same enzyme systems that break down other amino acids. Therefore the two most-commonly prescribed forms of levodopa include an amino-acid-decarboxylase (AADC) inhibitor: carbidopa (in Sinemet) or benzaseride (in Madopar). These drugs enable more levodopa to enter the brain and may reduce some side effects. Controlled-release formulations (Sinemet CR) can prolong the interval between doses. Carbidopa also prevents vitamin B6 (pyridoxin) from interfering with levodopa.
Catechol-O-methyltransferase (COMT) also breaks down levodopa. The COMT inhibitor entacapone (Comtan) prolongs the effects of levodopa and may moderate its fluctuations. Stalevo contains levodopa, carbidopa, and entacapone. Although the COMT inhibitor tolcapone (Tasmar) reduces the average required dosage of levodopa by 25%, it is no longer commonly used because of severe side effects and possible liver damage and failure.
Selegiline (deprenyl) inhibits monoamine oxidase B (MAO-B), which metabolizes dopamine in the brain. Selegiline can delay levodopa treatment for an average of nine months and also is used in combination with levodopa (Eldepryl) in early-stage PD. Common side effects include dyskinesias, dry mouth, and mood swings.
DOPAMINE AGONISTS. Dopamine agonists (DAs) are drugs that activate dopamine receptors, mimicking the effects of dopamine. In younger adults with early-stage PD, DAs appear to be more effective than levodopa. More often, DAs are used in conjunction with Sinemet to prolong the action of levodopa and reduce levodopa-induced dyskinesias. Although they are expensive, DAs may postpone or prevent the need for expensive neurosurgery at later stages of PD.
Side effects of DAs are similar to those of levodopa, including drowsiness and confusion. DAs may cause dyskinesias in at least 50% of patients. Pergolide has been associated with a type of heart disease.
ANTICHOLINERGIC DRUGS. The neurotransmitters dopamine and acetylcholine balance each other's effects in the brain. Anticholinergics help maintain this balance when dopamine levels fall. Although they may control tremors in early-stage PD, their side effects—including dry mouth, urine retention, severe constipation, blurred vision, confusion, memory loss, and hallucinations—are usually too severe for older patients or those with dementia. Anticholinergics rarely work for very long. Trihexyphenidyl (Artane) and benztropine (Cogentin) are the most common anticholinergics for PD.
Amantadine (Symmetrel) is an antiviral drug used in later-stage PD, particularly to treat tremors and levodopa-induced dyskinesias. Its effects include increased dopamine release and blocking of glutamate, an amino acid that destroys neurons. Side effects include swollen ankles and purple mottling of the skin.
Clozapine (Clozaril) is particularly effective for psychiatric symptoms of late-stage PD, including psychosis and hallucinations.
Although drug therapies can relieve most symptoms of early-stage PD, as the disease advances, drug responses begin to fluctuate and their overall effectiveness decreases.
Surgery
Surgery may be used to help manage severe or debilitating PD symptoms when drug treatments fail.
Pallidotomy uses an electrical current to destroy a small amount of brain tissue in the globus pallidus, which is over-stimulated by the corpus striatum in PD. Pallidotomy may relieve tremors and slow, rigid movements, and decrease dyskenisias caused by drug therapy, by interfering with the neural pathway between the globus pallidus and the thalamus (a major transmission center in the brain). The benefits often do not last and the surgery may cause slurred speech, disabling weakness, and vision problems, particularly with a double pallidotomy (surgery on both sides of the brain).
Thalamotomy reduces hand and arm tremors by destroying small amounts of tissue in the thalamus. Because a double thalamotomy leaves patients extremely weak and with slurred speech, it usually is performed on only one side of the brain, relieving tremors on the opposite side of the body.
With deep brain stimulation (DBS), a device similar to a heart pacemaker sends signals to fine electrodes implanted in the subthalamic nuclei or the globus pallidus (Activa Therapy). The electrical pulses appear to interrupt signals from the thalamus that are involved in tremors. DBS restores a balance between excitatory (tending to excite) and inhibitory (interfering or retarding) signals in brain signal transmission centers, thereby decreasing or abolishing dyskinesias without slowing normal movement. Patients use a magnetic device to adjust stimulation in one or both halves of the brain, as the response dictates. DBS usually results in a significant improvement in some motor symptoms, including tremors and peak-dose dyskinesias, and improves motor function and mobility. It also enables patients to take higher doses of levodopa.
The implantation of fetal cells to replace the dopamine-producing cells of the substantia nigra appears to benefit only patients under age 60. It can have serious side effects and about 15% of patients later develop severe dykinesia due to dopamine-overproduction.
The use of stem cells derived from embryos discarded by infertility clinics is a potentially useful treatment for PD. However, it remains morally and ethically controversial.
Prognosis
There is no way to predict the course of PD. Many people live active, productive lives for 12 to 15 years. However, in others the disease progresses rapidly. Regardless of treatment, PD symptoms worsen with time and become less responsive to drug therapy. Most people with PD experience some additional problem every year. A small number of patients eventually become completely incapacitated. Although PD is not fatal, its effects can lead to fatal accidents or illnesses.
Prevention
There are no clear risk factors or preventions for PD. Central body obesity may increase the risk. Some studies have found that coffee drinking or hormone replacement therapy (HRT) in postmenopausal women may decrease the risk of PD. However, heavy coffee drinking in combination with HRT appears to increase the risk of Parkinson's disease.
BOOKS
Federoff, Howard J., et al., editors. Parkinson's Disease: The Life Cycle of the Dopamine Neuron. New York: New York Academy of Sciences, 2003.
Foltynie Thomas, et al. Parkinson's Disease: Your Questions Answered. New York: Churchill Livingstone, 2003.
Kondracke, Morton. Saving Milly: Love, Politics, and Parkinson's Disease. New York: Public Affairs, 2001.
Mittel, Charles S., editor. Parkinson's Disease: Overview and Current Abstracts. New York: Nova Science, 2003.
Mosley, Anthony D., and Deborah S. Romaine. The Encyclopedia of Parkinson's Disease. New York: Facts on File, 2004.
Pahwa, Rajesh, et al., editors. Handbook of Parkinson's Disease. 3rd ed. New York: Marcel Dekker, 2004.
Weiner, William J., et al. Parkinson's Disease: A Complete Guide for Patients and Families. Baltimore: Johns Hopkins University Press, 2001.
PERIODICALS
Ascherio, A., et al. "Caffeine, Postmenopausal Estrogen, and Risk of Parkinson's Disease." Neurology 60, no. 5 (March 11, 2003): 790–95.
Powers, K. M., et al. "Parkinson's Disease Risks Associated with Dietary Iron, Manganese, and Other Nutrient Intakes." Neurology 60 (June 2003): 1761–66.
Van Camp, Guy, et al. "Treatment of Parkinson's Disease with Pergolide and Relation to Restrictive Valvular Heart Disease." Lancet 363, no. 9416 (April 10, 2004): 1179–83.
ORGANIZATIONS
American Parkinson Disease Association, Inc. 1250 Hylan Blvd., Suite 4B, Staten Island, NY 10305. 800-223-2732. apda@apdaparkinson.org. <http://www.apdaparkinson.com>.
Michael J. Fox Foundation for Parkinson's Research. Grand Central Station, P. O. Box 4777, New York, NY 10163. 800–708–7644. <http://www.michaeljfox.org>.
National Parkinson Foundation, Inc. 1501 NW Ninth Ave./Bob Hope Road, Miami, FL 33136–1494. 800–327–4545. <http://www.parkinson.org>.
Parkinson's Disease Foundation. 710 West 168th Street, New York, NY 10032-9982. 800–457–6676. 212–923–4778. info@pdf.org. <http://www.parkinsons-foundation.org>.
