Parkinson's disease

Definition

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 & symptoms

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:

• herbicide and pesticide exposure
• an as-yet-unidentified toxin or virus
• cellular damage from oxidation by free-radicals (atoms or molecules with an unpaired electron)
• loss of dopamine-secreting cells with age, particularly with accelerated aging
• fewer dopamine-secreting cells at birth

Symptoms

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
• incontinence
• constipation
• small, illegible handwriting
• frequent, dramatic swings in mobility and moods

Later-stage PD symptoms may include:

• frozen muscles that prevent the initiation of movement
• oily or very dry skin
• sweating
• digestive tract shutdown causing difficulties in swallowing, digesting, and elimination
• auditory and/or visual hallucinations
• progressive deterioration of intellectual function
• (dementia ), affecting 30 to 40% of those with late-stage PD
• loss of contact with reality (psychosis)

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:

• infection
• nausea
• trauma
• stroke
• exposure to manganese or other toxins
• medications for psychiatric disorders, such as haloperidol (Haldol) or chlorpromazine (thorazine)
• a chemical called MPTP, found as an impurity in some illegal drugs
• epilepsy
• alzheimer's disease
• other neurodegenerative diseases that sometimes are referred to as Parkinson's plus or parkinsonism plus syndromes

Brain scans, blood tests, lumbar puncture, or x rays may be used to rule out causes of parkinsonism other than PD.

Treatment

There is no cure for Parkinson's disease, nor is there a treatment that slows its progression.

Many factors can help relieve PD symptoms, at least temporarily:

• maintaining general health
• regular, moderate, muscle-building exercise
• erequent rest
• smaller, more frequent, meals to accomodate gastrointestinal slowdowns
• physical, occupational, and/or speech therapies
• encouragement and emotional support

Fatigue, anxiety , and depression can aggravate PD symptoms significantly.

Therapies that may relieve muscle tightness in PD:

• acupuncture
• massage
• yoga
• feldenkrais
• t'ai chi
• qigong
• meditation .

A physical therapist can design an appropriate exercise program and suggest strategies and techniques for improving balance and stimulating movement during slowdowns or freezing.

Supplementation therapies for PD:

• amino acids
• essential fatty acids including omega-3 and omega-6 fatty acids, fish oil, and flax oil
• antioxidants including carotenoids (dark green and orange fruits and vegetables) and other bioflavenoids (antioxidants derived from foods)
• vitamins A, B, C, and E
• selenium and zinc
• calcium and magnesium
• coenzyme Q10 (CoQ₁₀)

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.

Allopathic treatment

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
• agitation
• hallucinations

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.

DAs include:

• Bromocriptine (Parlodel
• Pergolide (Permax)
• Pramipexole (Mirapex)
• Ropinirole (Requip)

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.

OTHER DRUGS. Other common PD medications:

• Diphenhydramine (Benadryl), an antihistamine, and antidepressants such as amitryptiline (Elavil), have similar effects as anticholinergics and may be appropriate for older patients.
• 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.

Resources

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. [email protected]. <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 Alliance. P.O. Box 308, Kingston, NJ 08528-0308. 800–579–8440. [email protected]. <http://www.parkinsonalliance.net>.

Parkinson's Action Network. 1000 Vermont Ave. NW, Washington, DC 20005. 800–850–4725. 202–842–4101. info@ parkinsonsaction.org. <http://parkinsonsaction.org>.

Parkinson's Disease Foundation. 710 West 168th Street, New York, NY 10032-9982. 800–457–6676. 212–923–4778. [email protected]. <http://www.parkinsons-foundation.org>.

OTHER

NINDS Parkinson's Disease Information Page. National Institute of Neurological Disorders and Stroke. August 17, 2001 [cited May 12, 2004]. <http://www.ninds.nih.gov/health_and_medical/disorders/parkinsons_disease.htm>.

Talampanel in Parkinson Disease: Why the Excitement? National Parkinson Foundation, Inc. [Cited May 12, 2004]. <http://www.parkinson.org/talampanel_pd.htm.>.

Paula Ford-Martin

Margaret Alic, PhD

Parkinson's disease

Definition

Parkinson's disease (PD) is a neurodegenerative disorder that causes slowed movements, tremor, rigidity, and a wide variety of other symptoms. "Neurodegenerative" refers to the degeneration, or death, of neurons, the type of cell in the brain that is the basis for all brain activity.

Description

Parkinson's disease occurs when neurons (nerve cells) in a part of the brain called the substantia nigra degenerate, or die off. The loss of these cells disrupts the brain's normal control of movement, causing the person to experience slowed movements, stiffness or rigidity, and tremor.

Demographics

PD is one of the most common neurodegenerative diseases, second only to Alzheimer's disease in the number of people affected. Estimates suggest that approximately 750,000 Americans have PD. It affects older people much more than younger, and indeed, old age is the single greatest risk factor for PD. The average age at diagnosis is 62. Onset before age 40 is extremely rare. Men are slightly more likely to be affected than women.

Causes and symptoms

In the vast majority of cases, the cause of PD is un-known. Besides old age, there are several well-recognized risk factors. These include exposure to pesticides or herbicides, rural living, and drinking well water. Because of this, it is assumed that some type of environmental pollutant, either a pesticide or something associated with its use, is involved in causing PD. Other known risk factors include welding and exposure to manganese, further strengthening the case for an environmental toxin.

There is also evidence that genes play an important role in determining the risk of PD. PD can run in families, affecting members of the family at a much higher rate than expected by chance alone. Among identical twins, the situation is complex: if one twin develops the disease early, the other is more likely to as well; but if one twin has typical late-onset PD, the other is no more likely to develop the disease than would be expected by chance.

Several genes have been identified that cause PD in some people, but the number of people affected by these genes is quite small. Therefore, the interest of these genes is more in what they can reveal about the disease process than in providing the solution to the mystery of what causes PD in most people. Two of the genetic mutations identified involve a protein called alpha-synuclein, whose normal function is unknown. It is believed that the mutations prevent the normal breakdown of alpha-synuclein, leading it to accumulate in the neuron, where it then goes on to damage the cell. Another gene mutation that causes PD affects a protein called parkin, which normally helps break down proteins. It is believed that the loss of parkin causes build-up of proteins (though not of alpha-synuclein), again leading to damage. Researchers believe that environmental toxins may also cause similar problems, and it now seems likely that problems in protein breakdown are a significant step leading to PD, whether of genetic or environmental causation. Finally, a combination of genetic and environmental factors is likely to be important in most cases. For instance, a person with a genetically weaker ability to dispose of proteins, who was also exposed to pesticides, might develop PD, whereas a person with different genes but the same exposure might not.

Whatever the ultimate cause, people with PD share the same pathology, or disease process, in their brains. The symptoms of PD arise when cells in the substantia nigra (SN) degenerate. The SN is located at the base of the brain, near the top of the spinal column. Neurons of the SN receive messages from, and send messages to, several other portions of the brain, all of which are involved in the control of movement. By interacting with these other regions, the SN helps to ensure that movements will be smooth, fluid, and controlled.

SN cells communicate with other cells by releasing the chemical dopamine. Dopamine released by SN cells stimulates cells in other brain regions to act. As SN cells die, they release less dopamine, and the receiving cells are not stimulated as much. This leads to the disordered movement of PD. The SN is also involved in regulating numerous other types of brain behaviors, and late-stage PD is marked by a wide variety of symptoms that probably reflect loss of this regulation.

The earliest symptoms of PD, and the most widely recognized, are tremor, slowed movements (bradykinesia), and stiffness or rigidity. Symptoms often begin on one side of the body, and progress over time to involve both sides. The tremor of PD is a rest tremor—the shaking occurs when the patient is not trying to use the limb, and diminishes when the limb is in use. Bradykinesia and stiffness, along with loss of some balance reflexes, can combine to cause postural instability, and increase the likelihood of falling down.

Other symptoms of PD include:

• orthostatic hypotension , or loss of blood pressure upon standing, which can cause dizziness and fainting
• painful foot cramps
• micrographia, or reduced size of handwriting
• reduced voice volume
• reduced facial expression
• excessive sweating
• constipation
• decreased ability to smell
• male impotence
• drooling
• sleep disturbance
• depression
• anxiety
• panic attacks
• late-stage dementia

Diagnosis

Parkinson's disease is diagnosed by a careful neurological examination, testing movements, coordination, reflexes, and other aspects of function. If the physician suspects PD, the patient will usually be referred to a neurologist for definitive diagnosis. Unilateral (one-sided) tremor, slowed movements, and muscle stiffness are generally enough to confirm the diagnosis; two of the three are usually considered definitive. Several specialized tests may be used, including imaging of the brain with magnetic resonance imaging (MRI) or positron emission tomography (PET) . These are not essential to diagnosis in most cases, but may help to confirm the diagnosis in difficult cases and to distinguish PD from similar diseases such as progressive supranuclear palsy , corticobasal degeneration , or multiple system atrophy . Clues that the disease is one of these, rather than PD, include early or rapidly progressing dementia, loss of coordination, or early and prominent orthostatic hypotension (lightheadedness upon standing).

Certain medications can cause a PD-like syndrome, and it is important to rule these out. These drugs include certain antipsychotic medications (haloperidol) and antivomiting drugs (metoclopramide).

Treatment team

Treatment of PD is headed by a neurologist, who may be either a general neurologist or a movement disorders specialist. The movement disorders specialist is most likely to be aware of the most current trends in treatment. Since PD therapy continues to undergo rapid advances, it may be an advantage to see a specialist when possible. Other team members may include a speech/language pathologist for addressing voice and swallowing disorders , a geriatric medicine specialist to coordinate other medical and social issues, a neuropsychologist for expertise on cognitive aspects of PD and its treatment, and a neurosurgeon.

Treatment

There are no treatments that have been proven to slow the course of PD, although research published in 2003 suggested that coenzyme Q10 may offer a slight benefit in this regard. The study has not been replicated, and its authors noted it would be premature to recommend treatment with this very expensive supplement. Additional claims have been made that two medications used to treat PD symptoms—selegiline and dopamine agonists—may have

some disease-slowing effects. These claims are not widely accepted.

The treatment of the symptoms of PD is complex for several reasons. First, PD is a progressive disease, getting worse over time, so that the medications and doses that work well early in the disease are insufficient later on. Second, the most effective drugs have long-term side effects that are troubling and difficult to control. Third, there are a lot of different treatment options, and finding the right combination can be time consuming. Fourth, the PD patient is likely being treated for other conditions associated with advancing age, and these conditions or their treatment may interfere with treatment of PD. Finally, a major treatment option for late-stage PD is surgery, but the risks of surgery are significant, and determining when and what kind of surgery to perform is a complicated decision.

Once the diagnosis of PD has been made, a central question is when to begin treatment. Treatment is typically not started right away (unless the patient elects to use coenzyme Q10), but instead is delayed until symptoms begin to interfere with his or her ability to work or engage in activities of daily living. This may be a year or even more after diagnosis.

Drug treatment

The next question is what drug to begin with. The most powerful treatment for the symptoms of PD is levodopa, which is taken into the brain and substitutes for the dopamine no longer being made by the substantia nigra. Similar in effect are the dopamine agonists, which mimic the effect of dopamine on the cells that normally receive dopamine from the SN. Three other medications also commonly used in PD, whose effects are not nearly as strong as either levodopa or the dopamine agonists, are anti-cholinergics , selegiline, and amantadine . These are often prescribed early on, when symptoms are not severe, saving the more powerful medications for later on.

Anticholinergics include benztropine and trihexyphenidyl. The loss of SN activity means that another brain system that controls movement, the cholinergic system, is relatively overactive. Anticholinergics dampen the activity of this system, restoring some balance to the control of movement. Anticholinergics are usually well tolerated in younger patients, but their side effects can be a significant barrier to their use in the elderly. Side effects include sedation, confusion, hallucinations, delirium , dry mouth, constipation, and urinary retention.

Selegiline inhibits the action of monoamine oxidase B, an enzyme in the brain that breaks down dopamine. Thus, selegiline prolongs the activity of dopamine in the brain. It can cause insomnia and hallucinations, as well as orthostatic hypotension. It may also interact with certain types of antidepressants, and for this reason, selegiline may be discontinued when beginning treatment for depression. In the early 1990s, selegiline was examined for its potential for neuroprotection, or disease slowing. The results of that trial were inconclusive; selegiline had such a significant and long-lasting symptomatic benefit that it was difficult to examine its disease-slowing effects independently.

Amantadine improves PD symptoms through an un-known mechanism. It is beneficial for each of the major movement symptoms of PD, although its effects are not strong. It also can lessen dyskinesias, which are unwanted movements that develop late in PD due to treatment. Amantadine can cause orthostatic hypotension and confusion.

Most drugs have side effects, and drugs for PD are no exception. The most effective drugs for PD, levodopa and the dopamine agonists, cause a set of side effects called "dopaminergic" side effects, indicating they derive from mimicking the action of dopamine. Dopaminergic side effects include nausea and vomiting, orthostatic hypotension, excessive sleepiness, hallucinations, and dyskinesias (in more advanced patients). Nausea, vomiting, and orthostatic hypotension tend to lessen with use, and do not pose long-term problems for most patients. Excessive sleepiness is a problem for many patients. Dyskinesias are an unavoidable effect of dopaminergic treatments, although dopamine agonists tend to cause less of it than levodopa. Dyskinesias tend to appear after three or more years of successful treatment, and become worse over time. Episodes of dyskinesias can be lessened by reducing the dose of the dopaminergic drug, but may lose symptomatic benefit. Adjusting drugs to minimize dyskinesias while maintaining good symptom control is a central challenge of managing PD.

Levodopa is the most effective treatment for PD symptoms, and is the drug used most often at the beginning of disease in elderly patients, because it is less likely to cause hallucinations than dopamine agonists. It is given in a pill that also contains another medication, called carbidopa, which inhibits an enzyme that would act on dopamine in the bloodstream, thus allowing more of it to reach the brain. In order for levodopa to be taken up by the gut and to pass from the bloodstream to the brain, a carrier that also moves amino acids from food must transport the drug. For this reason, doctors typically suggest that patients avoid taking levodopa with or right after a proteinrich meal. Levodopa may also be given with another medication, called a COMT inhibitor, which further prevents its breakdown in the bloodstream. A new pill combines levodopa, carbidopa, and a COMT inhibitor.

Dopamine agonists are almost as effective as levodopa for combating PD symptoms, and have the advantage that their use does not lead to dyskinesias as frequently as levodopa does. For this reason, many movement disorder specialists begin their patients on a dopamine agonist rather than levodopa. This is especially true for younger patients, who can anticipate more years of dopaminergic therapy, and a higher likelihood of developing dyskinesias as a result. There are four major dopamine agonists available in the United States: pergolide, pramipexole, bromocriptine, and ropinirole. Each is taken as a pill, and can be taken alone or in combination with levodopa or other medications. Some patients respond better to one than another, and inadequate relief from one does not mean the same should be expected from another. The U.S. Food and Drug Administration was expected to approve a fifth dopamine agonist, called apo-morphine, by mid-2004. Unlike the others, it is injected, and provides very rapid, short-term symptomatic relief when a dose of levodopa wears off.

Excessive sleepiness is a potentially dangerous side effect for all the dopaminergic drugs (levodopa and the dopamine agonists). This can take the form of predictable, peak-dose sleepiness, or general increase in sleepiness during the day, or a sudden, unpredictable "attack" of sleepiness and falling asleep. The latter can be dangerous if it occurs while driving or performing another activity requiring full awareness. Patients are cautioned to be aware of changes in sleepiness especially after changing a medication, and to avoid driving whenever possible if excessive sleepiness does become a side effect issue.

Complications of advanced disease

After several years of successful treatment, most patients begin to develop one or more motor complications. These often begin with "wearing off," a reduction in the duration of effect of a given dose of levodopa, which initially can be countered by dosing more frequently. Another complication is "on-off," in which the symptomatic benefit of a given dose suddenly switches off and the patient becomes rigid, with tremor and slowed movements emerging. When this occurs at home, the patient will typically just take another dose of medication, and wait for it to begin to work. It is more of a problem when it occurs while the patient is out and about, and frequent on-off episodes may make the patient reluctant to leave the home. Apomorphine injection may be useful in this situation, since it works very rapidly (approximately seven minutes), and can therefore be used as a "rescue" for sudden off periods. Dyskinesias are a third motor complication. Dyskinesias are uncontrolled writhing movements that typically occur at the peak of effect of a levodopa dose. In some cases for some patients, dyskinesias are mild enough that they are not problematic. In other cases, they interfere with function, and attempting to reduce them becomes an important treatment issue. While drug adjustments can have some effect, as the disease progresses it becomes more and more difficult to maintain adequate symptom control while avoiding dyskinesias. At this stage, the patient may consider surgery for treatment of PD symptoms.

Other complications arise in advanced PD, especially in "non-motor" symptoms, those that do not affect movement. Low voice volume may be amenable to speech therapy treatment, with one of the most effective programs being Lee Silverman voice treatment , which focuses on conscious attempts to increase volume. Orthostatic hypotension may be treatable with increased salt intake, compression stockings, and medication. Drooling may become an issue in later-stage disease; there are both drug treatments and non-drug therapies available to reduce this problem. Constipation is a significant problem for many advanced PD patients, and can be treated with standard measures such as increasing the fiber in the diet and bulking laxatives.

Panic attacks and anxiety are common in PD. These can be addressed both through helping the patient understand that this is a feature of the disease, and through antianxiety medication. Depression affects many PD patients, and can worsen other aspects of the disease. It usually responds well to antidepressant medications. Dementia (loss of memory and impairment of other thinking functions) occurs more frequently in PD patients than in the population at large. Treatment is similar to that in non-PD patients, although some medications cannot be used because they have undesirable side effects for PD patients. Psychosis-hallucinations, paranoia, nightmares, and delusions may be a response to dopaminergic medications. If these side effects cannot be controlled through modification of treatments, an antipsychotic drug may be useful.

Surgery

Brain surgery is a treatment option in late-stage PD. The best candidate is the individual who continues to respond to levodopa, but whose treatment is complicated by unacceptable dyskinesias even after medication adjustment. Dementia or other significant health-related conditions may make the patient unsuitable for the rigors of surgery. The patient is usually evaluated by the neurologist, a neuropsychologist, and a neurosurgeon before deciding whether surgery is the right option.

There are two types of surgery for PD. An "ablative" lesion destroys a small portion of the brain, and in so doing, restores the balance of neural activity within the movement control circuits of the brain; ablation means to destroy or remove. The second option is deep brain stimulation (DBS), which accomplishes the same thing by implanting an electrode in the target brain region; electrical pulses shut the region down. Ablative lesions are simpler and less prone to long-term complications, but they are not adjustable after the lesion has been made. DBS is more complex, expensive, and time consuming, and carries a significant risk for infection or equipment malfunction, but it can be adjusted to more precisely target the brain region, thereby enhancing the surgical effect.

Three brain regions are targeted in PD surgery. Ablation of the thalamus (thalamotomy) is primarily effective in controlling tremor, and is not widely performed any-more since other, more effective targets are available. The globus pallidus internus (GPi) can either be ablated (pallidotomy ) or stimulated (GPi DBS), which is effective for all the major motor symptoms of PD (tremor, bradykinesia, rigidity), and can improve them by 25–60%. It is also effective for reducing dyskinesias by up to 90%. The subthalamic nucleus can be stimulated in STN DBS, and is highly effective for all the major motor symptoms and dyskinesias, to a somewhat greater extent than GPi DBS. An additional advantage of STN DBS is that it is safer to do on both sides of the brain (left and right, termed bilateral) than GPi DBS. Therefore, if the patient is affected by disabling symptoms on both sides, as is often the case in advanced PD, bilateral STN DBS may be a better choice.

Clinical trials

Parkinson's disease is the subject of intense research, and there are usually several large and important clinical trials going on at any time. Trials may focus on slowing the disease, determining the best drug treatment, or refining surgical methods and targets.

Two experimental forms of surgery have been the subject of recent clinical trials. The first is the implantation of cells into the substantia nigra to replace the lost dopamine-producing cells. The implanted cells come from fetal tissue. Fetal-tissue transplants have led to success, but also to uncontrolled dyskinesias in some patients. For this reason, such trials on are on hold until a better understanding of this problem is discovered and methods are developed to avoid it.

The second form of surgery delivers a growth factor to the substantia nigra via an implanted pump and tube. The growth factor, called GDNF, has been shown to slow cell death in experimental systems. A small group of patients undergoing this surgery has improved, although these results are quite preliminary.

Prognosis

PD is a progressive disease, and the loss of brain tissue in the SN is inevitable. PD patients tend to live almost as long as age-matched individuals without PD, although with an increasing level of disability. Loss of motor control can lead to an increased risk for falls, and swallowing difficulty can cause choking or aspiration (inhaling) of food. Aspiration pneumonia is a common cause of death in late-stage PD patients.

Resources

BOOKS

Cram, David L. Understanding Parkinson's Disease: A Self-Help Guide. Milford, CT: LPC, 1999.

Hauser, Robert, and Theresa Zesiewicz. Parkinson's Disease: Questions and Answers, 2nd edition. Coral Springs, FL: Merit Publishing International, 1997.

Jahanshahi, Marjan, and C. David Marsden. Parkinson's Disease: A Self-Help Guide. San Diego: Demos Medical Publishing, 2000.

WEBSITES

WE MOVE. <http://www.wemove.org> (April 27, 2004).

Parkinson's Disease Foundation. <http://www.pdf.org> (April 27, 2004).

Richard Robinson

Parkinson's disease

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

Usually beginning in a person's late 50s or early 60s, PD 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.

Genetic profile

Most 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 of the body where the protein is used. Some evidence suggests that the disease is transmitted by autosomal dominant inheritance. This implies that an affected parent has a 50% chance of transmitting the disease to any child. This type of inheritance is not commonly observed. The most recent evidence links 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.

Demographics

PD affects approximately 500,000 people in the United States, both men and women, with as many as 50,000 new cases being diagnosed each year.

Causes and 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 target muscles. 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.

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. 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 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 develop PD again as a consequence of normal decline.

Symptoms

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 typical facial expression called masked face, characterized by 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 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 disease. Most drugs treat only the symptoms of the disease, although one drug, selegiline (Eldepryl), may slow degeneration of the substantia nigra.

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 a 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 a physician or 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. A large, carefully controlled study of vitamin E demonstrated that it could not halt disease progression.

Drugs

The pharmacological treatment of Parkinson disease is complex. While there are a large number of drugs that can be effective, their effectiveness varies among individuals, 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.

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 persons 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 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

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.

effects, it is also frequently prescribed early in the disease before L-dopa is begun. Entacapone (Comtan) and tolcapone (Tasmar), two inhibitors of another enzyme system called catechol-O-methyltransferase (COMT), have recently been approved for use and marketed. 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 2001, include bromocriptine (Permax, Parlodel), pergolide (Permax), pramipexole (Mirapex), cabergoline (Dostinex), and ropinirole (Requip). 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 individuals or in persons with dementia. In addition, anticholinergics rarely work for very long. They are often prescribed for younger people who have predominant shaking. Trihexyphenidyl (Artane) is the most commonly prescribed drug.

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 persons. 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 that is 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 persons, these procedures lead to significant improvement for some motor symptoms, including peak-dose dyskinesias. This allows a person to receive more L-dopa, since these dyskinesias are usually responsible for any 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 surgical candidate selection are likely to increase successful outcomes.

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. Persons 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.

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 disease often the most troubling. These include difficulty sleeping, nightmares, intellectual impairment (dementia), hallucinations, and loss of contact with reality (psychosis).

Health care team roles

A physician usually makes an initial diagnosis of Parkinson's disease. Treatment is often managed by a family physician or internist. Neurologists may be asked for consultations. Occasionally, neurosurgeons perform surgery in the treatment of parkinsonism. Clinical nutritionists and physical therapists may assist in managing persons with PD. Nurses provide bedside care in the hospital, and administer the frequent patient neurologic evaluations. They also provide patient and family education about the diagnosis and home management.

Prevention

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

Resources

BOOKS

Adams, Raymond D., Maurice Victor, and Allan H. Ropper. Adam's & Victor's Principles of Neurology. 6th ed. New York: McGraw Hill, 1997.

Adler, Charles H., and J. Eric Ahlskog. Parkinson's Disease and Movement Disorders: Diagnosis and Treatment Guidelines for the Practicing Physician. Totowa, NJ: Humana Press, 2000.

Aminoff, Michael J. "Parkinson's Disease and Other Extra-pyramidal Disorders." In Harrison's Principles of Internal Medicine. 14th ed. Ed. Anthony S. Fauci, et al. New York: McGraw-Hill, 1998.

Argue, John. Parkinson's Disease & the Art of Moving. Oakland, CA: New Harbinger Publications, 2000.

Cote, Lucian J., Lola Sprinzeles, and Robin Elliott. Parkinson's Disease and Quality of Life. Binghamton, NY: Haworth Press, 2000.

Jankovic, Joseph. "Parkinsonism." In Cecil Textbook of Medicine. 21st ed. Ed. Lee Goldman and J. Claude Bennett. Philadelphia: W.B. Saunders, 2000.

Mouradian, Maral M. Parkinson's Disease: Methods and Protocols. Totowa, NJ: Humana Press, 2001.

Perkin, G. D. An Atlas of Parkinson's Disease and Related Disorders. New York: Parthenon Pub Group, 1998.

Tarsey, Daniel, and Jerrold Vitek. Surgical Treatment for Parkinson's Disease and Other Movement Disorders. Totowa, NJ: Humana Press, 2001.

PERIODICALS

Cesaro, P., M. Peschanski, and J. P. N'Guyen. "Treatment of Parkinson's Disease by Cell Transplantation." Functional Neurology 16, no. 1 (2001): 21-27.

Chan, D. T., et al. "Surgical Management of Parkinson's Disease: A Critical Review." Hong Kong Medical Journal 7, no. 1 (2001): 34-39.

Dowsey-Limousin, P., V. Fraix, A. L. Benabid, and P. Pollak. "Deep Brain Stimulation in Parkinson's Disease." Functional Neurology 16, no. 1 (2001): 67-71.

McMahon, D. G. "Parkinson's Disease and Parkinsonism in the Elderly." Age and Aging 30, no. 2 (2001): 180-181.

Olanow, C. W., R. L. Watts, and W. C. Koller. "An Algorithm (Decision Tree) for the Management of Parkinson's Disease (2001): Treatment Guidelines." Neurology 12, no. 56 (2001): S1-S88.

Tuite, P. J. "Parkinson's Disease. An Overview of Treatments and Research." Minnesota Medicine 84, no. 5 (2001): 42-47.

ORGANIZATIONS

American Academy of Neurology. 1080 Montreal Avenue, St. Paul, MN 55116. (651) 695-1940. <http://www.aan.com>.

American College of Physicians. 190 N. Independence Mall West, Philadelphia, PA 19106-1572. (800) 523-1546. <http://www.acponline.org>.

American Parkinson Disease Association. Inc., 1250 Hylan Boulevard, Suite 4B, Staten Island, NY 10305-1946. (800) 223-2732. <http://www.apdaparkinson.com>.

Parkinson's Disease Foundation. 710 West 168th Street, New York, NY 10032-9982. (800) 457-6676. <http://www.pdf.org>.

Parkinson's Disease Society (UK). 215 Vauxhall Bridge Road, London SW1V 1EJ. (020) 7931-8080. <http://www.parkinsons.org.uk>.

OTHER

American Academy of Family Physicians. <http://www.aafp.org/afp/990415ap/2155.html>.

Bowman Gray University School of Medicine. <http://www.bgsm.edu/bgsm/surg-sci/ns/pd.html>.

National Institute of Health. <http://www.nhgri.nih.gov/DIR/LGDR/PARK/about_parks.html>.

National Institute of Neurological Diseases and Stroke. <http://www.ninds.nih.gov>.

National Library of Medicine. <http://www.nlm.nih.gov/medlineplus/parkinsonsdisease.html>.

National Parkinson Foundation. <http://www.parkinson.org/sources.htm>.

Parkinson's Disease Web Ring. <http://www.pdring.com>.

United States Food and Drug Administration. <http://www.fda.gov/fdac/features/1998/498_pd.html>.

World Parkinson Disease Association. <http://www.wpda.org>.

L. Fleming Fallon, Jr., MD, DrPH

Parkinson's Disease

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

Usually beginning in a person's late 50s or early 60s, PD 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.

Genetic profile

Most 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 environ-mental 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 of the body where the protein is used. Some evidence suggests that the disease is transmitted by autosomal dominant inheritance. This implies that an affected parent has a 50% chance of transmitting the disease to any child. This type of inheritance is not commonly observed. The most recent evidence links 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.

Demographics

PD affects approximately 500,000 people in the United States, both men and women, with as many as 50,000 new cases being diagnosed each year.

Causes and 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 target muscles. 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.

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. 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 develop PD again as a consequence of normal decline.

Symptoms

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 typical facial expression called masked face, characterized by 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 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 disease. Most drugs treat only the symptoms of the disease, although one drug, selegiline (Eldepryl), may slow degeneration of the substantia nigra.

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 a 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 a physician or 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. A large, carefully controlled study of vitamin E demonstrated that it could not halt disease progression.

Drugs

The pharmacological treatment of Parkinson disease is complex. While there are a large number of drugs that can be effective, their effectiveness varies among individuals, 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.

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 persons 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 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 (Comtan) and tolcapone (Tasmar), two inhibitors of another enzyme system called catechol-O-methyltransferase (COMT), have recently been approved for use and marketed. 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 2001, include bromocriptine (Permax, Parlodel), pergolide (Permax), pramipexole (Mirapex), cabegoline (Dostinex), and ropinirole (Requip). 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 individuals or in persons with dementia. In addition, anticholinergics rarely work for very long. They are often prescribed for younger people who have predominant shaking. Trihexyphenidyl (Artane) is the most commonly prescribed drug.

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 persons. 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 that is 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 persons, these procedures lead to significant improvement for some motor symptoms, including peak-dose dyskinesias. This allows a person to receive more L-dopa, since these dyskinesias are usually responsible for any 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 surgical candidate selection are likely to increase successful outcomes.

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. Persons 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.

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 disease often the most troubling. These include difficulty sleeping, nightmares, intellectual impairment (dementia), hallucinations, and loss of contact with reality (psychosis).

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.

Health care team roles

A physician usually makes an initial diagnosis of Parkinson's disease. Treatment is often managed by a family physician or internist. Neurologists may be asked for consultations. Occasionally, neurosurgeons perform surgery in the treatment of parkinsonism. Clinical nutritionists and physical therapists may assist in managing persons with PD. Nurses provide bedside care in the hospital, and administer the frequent patient neurologic evaluations. They also provide patient and family education about the diagnosis and home management.

Prevention

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

Resources

BOOKS

Adams, Raymond D., Maurice Victor, and Allan H. Ropper. Adam's & Victor's Principles of Neurology. 6th ed. New York: McGraw Hill, 1997.

Adler, Charles H., and J. Eric Ahlskog. Parkinson's Disease and Movement Disorders: Diagnosis and Treatment Guidelines for the Practicing Physician. Totowa, NJ: Humana Press, 2000.

Aminoff, Michael J. "Parkinson's Disease and Other Extrapyramidal Disorders." In Harrison's Principles of Internal Medicine, 14th ed. Ed. Anthony S. Fauci, et al. New York: McGraw-Hill, 1998.

Argue, John. Parkinson's Disease & the Art of Moving. Oakland, CA: New Harbinger Publications, 2000.

Cote, Lucian J., Lola Sprinzeles, and Robin Elliott. Parkinson's Disease and Quality of Life. Binghamton, NY: Haworth Press, 2000.

Jankovic, Joseph. "Parkinsonism." In Cecil Textbook of Medicine, 21st ed. Ed. Lee Goldman and J. Claude Bennett. Philadelphia: W.B. Saunders, 2000.

Mouradian, Maral M. Parkinson's Disease: Methods and Protocols. Totowa, NJ: Humana Press, 2001.

Perkin, G. D. An Atlas of Parkinson's Disease and Related Disorders. New York: Parthenon Pub Group, 1998.

Tarsey, Daniel, and Jerrold Vitek. Surgical Treatment for Parkinson's Disease and Other Movement Disorders. Totowa, NJ: Humana Press, 2001.

PERIODICALS

Cesaro, P., M. Peschanski, and J. P. N'Guyen. "Treatment of Parkinson's Disease by Cell Transplantation." Functional Neurology 16, no. 1 (2001): 21-27.

Chan, D. T., et al. "Surgical Management of Parkinson's Disease: A Critical Review." Hong Kong Medical Journal 7, no. 1 (2001): 34-39.

Dowsey-Limousin, P., V. Fraix, A. L. Benabid, and P. Pollak. "Deep Brain Stimulation in Parkinson's Disease." Functional Neurology 16, no. 1 (2001): 67-71.

McMahon, D. G. "Parkinson's Disease and Parkinsonism in the Elderly." Age and Aging 30, no. 2 (2001): 180-181.

Olanow, C. W., R. L. Watts, and W. C. Koller. An Algorithm (Decision Tree) for the Management of Parkinson's Disease (2001): Treatment Guidelines." Neurology 12, no. 56 (2001): S1-S88.

Tuite, P. J. "Parkinson's Disease. An Overview of Treatments and Research." Minnesota Medicine 84, no. 5 (2001): 42-47.

ORGANIZATIONS

American Academy of Neurology. 1080 Montreal Avenue, St. Paul, MN 55116. (651) 695-1940. 〈http://www.aan.com〉.

American College of Physicians. 190 N. Independence Mall West, Philadelphia, PA 19106-1572. (800) 523-1546. 〈http://www.acponline.org〉.

American Parkinson Disease Association. Inc., 1250 Hylan Boulevard, Suite 4B, Staten Island, NY 10305-1946. (800) 223-2732. 〈http://www.apdaparkinson.com〉.

Parkinson's Disease Foundation. 710 West 168th Street, New York, NY 10032-9982. (800) 457-6676. 〈http://www.pdf.org〉.

Parkinson's Disease Society (UK). 215 Vauxhall Bridge Road, London SW1V 1EJ. (020) 7931-8080. 〈http://www.parkinsons.org.uk〉.

OTHER

American Academy of Family Physicians. 〈http://www.aafp.org/afp/990415ap/2155.html〉.

Bowman Gray University School of Medicine. 〈http://www.bgsm.edu/bgsm/surg-sci/ns/pd.html〉.

National Institute of Health. 〈http://www.nhgri.nih.gov/DIR/LGDR/PARK/about_parks.html〉.

National Institute of Neurological Diseases and Stroke. 〈http://www.ninds.nih.gov〉.

National Library of Medicine. 〈http://www.nlm.nih.gov/medlineplus/parkinsonsdisease.html〉.

National Parkinson Foundation. 〈http://www.parkinson.org/sources.htm〉.

Parkinson's Disease Web Ring. 〈http://www.pdring.com〉.

United States Food and Drug Administration. 〈http://www.fda.gov/fdac/features/1998/498_pd.html〉.

World Parkinson Disease Association. 〈http://www.wpda.org〉.

Parkinson's Disease

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

Parkinson's disease causes a progressive decline in movement control affecting the ability to control initiation, speed, and smoothness of motion. Symptoms of PD usually emerge in individuals over the age of 60; however, 15% of PD cases in the United States involve individuals under the age of 50.

Genetic profile

Most cases of PD are sporadic. This means 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 of the body where the protein is used. Some evidence suggests that the disease is transmitted by autosomal dominant inheritance. This implies that an affected parent has a 50% chance of transmitting the disease to any child. This type of inheritance is not commonly observed. The most recent evidence links 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.

Demographics

PD affects approximately 500,000 people in the United States, both men and women, with as many as 50,000 new cases being diagnosed each year.

Causes and 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 target muscles. 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.

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. 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 develop PD again as a consequence of normal decline.

Symptoms

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 typical facial expression called masked face, characterized by 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 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 disease. Most drugs treat only the symptoms of the disease, although one drug, selegiline (Eldepryl), may slow degeneration of the substantia nigra.

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 a 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 a physician or 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. A large, carefully controlled study of vitamin E demonstrated that it could not halt disease progression.

Drugs

The pharmacological treatment of Parkinson disease is complex. While there are a large number of drugs that can be effective, their effectiveness varies among individuals, 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.

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 persons develop motor fluctuations, including peak-dose dyskinesias (abnormal movements such as tics, twisting, or rest-lessness); 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 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 (Comtan) and tolcapone (Tasmar), two inhibitors of another enzyme system called catechol-O-methyltransferase (COMT), have recently been approved for use and marketed. 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 2001, include bromocriptine (Permax, Parlodel), pergolide (Permax), pramipexole (Mirapex), cabergoline (Dostinex), and ropinirole (Requip). 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 individuals or in persons with dementia. In addition, anticholinergics rarely work for very long. They are often prescribed for younger people who have predominant shaking. Trihexyphenidyl (Artane) is the most commonly prescribed drug.

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 persons. 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 that is 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 persons, these procedures lead to significant improvement for some motor symptoms, including peak-dose dyskinesias. This allows a person to receive more L-dopa, since these dyskinesias are usually responsible for any 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 surgical candidate selection are likely to increase successful outcomes.

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. Persons 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.

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.

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 disease often the most troubling. These include difficulty sleeping, nightmares, intellectual impairment (dementia), hallucinations, and loss of contact with reality (psychosis).

Caregiver concerns

A physician usually makes an initial diagnosis of Parkinson's disease. Treatment is often managed by a family physician or internist. Neurologists may be asked for consultations. Occasionally, neurosurgeons perform surgery in the treatment of parkinsonism. Clinical nutritionists and physical therapists may assist in managing persons with PD. Nurses provide bedside care in the hospital, and administer the frequent patient neurologic evaluations. They also provide patient and family education about the diagnosis and home management.

Prevention

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

Resources

BOOKS

Factor, Stewart A. D.O., William J. Weiner, M.D. Parkinson's Disease: Diagnosis and Clinical Management, 2nd. Ed. New York, Demos Medical Publishing, 2008.

Schwarz, Shelley Peterman. Parkinson's Disease: 300 Tips for Making Life Easier. New York, Demos Medical Publishing, 2006.

Weiner, William J., Lisa M. Shulman, and Anthony E. Lang. Parkinson's Disease: A Complete Guide for Patients and Families. Baltimore, The Johns Hopkins University Press, 2006.

PERIODICALS

“First Parkinson's Blood Test is Study Goal.(International Report).” Diagnostics & Imaging Week 11.1 (3 Jan, 2008):8.

Moran, Nuala. “First Parkinson's Gene Therapy Planned by Oxford Biomedica.” BioWorld International 13.11 (12 March,2008): 1–2

“New Michael J. Fox Foundation Initiative Will Drive Development of Web-Based Tools to Increase Patient Participation in Parkinson's Clinical Trials.” US Newswire (19 March,2008) NA.

“New Research Provides Genetic Clue to Parkinson's Disease.” Xinhua News Agency (20 March,2008) NA.

“Nonmotor Symptoms in PD After Deep Brain Stimulation of the Subthalamic Nucleus.” Neurology Alert (1 Jan 2008):NA.

ORGANIZATIONS

American Academy of Family Physicians, http://www.aafp.org/afp/990415ap/2155.html.

American Academy of Neurology, 1080 Montreal Ave, St. Paul, MN, 55116, (651) 695-1940, http://www.aan.com.

American Parkinson Disease Association, Inc., 1250 Hylan Boulevard, Suite 4B, Staten Island, NY, 10305-1946, (800) 223-2732, http://www.apdaparkinson.com.

Michael J. Fox Foundation for Parkinson's Research, Grand Central Station P.O. Box 4777, New York, NY, 10163, (212)509-0995, http://www.michaeljfox.org.

National Parkinson Foundation, http://www.parkinson.org/sources.htm.

NIH Neurological Institute, P.O. Box 5801, Bethesda, MD, 20824, (800) 352-9424, http://http://www.ninds.nih.gov.

Parkinson's Disease Foundation, 710 West 168th Street, New York, NY, 10032-9982, (800) 457-6676, http://www.pdf.org.

Parkinson's Disease Society (UK), 215 Vauxhall Bridge Road, London, UK, SW1V 1EJ, (020) 7931-8080, http://www.parkinsons.org.uk.

L. Fleming Fallon Jr., MD, DrPH

Lisa M. Piazza M.A.