Parkinson's Disease – causes, diagnosis, and treatments
What Is Parkinson's Disease?

Parkinson's disease is a slowly progressive disorder that affects movement, muscle control, and balance. It occurs when cells are destroyed in certain parts of the brain stem, particularly the crescent-shaped cell mass known as the substantia nigra. Nerve cells in the substantia nigra send out fibers to the corpus stratia -- gray and white bands of tissue located in both sides of the brain. There the cells release dopamine, an essential neurotransmitter (a chemical messenger in the brain). Dopamine is one of three major neurotransmitters known as catecholamines, which help the body respond to stress and prepare it for the fight-or-flight response. Loss of dopamine in the corpus stratia is the primary defect in Parkinson's disease. This loss negatively effects the nerves and muscles controlling movement and coordination, resulting in the major symptoms characteristic of Parkinson's disease.

What Causes Parkinson's Disease?

Parkinson's disease is sometimes referred to as idiopathic, which means that the primary cause is unknown, in order to distinguish it from parkinsonism, which are the symptoms occurring from a known cause. Although it is clear that dopamine deficiency is the primary defect in Parkinson's disease, researchers now must discover how this dopamine is lost. Studies indicate that the culprit is not a single cause, but is a combination of genetic susceptibility and environmental assaults.

Biologic Mechanisms and Genetic Factors

Studies suggest that genetic factors are important in causing Parkinson's, although a recent one found that they are rarely critical in cases which develop after the age of fifty. Nevertheless, identifying genetic abnormalities that cause early-onset Parkinson's disease may help researchers learn more about the basic mechanisms of the disease itself. Even with some understanding of the abnormal biological mechanisms in the brain that cause Parkinson's disease, no one knows at this time how long it takes before nerve damage and dopamine loss trigger symptoms. At this time, the best guess is about five years.

Defective Alpha Synuclein and Lewy Bodies.Some experts are studying abnormalities in a protein called alpha synuclein, which has been detected in some early-onset Parkinson's patients of European descent. A genetic defect causes the alpha synuclein proteins to collect and clump together, most likely forming fibrous deposits known as Lewy bodies in the substantia nigra -- the place in the brain where dopamine is first released. Lewy-body deposits are found not only in the brains of patients with Parkinson's disease, but are also present in smaller numbers in other neurologic diseases and in people without neurologic symptoms. It is not clear whether Lewy bodies are the major killers of the nerve cells or whether they are simply a byproduct of the degenerative process. Some experts believe that the formation of Lewy bodies occur in very early stages of Parkinson's, and may be a harbinger of the full-blown disease. In any case, the defective alpha synuclein protein itself appears to be rare and is unrelated to the much more common late-onset or most inherited cases of Parkinson's disease.

Parkin Gene. Researchers have also discovered a gene that may be responsible for a rare form of Parkinson's disease that occurs in children and adolescents. The gene regulates a newly found protein that the researchers call parkin and is similar to a protein known as ubiquitin found in Parkinson's disease and other neurologic diseases. Whether this defective protein will be relevant for late-onset Parkinson's is unknown.

Complex I and Oxygen-Free Radicals. Some research is focusing on the observation that some Parkinson's patients have a 30% to 40% decrease in an enzyme called complex I. This enzyme is found in mitochondria -- thread-like structures in cells that generate energy. Low amounts of complex I lead to energy loss and the inability of the cell to withstand the assault of oxygen free radicals, which are unstable molecules produced by the natural chemical processes in the body. Because free radicals are missing an electron, they tend to bind with other molecules in the body. This can set off a chemical chain reaction that damages any type of cell, including nerve cells in the brain, and even interferes with their DNA. People who have insufficient amounts of complex I, either from genetic abnormalities or other factors, may be more susceptible to developing Parkinson's disease from exposure to chemicals and toxins.

NMDA Receptors. Also of interest are processes that occur in an area of the brain called the subthalamic nucleus. Here, receptors known as glutamatergic N-methyl-D-aspartate (NMDA) become persistently overexcited and produce high levels of calcium ions within brain cells, which in turn leads to a cascade of events that trigger oxygen-free radicals.

Immune Factors. An overresponsive immune system may also play a role in perpetuating Parkinson's disease, by producing certain factors called cytokines (e.g., interleukin-1, tumor necrosis factor), in response to the initial damage, which can further injure cells in the brain.

Environmental Assaults and Oxygen-Free Radicals

Environmental toxins, infections, and other triggers can provoke excessive production in the body of oxygen free-radicals. Viral infections and intense exposure to environmental and industrial chemicals have each been associated with the development of parkinsonism. For example, one flu epidemic causing encephalitis in the early twentieth century left many of its victims with parkinsonism.

Aging Process

Most -- but not all -- Parkinson's victims are elderly. Some studies indicate that the very elderly are not susceptible to the disease, indicating that the aging process itself is not the major player in the disease. Aging does appear to reduce the concentration of dopamine in structures called dopamine transporters, which carry the neurotransmitter back and forth between nerve cells. Some researchers posit that any further stress on these transporters might trigger Parkinson's disease in the aging brain.

Causes of Parkinsonism and Diseases That Mimic Parkinson's Disease

In many patients, the symptoms of Parkinson's disease have an identifiable cause, in which cases the syndrome is known as parkinsonism.

Drugs. Certain drugs or medications account for about 4% of all cases of parkinsonism. According to recent studies patients who experience drug-induced parkinsonism may actually be at an increased risk of developing Parkinson's disease later in life. A number of drugs can cause these symptoms, including nearly all used to treat schizophrenia and other psychoses, e.g., haloperidol (Haldol), thioridazine (Mellaril), and chlorpromazine (Thorazine). Valproate (Depakote), used for epilepsy, also causes reversible parkinsonism. Metoclopramide (Octamide, Maxolon, Reglan), used for stomach disorders, is an important cause of these symptoms in the elderly; the symptoms persist sometimes for months after the drug has been withdrawn. The common antidepressants known as selective serotonin-reuptake inhibitors (SSRIs), which include fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil), may cause Parkinson-like symptoms.

Other Neurologic Conditions. Many medical conditions may cause symptoms of Parkinson's disease. Hardening of the arteries (arteriosclerosis) in the brain can cause multiple small strokes, which can produce loss of motor control. Coexisting Alzheimer's disease may confuse the diagnosis. In one study 23% of people with Alzheimer's also met the criteria for Parkinson's disease. A disease known as dementia with Lewy bodies has similar symptoms, but is marked by early dementia. Some people have a condition called essential tremor, which unlike the tremor of Parkinson's disease, often occurs in the head and voice and is usually worse during motion, as opposed to rest. Progressive supranuclear palsy has similar symptoms, but less tremor with earlier rigidity, and it tends to affect both sides of the body symmetrically. Other problems that may mimic Parkinson's disease include Wilson's disease, thyroid abnormalities, hydrocephalus, tumors, and a number of degenerative neurologic diseases.

Gluten. One study found that an immune response to a protein found in gluten, a substance in wheat, rye, and barley can cause muscle weakness and neurologic problems similar to parkinsonism.

What Are the Symptoms of Parkinson's Disease?

Tremors

Symptoms often start with an occasional tremor in one finger that spreads over time to involve the whole arm. The tremor is often rhythmic -- 4 to 5 cycles per second -- and frequently causes an action of the thumb and fingers known as the pill-rolling tremor. Tremor is present when the limb is at rest or held up in a stiff unsupported position and usually disappears briefly during movement. Tremors can also occur in the head, lips, tongue, and feet, although they do not occur during sleep. In one study, 44% of patients reported experiencing internal tremors lasting less than half an hour, but occurring several times a week. Symptoms can occur on one or both sides of the body.

Motion and Motor Impairment

Slowness of motion (bradykinesia) is one of the classic symptoms of Parkinson's disease. Patients may eventually develop a stooped posture and a slow, shuffling walk. The gait can be erratic and unsteady and cause a person to fall. After a number of years, muscles may freeze up or stall, usually when a patient is making a turn or passing through narrow spaces, such as a doorway. Intestinal motility -- e.g., swallowing, digestion, and elimination -- may also slow down, causing eating problems and constipation. The muscle rigidity (akinesia) experienced in Parkinson's disease often begins in the legs and neck. Muscle rigidity in the face can produce a mask-like, staring appearance. Hand deformities may develop in late stages, causing severe discomfort and limitation. Handwriting, for instance, often becomes diminutive. Normally spontaneous muscle movements, such as blinking, may need to be done consciously.

Speech Impairment

About half of Parkinson's patients develop some speech difficulty caused by rigidity of the facial muscles, loss of motor control, and impaired breath control. Tone can become monotonous, words may be repeated over and over, or the rate of speech may even be very fast. Swallowing may be difficult.

Depression and Mental Problems

Depression is often present as one of the first symptoms and is probably partially caused by a chemical imbalance in the brain. Because depression is common in old age or can be caused by other factors, the patient often does not connect it with other early symptoms of Parkinson's. Defects in thinking, memory, language, and problem solving skills often occur later on. Dementia occurs in almost 30% of Parkinson's patients, who are usually older individuals who have had major depression.

Other Symptoms of Parkinson's Disease

The sense of smell is impaired in about 70% of patients. Vision is also effected, including color perception. The patient may experience changes in sensations of temperature, hot flashes, excessive sweating, and cramps and burning in the legs. Parkinson symptoms that may occur after encephalitis include greasy skin and hair, tics, spasms, rapid and repetitive speech, and oculogyric crises -- disturbances in which the eyes become fixed in one direction for minutes or even hours. In people with a history of migraine, the onset of Parkinson's is associated with change in migraine symptoms (most often improvement). Constipation is a major problem for Parkinson patients and occurs both as a result of the disease and a side effect of its treatment. Laxatives, stool softeners, and other medications may be prescribed. The drug cisapride (Propulsid) appears to help some people with constipation and a poor response to levodopa (see Diet, in this report). Bladder control and urinary incontinence are also problems, which can be helped by taking Sudafed.

Who Gets Parkinson's Disease?

Risk Factors for Parkinson's Disease

Parkinson's disease affects people worldwide, including more than a million people in North America.

Age and Gender. The average age of onset is 55. The elderly are at higher risk for both parkinsonism and Parkinson's disease, although there is some evidence that the very elderly (over 75) are at low or no risk. About 10% of Parkinson's cases are in people younger than 40 years old. Having a first-degree relative who develops Parkinson's after age 50 does not usually pose any higher than average risk; having a parent or sibling with the disease earlier than age 50, however, does. One study suggested that the disease progresses more rapidly in men than women, but these results may have only indicate that men are less responsive to the treatments for Parkinson's. Older women seem to be more at risk for gait disturbance and men for rigidity and tremor.

Relatives. People with siblings or parents who developed Parkinson's at a younger age are at higher risk for Parkinson's disease, but relatives of those who were elderly when they had the disease appear to have an average risk.

Ethnicity and Geography. African- and Asian-Americans have a lower risk than European-Americans. A higher incidence of parkinsonism is found in people who live in rural areas, particularly those who drink private well water or are agricultural workers exposed to pesticides and herbicides. These risks, however, seem to vary depending on ethnicity, indicating that genetic factors are also at work.

Smoking. Cigarette smokers appear to have a lower risk for Parkinson's disease, This finding, of course, is no excuse to smoke, but such protection may help researchers develop new therapies.

Risk Factors for Parkinsonism

The symptoms of parkinsonism (tremor, gait disturbance, bradykinesia, and rigidity) appear in an estimated 8 million people over 65. In one study, parkinsonism occurred in about 15% of people 65 to 74 years of age, about 30% in those 75 to 84, and over half of people older than 85. It should be noted that this particular study included people with very mild symptoms and the percentages are higher than ones using stricter criteria.

How Serious Is Parkinson's Disease?

General Outlook

Parkinson's disease is not fatal, but it reduces longevity. It also seriously impairs the quality of life and may sometimes lead to severe incapacity within 10 to 20 years. Treatments are increasingly effective however in alleviating symptoms and even slowing progression of the disease. Over time, however, the side effects of many of these medications can be nearly as distressing as the disease itself, and the drugs may eventually lose their effectiveness. Parkinson's disease is sometimes categorized as either tremor predominant or postural instability and gait disturbed (PIGD). In younger patients tremor is usually predominant and progression of the disease is slow. Elderly people are more apt to have PIGD. Some studies have suggested that early PIGD symptoms predict a faster decline than having tremor predominant. Gait disturbance is a particularly serious sign in the elderly.

Impact on Emotions and Mental Status

The emotional and psychiatric impacts of the symptoms are devastating. Depression is extremely common, although one study found that only about 7% of patients met the criteria for major depression. Such patients were generally much older and already had mental or psychiatric problems. Depression in the remaining population was generally mild and most likely due to the emotional effect of the disease on the lives of both patients and their families -- not actual physical changes in the brain. Dementia is about six times more common in the elderly Parkinson patient than in the average older adult. In one study, 28% of all patients and two thirds of those over 85 had dementia. Nearly all drug treatments used for Parkinson's disease have side effects that cause neurologic and psychiatric disturbances. The physical and emotional impact on the family should not be underestimated as the patient becomes increasingly dependent on their support.

What Will Confirm the Diagnosis of Parkinson's Disease?

Underdiagnosis and misdiagnosis of Parkinson's disease are common and there is no objective laboratory test that can identify the disease. Early in the course of Parkinson's disease, symptoms can be very mild and may be confused with other problems, particularly in young adults. Too often, a younger person with Parkinson's may be diagnosed with mental illness, because even the physician may suspect the disease only in older people. About 15% of patients who are evaluated for Parkinson's disease turn out to have some other problem or are taking medications that trigger its symptoms. Therefore, a medical and personal history that includes any medications being taken and exposure to environmental toxins is very important. Often people who have parkinsonism -- but not Parkinson's disease -- have additional neurologic symptoms. Parkinson's is strongly suspected in patients who have a powerful early response to the drug levodopa, who have a tremor when their limb is relaxed, and whose symptoms appear on one side of the body. Early gait disturbance often indicates a disease other than Parkinson's disease. Even these criteria are not clear cut. For example, about 25% of Parkinson's patients will not have a tremor. Some patients with a condition called multiple system atrophy will have a good initial response to levodopa, but it is not sustained. Imaging tests, such as magnetic resonance imaging, are somewhat useful in ruling out other, rare neurologic conditions such as hydrocephalus or brain tumors. Showing great promise is the use of the imaging drug, Altropane, which is tagged with a radioisotope, in combination with the advanced imaging technique single photon emission computed tomography (SPECT). By revealing how the drug accumulates in the brain, this imaging technique may detect early Parkinson's and allow physicians to gauge disease progression and effectiveness of treatment.

In later stages of Parkinson's disease, the symptoms are usually unmistakable, and the problem can often be diagnosed using simple physical tests and a medical and personal history. Slowness and difficulty of movement are usually the first symptoms, so the patient will be asked to walk and probably to get out of a chair, preferably a deep one. The physician will also check for tremors and rapid movements of the hands and fingers, although sometimes the tremor is not present, making a definite diagnosis more difficult. Although imaging techniques are not usually necessary when physical symptoms of Parkinson's disease are obvious, they are occasionally used to rule out other medical problems.

What Are the Drug Treatments for Parkinson's Disease?

The goals of treatment for Parkinson's disease are to relieve disabilities and to balance the problems of the disease with the side effects of the medications. Treatment is very individualized for this complicated problem, and patients must work closely with physicians and therapists throughout the course of the disease to customize a program suitable for their particular and changing needs. Patients should never change their medications without consulting their physicians, and they should never stop taking their medications abruptly.

Treatments by Stage of Parkinson's Disease

Onset of Parkinson's Disease	Life-Style Changes (Exercise, Diet) Levodopa Anticholinergic Drugs Amantadine Selegiline Dopamine Agonists Catechol-O-Methyl Transferase Inhibitor
Long-Term Maintenance Therapy	Levodopa in combination with: Selegiline Dopamine Agonists Catechol-O-Methyl Transferase Inhibitors
Advanced Disease	Experimental Drugs Surgical Procedures: Pallidotomy Thalamotomy Radiosurgery Neurostimulation Tissue Implantation

Levodopa and General Guidelines for Treating the Stages of Parkinson's Disease

Onset of Parkinson's Disease. There is no standard method for treating the earliest symptoms. Before symptoms become disabling, some patients prefer trying lifestyle changes first, including exercise and diet. When the patient and physician determine that medication is necessary, the patient will start out with as low a dose as possible of any drug used.

Levodopa, or L-dopa (Laradopa), which is converted to dopamine in the brain, remains the gold standard for treating Parkinson's disease. The timing for its first administration in the development of the disease is controversial. Many physicians now initiate treatment with levodopa at the first sign of symptoms, particularly in people over 70. For younger people, who will require long-term treatment, however, physicians sometimes delay levodopa until symptoms become pronounced or after other drugs are no longer effective. Such physicians are responding to widely held beliefs that patients lose their response to the drug after a few years or that L-dopa may even become toxic over time. New studies indicate, however, that taking L-dopa for a long time does not harm remaining dopamine nerve cells, and in fact, may even promote recovery of those that are damaged. There is even some evidence that taking levodopa early in the course of the illness can even prolong life. It is true that certain symptoms may become less responsive to L-dopa, but most patients, if not all, derive substantial benefit from the drug throughout their lives.

Increasingly, however, drugs that can preserve residual dopamine are being used before L-dopa is even started. Selegiline is the most common of these drugs and is currently the first choice for younger adults; studies indicate that it may postpone the need for L-dopa up to several months and that it slows down the progression of disability. Other new drugs that are very promising for early onset Parkinson's include the dopamine agonists ropinirole and pramipexole and catechol-o-methyl transferase (COMT) inhibitors. Studies are indicating that both ropinirole and pramipexole are delaying the need for L-dopa and slowing the progression of the disease when it is in early stages. At one time, anticholinergics were the preferred drugs for initial therapy, but they have lost favor in the past few years because of side effects and because newer drugs are proving to be effective and tolerable. The drug amantadine stimulates dopamine release and may help early symptoms, although it loses effectiveness within about a year (For a description of individual drugs, see Drugs Used for Parkinson's Disease, below).

Long-Term Maintenance Therapy. Within four to six years of treatment with levodopa, the effects of the drug in many patients begin to last for shorter periods of time (called the wearing-off effect), and most patients start to experience motor fluctuations. For instance, patients often first notice slowness (bradykinesia) or tremor in the morning before the next dose is due. Less commonly, some patients experience painful dystonia -- muscle spasms that can cause sustained contortions, particularly of the neck, jaw, trunk, and eyes, but may also affect other parts of the body, including the feet. Patients must increase the frequency of levodopa doses. This puts them at risk for dyskinesia -- the inability to control their muscles -- which usually occurs when the drug's level peaks. Dyskinesia can take many forms, most often uncontrolled flailing of the arms and legs or chorea -- rapid and repetitive motions that can affect the limbs, face, tongue, mouth, and neck. Dyskinesia is not painful, but it is very distressing. In about 15% to 20% of patients the fluctuations become extreme, a phenomenon known as the on-off effect, which consists of unpredictable, alternating periods -- sometimes within minutes or seconds -- of dyskinesia and immobility. The transition may follow such symptoms as intense anxiety, sweating, and rapid heartbeats.

One study found that within the first five years of therapy, about 20% of patients had predictable wearing-off periods, and at 15 years, 70% of patients had off periods or dyskinesia. About 30% however, experienced neither side effect after 20 years of levodopa. Debate is ongoing about whether the wearing-off effect and dyskinesia are due to progression of the disease, the prolonged exposure to dopamine, or both. Some experts believe that the brain's dopamine neurons become incapable of storing dopamine and when the levodopa wears off, little or no natural dopamine remains. Some studies have suggested that as levodopa is metabolized, it produces oxygen free radicals, which in turn accelerates dopamine degradation.

To reduce the effects of fluctuation and the wearing-off effect, it is important to maintain as consistent a level of dopamine as possible. A number of strategies are being developed to accomplish this. A prolonged release version of levodopa (Sinemet CR) helps reduce the incidence of fluctuations for some people. In a recent study, although more expensive, this long-acting form allowed reduced doses and so the overall cost was lower than with the standard form. A liquid form of Sinemet may produce fewer fluctuations and a prolonged "on" time compared with the tablet.

In general, however, physicians are increasingly using combinations of levodopa and other drugs. Selegiline is the most common combination drug and may delay the wearing-off effect for six months to a year, although some people have experienced benefits for as long as two years. Selegiline does not have much impact on the on-off phenomenon itself. Other combination drugs are proving to be very effective; they include the dopamine agonists pramipexole and ropinirole and catechol-o-methyl transferase inhibitors. Some experts strongly recommend starting out with low doses of several drugs rather than high doses of a single one. (See discussions of individual drugs, below.)

Advanced Disease. Eventually symptoms, such as stooped posture, freezing, and speech difficulties, may not respond to drug treatment. Total unresponsiveness is unlikely, however, even after 20 years of treatment. Simply increasing the dose of levodopa or its frequency raises an unacceptable risk of the distressing side effects, including dyskinesia, confusion, and even hallucinations. Some physicians have tried hospitalizing patients, totally withdrawing the levodopa, and then readministering it, but benefits were seen for only a few months, and there were some dangerous risks to the process of withdrawal, including pneumonia and blood clots in the lungs. Surgical treatments, including pallidotomy, neurostimulation, and transplantation may help some patients. Research is on-going to develop drugs and procedures that will manage advanced disease and possibly even reverse the process.

Description of Individual Drugs Used for Parkinson's Disease

Levodopa in Early Stages. Levodopa, or L-dopa, is most effective against rigidity and slowness, but produces less benefit for tremor, balance, and gait. The standard preparations (Sinemet, Atamet) combine levodopa with carbidopa, which improves the action of levodopa and reduces some of its side effects, particularly nausea. Levodopa can also be combined with benserazide (Madopar) with similar results, but Sinemet is almost always used in America. Dosages vary, although the preparation is usually taken in three or four divided doses per day. If the symptoms do not improve after two or three months, the physician should look for problems other than Parkinson's, although some Parkinson's patients may have abnormalities in other brain sites that do not respond to L-dopa. Sometimes patients are so depressed they cannot tell if the drug is beneficial or not, and only a series of physical examinations by the doctor will indicate that the drug is actually helping. In half of Parkinson's patients, levodopa significantly improves the quality of life for many years. One study indicated that women may be more sensitive than men to the effects of L-dopa, although this finding needs to be confirmed in further trials. The observation could also simply indicate that the disease progresses more swiftly in men.

The toxic effects of levodopa with or without carbidopa are considerable. Nausea and low blood pressure are the most common problems during the first few weeks, particularly if the initial dose is too high. The addition of extra supplements of carbidopa reduces this effect to some degree. Taking the drug with food can alleviate the nausea. It should be noted, however, that proteins interfere with intestinal absorption of levodopa, and some physicians recommend not eating any protein until nighttime in order to avoid this interference. To offset low blood pressure, the patient should drink lots of fluids and possibly increase salt intake. The drugs can affect other organs, sometimes producing disturbances of heart rhythm or gastrointestinal bleeding. Major impacts, however, are psychiatric. Patients taking levodopa, especially in combination with other drugs, can experience confusion, extreme emotional states, vivid dreams, visual and possibly auditory hallucinations, anxiety, and even psychosis. The drug may even unmask dementia that had not been previously noticed. Because psychiatric side effects often occur at night, some physicians recommend reducing or stopping the evening dose. It should be noted that levodopa provokes fewer psychiatric side effects than other drugs used for Parkinson's disease, including anticholinergics, selegiline, amantadine, and dopamine agonists (see below). Some studies indicate that the drug clozapine (Clozaril), normally used in schizophrenia, may help offset the psychiatric side effects, but it has some dangerous side effects and needs to be used with caution. It should also be noted that switching to newer drugs, such as risperidone or olanzapine, which are often used at alternatives to clozapine, can worsen Parkinson's symptoms.

Selegiline and Other Monoamine Oxidase Inhibitors. Selegiline (Eldepryl, Movergan), also known as deprenyl, is an antioxidant drug that blocks the enzyme monoamine oxidase B, which degrades dopamine. Selegiline (Eldepryl, Movergan), or deprenyl, is the drug most commonly used in early-onset disease and in combination with levodopa for maintenance. It may actually have nerve-protective properties. Of great concern is a long-term study and its 1998 update that found an increased risk of death after people had taken Sinemet combined with selegiline (particularly in the third and fourth years) compared to those taking Sinemet alone. In the group taking Sinemet, those who died had a higher rate of dementia and history of falls. Shedding some light on these negative results was another study that reported a high incidence of orthostatic hypotension in some people taking the drug combination. Such a condition causes an abrupt and sometimes severe drop in blood pressure after standing and could indicate changes in the blood vessels that might contribute to more serious complications. On the encouraging side, a recent analysis of five long-term studies found no increased mortality rate using the combination. Some experts recommend that patients taking the drugs should be tested for orthostatic hypotension; those that show susceptibility should be withdrawn gradually. It is not clear whether those taking selegiline alone are at higher risk for hypotension (this side effect occurs in other Parkinson's drugs as well). Selegiline has adverse effects with nearly every antidepressant, some very serious. Patients suffering from depression should discuss all treatment options with their physician. Another, monoamine oxidase inhibitor, moclobemide, which is used as an antidepressant in Europe, may also be effective in enhancing the efficacy of L-dopa. It may also be safe when used with some of the more popular antidepressants, but it is not yet available in America. People taking any monoamine oxidase inhibitor are at risk for high blood pressure if they consume tyramine-containing foods or beverages, including aged cheeses, most red wines, vermouth, dried meats and fish, canned figs, fava beans, and concentrated yeast products.

Dopamine Agonists. The drugs known as dopamine agonists are being used in early-onset Parkinson's to delay the administration of L-dopa and are also used in long-term maintenance either alone or in combination with levodopa. These drugs stimulate dopamine receptors in the substantia nigra -- the part of the brain in which Parkinson's is thought to originate. Pramipexole (Mirapex) and ropinirole (Requip), are proving to be especially safe and effective for both initial therapy and in combination with L-dopa. In a 1998 study, ropinirole allowed lower dosages of L-dopa and produced better "off" times than the use of L-dopa alone. Pramipexole appears to have antidepressant properties. Such drugs do not produce oxygen-free radicals, as levodopa does, and may even have actions that protect the nerves from further damage. Side effects vary but include nausea, constipation, headache, dyskinesia, hypotension, and nasal congestion. The drugs can also cause nightmares, hallucinations, and even psychosis. Older dopamine agonists, such as bromocriptine (Parlodel), pergolide (Permax), and lisuride, are known as ergot-derived drugs and have more severe side effects than the newer dopamine agonists. Uncommon, but serious side effects reported with the use of ergot-derived drugs are scarring on the outside of the lungs or other organs and skin abnormalities. Experts recommend periodic monitoring for these side effects for patients taking any ergot-derived dopamine agonist. A long-acting dopamine agonist cabergoline (Dostinex) has also been developed, but is not yet available in America. Studies indicate that it can improve motor function during both on and off periods, allowing a reduction in the L-dopa dosage (cabergoline is also ergot-derived).

Apomorphine is a dopamine agonist used as a single daily injection. It is particularly effective when administered as a "rescue" drug in people experiencing severe on-off effects. It causes vomiting, however, and needs to be used with an additional anti-nausea drug, domperidone. Other side effects are excitability and aggression. Patches, nasal sprays, and forms of apomorphine are showing promise as alternatives to injections.

Catechol-O-Methyl Transferase Inhibitors. The catechol-O-methyl transferase (COMT) inhibitors, tolcapone (Tasmar) and entacapone, increase concentrations of existing dopamine in the brain. They are proving to be particularly useful in early treatment and for long-term maintenance with levodopa. They have shown impressive results in improving "on" time and reducing the requirements for L-dopa. Tolcapone appears to improve motor fluctuations. Side effects include occasional diarrhea and dyskinesia. Of concern, however, are reports of a few deaths from liver damage in patients taking tolcapone (at this time one in 20,000). The drug is now recommended only for patients who do not have severe movement abnormalities and who cannot take other treatments. Physicians should take blood tests for liver function once every two weeks. Patients themselves should watch out for symptoms of liver damage, including jaundice (yellowish skin), fatigue, and loss of appetite. If the patient does not respond to the drug within three weeks, it should be withdrawn. No one should withdraw abruptly from this drug.

Anticholinergic Drugs. Anticholinergics work best against tremor in the early stages, but are not as effective against bradykinesia and posture problems. They commonly cause dryness of the mouth (which can actually be an advantage in some people who experience drooling). Other side effects are nausea, urinary retention, blurred vision, and constipation. These drugs can also increase heart rate, worsen constipation, and cause urine retention in men with enlarged prostate. People with glaucoma should use these drugs cautiously. Anticholinergics can sometimes cause significant mental problems, including memory loss, confusion, and even hallucinations, which can be particularly problematic for elderly people with signs of existing dementia and people taking tricyclic antidepressants. Among the many anticholinergics are trihexyphenidyl (Artane, Trihexy), benztropine (Congentin), biperiden (Akineton), procyclidine (Kemadrin), and ethopropazine (Parisdol). Orphanadrine (Norflex) is a drug with anticholinergic properties but is also a muscle relaxant and does not cause urinary retention. Other drugs with anticholinergic properties, such as the antihistamine diphenhydramine (Benadryl) and tricyclic antidepressants, such as amitriptyline (Elavil, Endep) and doxepin (Adapin, Sinequan), may be used in combination therapies or for elderly people who cannot tolerate the more powerful drugs. These drugs have some side effects that are different from the anticholinergic agents, which should be discussed with the doctor. Withdrawal from anticholinergics or any drug used for Parkinson's disease should be gradual in order to avoid aggravating Parkinson symptoms.

Amantadine. Amantadine (Symadine, Symmetrel) stimulates the release of dopamine and may also be used for patients with early mild symptoms. According to some studies, it can also benefit patients in advanced stages who are unresponsive to other drugs. Unlike the anticholinergics, it has some benefit against muscle rigidity and slowness. It is less powerful than levodopa, however, and may lose its effectiveness after about half a year. Side effects are similar to those of anticholinergic drugs and also may include swollen ankles and mottled skin. Overdose can cause serious and even life-threatening toxicity. Patients with Parkinson's should not withdraw from this drug abruptly, which in rare instances, can cause acute delirium or a life-threatening condition called neuroleptic malignant syndrome. Pregnant or nursing women should not use this drug.

Experimental Drugs. A number of experimental drugs, including remacemide, dextromethorphan, riluzole, and lamotrigine, block the actions of glutamate -- an amino acid that is a particularly potent nerve cell killer. A class of drugs called adenosine receptor antagonists is showing promise in animal studies. Tests of compounds called neuroimmunophilin ligands are reporting nerve regeneration in the brains of animals. Another area of research is therapy that administers genes that code proteins responsible for producing dopamine or protect or even heal nerve cells damaged by Parkinson's disease. Nicotinic acetylcholine receptor agonists are other promising drugs. A recent study suggests that a nicotine patch may improve motor function and cognition in patients with early to moderate Parkinson's disease.

Hormone Replacement Therapy

Studies indicate that taking hormone replacement therapy after menopause reduces the risk of developing Parkinson's. Other studies show that it may also reduce the severity of early-onset Parkinson's as well as dementia related to the disorder.

What Are Surgical Procedures for Parkinson's Disease?

Pallidotomy

Pallidotomy is a surgical procedure that may be appropriate for some patients when drug therapy no longer works. It was used years ago with very limited success and was abandoned when levodopa was introduced. Pallidotomy has been revived recently because advances in imaging and new techniques that use a microelectrode recording allow surgeons to pinpoint the critical areas much more exactly. In some patients, brain scans have revealed that surgery restores normal brain activity related to voluntary movement. It does not cure the disease, however, and its primary benefit is to allow people to continue on Sinemet without incurring its side effects. The procedure is irreversible. The neurosurgeon drills a small hole into the skull and inserts an electrode, which generates a current and heat to destroy small amounts of tissue in the globus pallidus, a part of the brain responsible for many Parkinson's symptoms, particularly those that develop after long-term use of levodopa. The patient is awake during the operation, which takes about six hours. The hospital stay averages two days. The best results occur in symptoms that ordinarily respond to L-dopa. In a two-year study, dyskinesia significantly improved on the opposite side to the surgery, as did tremor, bradykinesia, and rigidity, and such benefits persisted. To a lesser degree, these symptoms initially improved on the same side of the body as the surgery, but benefits on this side were not sustained over time. Although instability, freezing, and gait improved in the first six months, such benefits did not last in many patients. The only reported benefit experienced from the procedure during the on periods was improvement in normal daily functioning. About half of the patients went from being dependent to independent, particularly in being able to feed and dress themselves, and remained that way for the next two years.

Unfortunately, only about 5% to 10% of Parkinson's patients are candidates. The procedure is generally not recommended for people who do not respond to levodopa, who are very elderly, whose primary symptom is tremor, whose predominant symptoms are freezing and falling (especially during on-periods), who have serious medical or mental disorders, or those with parkinsonism (as opposed to idiopathic Parkinson's disease). Surgical experience is improving outcomes, but even in centers with high track records, serious permanent complications occur in 1% to 3% of cases and include stroke, paralysis, numbness, and impaired peripheral vision -- even blindness. Studies show that neuropsychologic problems such as a decline in memory capacity may also occur.

Thalamotomy

Thalamotomy uses the same techniques as in pallidotomy, but it is performed on the thalamus, which is a major brain center for relaying messages. Thalamotomy is being used to reduce tremor in patients in whom this is the major disability and it is being tested to prevent or reduce dyskinesia. Results have been mixed, and some experts believe that a number of pathways are responsible for this side effect and that surgical procedures will probably have no real impact. About 80% to 90% of patients, however, report a major reduction or complete loss of tremor. Complications are similar to pallidotomy, except there is no danger of vision loss.

Neurostimulation

Procedures that use pulse generators to control symptoms are showing promise. One, called the Activa Tremor Control System, uses a tiny pulse generator surgically implanted near the collar bone. It is connected to four electrodes that have been implanted in the thalamus of the brain. The generator delivers programmed pulses to the thalamus that the patient turns on and off using a magnet held over the skin. When the pulses are turned on, the tremor is suppressed. In one study, the procedure significantly improved tremor in 67% of patients, although only on one side of the body. (Double implants are being studied.) Long-term effects are still unknown, although recent studies are indicating that it is safe and effective. The generator must be replaced every three to five years, and the procedure is very expensive -- around $20,000. This procedure in the thalamus helps only those with tremor.

Researchers are also investigating pulse generators implanted in other parts of the brain, including the globus pallidus and the subthalamic nucleus, which control symptoms of rigidity and involuntary motion. Small early trials are showing success in reducing symptoms and allowing reduction in medication in most patients.

Like pallidotomy and thalamotomy, neurostimulation is not a cure; on the other hand, it does not remove brain tissue and is reversible. Of some concern, however, is a possible risk for hemorrhage during implantation, and some experts are not convinced of the safety of implanting a polyurethane device in the brain.

Tissue Implantation

Experimental surgery is showing remarkable promise using fetal brain cells rich in dopamine implanted in the substantia nigra, but more work is needed to see if improvement is sustained over the long term. Fetal cells are the best replacements available, since these early cells have the capacity to develop into every cell found in the adult. Implantation best improves rigidity, slow movements, and the on-off effect; it has no effect on tremor. It can reduce the need for medication by up to half, but it takes up to 6 months for improvement to occur. In one long-term study six patients reported significant improvement that had lasted at least two years. The transplanted tissue was still in place after six years in one patient. The use of fetal tissue is extremely controversial, however, and research is on-going for alternatives, including the use of cells from other mammals or human placentas, and the use of synthetic microspheres to deliver dopamine directly to the brain. Some researchers hope to use cloning techniques on animal fetuses as a source for dopamine-producing nerve cells. Animal and laboratory studies are also using gene therapies and other advanced treatments for transplanting dopamine-producing cells or nerve-protecting cells into the brain. An exciting experimental technique involves replacing damaged cells in the brain with dopamine-producing nerve cells grown under laboratory conditions.

Radiosurgery

Radiosurgery is a non-invasive surgical technique typically used for brain cancer that is now being investigated for both thalamotomy and pallidotomy in patients who are not candidates for standard surgery. It employs a so-called gamma knife, which is not a knife at all, but 300 intersecting radiation beams that are directed through holes in a helmet to target precisely affected sites in the brain. Early studies are showing that it improves symptoms after about six to eight weeks. The only side effect reported so far has been swelling in the brain in a few patients, which appears to resolve over time.

What Lifestyle Changes Can Help Parkinson's Disease?

Diet

No special diets or natural foods have been shown to slow down the progression of Parkinson's disease. High levels of proteins, however, compete with levodopa for transport to the brain and reduce its effectiveness. Some experts advise a low protein diet during the day with almost all protein eaten in the evening meal. Loading proteins at night, however, can produce a severe "off" period during sleep, causing some people to awaken unable to move. Avoiding protein altogether is not the solution, since malnutrition can result. Most experts now recommend trying to maintain a carbohydrate-to-protein ratio of 7:1 throughout the day. This may be difficult to calculate and some physicians recommend simply keeping proteins to 12% of total daily calories. As an aid in calculation, it may be helpful to note that food labels indicate proteins in grams and that one gram of protein equals four calories. Good control of protein intake may help minimize fluctuations and wearing-off and may allow some patients to reduce their daily levodopa dosage. Animal studies indicate that restricting the intake of total calories increases resistance to toxic effects on nerve cells.

No evidence exists that vitamins improve the outlook of Parkinson's disease. However, some people believe that vitamin B6 (pyridoxine) is beneficial because it is necessary in the production and metabolism of dopamine. Most B vitamins play important roles in the brain and central nervous system. Although the major food sources of B vitamins are meats and dairy products, which are high in protein, these vitamins are also found in whole grains and are added as supplements to commercial cereals. Certain vitamins, such as C and E, are antioxidants that some people think can be protective. High doses (2000 IU per day) of vitamin E have shown no benefit in Parkinson's disease. Some vitamins can be toxic in high doses, patients wishing to take more than the recommended daily allowance of any vitamin supplement should consult their physicians. Eating whole grains and fresh fruits and vegetables is the best way to obtain antioxidant vitamins and other protective plant nutrients. A diet rich in fruits and vegetables may help protect nerve cell function. Many of these foods are also often rich in fiber, which is particularly important for helping to prevent constipation. People whose diets have been low in fiber should increase it gradually. It is best to obtain dietary fiber, soluble or insoluble, in the natural form of whole grains, nuts, legumes, fruits and vegetables; if it proves difficult to do so, psyllium, a grain naturally found in India, is an excellent soluble fiber supplement (Metamucil, Fiberall, Perdiem Fiber). Non-caffeinated beverages are particularly important in preventing constipation. People have found that herb tea made from Senna is helpful. Coffee and tea can actually reduce fluids by increasing urination.

Exercise and Physical Therapy

Physical therapy is extremely important for the Parkinson's patient and usually follows an approach that uses active and passive exercise, gait training, practice in normal activities, and if needed, hot or cold treatments, water therapy, and electrical stimulation. Passive exercise, mostly stretching and manipulation of muscles by a physical therapist, are aimed at preventing muscles from shortening. An active exercise program that begins with slow and gentle exercises and becomes progressively more intense may improve mobility in patients with early and mid-stage Parkinson's disease. Active exercises are used to help range-of-motion, coordination, and speed. Exercise is also essential for well-being; it is a common denominator in patients who are able to maintain productive years. Patients should continually make efforts to practice movement, even simple ones, such as marching in place, making circular arm movements, and raising the legs up and down while sitting. Patients who enjoy sports, such as swimming, golf, and tennis, or the use of exercise equipment should continue with these activities even if their skills diminish, assuming there are no other medical conditions that would prevent them.

Gait Training. Practicing new methods for standing, walking, and turning are important for retaining balance. Experts recommend taking large steps when walking, raising the toes at the forward step, and hitting the ground with the heel. Small steps should be taken while turning. When walking or turning, the legs should be 12 to 15 inches apart to provide a wide base. Patients should not wear rubber or crepe-soled shoes because they grip the floor and may cause the patient to fall forward. The use of rhythmic stimulation, such as the use of a metronome (a simple device used by musicians to keep time), may be even more effective than music in enabling some patients to walk faster and take longer steps. One study found that setting a metronome rhythm to about 10% faster than the patient's fastest gait offers significant improvement over walking to no rhythm at all or to a rhythm that matches the gait.

Reducing Muscle Freezing. The patient should practice regular daily activities that simplify actions and reduce the incidence of muscle freezing. Most often, freezing occurs when a patient begins to move or is presented with an obstacle. Sometimes, simply being touched by another person can release the patient (although a Parkinson's patient should never be pulled or pushed). If the legs feel frozen, sometimes simply lifting the toes frees the spasm. Rocking from side to side is useful, and some people have found that humming a marching tune helps. Because trying to coordinate a number of physical operations at the same time can cause freezing, the patient might find it helpful to divide actions into separate events. For instance, when going through a doorway, a patient should approach the door, stop, open the door, stop, then walk through the doorway. Music has been shown to help people move and to get out of bed in the morning. Some report that wearing a Walkman and turning music on in situations associated with freezing, such as crossing a street, is helpful.

Other Forms of Therapy

Some studies indicate that being mentally fit may be as important for Parkinson's patients as being physically fit. Mental training may actually increase dopamine in the brain. Some experts recommend selecting or learning new hobbies that require finger and hand mobility, such as sewing, carpentry, fishing, or playing cards. Speech therapy may be required for those who develop a monotone and lose volume. Deep breathing and relaxation exercises are important; they may help maintain proper speech control, control tremor, and reduce anxiety. Psychologic therapy and support is important for the depression and loss of motivation that often accompany this difficult condition. One study suggests that marital stress can even encourage loss of mobility. Although psychologic and behavioral therapies can be expensive, a number of support programs and groups that can be invaluable for the patient and the family are available at little or no cost (see Where Else Can Help Be Obtained for Parkinson's Disease, below).

Equipment and Devices

A number of devices can be helpful. Rails can be installed where the patient needs support in getting up or down, such as along the bed and in the bathroom. Walkers with locking wheels are helpful. Chairs should have straight backs, with firm seats and arm rests. Firm mattresses and satin sheets or less expensive sheets with high thread counts are useful for helping patients slide out of bed.

Personal Emergency Response System

People with Parkinson's disease should consider a personal emergency response system (PERS) such as Lifeline, which is offered by the American Red Cross. It provides patients with a battery-powered button to be worn around the neck or on the wrist and a machine that dials into a central location when the button is pushed. At this location, people will notify emergency units, family members, or other caretakers after verifying that the patient has fallen or needs assistance. The system can be rented.