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Parkinson's Disease

WHAT IS PARKINSON'S DISEASE AND WHAT CAUSES IT?

Parkinson's disease (PD) is a slowly progressive disorder that affects movement, muscle control, and balance. Parkinson's disease is referred to as idiopathic, which means that the cause is unknown. This term distinguishes the primary disease from parkinsonism, which are the symptoms occurring from a known cause.

Parkinson's Disease and Dopamine Loss

Parkinson's disease occurs from the following process in the brain:

PD develops as 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). Loss of dopamine in the corpus stratia is the primary defect in Parkinson's disease.
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 negatively affects the nerves and muscles controlling movement and coordination, resulting in the major symptoms characteristic of Parkinson's disease.
The disease process also may impair nerve endings in the heart that regulate the release of norepinephrine, a hormone that regulates blood pressure, pulse rate, perspiration, and other automatic responses to stress. Such effects could be responsible for the abrupt drops in blood pressure when standing that some patients experience. Further research is underway to determine if the loss of nerve terminals is confined to the heart or if it affects other organs as well.

Although it is clear that dopamine deficiency is the primary defect in Parkinson's disease, it is not clear what causes dopamine loss. The culprit is less likely to be a single cause than a combination of genetic and biologic factors, which are triggered by some environmental assault.

Biologic Factors

Abnormal Apoptosis (Programmed Cell Death). In everyone, cells in the body are programmed to naturally die through a genetically regulated process called apoptosis. In Parkinson's disease, there is some evidence that this process goes awry in nerve cells.

Proteins Involved in Parkinson's Disease Important research now suggests that three molecules are critical in the development of inherited PD: parkin, alpha synuclein (specifically alphaSp22), and ubiquitin, which all interact in the normal brain. AlphaSp22 is produced in the nerve cells involved with the dopamine pathway. Parkin normally causes alpha synuclein to bind with a molecule called ubiquitin, which then triggers apoptosis causing this compound to self-destruct. In many cases of inherited Parkinson's disease, however, parkin is abnormal and fails to bind alpha synuclein to ubiquitin. Apoptosis does not take place and, instead of dying, synuclein accumulates in Lewy bodies , deposits of fibrous tissue found in all patients with PD.

Another protein that may be critical in the disease process is beta amyloid, which builds up in the brains of Alzheimer's patients and is a major factor in that disease. Beta amyloid also increases the build-up of synuclein and may help explain the connection between Alzheimer's and Parkinson's disease in many patients.

Lewy Bodies. Fibrous deposits known as Lewy bodies are the hallmark signs of Parkinson's disease. They are found in the substantia nigra, the place in the brain where dopamine is first released. 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. They are found not only in the brains of patients with Parkinson's disease, but, in rare cases, may show up in cells in other parts of the body (the heart, intestine), causing severe disabling symptoms. These substances are also present in other diseases that cause dementia, such as Alzheimer's, and can occur in people without neurologic symptoms.

Complex I and Oxygen-Free Radicals. Some research has observed that certain Parkinson's patients have a 30% to 40% reduction in an enzyme called complex I. This enzyme is found in the mitochondria, sausage-like structures in cells that generate energy. Some theories suggest that low amounts of complex I may make nerve cells vulnerable to the assault of oxygen free radicals (also called oxidants). Oxidants are unstable molecules that bind to other molecules in the body. They are normally produced by the natural chemical processes in the body. If the body is subjected to environmental stresses, however, they can be over-produced. And, in access, they can damage any cell, including nerve cells in the brain, and even interferes with their DNA.

NMDA Receptors. Also of interest in PD 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. This in turn leads to a cascade of events that trigger oxygen-free radicals and cell damage.

Immune Factors and the Inflammatory Response. An over-responsive immune system triggered by initial damage may also play a role in perpetuating Parkinson's disease. When the immune system becomes over-active, it produces excessive numbers of potent factors called cytokines, which cause inflammation and further injury in brain cells. Important cytokines under investigation are interleukin-1 and tumor necrosis factor.

Genetic Factors

Specific genetic factors appear to play a strong role only in early-onset Parkinson's disease. Multiple genetic factors are likely to contribute to the great majority of Parkinson's cases, which occur in older people. Nevertheless, the study of even rare genetic cases is proving to be useful in understanding the nature of degenerative nerve diseases in general.

Early Onset PD. The cases of genetic early-onset Parkinson's disease have most often been detected in specific family groups.

Defective genes that regulate the molecules alpha synuclein and parkin, which are important in the PD disease process, may be responsible for a number of early-onset cases. [ See Biologic Factors, above.] For example, genetic abnormalities the alpha synuclein protein has been detected in some early-onset Parkinson's patients of European descent.
The parkin gene may be the cause of many cases of early-onset Parkinson's in young adults. (Parkinson's cases associated with this mutation tend to progress slowly and respond well to treatment, even after years of symptoms. Dementia is also rare with this form.)

Late Onset PD. The role of genes in late-onset, the much more common form of the disorders, is not yet clear and appears to be weak. Still, some may be important:

Research published in 2001 has targeted the gene for the tau protein, which in its healthy state is important for the support structure in nerve cells that allows the flow of nutrients through them. A defective tau gene may increase susceptibility for idiopathic late-onset Parkinson's disease.
Investigators have observed iron deposits in the brains of PD patients. Animal research suggests that genetic factors that impair iron metabolism may play a role in late-onset PD.

Environmental Assaults and Oxygen-Free Radicals

Environmental toxins, infections, and other triggers can provoke excessive production in the body of oxygen free-radicals, damaging particles that may play a major role in the deterioration of nerve cells that lead to Parkinson's.

Infectious Agents. Some research has identified immune factors that suggest a viral presence in the Lewy bodies and swollen nerve pathways of Parkinson's brains. Influenza and other potent viruses have long been known to be a cause of parkinsonism. In one well-known example, a major flu epidemic causing encephalitis in the early twentieth century left many of its victims with parkinsonism.

Environmental and Industrial Chemicals. Intense exposure to certain environmental and industrial chemicals is also being studied.

• Pesticides and Herbicides. Some evidence implicates pesticides and herbicides as important factors in many cases of Parkinson's disease. A higher incidence of parkinsonism has long been noted in people who live in rural areas, particularly those who drink private well water or are agricultural workers. A large 2000 study found a strong link between high exposure to insecticides and herbicides at home and a 50% to 70% increase in risk of Parkinson's. Important studies are implicating rotenone, a common organic chemical in pesticides, which may release powerful destructive oxidants that target the dopamine nerve cells that are important in PD. Rotenone is very unstable, however, and some research suggests that it becomes inactive too quickly to affect human brains.

• Other Chemicals. Intense exposure to other industrial chemicals and metals (manganese, copper, lead, iron, mercury, zinc, aluminum, and others) has also been linked with parkinsonism, which is often reversible. The role of long-term exposure in the development of Parkinson's disease is unclear.

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 excessive stress on these transporters might trigger Parkinson's disease in the aging, and more vulnerable, brain.

WHAT ARE THE SYMPTOMS OF PARKINSON'S DISEASE?

Tremors

Parkinson's disease (PD) symptoms often start with tremor, which may occur in the following way.

Tremors may first be only occasional, starting in one finger and spreading 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 pill rolling.
Tremors can occur when the limb is at rest or when it is held up in a stiff unsupported position. They usually disappear briefly during movement and do not occur during sleep.
Tremors can also eventually occur in the head, lips, tongue, and feet. Symptoms can occur on one or both sides of the body. In one study, 44% of patients reported experiencing internal tremors lasting less than half an hour, but occurring several times a week.

In younger patients tremor is usually predominant and its presence often suggests a slower progression of the disease. Some evidence suggests that tremor in PD may occur from mechanisms in the brain that are different from those that cause other PD symptoms.

Motion and Motor Impairment

A number of PD symptoms involve motor impairment caused by the abnormalities in the brain that regulate movement:

Slowness of motion ( bradykinesia) is one of the classic symptoms of Parkinson's disease. 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.
Patients may eventually develop a stooped posture and a slow, shuffling walk. The gait can be erratic and unsteady.
Intestinal motility (the ability to swallow, digest, and eliminate) may slow down, causing eating problems and constipation.
Muscles may become rigid ( akinesia). This symptoms often begins in the legs and neck. Muscle rigidity in the face can produce a mask-like, staring appearance.
Motor abnormalities that limit action in the hand may develop in late stages. Handwriting, for instance, often becomes diminutive.
Normally spontaneous muscle movements, such as blinking, may need to be done consciously.

Other Symptoms of Parkinson's Disease

Other symptoms include the following:

Depression. Depression caused by chemical changes in the brain may be an early symptom of Parkinson's. Depression is a common problem in older people, however, and it is likely not to be recognized as a symptom.
Orthostatic hypotension. Some patients experience a sudden drop in blood pressure when they stand. This can cause dizziness and fainting.
Changes in sensations of temperature, hot flashes, and excessive sweating.
Leg disorders. Cramps and burning sensations in the legs are common. Restless legs syndrome affects some patients. This is an irresistible urge to move the calves, which often occurs at night, disturbing sleep. [ See the Report Leg Disorders .]
Changes in migraine symptoms. In people with a history of migraine, the onset of Parkinson's is associated with change in migraine symptoms (most often improvement).

WHO GETS PARKINSON'S DISEASE?

Parkinson's disease affects about 3% of Americans over 65 years old. Experts estimate that this percentage could double in the next 30 to 40 years. The symptoms of parkinsonism (tremor, gait disturbance, bradykinesia, and rigidity) occur in even more people, estimated to be 8 million over 65. In a study that included very mild symptoms, 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.

Age

The average age of onset of Parkinson's disease is 55. About 10% of Parkinson's cases are in people younger than 40 years old. Older adults are at higher risk for both parkinsonism and Parkinson's disease. There is some evidence, however, that the risk declines significantly after 75 and that the very elderly are at low risk.

Gender

Some research indicates that men may face up to twice the risk as women. Estrogen may offer some protection for women up until menopause. A 2001 study, for example, reported a higher rate of Parkinson's disease in women who had undergone hysterectomy. One study suggested that the disease also progresses more rapidly in men than women. 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

African- and Asian-Americans have a lower risk than European-Americans. Some evidence suggests that non-Caucasians may be more vulnerable to an atypical form of PD, which causes early impairment in thinking and has a poor response to levodopa, the primary PD treatment.

The Effect of Cigarettes and Coffee on Parkinson's Disease

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

Coffee Consumption. In a 30-year 2000 study of Japanese-American men, coffee consumption was associated with a lower risk for Parkinson's disease and the more coffee they drank, the lower their risk became. Caffeine, which is a known central nervous system stimulant, appears to be the protective factor. The study did not prove that coffee actually protects against Parkinson's, however, and further research is needed.

HOW SERIOUS IS PARKINSON'S DISEASE?

General Outlook

Parkinson's disease is not fatal, but it reduces longevity. The disease progresses more quickly in older than younger patients, and may lead to severe incapacity within 10 to 20 years. Older patients also experience freezing and greater declines in mental function and daily functioning.

Parkinson's disease can seriously impair the quality of life in any age group. The physical and emotional impact on the family should not be underestimated as the patient becomes increasingly dependent on their support.

Treatment advances are increasingly effective in alleviating symptoms and even slowing progression of the disease. Taking many of the medications over time, however, can produce significant side effects. Newer agents may help reduce these occurrences.

Motor Impairment

The negative effect of overall motor and muscle impairment on daily life can be considerable in Parkinson's patients. Some motor complications can be life threatening.

Disturbed gait and unstable posture are common and serious problems in elderly PD patients, since they increase the risk for falling and injury. Some studies have suggested that the appearance of these symptoms early in the course of the disease predict a faster decline than having tremor as the predominant symptom.
Swallowing problems (dysphagia). The presence of dysphagia is associated with shorter survival time. Motor impairment of the muscles in the throat not only impairs swallowing but it also poses a risk for aspiration pneumonia.
Constipation is a major problem 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 important complications of PD. [ See the Report Incontinence.]
Speech problems occur in more than 70% of Parkinson's patients, by some estimates. Speech difficulty can be 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.

Impact on Emotions

Depression is extremely common, affecting up to 40% of Parkinson's patients. PD poses a triple threat on the emotional health of its victims:

The disease process itself causes changes in chemicals in the brain that effect mood and well being.
The complications of its symptoms have a profound impact on daily life that can be emotionally devastating without help and support.
All drug treatments used for Parkinson's disease have side effects that can cause neurologic and emotional disturbances.
Treating depression and insomnia in patients who have these complications plus problems in thinking may, in fact, also improve mental functions.

Effects on Thinking and Mental Status

Impaired Thinking (Cognitive Impairment). Defects in thinking, memory, language, and problem solving skills may occur early on in untreated patients or late in the course of the disease. Medications may play a role in thinking problems. In one study, for example, patients with PD were slower in detecting associations, although (unlike in Alzheimer's disease) once they discovered them they were able to apply this knowledge to other concepts. After they were taken off medication, however, they had no problems with the tasks.

Dementia. Dementia is about six times more common in the elderly Parkinson patient than in the average older adult. It is most likely to occur in older patients who have had major depression. Unlike in Alzheimer's, language is not usually affected in Parkinson's related dementia. Visual hallucinations occur in about a third of people on long-term medications that increase dopamine, possibly because of some genetic susceptibility.

Other Problems that Impair Daily Life

A number of other problems associated with Parkinson's disease affect daily life:

Sleep disorders are common in PD, both from the disease itself and from its treatments. In general, patients have a higher risk for disturbed sleep and daytime sleepiness, including suddenly falling asleep. Many PD patients also suffer from nighttime let cramps and restless legs syndrome. And, some of the medications cause vivid dreams as well as waking hallucinations.
Sexuality is also reduced. This is an area not often studied but which is important for many patients' well-being. A 2000 study reported that not only did sexual dysfunction occur, but also affectionate touching and expression of feelings were reduced, even though both partners maintained a desire for intimacy.
The sense of smell is impaired in about 70% of patients.
Vision is also affected, including color perception.

WHAT WILL CONFIRM THE DIAGNOSIS OF PARKINSON'S DISEASE?

It is difficult to diagnose Parkinson's in early stages. At this time the disease is diagnosed almost primarily by its symptoms, and studies indicate that physicians make an incorrect initial diagnosis of Parkinson's disease in between 8% and 35% of cases. Even general neurologists have difficulties in correctly identifying the disease. Researchers are hopeful that objective and simple blood or imaging tests will be available in the near future to identify the disease early in its development.

Medical and Personal History

A medical and personal history should include any relevant symptoms as well as any medications being taken, and exposure to environmental toxins is very important.

Diagnosing by Symptoms

Early Symptoms. Early treatment may help slow progression, so an early diagnosis of Parkinson's is highly desirable. Early symptoms are often mild however, so Parkinson's disease can be missed, particularly in young adults. Repeated assessment of symptoms over time is important to improving the accuracy of diagnosis. Too often, for example, a younger person with Parkinson's may be diagnosed with mental illness, because even the physician may suspect the disease only in older people.

Parkinson's may be suspected in patients with the following symptoms:

• Slowness and difficulty of movement. These 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. (Early gait disturbance, however, often indicates a disease other than Parkinson's disease.)

• A tremor when their limb is relaxed. (As many as 25% of Parkinson's patients, however, will not have a tremor.)

• Symptoms on one side of the body.

• A powerful early response to the drug levodopa (the primary treatment for Parkinson's). It should be noted that some patients with a very similar condition called multiple system atrophy will have a good initial response to levodopa, but it is not usually sustained.

Later Symptoms. 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.

Imaging Techniques

Although imaging techniques, such as computerized tomography (CT), magnetic resonance imaging (MRI), or positron-emission tomographic (PET), are not usually necessary when physical symptoms of Parkinson's disease are obvious, they may be very useful in ruling out disorders with similar symptoms, such as progressive supranuclear palsy.

Research is ongoing to determine if imaging tests can detect early and late stages of Parkinson's and allow physicians to gauge disease progression and effectiveness of treatment. Single photon emission computed tomography (SPECT) is an advanced imaging technique showing great promise.

Ruling out Causes of Parkinsonism and Diseases that Mimic Parkinson's Disease

When symptoms resemble Parkinson's disease but have an identifiable cause, the syndrome is known as parkinsonism. People who have parkinsonism, but not Parkinson's disease, often have additional neurologic symptoms. A number of conditions can also have similar or some of these 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.

Alzheimer's disease can be very similar. In one study 23% of people with Alzheimer's also met the criteria for Parkinson's disease. The two diseases also often coexist, and research suggests that Alzheimer's and Parkinson's disease may sometimes share a common biologic origin, the accumulation of the protein alpha synuclein and Lewy bodies in the brain.

• Lewy bodies variant (LBV), also called dementia with Lewy bodies, is a separate disease from both Alzheimer's and Parkinson's disease. It has similar symptoms to both but is marked by early dementia.

• Encephalitis caused by influenza has been known to cause parkinsonism.

• 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 involves less tremor and earlier rigidity, and it tends to affect both sides of the body symmetrically. Magnetic resonance imaging scans that measure parts of the midbrain may be a reliable method for distinguishing between PD and progressive supranuclear palsy.

• Multiple system atrophy (previously called Shy-Drager syndrome) is a degenerative nerve disease that also affects movement and blood pressure and has many of the symptoms of Parkinson's disease. Some research suggests that a trial using the drug apomorphine may help differential between the two; patients with PD respond to the drug with higher levels of growth hormone than patients with multiple system atrophy.

• There have been reports of parkinsonian symptoms developing or worsening as a result of subdural hematomas (a collection or clot of blood on the surface of the brain). Such patients recover after removal of the hematomas.

• Other problems that may mimic Parkinson's disease include Wilson's disease, thyroid abnormalities, hydrocephalus, tumors, having the fragile X trait (but not the full disorder), and a number of degenerative neurologic diseases.

Drugs. Certain drugs or medications account for about 4% of all cases of parkinsonism. According to some 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 antipsychotic and antiseizure agents. Any with parkinsonism should discuss their medications with their physician.

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 GENERAL GUIDELINES FOR TREATING THE STAGES OF PARKINSON'S?

Overall Goals

The goals of treatment for Parkinson's disease are twofold:

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 disease. 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 Mild Symptoms	Life-Style Changes (Exercise, Diet) Drugs: Amantadine Selegiline Anticholinergic (for tremor)
Onset of Moderate Symptoms	Levodopa (L-dopa) Dopamine Agonists supplemented with L-dopa as necessary Catechol-O-Methyl Transferase Inhibitor
Long-Term Maintenance Therapy	Levodopa in combination with: Selegiline Dopamine Agonists Catechol-O-Methyl Transferase Inhibitors Amantadine
Advanced Disease	Experimental Drugs Surgical Procedures: Pallidotomy Thalamotomy Radiosurgery Neurostimulation

Treatments for 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, is converted to dopamine in the brain and so acts as a replacement drug. L-dopa has been used for years and is the gold standard for treating Parkinson's disease. It is used in nearly all phases of the disease. The standard preparation combines levodopa with an anti-nausea agent carbidopa (Sinemet, Atamet). [For more details, see What Is Levadopa (L-Dopa)? and What Are the Other Drugs Used for Parkinson's Disease?, below.]

The timing and treatments for treatment of symptom onset may be as follows:

Early mild symptoms may be treated with physical therapy and certain drugs (amantadine, anticholinergic drugs, selegiline).
Significant symptoms in people over 70 are almost always first treated with L-dopa.
Moderate symptoms in younger adults, who will require treatment for decades, may be treated first with dopamine agonists. These agents make use of any residual natural dopamine rather than simply replacing it, as L-dopa does. When symptoms become pronounced or other drugs are no longer effective, then L-dopa is given to the patient. There is major debate, however, about delaying L-dopa treatment and using the newer dopamine agonists first in younger adults other than those with early-onset disease. [ See Box Debate Concerning Early Use of L-Dopa versus Dopamine Agonists.]

Early Use of Dopamine Agonists versus L-Dopa

According to 2001 guidelines, dopamine agonists should be used as the first treatment for most PD patients. Controversy still exists over their first use.

Arguments for Early Use of Dopamine Agonists. The basic motive for early use of dopamine agonists is delay the complications of L-dopa, which tend to occur after five to fifteen years of treatment. Some 2000 studies reported that newer agents (pergolide, pramipexole, ropinirole) delayed the time for complications by about a year.

There is also some belief that L-dopa may harm nerve cells and become toxic over time.

Arguments for Early Use of L-Dopa. Experts who believe that L-dopa should be used early on in most adults are supported by the following arguments and studies:

Careful reviews of studies indicate 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 some evidence that taking levodopa early in the course of the illness can prolong life.
The newer drugs still have not been proven to be better than L-dopa. Studies in 2000 reported, in fact, reported that although they control the disease effectively early on, L-dopa still appears to achieve better motor control. And, after three years, there is no difference in disease progression among patients taking any of these drugs.
The first five years of the disease is generally marked by mild symptoms. And, although dopamine agonists delay L-dopa complications, these drugs can have severe side effects (such as nausea and hallucinations). Younger adults, then, who take L-dopa might have a better quality of life during those early years when they are most active.
It is well known that the effects of L-dopa begin to wear-off in increasingly shorter times the longer a patient has been on the drug. A 1999 controlled study reported, however, that the drug was still effective in 80% of patients after first five years of therapy. And other studies suggest that most patients, if not all, derive substantial benefit from the drug throughout their lives.

Long-Term Maintenance Therapy

To reduce the effects of complications of L-dopa (fluctuation and the wearing-off effect) during maintenance therapy, it is important to maintain as consistent a level of dopamine as possible. In general, physicians are increasingly using combinations of levodopa and other drugs to reduce adverse effects. Such drugs include the following:

Monoamine oxidase inhibitors. Selegiline agent is most commonly used and may delay the wearing-off effect for six months to a year, although some people have experienced a delay as long as two years. Selegiline does not have much impact on the on-off phenomenon itself.
Dopamine agonists. (Newer ones: pramipexole and ropinirole. Older one: pergolide). These are useful for both early wearing off and for on-off motor fluctuations.
Catechol-o-methyl transferase (COMT) inhibitors. Entacapone, the standard COMT inhibitor, is useful for wearing-off and motor fluctuations if dyskinesia is not a factor.
Amantadine. This drug is helpful as an additional drug for patients with dyskinesia. It may also be beneficial for patients with atypical PD (early problems in thinking and poor response to levodopa), who tend to be non-Caucasians.

Some experts strongly recommend starting out with low doses of several drugs rather than high doses of a single one. [ For descriptions of these agents, see What Are Other Drugs Used for Parkinson's Disease?, below.]

Few comparative studies have been conducted to reliably prove advantages of some of these groups over others. In one 2000 comparative study of COMT inhibitors and dopamine agonists, pergolide, pramipexole, and entacapone achieved the best reductions in "off" times (during which immobility occurs). Pramipexole and entacapone achieved the lowest doses of L-Dopa and had the fewest side effects. There are many options, however, and there is no one optimal approach for all patients.

Treating 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.) The following approaches may be tried:

Simply increasing the dose of levodopa or its frequency raises an unacceptable risk of the distressing side effects. 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. [ See What Are Surgical Procedures for Parkinson's Disease? below.]
Research is ongoing to develop drugs and procedures that will manage advanced disease and possibly even reverse the process. [ See What Are Other Drugs Used for Parkinson's Disease? below.]

WHAT IS LEVADOPA (L-DOPA)?

Levodopa, or L-dopa, which is converted to dopamine in the brain, remains the gold standard for treating Parkinson's disease. 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.

Indications of Early Treatment Success or Failures

In general L-Dopa has the following effects on Parkinson's disease:

It is most effective against rigidity and slowness.
It produces less benefit for tremor, balance, and gait.

In half of Parkinson's patients, levodopa significantly improves the quality of life for many years. In some cases symptoms do not improve after two or three months.

There may be different reasons for failure:

Other neurologic problems may be causing the symptoms.
Some Parkinson's patients 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.
One study indicated that men may be less responsive to L-dopa than women, although this finding needs to be confirmed in further trials. The observation could also simply indicate that the disease progresses more swiftly in men.

Toxic Effects

The toxic effects of levodopa with or without carbidopa are considerable.

Physical Side Effects. The physical side effects are as follows:

Low blood pressure. Low blood pressure is a common problem 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. The patient should drink lots of fluids and possibly increase salt intake to maintain normal blood pressure.
Arrythmias. In some cases the drug may cause abnormal heart rhythms.
Gastrointestinal effects. Stomach and intestinal side effects are common even with carbidopa. 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. The drug can also cause gastrointestinal bleeding.
Effects in the lung. Levodopa can cause disturbances in breathing function, although it may benefit PD patients who have upper airway obstruction. The mechanism of such actions are unclear.
Hair loss.

Psychiatric and Mental Side Effects. The major adverse effects of the drug are psychiatric. Patients taking levodopa, especially in combination with other drugs, can experience the following:

• Confusion.

• Extreme emotional states, particularly anxiety.

• Vivid dreams.

• Visual and possibly auditory hallucinations. The drug may even unmask dementia that had not been previously noticed.

• Effects on learning. L-dopa appears to have mixed effects on learning. It may actually improve working memory. However, some evidence suggests that it floods and impairs areas of the brain related to other learning functions (specifically as the ability to apply different rules of behavior in similar situations.)

• Sleepiness and sleep attacks.

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 ]. Because psychiatric side effects often occur at night, if they are severe some physicians recommend reducing or stopping the evening dose.

The Wearing-Off Effect and Dyskinesia (Inability to Control Muscles)

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 the following pattern may occur:

Patients may first notice slowness ( bradykinesia) or tremor in the morning before the next dose is due.
Less commonly, some experience painful dystonia, muscle spasms that can cause sustained contortions of various parts of the body, particularly the neck, jaw, trunk, and eyes and possibly the feet.
Patients must increase the frequency of levodopa doses. This puts them at risk for dyskinesia (the inability to control muscles), which usually occurs when the drug 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 some people, eventually L-dopa is effective only for one to two hours and most patients start to experience motor fluctuations. In about 15% to 20% of patients such fluctuations become extreme, a phenomenon known as the on-off effect , which consists of unpredictable, alternating periods of dyskinesia and immobility. Sometimes the symptoms switch back in forth within minutes or even seconds. (The transition may follow such symptoms as intense anxiety, sweating, and rapid heartbeats.)

Reasons for the Wearing-Off Effect. Debate is ongoing about the cause of the wearing-off effect and dyskinesis. Some theories suggested for these effects are the following:

The disease progresses beyond the ability of levodopa to control it.
Some patients become tolerant to prolonged exposure to dopamine and, at the same time, the disease is progressing.
The brain's own dopamine neurons become incapable of storing dopamine and when the levodopa wears off, little or no natural dopamine remains.
Levodopa itself accelerates the disease by producing oxygen free radicals, unstable particles that increase injuries to the brain and dopamine degradation.

Preventing the Wearing-Off Effect. To reduce the effects of fluctuation and the wearing-off effect, it is important to maintain as consistent a level of dopamine as possible. Unfortunately, levodopa is poorly absorbed and may remain in the stomach a long time. A number of strategies are being developed to take care of these problems:

Some patients take multiple small doses on an empty stomach, crushing the pills and mixing them with a lot of liquid.
A liquid form of Sinemet may produce fewer fluctuations and a prolonged "on" time compared with the tablet.
A prolonged release version of levodopa and carbidopa (Sinemet CR) is also available to control fluctuations for some people. (Some evidence suggests that there is no actual difference in symptom control between the sustained and immediate release forms, but patients on Sinemet CR tend to experience a better quality of life.)

WHAT ARE OTHER DRUGS USED FOR PARKINSON'S DISEASE?

Selegiline and Other Monoamine Oxidase Inhibitors

Benefits. Selegiline (Eldepryl, Movergan), also known as deprenyl, is an antioxidant drug that blocks monoamine oxidase B (MAOB), an enzyme that degrades dopamine. Until recently, selegiline (Eldepryl, Movergan), or deprenyl, was the drug most commonly used in early-onset disease and in combination with levodopa for maintenance. A 2001 study reported that it may help delay the onset of gait freezing. Rasagiline, another MAO-B inhibitor, is showing promise in trials.

Other Adverse Effects. Selegiline has important side effects:

One of the most important side effects is orthostatic hypertension, particularly in people taking Sinemet plus selegiline.
It has adverse interactions with nearly every antidepressant, some very serious. Patients suffering from depression should discuss all treatment options with their physician.
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.

Debate over Mortality Rates. Of great concern was a long-term study and its 1998 update that suggested 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. The high incidence of orthostatic hypotension in some people taking Sinemet plus selegiline may account for this. (It should be noted that orthostatic hypotension can occur with other Parkinson's drugs and the condition my itself indicates a more serious condition, regardless of the drug taken.) On the encouraging side, an analysis of five long-term studies found no increased mortality rate using the combination. And a 2000 study in Scotland also found that patients taking selegiline in combination with L-dopa were no more likely to die than people without Parkinson's. In fact, in this study, those taking the combination had the same mortality rate as people without Parkinson's, while those taking levodopa alone had the highest death rate.

Dopamine Agonists

Dopamine agonists stimulate dopamine receptors in the substantia nigra, the part of the brain in which Parkinson's is thought to originate. Comparison studies with L-dopa in 2000 reported that two of these agents, pergolide (an older agent) and pramipexole (a newer one) delayed motor complications of PD during the first one or two years of treatment. Compared to three of these agents, however, L-dopa produced greater improvement in motor function, and by year there appeared to be no difference in disease progression among these agents. Some studies suggest that, like L-dopa, they increase the risk for dyskinesia (uncontrolled movements). One study suggested a lower risk with ropinirole; however, a 2001 study reported that this supposed benefit was only because it postponed the initiation of L-dopa therapy.

Newer Dopamine Agents. Pramipexole (Mirapex) and ropinirole (Requip) are proving to be safe and effective for both initial sole therapy and in combination with L-dopa. Pramipexole appears to be more effective and have fewer side effects than ropinirole.

Ropinirole has shown the following recent results:

A five-year comparison study with L-dope reported that ropinirole was more than twice as effective in controlling dyskinesias. In fact, patients taking ropinirole alone experienced no progression of dyskinesia. There were no significant differences in the number and severity of complications. Overall, however, the effectiveness of the two drugs was comparable in terms of daily living, probably because L-dopa still controlled motor symptoms better.

Pramipexole has shown the following recent results:

A 2001 analysis of controlled studies reported that pramipexole reduced off time, improved impaired movements and disability compared to placebo. Patients had a higher incidence of dyskinesia and hallucinations. (These studies did not compare it to L-dopa.)
A large, US-Canadian 2000 study comparing L-dopa to pramipexole found that 72% of patients who took pramipexole as their first therapy remained free of dyskinesia for two years, compared to 49% of those taking levodopa. Pramipexole therapy, however, resulted in fewer benefits in symptoms overall than L-dopa, and a greater incidence of sleepiness, fluid build-up, and hallucinations.

Side effects of pramipexole and ropinirole vary but can be severe and include the following:

Gastrointestinal side effects (nausea and constipation). Nausea can be controlled by drugs, such as domperidone.
Headache.
Orthostatic hypotension (sudden drop in blood pressure upon standing up).
Nasal congestion.
Nightmares, hallucinations, and even psychosis. (More severe than with L-dopa for both agents.)
Sudden sleep attacks. These can be very serious, particularly if patients are driving. (Although sleep attacks have been most recently associated with the new dopamine agonists, other PD drugs also have this side effect.)

Pergolide. Pergolide (Permax) is an older agent and the most powerful of all dopamine agonists. In a 2000 study comparing it to L-dopa, patients taking pergolide had fewer complications than those taking L-dopa. After three years, however, there was no difference in complications or disease progression. And, those taking L-dopa achieved better improvement in motor function. Pergolide is not as selective as the newer agonists and therefore may have more widespread side effects. No direct comparative studies have been conducted at this time, however, to demonstrate whether the new agonists are any better or more tolerable.

Side effects include nausea, dizziness, insomnia, and weight loss. Uncommon, but serious side effects have been reported, including 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.

Other Dopamine Agonists.

Apomorphine is a dopamine agonist used as a single daily injection. It is particularly effective when administered as a "rescue" drug in people experiencing on-off effects severe enough to require going off L-dopa for a few days. A 2001 study suggested that patients may be able to employ injections at home to treat off states that do not response to oral agents. It causes vomiting and needs to be used with an anti-nausea drug, such as domperidone. Other side effects are excitability and aggression. Patches, nasal sprays, and other forms of apomorphine are showing promise as alternatives to injections. Apomorphine may also be particularly helpful in alleviating nighttime symptoms, including pain and restless legs syndrome.
Other dopamine agonists include bromocriptine (Parlodel), lisuride, and cabergoline (a long-acting agent showing modest effects, but not yet available in the US).

Catechol-O-Methyl Transferase Inhibitors

Entacapone (Comtan) is a catechol-O-methyl transferase (COMT) inhibitors, which increases concentrations of existing dopamine in the brain. It improves motor fluctuations related to the wearing-off effect and has shown impressive results in improving on time and reducing the requirements for L-dopa.

Side Effects. Side effects include the following:

Involuntary muscle movements.
Mental confusion and hallucinations.
Nausea and vomiting.
Cramps.
Headache.
Urine discoloration. (This is a harmless side effect but should be reported.)
Diarrhea.
Less commonly, constipation, susceptibility to respiratory infection, sweating, dry mouth.
Of major concern are reports of a few deaths from liver damage in patients taking tolcapone (Tasmar), another COMT inhibitor. The drug has been taken off the market in many countries and is recommended in the US only for patients who cannot tolerate another other agents. Entacapone does not appear to have the same effects on the liver. Still, patients 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 these drugs.

Anticholinergic Drugs

Anticholinergics were the first drugs used for PD but have largely been replaced by dopamine agents. They are generally used only against tremor in the early stages. They are not as effective against bradykinesia and posture problems and may increase the risk for dementia in late stages. 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.

Side effects of Anticholinergics. Anticholinergics 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. 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. People with glaucoma should use these drugs cautiously.

Amantadine

Amantadine (Symadine, Symmetrel) stimulates the release of dopamine and may be used for patients with early mild symptoms. It has some benefit against muscle rigidity and slowness and may help some patients in advanced stages who are unresponsive to other drugs. It is less powerful than levodopa and may lose its effectiveness after about half a year. It may also reduce motor fluctuations brought on by levadopa, however, and these benefits appear to persist for at least a year.

Side Effects. Side effects are similar to those of anticholinergic drugs and also may include swollen ankles and mottled skin. It can also cause visual hallucinations. Overdose can cause serious and even life-threatening toxicity. Patients with Parkinson's should not withdraw from this drug abruptly: in rare instances it can cause acute delirium or a life-threatening condition called neuroleptic malignant syndrome. Pregnant or nursing women should not use this drug.

Hormone Replacement Therapy

Studies indicate that 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.

Investigative Agents

Nicotine Replacement. Investigators have been studying nicotine administration because of the observation that smokers appear to have a lower risk for Parkinson's disease. Nicotine also appears to promote development of new blood vessels. Studies on nicotine patches have been conflicting, however, with some short-term studies reporting no benefits. One 1999 study even reported worsening motor control in patients who wore 35 mg patches.

Glutamate Blockers. A number of experimental drugs are being investigated for Parkinson's disease because they block the actions of glutamate, an amino acid that is a particularly potent nerve cell killer. Some of these drugs block a receptor group to glutamate called N-methyl-D-aspartate (NMDA). NMDA antagonists are showing some promise for reducing symptoms of Parkinson's disease, particularly tremor. They include remacemide, memantine, and budipine.

Genetic Therapy. Another area of research is therapy that administers genes that code proteins responsible for producing dopamine to protect or even heal nerve cells damaged by Parkinson's disease.

Treatments for Disorders Associated with Parkinson's or its Treatments

Conditions associated with motor impairment and other symptoms of Parkinson's disease may require a variety of treatments. The following is a brief sample of some of them.

Treatments for Depression. Although depression is very common in PD, there have been surprisingly few controlled studies that will help physicians determine the right antidepressant for these patients. Antidepressants used for PD include tricyclics, particularly nortriptyline (Pamelor, Aventyl), and selective serotonin-reuptake inhibitors (SSRIs), which include fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil). A number of studies suggest, however, that SSRIs may worsen Parkinson symptoms. Patients taking SSRIs should be monitored. Of particular interest was the incidental discovery in 1999 that the unique antidepressant mirtazapine (Remeron), which affects dopamine, reduced tremors and dyskinesia in a small group of patients. This finding certainly warrants more study. This agent and others that affect dopamine may have specific benefits for PD.

Treatments for Dyskinesia. Nabilone (Cesamet), an agent derived from marijuana, may help reduce dyskinesia in L-dopa treated patients.

Medications for Psychotic Side Effects. Some studies indicate that the drug clozapine (Clozaril) and quetiapine (Seroquel), normally used in schizophrenia, may be the optimal agents at this time to help offset the psychiatric side effects. In one study quetiapine also improved memory and concentration. These drugs have some serious side effects and need to be used with caution. (Similar drugs, such as risperidone or olanzapine, that are alternative agents used for schizophrenia, can actually worsen Parkinson's symptoms.)

Treatment of Daytime Sleepiness. Modafinil (Provigil), an agent used to treat narcolepsy, is proving to be very helpful for PD patients with sleepiness related to their disease.

Botulism Toxin for Drooling. In search of a simple solution to the problem of drooling, scientists have reported that injections of very small amounts of botulinum toxin A effectively reduce saliva production and drooling. In such small amounts the toxin is safe.

Collagen Injections to Treat Voice Loss. A relatively simple procedure using collagen injections in the neck appears to be a safe and effective method of improving the voice and speech disorders caused by PD. The procedure augments the collagen in the vocal fold and works best in patients who can still initiate speech. A 2001 study reported improvements that lasted from two to seven months in 61% of patients.

Treatment for Impotence. Sildenafil (Viagra) is proving to be very helpful for men who suffer from impotence from Parkinson's disease. However, the agent may worsen orthostatic hypotension, which may be a side effect of some of the PD medications.

WHAT ARE SURGICAL PROCEDURES FOR PARKINSON'S DISEASE?

Surgical procedures are now available for specific patients who no longer respond to drug treatments. Many have shown significant improvements in symptoms, although the benefits do not last. Studies, in general, are weak, partly because of the following reasons:

Long-term studies are difficult to conduct because about half of patients either can't be located for follow-up or they have had additional surguries that distort the results.
It is difficult to compare medications to surgery, because procedures generally involve a much smaller subset of patients, who are also often older and sicker in general than those on medications.
Most studies base their results on scales that measure symptoms but do not actually assess the effects of the surgery on a patient's quality of life.

It is difficult, then, to determine with any certainty how long the benefits last, how they compare to medications, what patients may benefit from specific procedures, and what patients actually feel about their surgery afterward. Patients should discuss surgery carefully with their physicians.

Pallidotomy

The Procedure. Pallidotomy is a surgical procedure that may restore normal brain activity related to voluntary movement in some patients. It is not a cure, however, and its primary benefit is to allow people to continue on medications without incurring some of the side effects. The procedure is irreversible and generally works as follows:

The patient's head is immobilized using a stereotactic frame and imaging techniques are used to visualize the injured areas.
The neurosurgeon drills a small hole into the skull and inserts an electrode.
The electrode 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.

To date, the standard procedure involves one side of the brain (unilateral pallidotomy). Bilateral pallidotomy (surgery on both sides of the brain) is currently being researched.

Candidates. In general, appropriate candidates for unilateral pallidotomy are patients with advanced disease who no longer benefit from drug treatments.

Unfortunately, only about 5% to 10% of Parkinson's patients are candidates. The procedure is generally not recommended for the following:

Patients who do not respond to levodopa.
The very elderly.
Patients whose primary symptom is tremor.
Patients whose predominant symptoms are freezing and falling (especially during on-periods).
Patients who have serious medical or mental disorders.
Patients with parkinsonism (as opposed to idiopathic Parkinson's disease).

Benefits. The best results occur in patients with the following symptoms:

Dyskinesia (uncontrolled movements).
Rigidity.
Tremor.

Significant improvements in these symptoms typically occur on the side of the body opposite to where the surgery occurred and such benefits persist in many patients for at least five years. (To a lesser degree, symptoms initially may improve on the same side of the body as the surgery but effect last for a much shorter period of time than the other side.) In one study, half of the patients went from being completely dependent to being able to perform independently, including feeding and dressing themselves. The improvement in daily functioning diminishes over time, although relief even for a few years may be worth it.

Surgery has less effect on the following symptoms:

Balance, gait disorders, and freezing. (In one study, however, about half of patients who could stand independently before the procedure reported better stability and fewer falls. The procedure does not restore the ability to stand independently in patients who could not do so before surgery.)
Voice volume. (Some studies have reported, however, that voice volume improved considerably after surgery in some patients with mild problems, especially when it was performed on the patient's right side.)

Complications. Surgical experience is improving outcomes, but even in centers with high track records, serious and permanent complications occur in 0.41% to 23% of cases. Serious complications include stroke, paralysis, numbness, and impaired peripheral vision, perhaps even blindness. Studies show that neuropsychologic problems such as a decline in memory capacity and verbal fluency (particularly after left-side operations), and apathy may also occur. The procedure can even be fatal. Patients should have the surgery performed only in centers that have experience with the procedure.

Stereotactic 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 has been reported to significantly reduce or completely stop tremor in 80% to 90% of patients. It does not appear to have much effect on other symptoms. Because tremor is not as significant a disability as other Parkinson's symptoms, the value of this procedure is limited. Complications are similar to pallidotomy, except there is no danger of vision loss.

Neurostimulation (Deep Brain Stimulation)

Procedures called neurostimulation, also called deep brain stimulation, use electric pulse generators to control symptoms. They are proving to be safe and effective alternatives to surgery. Appropriate candidates are similar to those for surgery. (Patients being given neurostimulation, however, should not have pacemakers.) Like pallidotomy and thalamotomy, neurostimulation is not a cure; on the other hand, it does not remove brain tissue and is reversible.

Neurostimulation of the Thalamus. Neurostimulation of thalamus helps patients with tremor and is proving to be as effective and safer than thalamotomy. One procedure (Activa Tremor Control Therapy) involves the following:

The surgeon implants a tiny pulse generator near the collar bone, which is connected to four electrodes that have been implanted in the thalamus of the brain.
The generator delivers programmed pulses to the thalamus, which the patient can turn on and off using a magnet held over the skin.
When the pulses are turned on, the tremor is suppressed.

Studies are reporting improvement in tremor in up to 85% of patients, although only on one side of the body. Long-term effects are still unknown, although studies are indicating that it is safe and effective. The generator must b e replaced every three to five years, and the procedure is very expensive. Such unilateral procedures have little effect on daily living activities or motor function.

Neurostimulation of the Subthalamic Nucleus or Globus Pallidus. Neurostimulation using double (bilateral) implants in the subthalamic nucleus (STN) or stimulation of globus pallidus affects areas that control symptoms of rigidity and involuntary motion. Evidence suggests that STN is somewhat more effective than globus pallidus stimulation and is the preferred approach. (The subthalamic approach also appears to require fewer battery replacements.) Some studies have reported improved gait, walking ability, and less upper limb rigidity. For example, in one 2001 study six months after the subthalamic procedure, patients reported good mobility (without dyskinesia) 74% of the time, compared to only 27% of the time before the procedure. The procedure may also reduce some of the on-off effects of L-dopa.

Complications of Both. Complications occur in 2% to 4% of operations. The most serious ones are bleeding in the brain and infection. A 2001 study reported a moderate decrease in verbal memory and mental tasks involving visual-spatial functions. (Some other mental functions improved.) Of concern was a small study suggesting that the procedure may actually accelerate mental decline in some patients, particularly those over 69 years old. Some experts are not convinced of the safety of implanting a polyurethane device in the brain.

Tissue Implantation

Fetal Cell Implantation. Experimental surgery has shown promise using fetal brain cells rich in dopamine implanted in the substantia nigra. The procedure is useful only in younger adults. Of great concern were studies reporting severe dyskinesias (uncontrolled movements) in implant patients. In some cases it was severe enough to make walking impossible or require pallidotomy. This has been a major setback for this approach although techniques that put implants only in areas where dopamine is most depleted may reduce the risk for dyskinesia. (Dyskinesia is due to excessive dopamine.)

Alternative Implant Sources. The use of fetal tissue is extremely controversial, and research is ongoing for alternatives, including the use of cells from other mammals, cells from human placentas or umbilical cords, and synthetic microspheres that deliver dopamine dire