Introduction to Parkinson's Disease
Parkinson's disease may be one of the most baffling and complex of the neurological disorders. Its cause remains a mystery but research in this area is active, with new and intriguing findings constantly being reported.
Parkinson's disease was first described in 1817 by James Parkinson, a British physician who published a paper on what he called "the shaking palsy." In this paper, he set forth the major symptoms of the disease that would later bear his name. For the next century and a half, scientists pursued the causes and treatment of the disease. They defined its range of symptoms, distribution among the population, and prospects for cure.
In the early 1960s, researchers identified a fundamental brain defect that is a hallmark of the disease: the loss of brain cells that produce a chemical -- dopamine -- that helps direct muscle activity. This discovery pointed to the first successful treatment for Parkinson's disease and suggested ways of devising new and even more effective therapies.
Society pays an enormous price for Parkinson's disease. According to the National Parkinson Foundation, each patient spends an average of $2,500 a year for medications. After factoring in office visits, Social Security payments, nursing home expenditures, and lost income, the total cost to the Nation is estimated to exceed $5.6 billion annually.
What is Parkinson's Disease?
Parkinson's disease belongs to a group of conditions called motor system disorders. The four primary symptoms are tremor or trembling in hands, arms, legs, jaw, and face; rigidity or stiffness of the limbs and trunk; bradykinesia or slowness of movement; and postural instability or impaired balance and coordination. As these symptoms become more pronounced, patients may have difficulty walking, talking, or completing other simple tasks.
The disease is both chronic, meaning it persists over a long period of time, and progressive, meaning its symptoms grow worse over time. It is not contagious nor is it usually inherited -- that is, it does not pass directly from one family member or generation to the next.
Parkinson's disease is the most common form of parkinsonism, the name for a group of disorders with similar features (see section entitled "What are the Other Forms of Parkinsonism?"). These disorders share the four primary symptoms described above, and all are the result of the loss of dopamine-producing brain cells. Parkinson's disease is also called primary parkinsonism or idiopathic Parkinson's disease; idiopathic is a term describing a disorder for which no cause has yet been found. In the other forms of parkinsonism either the cause is known or suspected or the disorder occurs as a secondary effect of another, primary neurological disorder.
What Causes the Disease?
Parkinson's disease occurs when certain nerve cells, or neurons, in an area of the brain known as the substantia nigra die or become impaired. Normally, these neurons produce an important brain chemical known as dopamine. Dopamine is a chemical messenger responsible for transmitting signals between the substantia nigra and the next "relay station" of the brain, the corpus striatum, to produce smooth, purposeful muscle activity. Loss of dopamine causes the nerve cells of the striatum to fire out of control, leaving patients unable to direct or control their movements in a normal manner. Studies have shown that Parkinson's patients have a loss of 80 percent or more of dopamine-producing cells in the substantia nigra. The cause of this cell death or impairment is not known but significant findings by research scientists continue to yield fascinating new clues to the disease.
One theory holds that free radicals -- unstable and potentially damaging molecules generated by normal chemical reactions in the body -- may contribute to nerve cell death thereby leading to Parkinson's disease. Free radicals are unstable because they lack one electron; in an attempt to replace this missing electron, free radicals react with neighboring molecules (especially metals such as iron), in a process called oxidation. Oxidation is thought to cause damage to tissues, including neurons. Normally, free radical damage is kept under control by antioxidants, chemicals that protect cells from this damage. Evidence that oxidative mechanisms may cause or contribute to Parkinson's disease includes the finding that patients with the disease have increased brain levels of iron, especially in the substantia nigra, and decreased levels of ferritin, which serves as a protective mechanism by chelating or forming a ring around the iron, and isolating it.
Some scientists have suggested that Parkinson's disease may occur when either an external or an internal toxin selectively destroys dopaminergic neurons. An environmental risk factor such as exposure to pesticides or a toxin in the food supply is an example of the kind of external trigger that could hypothetically cause Parkinson's disease. The theory is based on the fact that there are a number of toxins, such as 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) and neuroleptic drugs, known to induce parkinsonian symptoms in humans. So far, however, no research has provided conclusive proof that a toxin is the cause of the disease.
A relatively new theory explores the role of genetic factors in the development of Parkinson's disease. Fifteen to twenty percent of Parkinson's patients have a close relative who has experienced parkinsonian symptoms (such as a tremor). After studies in animals showed that MPTP interferes with the function of mitochondria within nerve cells, investigators became interested in the possibility that impairment in mitochondrial DNA may be the cause of Parkinson's disease. Mitochondria are essential organelles found in all animal cells that convert the energy in food into fuel for the cells.
Yet another theory proposes that Parkinson's disease occurs when, for unknown reasons, the normal, age-related wearing away of dopamine-producing neurons accelerates in certain individuals. This theory is supported by the knowledge that loss of antioxidative protective mechanisms is associated with both Parkinson's disease and increasing age.
Many researchers believe that a combination of these four mechanisms -- oxidative damage, environmental toxins, genetic predisposition, and accelerated aging -- may ultimately be shown to cause the disease.
Who Gets Parkinson's Disease?
About 50,000 Americans are diagnosed with Parkinson's disease each year, with more than half a million Americans affected at any one time. Getting an accurate count of the number of cases may be impossible however, because many people in the early stages of the disease assume their symptoms are the result of normal aging and do not seek help from a physician. Also, diagnosis is sometimes difficult and uncertain because other conditions may produce some of the symptoms of Parkinson's disease. People with Parkinson's disease may be told by their doctors that they have other disorders or, conversely, people with similar diseases may be initially diagnosed as having Parkinson's disease.
Parkinson's disease strikes men and women in almost equal numbers and it knows no social, economic, or geographic boundaries. Some studies show that African-Americans and Asians are less likely than whites to develop Parkinson's disease. Scientists have not been able to explain this apparent lower incidence in certain populations. It is reasonable to assume, however, that all people have a similar probability of developing the disease.
Age, however, clearly correlates with the onset of symptoms. Parkinson's disease is a disease of late middle age, usually affecting people over the age of 50. The average age of onset is 60 years. However, some physicians have reportedly noticed more cases of "early-onset" Parkinson's disease in the past several years, and some have estimated that 5 to 10 percent of patients are under the age of 40.
What are the Early Symptoms?
Early symptoms of Parkinson's disease are subtle and occur gradually. Patients may be tired or notice a general malaise. Some may feel a little shaky or have difficulty getting out of a chair. They may notice that they speak too softly or that their handwriting looks cramped and spidery. They may lose track of a word or thought, or they may feel irritable or depressed for no apparent reason. This very early period may last a long time before the more classic and obvious symptoms appear.
Friends or family members may be the first to notice changes. They may see that the person's face lacks expression and animation (known as "masked face") or that the person remains in a certain position for a long time or does not move an arm or leg normally. Perhaps they see that the person seems stiff, unsteady, and unusually slow.
As the disease progresses, the shaking, or tremor, that affects the majority of Parkinson's patients may begin to interfere with daily activities. Patients may not be able to hold utensils steady or may find that the shaking makes reading a newspaper difficult. Parkinson's tremor may become worse when the patient is relaxed. A few seconds after the hands are rested on a table, for instance, the shaking is most pronounced. For most patients, tremor is usually the symptom that causes them to seek medical help.
What are the Major Symptoms of the Disease?
Parkinson's disease does not affect everyone the same way. In some people the disease progresses quickly, in others it does not. Although some people become severely disabled, others experience only minor motor disruptions. Tremor is the major symptom for some patients, while for others tremor is only a minor complaint and different symptoms are more troublesome.
As the disease progresses, walking may be affected. Patients may halt in mid-stride and "freeze" in place, possibly even toppling over. Or patients may walk with a series of quick, small steps as if hurrying forward to keep balance. This is known as festination.
Various other symptoms accompany Parkinson's disease; some are minor, others are more bothersome. Many can be treated with appropriate medication or physical therapy. No one can predict which symptoms will affect an individual patient, and the intensity of the symptoms also varies from person to person. None of these symptoms is fatal, although swallowing problems can cause choking.
Memory loss and slow thinking may occur, although the ability to reason remains intact. Whether people actually suffer intellectual loss (also known as dementia) from Parkinson's disease is a controversial area still being studied.
What are the Other Forms of Parkinsonism?
Other forms of parkinsonism include the following:
How do Doctors Diagnose Parkinson's Disease?
Even for an experienced neurologist, making an accurate diagnosis in the early stages of Parkinson's disease can be difficult. There are, as yet, no sophisticated blood or laboratory tests available to diagnose the disease. The physician may need to observe the patient for some time until it is apparent that the tremor is consistently present and is joined by one or more of the other classic symptoms. Since other forms of parkinsonism have similar features but require different treatments, making a precise diagnosis as soon as possible is essential for starting a patient on proper medication.
How is the Disease Treated?
At present, there is no cure for Parkinson's disease. But a variety of medications provide dramatic relief from the symptoms.
When recommending a course of treatment, the physician determines how much the symptoms disrupt the patient's life and then tailors therapy to the person's particular condition. Since no two patients will react the same way to a given drug, it may take time and patience to get the dose just right. Even then, symptoms may not be completely alleviated. In the early stages of Parkinson's disease, physicians often begin treatment with one or a combination of the less powerful drugs -- such as the anticholinergics or amantadine (see section entitled "Are There Other Medications Available for Managing Disease Symptoms?"), saving the most powerful treatment, specifically levodopa, for the time when patients need it most.
Without doubt, the gold standard of present therapy is the drug levodopa (also called L-dopa). L- Dopa (from the full name L-3,4-dihydroxyphenylalanine) is a simple chemical found naturally in plants and animals. Levodopa is the generic name used for this chemical when it is formulated for drug use in patients. Nerve cells can use levodopa to make dopamine and replenish the brain's dwindling supply. Dopamine itself cannot be given because it doesn't cross the blood-brain barrier, the elaborate meshwork of fine blood vessels and cells that filters blood reaching the brain. Usually, patients are given levodopa combined with carbidopa. When added to levodopa, carbidopa delays the conversion of levodopa into dopamine until it reaches the brain, preventing or diminishing some of the side effects that often accompany levodopa therapy. Carbidopa also reduces the amount of levodopa needed.
Levodopa's success in treating the major symptoms of Parkinson's disease is a triumph of modern medicine. First introduced in the 1960s, it delays the onset of debilitating symptoms and allows the majority of parkinsonian patients -- who would otherwise be very disabled -- to extend the period of time in which they can lead relatively normal, productive lives.
Although levodopa helps at least three-quarters of parkinsonian cases, not all symptoms respond equally to the drug. Bradykinesia and rigidity respond best, while tremor may be only marginally reduced. Problems with balance and other symptoms may not be alleviated at all.
People who have taken other medications before starting levodopa therapy may have to cut back or eliminate these drugs in order to feel the full benefit of levodopa. Once levodopa therapy starts people often respond dramatically, but they may need to increase the dose gradually for maximum benefit.
Because a high-protein diet can interfere with the absorption of levodopa, some physicians recommend that patients taking the drug restrict protein consumption to the evening meal.
Levodopa is so effective that some people may forget they have Parkinson's disease. But levodopa is not a cure. Although it can diminish the symptoms, it does not replace lost nerve cells and it does not stop the progression of the disease.
Side Effects of Levodopa
Although beneficial for thousands of patients, levodopa is not without its limitations and side effects. The most common side effects are nausea, vomiting, low blood pressure, involuntary movements, and restlessness. In rare cases patients may become confused. The nausea and vomiting caused by levodopa are greatly reduced by the combination of levodopa and carbidopa which enhances the effectiveness of a lower dose. A slow-release formulation of this product, which gives patients a longer lasting effect, is also available.
Dyskinesias, or involuntary movements such as twitching, nodding, and jerking, most commonly develop in people who are taking large doses of levodopa over an extended period. These movements may be either mild or severe and either very rapid or very slow. The only effective way to control these drug-induced movements is to lower the dose of levodopa or to use drugs that block dopamine, but these remedies usually cause the disease symptoms to reappear. Doctors and patients must work together closely to find a tolerable balance between the drug's benefits and side effects.
Other more troubling and distressing problems may occur with long-term levodopa use. Patients may begin to notice more pronounced symptoms before their first dose of medication in the morning, and they can feel when each dose begins to wear off (muscle spasms are a common effect). Symptoms gradually begin to return. The period of effectiveness from each dose may begin to shorten, called the wearing-off effect. Another potential problem is referred to as the on-off effect -- sudden, unpredictable changes in movement, from normal to parkinsonian movement and back again, possibly occurring several times during the day. These effects probably indicate that the patient's response to the drug is changing or that the disease is progressing.
One approach to alleviating these side effects is to take levodopa more often and in smaller amounts. Sometimes, physicians instruct patients to stop levodopa for several days in an effort to improve the response to the drug and to manage the complications of long-term levodopa therapy. This controversial technique is known as a "drug holiday." Because of the possibility of serious complications, drug holidays should be attempted only under a physician's direct supervision, preferably in a hospital. Parkinson's disease patients should never stop taking levodopa without their physician's knowledge or consent because of the potentially serious side effects of rapidly withdrawing the drug.
Are There Other Medications Available for Managing Disease Symptoms?
Levodopa is not a perfect drug. Fortunately, physicians have other treatment choices for particular symptoms or stages of the disease. Other therapies include the following:
Research scientists are still trying to answer questions about selegiline use: How long does the drug remain effective? Does long-term use have any adverse effects? Evaluation of the long-term effects will help determine its value for all stages of the disease.
Is Surgery Ever Used to Treat Parkinson's Disease?
Treating Parkinson's disease with surgery was once a common practice. But after the discovery of levodopa, surgery was restricted to only a few cases. One of the procedures used, called cryothalamotomy, requires the surgical insertion of a supercooled metal tip of a probe into the thalamus (a "relay station" deep in the brain) to destroy the brain area that produces tremors. This and related procedures are coming back into favor for patients who have severe tremor or have the disease only on one side of the body. Investigators have also revived interest in a surgical procedure called pallidotomy in which a portion of the brain called the globus pallidus is lesioned. Some studies indicate that pallidotomy may improve symptoms of tremor, rigidity, and bradykinesia, possibly by interrupting the neural pathway between the globus pallidus and the striatum or thalamus. Further research on the value of surgically destroying these brain areas is currently being conducted.
Can Diet or Exercise Programs Help Relieve Symptoms?
Diet. Eating a well-balanced, nutritious diet can be beneficial for anybody. But for preventing or curing Parkinson's disease, there does not seem to be any specific vitamin, mineral, or other nutrient that has any therapeutic value. A high protein diet, however, may limit levodopa's effectiveness.
Despite some early optimism, recent studies have shown that tocopherol (a form of vitamin E) does not delay Parkinson's disease. This conclusion came from a carefully conducted study supported by the NINDS called DATATOP (Deprenyl and Tocopherol Antioxidative Therapy for Parkinson's Disease) that examined, over 5 years, the effects of both deprenyl and vitamin E on early Parkinson's disease. While deprenyl was found to slow the early symptomatic progression of the disease and delay the need for levodopa, there was no evidence of therapeutic benefit from vitamin E.
Exercise. Because movements are affected in Parkinson's disease, exercising may help people improve their mobility. Some doctors prescribe physical therapy or muscle-strengthening exercises to tone muscles and to put underused and rigid muscles through a full range of motion. Exercises will not stop disease progression, but they may improve body strength so that the person is less disabled. Exercises also improve balance, helping people overcome gait problems, and can strengthen certain muscles so that people can speak and swallow better. Exercises can also improve the emotional well-being of parkinsonian patients by giving them a feeling of accomplishment. Although structured exercise programs help many patients, more general physical activity, such as walking, gardening, swimming, calisthenics, and using exercise machines, is also beneficial.
What are the Benefits of Support Groups?
One of the most demoralizing aspects of the disease is how completely the patient's world changes. The most basic daily routines may be affected -- from socializing with friends and enjoying normal and congenial relationships with family members to earning a living and taking care of a home. Faced with a very different life, people need encouragement to remain as active and involved as possible. That's when support groups can be of particular value to parkinsonian patients, their families, and their caregivers.
A list of national volunteer organizations that can help patients locate support groups in their communities appears at the end of this brochure.
Can Scientists Predict or Prevent Parkinson's Disease?
As yet, there is no way to predict or prevent the disease. However, researchers are now looking for a biomarker -- a biochemical abnormality that all patients with Parkinson's disease might share -- that could be picked up by screening techniques or by a simple chemical test given to people who do not have any parkinsonian symptoms.
Positron emission tomography (PET) scanning may lead to important advances in our knowledge about Parkinson's disease. PET scans of the brain produce pictures of chemical changes as they occur in the living brain. Using PET, research scientists can study the brain's dopamine receptors (the sites on nerve cells that bind with dopamine) to determine if the loss of dopamine activity follows or precedes degeneration of the neurons that make this chemical. This information could help scientists better understand the disease process and may potentially lead to improved treatments.
What Research is Being Done?
In the last decade research has laid the groundwork for many of today's promising new clinical trials, technologies, and drug treatments. Scientists, physicians, and patients hope that today's progress means tomorrow's cure and prevention.
Parkinson's disease research focuses on many areas. Some investigators are studying the functions and anatomy of the motor system and how it regulates movement and relates to major command centers in the brain. Scientists looking for the cause of Parkinson's disease will continue to search for possible environmental factors, such as toxins that may trigger the disorder, and to study genetic factors to determine if one or many defective genes play a role. Although Parkinson's disease is not directly inherited, it is possible that some people are genetically more or less susceptible to developing it. Other scientists are working to develop new protective drugs that can delay, prevent, or reverse the disease.
Since the accidental discovery that MPTP causes parkinsonian symptoms in humans, scientists have found that by injecting MPTP into laboratory animals, they can reproduce the brain lesions that cause these symptoms. This allows them to study the mechanisms of the disease and helps in the development of new treatments. For instance, it was from animal studies that researchers discovered that the drug selegiline can prevent the toxic effects of MPTP. This discovery helped spark interest in studying selegiline as a preventive treatment in humans.
Scientists are also investigating the role of mitochondria, structures in cells that provide the energy for cellular activity, in Parkinson's disease. Because MPTP interferes with the function of mitochondria within nerve cells, some scientists suspect that similar abnormalities may be involved in Parkinson's disease.
Today, an array of promising research involves studying brain areas other than the substantia nigra that may be involved in the disease. One group of NINDS-supported scientists is studying the consequences of dopamine cell degeneration in the basal ganglia -- brain structures located deep in the forebrain that help control voluntary movement. In laboratory animals, MPTP-induced reduction of dopamine results in overactivity of nerve cells in a region of the brain called the subthalamic nucleus, producing tremors and rigidity and suggesting that these symptoms may be related to excessive activity in this region. Destroying the subthalamic nucleus results in a reversal of parkinsonian symptoms in the animal models.
Scientists supported by the NINDS are also looking for clues to the cause of Parkinson's disease by studying malfunctions in the structures called "dopamine transporters" that carry dopamine in and out of the synapse, or narrow gap between nerve cells. For example, one research group recently found an age-related decrease in the concentration of dopamine transporters in healthy human nerve cells taken from areas of the brain damaged by Parkinson's. This decline in transporter concentration means that any further threat to the remaining dopamine transporters could result in Parkinson's disease.
The search for more effective medications for Parkinson's disease is likely to be aided by the recent isolation of at least five individual brain receptors for dopamine. New information about the unique effects of each individual dopamine receptor on different brain areas has led to new treatment theories and clinical trials.
Scientists are also studying new methods for delivering dopamine to critical areas in the brain. NINDS-supported investigators, using an animal model of the disease, implanted tiny dopamine-containing particles into brain regions affected by the disease. They found that such implants can partially ameliorate the movement problems exhibited by these animals. The results suggest that similar techniques may one day work for people with Parkinson's disease.
A recent study revealed that when the experimental drug Ro 40-7592 is added to the standard drug treatment for Parkinson's disease, levodopa-carbidopa, symptom relief is prolonged by more than 60 percent. Although levodopa-carbidopa restores normal movement early in the disease's course, the treatment loses effectiveness as the disease progresses (wearing-off effect). NINDS scientists found, however, that patients treated with both levodopa-carbidopa and Ro 40-7592 experienced longer periods of improved movement. This promising new drug that blocks the breakdown of dopamine and levodopa would allow patients to take fewer doses and smaller amounts of levodopa-carbidopa and to decrease the problems of the wearing-off effect. At the present time, Ro 40-7592 is still in the experimental stage. Scientists are continuing to study the drug to learn whether it can be given in multiple daily doses to provide even further improvement.
Also under investigation are additional controlled-release formulas of Parkinson's disease drugs and implantable pumps that give a continuous supply of levodopa to help patients who have problems with fluctuating levels of response. Another promising treatment method involves implanting capsules containing dopamine-producing cells into the brain. The capsules are surrounded by a biologically inert membrane that lets the drug pass through at a timed rate.
Neural grafting, or transplantation of nerve cells, is an experimental technique proposed for treating the disease. NINDS-supported investigators have shown in animal models that implanting fetal brain tissue from the substantia nigra into a parkinsonian brain causes damaged nerve cells to regenerate. In January 1994, the NINDS awarded a research grant to a group of scientists from three institutions to conduct a controlled clinical trial of fetal tissue implants in humans. The treatment attempts to replace the lost or damaged dopamine-producing neurons with healthy, fetal neurons, and thereby improve movement and response to medications. A new and promising approach may be the use of genetically engineered cells -- that is, cells such as modified skin cells that do not come from the nervous system but are grown in tissue culture -- that could have the same beneficial effects. Skin cells would be much easier to harvest and patients could serve as their own donors.
Source: National Institute of Neurological Disorders and Stroke, National Institutes of Health, September 1994