Parkinson Disease.

Parkinson Disease. I INTRODUCTION Parkinson Disease, disorder of the nervous system that affects muscle control. Marked by trembling of the arms and legs, muscular rigidity, and poor balance, Parkinson disease is slowly progressive, worsening over time. Eventually symptoms may cause problems with walking or talking and, in some people, difficulty thinking. Physicians do not know how to cure Parkinson disease, but drug therapy or surgery may alleviate some of the most troubling symptoms. The disease is named for British physician James Parkinson, who first described it in 1817. In a report describing six patients, Parkinson called the disorder paralysis agitans, Latin words that mean "shaking palsy." The National Parkinson Foundation based in Miami, Florida, estimates that 1.5 million people in the United States are affected with Parkinson disease, although estimates are difficult to make because symptoms of the disease are often mistaken for the normal effects of aging or are attributed to other diseases. Parkinson disease occurs in people all over the world, with the incidence in men slightly higher than in women. Caucasians have a higher incidence of the disease than people of other races. People most commonly develop Parkinson disease around the age of 60, and the incidence rises with age. However, at least 10 percent of cases occur in people under age 40, and a rare form of the disease affects teenagers. Parkinson disease may initially be mistaken for one or more of a group of nervous system diseases collectively known as parkinsonism (also known as Parkinson Plus diseases), all of which have certain symptoms in common. Unlike most cases of Parkinson disease, most forms of parkinsonism develop from an identifiable cause, such as exposure to certain chemicals, drugs, or viruses. Often initially diagnosed as Parkinson disease, parkinsonism diseases do not respond to the drug therapies that treat Parkinson disease symptoms effectively. Physicians have also noted that the changes in the nervous system in people who have parkinsonism differ from those in patients who have Parkinson disease. II CAUSE Parkinson disease develops as a part of the brain known as the substantia nigra degenerates. The substantia nigra is located in the midbrain, halfway between the cerebral cortex and the spinal cord. In healthy people, the substantia nigra contains certain nerve cells, called nigral cells, that produce the chemical dopamine. Dopamine travels along nerve cell pathways from the substantia nigra to another region of the brain, called the striatum. In the striatum, dopamine activates nerve cells that coordinate normal muscle activity. In people with Parkinson disease, nigral cells deteriorate and die at an accelerated rate, and the loss of these cells reduces the supply of dopamine to the striatum. Without adequate dopamine, nerve cells of the striatum activate improperly, impairing a person's ability to control movement. A study published in 2000 found that people with Parkinson disease have a decreased number of nerve fibers in the heart. These results suggest that the disease affects nerves in organs outside the brain and may explain symptoms common in people with Parkinson disease, such as a drop in blood pressure when a person stands up, constipation, and difficulty urinating. Scientists do not understand the mechanisms underlying nerve cell death in Parkinson disease. Most researchers believe that Parkinson disease results from a combination of factors involving genetics, environmental agents, and abnormalities in cellular processes. A Genetics Studies suggest that genetic makeup may place a person at higher risk for developing Parkinson disease. Fifteen percent of people with Parkinson disease have one or more family members who also have the disease. In studies of families in which members from at least three generations have been diagnosed with the disease, scientists have identified three genes that, when mutated, may play a role in the development of Parkinson disease. Genes provide coded instructions for the manufacture of proteins. One of the suspect genes codes for a protein called alpha-synnuclein. A second gene codes for a protein called parkin, and a third gene codes for a protein belonging to a family of proteins known as ubiquitin. Researchers still do not understand the function of alpha-synnuclein, but parkin and ubiquitin may play a role in cleaning up abnormal deposits of proteins in the cell. When the genes that produce these proteins are mutated, parkin and ubiquitin are unable to prevent protein deposits from building up. The accumulation of these deposits may play a role in nigral cell degeneration. A recent study among identical twins also suggests that genetics plays a role in Parkinson disease. In the study, doctors found that if one twin developed the disease before age 50, the chance was higher that the other twin would develop the disease if the twins were identical than it was if they were fraternal. Identical twins have the same genetic makeup, whereas the genes of fraternal twins are as different as those of any two siblings. This study suggests that the identical twins both have a gene that places them at risk for the disease. B Environmental Factors Given the obvious symptoms associated with Parkinson disease, such as tremor and imbalance, it is odd that the first description of the disease did not appear until 1817. Some researchers propose that the disease may have been uncommon before the Industrial Revolution, the period starting in the 18th century when machinery began replacing manual labor. The increased number of patients diagnosed with the disease today may be related to the presence of an environmental toxin (poisonous chemical) released as a byproduct from machines and other technology. Alternatively, the higher incidence of the disease may be related to increasingly longer life spans that enable people to reach an age when the physical effects of Parkinson disease become more apparent. Scientists have yet to identify a particular drug or toxin that causes Parkinson disease, although they have identified a number of drugs, chemicals, and viruses that cause diseases that resemble Parkinson disease. The chemical MPTP, a byproduct created in the synthesis of certain illicit drugs, is linked to the development of a disease in some drug abusers that closely resembles Parkinson disease. People who use some common garden pesticides and insecticides also seem to have a higher incidence of Parkinson disease, although a direct link between Parkinson disease and these chemicals has not yet been established. Certain people may develop parkinsonism if they are exposed to other agents, including carbon monoxide, cyanide, manganese, certain tranquilizers, and some rare viruses, or if they suffer head injuries or strokes. These parkinsonism diseases may be initially mistaken for Parkinson disease. C Free Radicals Some research on Parkinson disease focuses on the role of free radicals, potentially damaging molecules produced in cells as part of normal cell activity or in response to injury. Certain free radicals can cause cell damage, injuring the lining of cell membranes, destroying mitochondria (the cell's energy-producing organelles), and triggering cell death. Studies show that dopamine-producing cells are particularly vulnerable to free-radical destruction. Healthy people typically have adequate quantities of antioxidants, molecular scavengers that defend cells from free-radical destruction. Further research may identify antioxidants that may be useful in blunting the actions of free radicals. III SYMPTOMS Parkinson disease most notably affects motor control (muscle activity). The disease progresses differently for each individual--symptoms develop swiftly in some people and slowly in others. Some Parkinson patients may develop problems that affect their intellect or ability to reason, or they may suffer from depression or anxiety. A Motor Control Problems Doctors look for the presence of four principal symptoms in patients they suspect may have Parkinson disease. Tremor (the involuntary shaking of limbs) is the major symptom for most people who have Parkinson disease, although at least a third of people diagnosed with the disease do not develop this symptom. Tremor typically begins in one hand but may eventually progress to the other hand, as well as to the arms, legs, and jaw. Parkinson disease may also produce stiffness of the joints, similar to arthritis, and rigidity of the limbs, in which muscles are tensed, or contracted. This rigidity makes movement difficult and may contribute to muscle ache and fatigue. Often the rigidity impairs the small muscles of the hand, making everyday tasks such as buttoning a shirt or writing difficult. The most disabling symptom of Parkinson disease is bradykinesia, which causes slowness in all voluntary movement and speech and contributes to varied problems, such as a distinctive shuffling walk and small, cramped handwriting. Parkinson disease also causes postural instability, in which a person has difficulty adjusting to changes in body position. A healthy person who trips and starts to fall is able to quickly move the trunk and limbs to prevent or ease the fall. But people with postural instability who trip cannot move fast enough to stop or lessen their fall. This impaired reflex typically appears as unsteadiness or lack of balance. Several secondary symptoms accompany Parkinson disease, some of which are caused by one or more of these principal symptoms. For example, many people with Parkinson disease have difficulty walking, resulting from a combination of bradykinesia and postural instability. Their walking is marked by short, shuffling steps that sometimes inadvertently quicken into a short run. Their balance problems may cause them to stagger forward or backward, giving them a lurching gait. They may have difficulty turning or stopping as they walk, or sometimes may inexplicably come to an abrupt stop. Other secondary symptoms include difficulty speaking or swallowing, an unchanging or masklike facial expression, drooling, dizziness when moving from a seated to a standing position, difficult urination, and impotence. Many patients find these secondary symptoms more troubling than the principal symptoms. B Mental Disorders Around 30 percent of Parkinson patients develop dementia, a decline in intellect marked by failing memory, short attention span, and personality changes. Sometimes dementia in Parkinson patients resembles Alzheimer's disease, which has a number of the same symptoms, including certain motor control problems. Twenty percent of people with Parkinson disease develop an impairment in which information processing slows. These people may have difficulty completing formerly simple tasks, such as balancing a checkbook. This impairment of information processing may be a forerunner of dementia. Depression, a condition marked by hopelessness, low self-esteem, sadness, apathy, and pessimism, occurs in 40 percent of people with Parkinson disease. A majority of people with Parkinson disease experience anxiety, which may produce panic attacks--sudden, overpowering fears, accompanied by breathlessness, sweating, chest pain, choking, and dizziness (see Panic Disorder). Depression or anxiety may appear before motor symptoms develop or they may appear as a reaction to motor symptoms. Many people with Parkinson disease also suffer from an inability to sleep at night coupled with daytime drowsiness. This sleep disturbance may be caused by anxiety or depression, or it could be a side effect of drugs used to treat Parkinson symptoms. It may also be a mechanism of the disease--the sleep centers in the brain lie near the substantia nigra and may be altered by the disease. C Diseases with Similar Symptoms Some medical conditions initially produce symptoms similar to those of Parkinson disease, but within two to five years additional symptoms usually develop that enable doctors to distinguish the conditions from Parkinson disease. For example, a disease called progressive supranuclear palsy (PSP) produces slowness of movement and difficulty with balance, resembling Parkinson disease. However, people with PSP also develop eye movement problems that prevent them from looking up, down, or sideways without moving the head, and these symptoms can be used to distinguish this condition from Parkinson disease. Parkinson disease-amyotrophic lateral sclerosis of Guam is found only among the Chamorro populations of Guam and the Mariana Islands. This rare disease produces muscle loss throughout the body, similar to the symptoms of amyotrophic lateral sclerosis, also known as Lou Gehrig's disease. Multiple system atrophy (MSA), also known as Shy-Drager syndrome, displays symptoms similar to those of Parkinson disease. In addition, MSA affects the autonomic nervous system, producing problems with blood pressure regulation, heart rate, and bladder function. Parkinson disease also affects the autonomic nervous system, but the symptoms of MSA are usually more severe. Another way that these diseases can be distinguished from Parkinson disease is that they respond poorly to the drugs used to treat Parkinson disease. IV DIAGNOSIS Diagnosing Parkinson disease may be difficult, particularly in the early stages of the disease when symptoms resemble other medical conditions, and misdiagnosis occurs occasionally. No single laboratory test can diagnose the disease. Blood tests are performed to eliminate conditions such as a low thyroid, which may result in slowness of movement. Brain imaging techniques, such as magnetic resonance image (MRI), positron emission tomography (PET scan), and single photon emission computed tomography (SPECT), may be used to help doctors exclude other medical conditions, such as stroke or brain tumors, that produce symptoms similar to those of Parkinson disease. Doctors quiz patients about their exposure to drugs, viruses, and environmental toxins to determine if a particular factor may be causing a parkinsonism disorder. They document the medical history of the patient's blood relatives to determine the likelihood of a genetic predisposition for Parkinson disease or other disorders. And they carefully observe a patient's muscular activity over a period of time--as the disease progresses, motions particular to Parkinson disease become more obvious. Doctors usually diagnose Parkinson disease if a patient develops two or more of the principal symptoms, at least one of which is tremor or bradykinesia. The diagnosis is usually confirmed if people with suspected Parkinson disease respond well to drug treatment. Those with parkinsonism disorders or other medical conditions with similar symptoms typically do not respond to the drugs used in treating Parkinson disease. V TREATMENT There is no known cure for Parkinson disease--that is, no treatment that prevents the disease from progressing. But the symptoms of the disease can be controlled by various drugs and, in some cases, by surgery. A Drug Therapy Most symptoms of Parkinson disease arise from a deficiency of dopamine in the brain. But simply giving a patient a dose of dopamine to restore depleted stores is ineffective because dopamine cannot pass from the bloodstream to the brain. Drugs that treat Parkinson disease, known as antiparkinson drugs, use other methods to temporarily restore dopamine in the brain or closely mimic dopamine's actions. In this section, each drug is designated by its generic name, followed by trade name examples in parentheses. A1 Levodopa The most effective antiparkinson drug available is levodopa (Laradopa), an oral drug introduced in 1967 that treats bradykinesia, rigidity, tremor, and difficulty walking. Levodopa's structure enables it to enter the brain, where it transforms into dopamine. When levodopa is taken alone, however, the body breaks down about 95 percent of the drug into dopamine before it reaches the brain. Instead of being used by the brain, the dopamine travels throughout the body, producing side effects, including nausea and vomiting, before it is broken down, or metabolized, by the liver and other tissues. Combining levodopa with a drug such as carbidopa enables more levodopa to enter the brain before it converts into dopamine. Carbidopa/levodopa (Atamet, Sinemet) lessens rigidity and bradykinesia but is less effective in treating tremor or balance problems. A similar drug combining carbidopa and benserazide (Madopar) is available in Canada and Europe. Carbidopa/levodopa produces side effects in some people. As many as half of the people who take this drug for two to five years begin to notice fluctuations in the drug's effectiveness, known as an on-off effect. Others develop dyskinesia--involuntary movements such as jerking or twitching. As Parkinson disease progresses, the effectiveness of carbidopa/levodopa decreases and patients need higher and more frequent doses to control their symptoms. Depending upon the severity of symptoms, most doctors combine carbidopa/levodopa with other drugs to enhance levodopa's effects. A2 Dopamine Agonists Dopamine agonists mimic the action of dopamine by activating nerve cells in the striatum. Dopamine agonists are increasingly used alone in the early stages of Parkinson disease in order to lower a patient's risk of developing the dyskinesia associated with levodopa therapy. Later in the course of the disease they are more likely to be combined with carbidopa/levodopa to alleviate that drug's on-off effects. Side effects range from nausea, headache, and nasal congestion to nightmares and hallucinations. Dopamine agonists include pergolide (Permax), paramipexole (Mirapex), and ropinerole (Requip). A3 Drugs That Sustain Levodopa's Effect Levodopa does not permanently restore dopamine in the brain, and the drug may wear off at a certain point after each dose, diminishing dopamine levels. This may produce intermittent or discontinuous symptom relief, which may contribute to the on-off effect experienced by some Parkinson disease patients. A number of drugs are available that can prolong levodopa's effectiveness. A sustained or controlled-release form of carbidopa/levodopa (Sinemet CR) releases a smaller amount of levodopa over a longer period, extending the time that levodopa is effective. Some drugs prolong relief from symptoms by blocking the enzyme catechol-O-methyl transferase (COMT). These drugs, called COMT inhibitors, delay the break down of levodopa before it reaches the brain. Taken at the same time as levodopa drugs, COMT inhibitors--including entacapone (Comtan)--increase the time that levodopa is effective in the brain and reduce the on-off effect. Working in a similar manner, drugs that block the action of the enzyme monoamine oxidase-B, called MAO-B inhibitors, prevent this enzyme from breaking down dopamine in the brain. Used alone or in combination with carbidopa/levodopa, MAO-B inhibitors, including selegiline (Eldepryl), do not prolong the actions of levodopa as well as COMT inhibitors. A4 Anticholinergics When dopamine levels in the brain drop, another neurotransmitter called acetylcholine becomes overactive, and the resulting dopamine and acetylcholine imbalance affects motor skills. Drugs called anticholinergics block the action of acetylcholine. Typically used in the early stages of the disease when symptoms are mild, anticholinergic drugs such as trihexiphenidyl (Artane) and biperidine (Akineton) may lessen tremor and drooling but are not effective in treating bradykinesia or posture instability. A5 Amantadine The drug amantadine (Symmetrel), originally developed as an antiviral drug, was later found effective in treating Parkinson disease. Scientists are unsure how amantadine works--it may have an anticholinergic effect, and more recent studies show that it also blocks the action of glutamate, a brain chemical that triggers production of free radicals. Amantadine is usually used in combination with carbidopa/levodopa and has been found effective in lessening dyskinesia. B Surgical Treatment In the 1950s and 1960s, brain surgery was a common method for treating tremor and rigidity in Parkinson patients, even though the success rate of surgery varied and life-threatening complications often developed. But surgery fell out of favor with the introduction in 1967 of levodopa, a safer and more effective treatment alternative. In recent years the advent of new brain-imaging techniques has improved surgical precision, and surgery has gained renewed popularity as a treatment for some people with Parkinson disease who no longer respond to drug therapy. Two similar surgical procedures that have been used to treat Parkinson disease involve destroying part of the brain. To control tremor and rigidity, surgeons perform a thalamotomy to destroy a small region of the thalamus, a part of the brain that relays signals coordinating movement. Pallidotomy targets the globus pallidus, a part of the brain that produces uncontrolled spasmodic movements in Parkinson disease patients. Doctors now prefer to perform a more effective surgical procedure called deep brain stimulation. In this procedure, the patient's head is immobilized in a halo-like device called a stereotaxic frame. Using an MRI, the surgeon locates the thalamus, the globus pallidus, or a related region called the subthalamic nucleus in the brain. After drilling a small hole in the skull, the surgeon inserts a probe deep into the brain to the target tissue. A short burst of electricity sent through the probe normalizes the electrical activity in the brain region, reversing the symptoms of Parkinson disease. This surgery is reasonably safe, and symptom relief is immediate. But as with any surgery, risks are involved, including the chance that a stroke may develop. In a surgical procedure still in the experimental stage, doctors transplant dopamine-producing cell tissue into the brain (see Medical Transplantation). In this procedure, doctors use different sources of cell tissue that make dopamine, including cells from aborted fetuses and pig embryos. Some studies have shown that these procedures have alleviated symptoms in some Parkinson patients. Some doctors are also investigating the use of human stem cells, immature cells that can be manipulated to become dopamine-producing cells. Stem cells are hardy and easy to reproduce--one stem cell can generate billions of copies. The use of stem cells is controversial because some studies have obtained stem cells from aborted human embryos. But other sources of human stem cells are available, including the discarded umbilical cord from healthy babies and the bone marrow of adults. Using stem cells from these sources may make this treatment more acceptable. So far studies on the effectiveness of this procedure have provided conflicting results. Other doctors are performing animal experiments in which a gene that produces dopamine is inserted into the brain cells of an animal with Parkinson disease. The gene causes brain cells to make dopamine. This procedure, called gene transfer, may one day help alleviate symptoms or cure Parkinson disease in humans. Contributed By: Abraham Lieberman Microsoft ® Encarta ® 2009. © 1993-2008 Microsoft Corporation. All rights reserved.