Parkinson's disease is a chronic, progressive neurodegenerative movement disorder. Tremors, rigidity, slow movement (bradykinesia), poor balance, and difficulty walking (called parkinsonian gait) are characteristic primary symptoms of Parkinson's disease.
Idiopathic Parkinson's disease is the most common form of parkinsonism, a group of movement disorders that have similar features and symptoms. Parkinson's disease is called idiopathic Parkinson's because the cause is unknown. In the other forms of parkinsonism, a cause is known or suspected.
Parkinson's results from the degeneration of dopamine-producing nerve cells in the brain, specifically in the substantia nigra and the locus coeruleus. Dopamine is a neurotransmitter that stimulates motor neurons, those nerve cells that control the muscles. When dopamine production is depleted, the motor system nerves are unable to control movement and coordination. Parkinson's disease patients have lost 80% or more of their dopamine-producing cells by the time symptoms appear.
Incidence and Prevalence
Parkinson's disease afflicts 1 to 1 1/2 million people in the United States. The disorder occurs in all races but is somewhat more prevalent among Caucasians. Men are affected slightly more often than women.
Symptoms of Parkinson's disease may appear at any age, but the average age of onset is 60. It is rare in people younger than 30 and risk increases with age. It is estimated that 5% to 10% of patients experience symptoms before the age of 40.
In a small number of cases worldwide there is a strong inheritance pattern. A genetic predisposition for Parkinson's disease is possible, with the onset of disease and its gradual development dependant on a trigger, such as trauma, other illness, or exposure to an environmental toxin.
The risk increases with age, as Parkinson's disease generally manifests in the middle or late years of life.
The cause of Parkinson's disease is unknown. Many researchers believe that several factors combined are involved: free radicals, accelerated aging, environmental toxins, and genetic predisposition.
It may be that free radicals-unstable and potentially damaging molecules that lack on electron-are involved in the degeneration of dopamine-producing cells. Free radicals add an electron by reacting with nearby molecules in a process called oxidation, which can damage nerve cells. Chemicals called antioxidants normally protect cells from oxidative stress and damage. If antioxidative action fails to protect dopamine-producing nerve cells, they could be damaged and, subsequently, Parkinson's disease could develop.
Dysfunctional antioxidative mechanisms are associated with older age as well, suggesting that the acceleration of age-related changes in dopamine production may be a factor.
Exposure to an environmental toxin, such as a pesticide, that inhibits dopamine production and produces free radicals and oxidation damage may be involved.
Roughly one-fifth of Parkinson's disease patients have at least one relative with parkinsonian symptoms, suggesting that a genetic factor may be involved. Several genes that cause symptoms in younger patients have been identified. Most researchers believe, however, that most cases are not caused by genetic factors alone.
The body's ability to produce smooth, controlled, muscular activity is a product of many complex, interrelated functions. Few, however, are as critical as the functioning of the nerve cells, or neurons, in the part of the brain called the substantia nigra. These neurons produce the brain chemical dopamine, which is responsible for transmitting signals associated with muscular activity between the substantia nigra and another part of the brain, the corpus striatum.
Parkinson's disease occurs when these neurons die or cease to function properly. Without enough dopamine to control them, the neurons of the corpus striatum cannot function in their usual, coordinated manner, and the result is an inability to direct or control the body's movements normally.
Research has found the typical Parkinson's patient has an 80% or greater deficiency of dopamine-producing cells in the substantia nigra. It is as yet impossible to state conclusively why these cells die or become impaired, but there are several theories.
One suggests the nerve cells are damaged by free radicals-unstable molecules generated by normal chemical reactions in the body. Free radicals lack one electron, and attempt to replace it by reacting with nearby molecules in a process called oxidation, which is potentially damaging to tissues, including neurons. This damage normally is controlled by other chemicals called antioxidants. Some imperfectly understood mechanism, possibly associated with the aging process, prevents this balance from occurring, the theory maintains.
Another theory holds that some form of toxin, either external or internal, destroys the dopamine-producing neurons. Exposure to pesticides or a toxic substance in the food supply is thought to be the cause, but research has not yet been able to prove this theory conclusively.
Genetic factors also are being investigated. Because roughly one-fifth of Parkinson's patients have at least one close relative with some form of parkinsonian symptom, scientists are investigating the possibility that the roots of Parkinson's disease might be locked within an as-yet unexplored facet of DNA.
Signs and Symptoms
People with idiopathic Parkinson's disease may develop several symptoms over time, but they typically develop the primary symptoms bradykinesia, tremor, rigidity, and parkinsonian gait. Most people with Parkinson's do not develop all of the symptoms associated with the disease.
The disease may progress quickly or gradually over years. Many people become profoundly disabled and others function relatively well.
Symptoms may vary from day to day or even moment to moment. There is no clear reason for the fluctuation of symptoms. Variance may be attributable to the disease process or to antiparkinson medications.
Bradykinesia is slowness in voluntary movement. It produces difficulty initiating movement as well as difficulty completing movement once it is in progress. The delayed transmission of signals from the brain to the skeletal muscles, due to diminished dopamine, produces bradykinesia.
Tremors in the hands, fingers, forearm, or foot tend to occur when the limb is at rest but not when performing tasks. Tremor may occur in the mouth and chin as well.
Rigidity, or stiff muscles, may produce muscle pain and an expressionless, mask-like face. Rigidity tends to increase during movement.
Poor balance is due to the impairment or loss of the reflexes that adjust posture in order to maintain balance. Falls are common in people with Parkinson's.
Parkinsonian gait is the distinctive unsteady walk associated with Parkinson's disease. There is a tendency to lean unnaturally backward or forward, and to develop a stooped, head-down, shoulders-drooped stance. Arm swing is diminished or absent and people with Parkinson's tend to take small shuffling steps (called festination). Someone with Parkinson's may have trouble starting to walk, appear to be falling forward as they walk, freeze in mid-stride, and have difficulty making a turn.
The progressive loss of voluntary and involuntary muscle control produces a number of secondary symptoms associated with Parkinson's. Most patients do not experience all of them, and symptoms vary in intensity from person to person.
Some secondary symptoms of Parkinson's disease include the following:
Diagnosis is based on symptoms and ruling out other disorders that produce similar symptoms.
A patient must have two or more of the primary symptoms, one of which is a resting tremor or bradykinesia. In many cases, this diagnosis is made after observing that symptoms have developed and become established over a period of time.
After a thorough neurological exam and medical history, the neurologist may order computerized tomography (CT scan) or magnetic resonance imaging (MRI scan) to meet the other criterion for a diagnosis of Parkinson's disease: ruling out disorders (e.g., brain tumor, stroke) that produce parkinsonian symptoms.
Some examples follow:
Blood and/or cerebrospinal fluid (CSF) analysis may be ordered to look for specific abnormalities associated with other disorders.
As noted earlier, even experienced neurologists often find it difficult to diagnose the early stages of Parkinson's disease accurately. No blood or laboratory tests presently exist to aid in diagnosis, and the physician must rely on his or her observation of the patient. In many cases this must be done over a period of time, typically as tremor or other classic symptoms becomes consistently present. Accurate diagnosis is crucial, because other forms of parkinsonism often have similar features, but require different treatments.
In many cases, after a thorough neurological exam and history are performed, the neurologist can make a presumptive diagnosis of PD. There are a number of other disorders, which have some similar features and can be mistaken for Parkinson's disease. Specific diagnostic testing can rule these out in most cases. CT scan (computerized tomography) and MRI scan (magnetic resonance imaging) are often performed.
They can rule out brain tumor, stroke or other focal lesions that may cause a similar clinical picture. Laboratory analysis may also be done, looking for particular blood abnormalities that may be associated with other disorders.
Other Disorders with Similar Symptoms
The term Parkinsonism is used to describe the clinical features that are seen in true Parkinson's Disease, but occur because of some other etiology.
These other causes of rigidity, bradykinesia and in some cases of tremor, include:
There is no cure for Parkinson's disease. Treatment centers on the administration of medication to relieve symptoms. The Food and Drug Administration (FDA) also has approved a surgically implanted device that lessens tremors.
In some severe cases, a surgical procedure may offer the greatest benefit.
Medication selection and dosage is tailored to the individual. The physician considers factors such as severity of symptoms, age, and presence of other medical conditions. No two persons respond identically to a particular drug or dosage level, so this process involves experimentation, persistence, and patience.
As the disease progresses, drug dosages may have to be modified and medication regimens changed. Sometimes a combination of drugs is given.
Levodopa and carbidopa combined (Sinemet®) is the mainstay of Parkinson's therapy. Levodopa is rapidly converted into dopamine by the enzyme dopa decarboxylase (DDC), which is present in the central and peripheral nervous systems. Much of levodopa is metabolized before it reaches the brain.
Carbidopa inhibits DDC. Combining levodopa with carbidopa increases the amount of levodopa that reaches the brain. Levodopa is most effective in treating bradykinesia and rigidity, less effective in reducing tremor, and often ineffective in relieving problems with balance.
Side effects include gastrointestinal distress, especially early in treatment, low blood pressure (hypotension), and abnormal movements (dyskinesias). Slow dosage adjustment and taking medication with food can reduce these effects and using the lowest effective dose may prevent or delay the appearance of motor dysfunction. Levodopa can become ineffective over time.
Depression, confusion, and visual hallucinations also may occur, especially in the elderly.
Dopamine agonists mimic dopamine's function in the brain. They are used primarily as adjuncts to levodopa/carbidopa therapy. They can be used as monotherapy but are generally less effective in controlling symptoms. Side effects are similar to those produced by levodopa and include nausea, sleepiness, dizziness, and headache.
In March 2007, pergolide was removed from the market due to an increased risk for severe heart valve damage. Patients using this medication should speak with their physician about alternative treatments and should not discontinue use of the drug abruptly. Symptoms of heart valve damage include fatigue, shortness of breath, and palpitations.
The FDA approved Neupro® (rotigotine transdermal system) for the treatment of early Parkinson's disease in May 2007. Neupro, which is a patch that is applied to the skin once a day, provides the dopamine agonist rotigotine continuously over a 24-hour period. Application site reaction is a possible side effect of this medication.
Amantadine (Symmetryl®) is an antiviral drug with dopamine agonist properties. It increases the release of dopamine. It is often used to treat early-stage Parkinson's disease, either alone, with an anticholinergic drug, or with levodopa. Generally, it loses its effectiveness within 3 to 4 months.
Side effects include mottling of the skin, edema, confusion, blurred vision, insomnia, and anxiety.
Dopamine is oxidized by monoamine oxidase B (MAO-B). Selegiline (Carbex®) inhibits MAO-B, increasing the amount of available dopamine in the brain. MAO-B inhibitors boost the effects of levodopa.
Side effects may include nausea, dizziness, abdominal pain, confusion, hallucinations, and dry mouth. Selegiline is contraindicated for patients taking tricyclic antidepressants (e.g., Pamelor®) , SSRIs (e.g., Prozac®), or meperidine (Demerol®) and other opiates.
Anticholinergics reduce the relative overactivity of the neurotransmitter acetylcholine to balance the diminished dopamine activity. This class of drugs is most effective in the control of tremor, and they are used as adjuncts to levodopa.
Side effects associated with anticholinergic drugs include dry mouth, blurred vision, constipation, and urinary retention.
COMT (catechol-O-methyl transferase) Inhibitors
These new class of Parkinson's medications augment levodopa therapy by inhibiting the COMT enzyme, which metabolizes levodopa before it reaches the brain. Inhibiting COMT increases the amount of levodopa that enters the brain. These drugs are only effective when used with levodopa.
Side effects include vivid dreams, visual hallucinations, nausea, sleep disturbances, daytime drowsiness, headache, and dyskinesias.
Carbidopa, levodopa, and entacapone are combined in Stalevo®, which is available in flexible dosing and indicated for patients who experience a reduced effectiveness of their PD medication.
Common side effects of Stalevo® include dyskinesias and nausea, which may be controlled by altering the dosing schedule.
Other side effects include the following:
The Exelon® Patch (rivastigimine transdermal system) has been approved by the FDA to treat mild-to-moderate dementia associated with Parkinson's disease. This patch is applied to the skin (usually on the back, chest, or upper arm) and delivers medication continuously for 24 hours. Side effects include nausea, vomiting, diarrhea, and loss of appetite. Higher dosages of the medication increase the risk for these side effects.
Surgery is another method of controlling symptoms and improving quality of life when medication ceases to be effective or when medication side effects, such as jerking and dyskinesias, become intolerable.
Not everyone is a good candidate for surgery. For example, if a patient never responded to, or responded poorly to levodopa/carbidopa, surgery may not be of any help. Only about 10% of Parkinson's patients are estimated to be suitable candidates.
Those who are suitable but forgo surgery may feel the risk outweighs the benefit. Every surgical procedure carries inherent risk. Additionally, there is the risk that symptoms will not improve or will worsen following the operation.
There are three surgical procedures for treating Parkinson's disease: ablative surgery, stimulation surgery or deep brain stimulation (DBS), and transplantation or restorative surgery.
This procedure locates, targets, and then destroys (ablates) a clearly defined area of the brain affected by Parkinson's. The object is to destroy tissue that produces abnormal chemical or electrical impulses that produce tremors and dyskinesias.
A heated probe or electrode is inserted into the targeted area. It is often difficult to estimate how much tissue to destroy and the amount of heat to use. It is always safer to burn a small area and risk the tremor returning or not being eliminated, rather than burning a larger region and risking serious complications such as paralysis or stroke.
The patient remains awake during this procedure to determinine if the tremor or dyskinesia has been eliminated. A local anesthetic is used to dull the outer part of the brain and skull. The brain is insensitive to pain, so it can be manipulated and probed without the patient feeling it.
This type of surgery involves either pallidotomy or thalamotomy. Pallidotomy-ablation in the part of the brain called the globus pallidus-involves putting a hole (i.e., otomy) in the globus pallidus, the globe-shaped structure located deep inside the brain. This procedure is performed to eliminate uncontrolled dyskinesias.
Thalamotomy-ablation of brain tissue in the thalamus-involves creating an otomy in the thalamus. This structure is located below the globus pallidus. The procedure is performed to eliminate tremors.
A related procedure, cryothalamotomy, uses a supercooled probe that is inserted into the thalamus to freeze and destroy areas that produce tremors.
Deep Brain Stimulation (DBS)
DBS targets the subthalamic nucleus, which is located below the thalamus and is difficult to reach, the globus pallidus, or the thalamus. In DBS, the targeted region is inactivated, not destroyed, by an implanted electrode.
The electrode is connected via a wire running beneath the skin to a stimulator and battery pack in the patient's chest. It is reversible-just turn off the current-and allows for precise calibrated symptom control.
The risk for hemorrhage or stroke is reduced, but the electrode can become infected, the simulator may have to be periodically programmed, and the battery must be replaced every 5 years. Battery replacement involves minor surgery.
Transplantation or Restorative Surgery In transplantation, or restorative, surgery dopamine-producing cells are implanted into the striatum. The cells used for transplantation may come from one of several sources: the patient's body, human embryos, pig embryos.
Using cells from the patient's body has been unsuccessful because of an insufficient supply of dopamine cells and the inability of the implanted cells to survive.
To use fetal cells, between three and eight embryos are needed per procedure, and even under the most favorable conditions, 90% of transplanted cells do not survive. This procedure is only moderately effective in some patients and usually in those younger than age 60.
Preliminary studies have shown that pig embryo cells do survive transplantation and have an effect on symptoms.
Stem cells, primitive cells that can grow into nerve cells, are able to survive and reproduce. Once they grow as nerve cells, they can be transformed into dopamine-producing cells.
Stem cells are obtained from discarded blood in a newborn's umbilical cord, the bone marrow of an adult, or an aborted embryo.
A number of modalities and nutritional supplements can help relieve symptoms and improve quality of life. It is imperative that patients inform their physician of any over-the-counter medications, herbs, or other supplements that they use on a regular basis, because they may interact with medication and because drug dosages may need to be adjusted.
Physical therapy can help strengthen and tone underused muscles, and give rigid muscles a better range of motion. The goal is to help build body strength, improve balance, overcome gait problems, and improve speaking and swallowing.
Simple physical activity such as walking, gardening, and swimming can improves one's sense of well-being.
Gentle, soothing massage techniques may provide relief from muscle rigidity and may have some neuromuscular benefit as well.
The slow flowing movements of Tai Chi help maintain flexibility, balance, and relaxation. The Struthers Parkinson's Center in Minneapolis, which teaches a modified form of Tai Chi, consistently reports benefits achieved by patients in all stages of Parkinson's.
Support groups provide a caring supportive environment in which patients and their loved ones can ask questions about Parkinson's, expressing their frustrations, and obtain advice about coping with and treating symptoms from people who share the same problem.
Parkinson's appears to progress more slowly in those who remain involved in activities that they enjoyed before the onset of symptoms and in those who engage in new interests.
As anyone will recall who has read the book, Awakenings, by neurologist Dr. Oliver Sacks, or seen the movie made from it, a severe viral disease called encephalitis lethargica struck down almost 5 million people worldwide in the years just after World War I. It disappeared during the 1920s, but not before it killed one-third of its victims and cast others into a seemingly catatonic state. This "sleeping sickness," as it was called in the United States, was postencephalitic parkinsonism, a disabling neurological disorder which often developed years after the acute phase of encephalitis lethargica had passed. Other viral infections, including western equine encephalomyelitis, eastern equine encephalomyelitis and Japanese B encephalitis, have been known to cause parkinsonian symptoms as well, though rarely.
Sometimes the use of certain drugs can produce parkinsonian symptoms. These include chlorpromazine and haloperidol, drugs which are prescribed for psychiatric patients, metoclopramide, often used to treat stomach disorders, and reserpine, a blood pressure controlling drug. Changing the medication or adjusting its dosage usually moderates or eliminates the symptoms.
This condition is characterized by mild problems in the substantia nigra, but severe damage to other parts of the brain that usually are less affected by primary Parkinson's disease. Patients with striatonigral degeneration usually have greater muscular rigidity, and their disease progresses rapidly.
Arteriosclerotic Parkinsonism or Pseudoparkinsonism
A condition in which multiple small strokes cause damage to blood vessels in the brain, arteriosclerotic parkinsonism rarely causes tremors, but most people afflicted with it suffer dementia. The usual drugs used to treat parkinsonian symptoms are largely ineffective with pseudoparkinsonism.
Some toxins are known to cause parkinsonism. These include manganese dust, carbon disulfide, carbon monoxide and a chemical known as MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine).
Parkinsonian symptoms also are known to appear in conjunction with other neurological disorders. Among these diseases are progressive supranuclear palsy, Huntington's disease, Alzheimer's disease, Creutzfeldt-Jakob disease and post-traumatic encephalopathy.