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Overview

Parkinson’s disease is a chronic, progressive neurodegenerative movement disorder. Tremors, rigidity, slow movement (called 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 one to one and a half 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.

Risk Factors

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.

Causes

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.

Treatment

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
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. Slow dosage adjustment and taking medication with food can reduce these effects. Hypotension may occur.

Abnormal movements (dyskinesias) and motor symptom fluctuations are common. Using the lowest effective dose may prevent or delay the appearance of motor dysfunction.

Depression, confusion, and visual hallucinations may occur, especially in the elderly.

Dopamine Agonists
Dopamine agonists 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.

• Bromocriptine (Parlodel®)
• Pergolide (Permax®)
• Pramipexole (Mirapex®)
• Ropinirole (Requip®)

Side effects are similar to those produced by levodopa.

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.

MAO-B Inhibitors
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 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.

• Benztropine mesylate (Cogentine®)
• Biperiden (Akineton®)
• Diphenhydramine (Benadryl®)
• Trihyxyphenidyl (Artane®)

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.

• Entacapone (Comtan®)
• Tolcapone (Tasmar®)

Side effects include vivid dreams, visual hallucinations, nausea, sleep disturbances, daytime drowsiness, headache, and dyskinesias.

Surgery
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 (or destructive) surgery, stimulation surgery or deep brain stimulation (DBS), and transplantation or restorative surgery.

Ablative Surgery
This procedure locates, targets, and then ablates (or destroys) 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.

Complementary Treatments
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.

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