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.

A.1.

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.

A.2.

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).

A.3.

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.

A.4.

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.

A.5.

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.