Encephalitis lethargica

Most people probably envision someone afflicted with Parkinson's disease as a frail, stooped figure, walking with shuffling steps, with one or both hands trembling in uncontrolled movements. This once was the typical patient, but no longer. Although there is no cure for Parkinson's, modern drugs have made it possible for most patients to remain independent for more years than they might have otherwise.

What is this mysterious disease that affects about 500,000 people in United States? A mdedical definition of Parkinson's disease is "a chronic central nervous ssytem disorder characterized by slowness and poverty of purposeful movement, muscular rigidity, and tremor." The symptoms were first described by dr. James Parkinson, a London physician, who thus endowed the syndrome with a name. His "Essay on the Shaking Palsy" was published in 1817; yet nearly 150 years passed before scientists were able to pinpoint the brain defect that is the root of this disorder.

Parkinson's disease does not come on suddenly; in fact, it is so insidious that victims often don't realize anything is wrong, although family and friends may notice subtle changes.

The early symptoms, such as a little shakiness or a general sense of slowing down, may be dismissed as part of growing old. (The average age of a patient at diagnosis is 65.) A slight tremor then appears, often in the form of a "pill rolling" movement involving the fingers and thumb of one hand. Classically, the tremor is most pronounced at rest and is less severe when the affected limb is in motion.

Another characteristic symptom is rigidity of the arms and legs. Muscles remain tight, instead of relaxing. If another person tries to move a patient's arm, the movements will be sort and jerky, as though the arm is being moved by a gear.

A third, and very definite, sign of Parkinson's disease is a slowness of movement, known medically as "bradykinesia." There is a loss of facial expression, the patient's voice becomes low and monotonous, and eye blinking decreases. Handwriting that gets smaller and more cramped after the first words is another telltale sign.

As the disease progresses, the patient finds it hard to start walking and, once movement is started, takes short steps with a shuffling gait. Another characteristic is a slight forward lean, which causes the patient to take a series of quick, small steps forward to "catch up" with a changed center of gravity. At times the patient may actually fall down when confronted with an obstacle, for stopping can be as hard as starting.

A backward lean also may develop in advanced cases. This may make the patient step backwards when starting to walk or when bumped from the front. Patients often have difficulty maintaining a stable posture.

As time goes on, the loss of spontaneous movements may worsen. There may be times when the person can't move at all. This "frozen" state affects walking most dramtically and may be triggered by an open doorway or a line drawn on the floor.

Other late symptoms include drooling, due to decreased function of the throat muscles, and an overproduction of normal skin oils. Most patients continue to think clearly, though late in the course of the illness some may suffer loss of mental skills. Parkinson's patients may also feel depresed.

The symptoms of Parkinson's themselves are not fatal. Death most often results from some other illness acquired during the later stages of the disease.

In the 1960s, studies were conducted of the brains of Parkinson's patients to get clues to the cause of the disease. The studies found diminished concentratoins of dopamine, a chemical messenger that transmits signals from one nerve cell to another. Produced by nerve cells in the substantia nigra, located in the brain stem, dopamine is sent to higher brain centers that control slow or subtle movement. Without a constant supply of dopamine, movement fails.

As people grow older, the supply of dopamine dwindles, apparently because of a loss of producer cells in the substantia nigra. Even so, most people can continue to function. However, if more than 80 percent of the dopamine-producing cells are lost, Parkinson's symptoms begin to appear.

Why these cells die is still a mystery. Heredity has been generally ruled out, leaving environmental factors as possible causes. Parkinson-like symptoms do develop as a result of carbon monoxide or manganese poisoning. Or these symptoms may appear with use of certain antipsychotic drugs, notably Thorazine and other drugs of the phenothiazine class, but they disappear when the drug is stopped. Severe parkinsonism has also followed accidental exposure to a toxic chemical known by the acronym MPTP.

Then there is the possibility that Parkinson's disease might be caused by a latent virus. Many people developed the "shaking palsy" years after they had encephalitis lethargica (sleeping sickness) during an epidemic that swept the world from 1919 to 1924.

Still, for most Parkinson's patients there is no known explanation why they have this condition and others do not.

There is hardly a drug that hasn't been tried in the treatment of Parkinson's disease, including--without success--such toxic compounds as strychnine and cigarettes made from the foul-smelling jimsonweed (Bulgarian stramonium).

Today there are three basic categories of anti-parkinsonism drugs: anticholinergics, levodopa-containing compounds, and one dopamine agonist (which stimulates the production of dopamine).

Anticholinergics

Normally, there is a fine balance betwen the activity of dopamine and the of acetylcholine, another chemical that transmits nerve impulses. When the inhibiting effect of dopamine is lost, as the dopamine-producing cells degenerate, the functioning of acetylcholine-releasing cells becomes overactive, causing parkinsonian symptoms. This hyperactivity can be blocked with anticholinergic drugs. One such drug, scopolamine, was used in the 19th century, long before acetylcholine's role as a neurotransmitter was discovered. Despite the advent of newer treatments that act directly on the dopamine system, anticholinergics are often the first treatment prescribed for Parkinson's patients.

The anticholingergic drugs include trihexyphenidyl hydrochloride (Artane, Tremin), benztropine mesylate (Cogentin), diphenhydramine hydrochloride (Benadryl), biperiden (Akineton), and procyclidine hydrochloride (Kemadrin).

These drugs have a modest effecton tremor and rigidity but little or none on bradykinesia (slowed movements). They control drooling, probably because they cause dryness of the mouth.

Patients on these drugs also may experience occasional gingivitis (inflammation of the gums), constipation, mild dizziness, nausea, nervousness and slight blurring of vision. More serious side effects include confusion, urinary retention and psychosis.

Levodopa-containing Compounds

Since the cause of Parkinson's is a loss of dopamines, the logical treatment is to put dopamine back into the brain. Dopamine can't be carried in the blood to the brain, but levodopa, its immediate precursor, can. Once in the brain, levodopa (also called L-dopa) is transformed into dopamine.

Introduced in the 1960s, L-dopa reduces all the primary symptoms of Parkinson's disease. Unfrtunately, many patients find that L-dopa's effectiveness early in the course of treatment may not persist beyond several years. Because of this limited period of usefulness, some physicians choose not to begin treatment with L-dopa until the patient's symptoms are more severe.

Initially, side effects of L-dopa, such as nausea and undirected involuntary movements, made it difficult to give a dose high enough to be effective in some cases. The reason: Some of the L-dopa was being changed into dopamine before it reached the brain. This premature transformation is prevented by the drug carbidopa, which is combined with L-dopa under the trade name Sinemet. Levodopa alone is sold under the trade names Larodopa and Dopar.

Besides nausea and involuntary movements, side effects associated with L-dopa include mental changes, cardiac irregularities, and urinary retention. One particularly troubling problem that develops after three to five years of treatment is called the "on-off" reaction. The patient rapidly shifts from a state of uncontrolled movement to one of total lack of movement. The reasons for this troubling reaction are not known, though several theories have been offered.

Another problems is "end-of-dose akinesia"--the return of the Parkinson's symptoms three to four hours after taking medication. Such problems are often relieved by giving the patient a "drug holiday," a three-to seven-day period of hospitalization when no drugs are given. During this time, some patients participate in physical, occupational and speech therapy programs to reduce the hazards of stopping the medication.

Monoamine oxidase inhibitors, used to treat depression, should not be given along with L-dopa. Vitamin B.sub.6 reverses the effectiveness of these anti-parkinsonism drugs, so supplements of this vitamin should be avoided.

Dopamine Agonist

The one drug in this class, bromocriptine (Parlodel), stimulates dopamine receptors in the brain. Clinical studies have shown that bromocriptine, used in conjunction with L-dopa, reduces the end-of-dose phenomenon in many patients and occasionally benefits those with the "on-off" response. However, safety during long-term use (for more than two years) has not been established.

Patients should not take this drug if they a history of coronary or peripheral vascular disease, gastrointestinal ulcers or psychosis. Side effects include hypotension, confusion, nasal stuffiness, blurred vision, liver problems, and swelling of the feet.

Another drug used in treatment of Parkinson's disease is amantadine hydrochloride (Symmetrel), which is also used to treat respiratory tract illnesses caused by influenza A viruses. The mode of action is not know, but amantadine has been shown to increase dopamine release in animal brains. It can provide rapid improvement when given together with L-dopa.

The most frequent side effects of amantadine include depression, congestive heart failure, hypotension, and urinary retention.

COPYRIGHT 1985 U.S. Government Printing Office
COPYRIGHT 2004 Gale Group