A Brief Synopsis of Parkinson's Disease


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Parkinson's Disease is a slowly progressive neurological disorder caused by the loss of dopamine-containing cells in the nigrostriatal pathway. Prominent symptoms involve motor function, but psychiatric complications may also occur.

Etiology & Incidence

The symptoms of the disease are caused by the loss of dopamine cells in the nigrostriatal system (A9) with some concomitant loss to A10 cells likely. The reason for this cell loss is unknown, with speculations ranging from virial infection to metal poisoning. The onset is usually after 40 years, with a mean age of onset at 57 years. The disease sometimes begins in childhood which is termed juvenile parkinsonism. Parkinson's disease affects about 1% of people aged 50 years and over, but as many as 10% aged 60 years and over may have undiagnosed, early stages of the disease. The incidence is women is about 1 1/2 times higher than in men.

Symptoms

Difficulty initiating movement, shuffling gait, "cogwheel" rigidity, and tremor at rest are the most prominent symptoms.

Diagnosis

Diagnosis is usually made through neurologic examination identifying the prominent symptoms and by ruling out other causes.

Prognosis

Left untreated, Parkinson's disease is a progressive disorder that eventually leads to premature death. With appropriate treatment, life-expectancy may be somewhat lessened but is improved dramatically.

Treatment

For over thirty years the first choice of treatment has been levodopa (L-dopa) therapy. The dopamine precursor is taken up by dopamine synthesizing cells and decarboxylated to dopamine. This effectively boosts CNS dopamine levels, partially compensating for the dopamine loss through neuronal degeneration. To increase the amount of levodopa actually reaching the brain and to diminish the side-effects caused by excessive peripheral dopamine synthesis, a peripheral dopa decarboxylase inhibitor (carbidopa) is often combined with the levodopa therapy.
 
Selecting the correct dosage of levodopa can be difficult, requiring the expertise of a physician experienced at treating this disorder. Levodopa and the other medications used to treat Parkinson's disease can also produce side-effects ranging from uncontrolled movements (dyskinesias) to psychiatric problems (e.g., hallucinations, paranoia).

Levodopa/carbidopa therapy is usually highly effective for the first 2 to 5 years of treatment. After this time over half of the patients begin experiencing a prominent on-off effect from their levodopa. Shortly after taking the medication, the patient is fully ambulatory often showing hyperactivity and dyskinesia. As the medication levels drop, the patient loses mobility and returns to an akinesic state resembling untreated Parkinson's disease. This on-off cycling effect prompts patients to request higher doses of levodopa administered more frequently, but the medication exacerbates the dyskinesias and can lead to psychiatric complications (e.g., agitation, hyperactivity, paranoia) in many patients. Indeed, patients who responsible for taking their own medication tend to take their levodopa more often than prescribed by their physician, thus exacerbating the dyskinesias and psychiatric complications.
 

Chronic treatment with dopamine agonists or with dopamine antagonists actually increases the sensitivity of dopamine receptors. These conditions are termed sensitization and supersensitivity, respectively -- the two terms actually refer to the same condition produced by opposite experimental manipulations. 

Changes in receptor sensitivity are probably related to the dopamine system's attempt to regulate its own level of activity and may explain why considerable dopamine-cell loss occurs before any clinical symptoms emerge. Interestingly, enhanced dopamine sensitivity has also been suggested to underlie some forms of mental illness (e.g., schizophrenia) and drug addiction. 



Changes in the sensitivity of dopamine receptors complicates treatment and is most likely the cause of the dyskinesic and psychiatric side-effects seen with long-term management of Parkinson's disease. Experimental treatments have been explored that may prevent the changes in dopamine-receptor sensitivity and thereby prolong the usefulness of levodopa and other therapies (e.g., Pudiak & Bozarth, 1997).

More recently direct-acting dopamine agonists (e.g., bromocriptine, pergolide) have been used in patients unresponsive to levodopa and in patients showing a strong on-off effect. The original rationale for using direct-acting agonists was that after the levodopa loses effectiveness due to continued dopamine cell loss, the direct activation of postsynaptic receptors is necessary to obtain a therapeutic effect. Unfortunately, direct-acting dopamine agonists have strong side effects (e.g., nausea, confusion, delirium, psychosis) which limit their usefulness. Nonetheless, some physicians have recently suggested that the direct-acting agonists delay the development of the on-off and other side-effects and have recommended that they be used as the first choice in treating Parkinson's disease.

Both levodopa and direct-acting dopamine agonist therapies fail to slow the progression of the dopamine cell loss in the substantia nigra: eventually, these treatments become ineffective as more dopamine cell die. For these patients there is the possibility of participating in experimental brain surgery that may restore some of the dopamine cells.

Notable Cases

Mohammed Ali
Michael J. Fox
Janet Reno
Adolf Hitler (possibly)

Online Resources

THE MERCK MANUAL, Sec. 14, Ch. 179, Disorders Of Movement

National Institute of Neurological Disorders & Stroke: Parkinson's Disease Backgrounder

National Insttitue of Neurological Disorders & Stroke: Emotional and Cognitive Aspects Working Group

Update on Parkinson's Disease - April 15, 1999 - American Academy of Family Physicians

Functional neurosurgery for Parkinson's disease


Copyright 2001 Michael A. Bozarth
Revised 15 November 2001 00:07 EST
Report technical problems to: bozarth@buffalo.edu