For every 100,000 people, 150 have Parkinson's disease, and 20 new cases are diagnosed each year. In addition to substantial morbidity and mortality, this disorder has significant costs such as medical care and drug treatment, and loss of earnings. A review by Schapira emphasizes the heterogeneity of the condition and the importance of selecting therapies specific to the needs and tolerances of each patient.
The cause of Parkinson's disease is loss of dopaminergic neurons in the substantia nigra of the midbrain. By the time the classic symptoms of bradykinesia, rigidity and resting tremor become apparent, as much as 70 to 80 percent of the dopaminergic neurons may already have died. It is now apparent that Parkinson's disease can result from any condition that attacks the dopaminergic neurons and is best conceptualized as a syndrome with multiple potential causes. Epidemiologic studies and studies of families with specific subtypes of Parkinson's disease indicate a genetic component, probably linked to aberrations on chromosomes 2, 4 and 6. The only environmental toxin currently linked to Parkinson's disease is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), but various pesticides and herbicides are suspected of contributing to development of the disease.
Current therapy for Parkinson's disease aims to balance amelioration of symptoms with the long-term side effects of medications. Levodopa, enhanced by combination with a dopa decarboxylase inhibitor, is the most common medication in current use; however, its usefulness is limited by motor complications. After five years of treatment, approximately one half of patients treated with levodopa experience dyskinesias and fluctuations in symptom control. Some neurologists recommend initial therapy with a dopamine agonist, beginning with low dosages and initially adding domperidone to relieve nausea and other side effects. The newer dopamine agonists have fewer side effects and may control symptoms for up to four years in a substantial proportion of patients, allowing levodopa to be reserved for more advanced disease with more significant symptoms. Use of selegiline prolongs the action of dopamine and delays the need for additional therapy for about nine months to one year. Recently, concerns have been raised about the safety of selegiline. Other treatments, such as antimuscarinic agents and amantadine, are being used as alternatives to dopamine-related drugs but have significant side effects. Newer drugs include catechol O-methyltransferase (COMT) inhibitors, but there is a risk of hepatotoxicity with these agents. Drugs in development based on biochemical pathways include dopamine reuptake inhibitors and adenosine antagonists.
Two new lines of research focus on neurons rather than biochemical pathways. At least part of the action of current drugs such as selegiline may consist of “neuroprotection” through influence on apoptotic pathways. Studies of cyclosporin A and its derivatives may lead to such drugs, but these will need to be highly selective to avoid adverse effects on the immune system. Other areas of research concern antioxidants, drugs that reduce glutamate neurotoxicity and agents that modulate immune and inflammatory systems only in the relevant areas of the brain.
Surgical treatments are being developed for use in selected patients. Pallidotomy can benefit patients with significant dyskinesias, bradykinesia and rigidity. Tremor may be improved by thalamotomy and by deep brain stimulation of the globus pallidus or the subthalamic nucleus. Experimental fetal nigral implants have improved symptoms in selected patients.