Mid-stage parkinsonism with mild motor fluctuations.

Most patients with Parkinson's disease who undergo levodopa therapy eventually develop fluctuations in the diurnal control of their symptoms. These fluctuations, when mild, consist mostly of the "wearing-off" effect--the re-emergence of symptoms several hours after the ingestion of each dose of levodopa. In some patients, "wearing-off" in the daytime is preceded by, or associated with, the development of nocturnal and early morning akinesia. Some patients at this stage also have mild (mostly peak dose or square-wave) choreoathetoid dyskinesias. In patients with "wearing-off," "on" periods tend to occur when plasma levels of levodopa are high; nocturnal and early morning akinesia and diurnal "off" periods tend to occur at times when plasma levodopa levels are low, reflecting insufficient concentrations of dopamine in the striatum. Treatment strategies in patients with mid-stage parkinsonism and mild fluctuations are primarily directed toward enhancing dopaminergic transmission in the striatum. This is achieved by increasing the supply of levodopa to the brain or by administering drugs that either prolong the effect of synaptic dopamine from levodopa, or activate postsynaptic dopamine receptors. This presentation will discuss the advantages and possible drawbacks of these different strategies, which include the use of controlled-release levodopa preparations, deprenyl, and the new monoamine oxidase (MAO)-B inhibitors, catechol-O-methyl transferase (COMT) inhibitors, and the various "direct" dopamine agonists.