Methods of managing levodopa-induced dyskinesias.

Levodopa-induced dyskinesias result in considerable functional impairment for patients and formidable therapeutic challenges for physicians. A practical method of treating such dyskinesias is first to classify the levodopa dyskinesias according to their temporal profile after drug administration, namely, into predictable (interdose, biphasic and 'off-period') and unpredictable ('on-off') dyskinesias. Treatment of each type of dyskinesia requires a different and relatively specific therapeutic strategy. With progression of Parkinson's disease, the threshold for interdose dyskinesia lowers, while the threshold for antiparkinsonian efficacy is unchanged; therefore, the strategy is to maintain levodopa concentrations between these 2 thresholds and avoid high concentrations. Frequent small doses of liquid levodopa preparations may be indicated. Clozapine appears to increase the threshold for dyskinesia. However, its usefulness is limited primarily by dose-related sedation and by dose-unrelated agranulocytosis. Buspirone and fluoxetine may have specific antidyskinetic benefit. Surgical treatment may aid selected patients, although criteria for selection are not fully established. The biphasic dyskinesias occur just before and just after an oral dose of levodopa. They result when levodopa concentrations fall below or rise above the threshold for therapeutic efficacy; therefore, the strategy is to maintain concentrations as nearly constant as possible above that threshold. Dopamine agonists such as subcutaneous apomorphine combined with domperidone may be particularly helpful. Thalamic stimulation can also benefit selected patients. 'Off-period' dyskinesias occur at times of predicted low concentrations of levodopa. The treatment strategy is to provide sufficient levodopa or dopaminergic stimulation during those intervals. Dopamine agonists (e.g. bromocriptine at night) may help the characteristic early foot dystonia. Anticholinergic agents may also help. The unpredictable ('on-off') dyskinesias are first analysed to establish a pattern of response. Then, on the basis of that pattern, they are treated by maintaining levodopa concentrations or dopaminergic tone during the periods that would ordinarily be 'off.' Administration of liquid levodopa preparations, addition of dopaminergic agents, restriction of treatment during the morning hours as well as restriction of the majority of dietary protein in the evening meal may provide a period of predictable good function early in the day. Clozapine, even early in treatment, appears to reduce the incidence of these dyskinesias. Rescue with apomorphine during a malignant prolonged 'off' phase is particularly valuable.