When do levodopa motor fluctuations first appear in Parkinson's disease?

Although levodopa provides therapeutic benefit over the entire course of Parkinson's disease, most patients eventually notice a decline in the duration of benefit from each dose, a phenomenon termed 'wearing-off' or 'end of dose' deterioration. This is an important indicator that the patient is entering a more complex phase of the disease. Wearing-off has been classically associated with the later stages of Parkinson's disease, but it is becoming apparent that patients with early disease, presenting as well controlled, may already be experiencing fluctuations in their response to levodopa. However, neither the pathophysiology nor the clinical relevance of the early emergence of wearing-off has been properly explored. We now review the preclinical and clinical evidence that suggests that even patients who are apparently still in the honeymoon phase of drug treatment may have early fluctuations in their motor response to dopaminergic therapy. It is important that early wearing-off is recognized as it has important consequences for the long-term outcome and for the medication regimens to be used.