Motor fluctuations in Parkinson's disease

Abstract

Almost all patients with Parkinson's disease will eventually require levodopa during the course of their disease. The effectiveness of levodopa is evident, but earlier use and higher doses are causative of the emergence of motor fluctuations. About one half of patients develop motor fluctuations 4–6 years after starting levodopa therapy for parkinsonian symptoms. Peripheral and central pharmacokinetic mechanisms are related to motor fluctuations. It was reported that time to peak concentration (Tmax) and elimination half-life (T1/2) of levodopa decreased especially in patients with wearing-off (peripheral pharmacokinetics). On the other hand, there are several reports demonstrating no change in peripheral pharmacokinetics in patients on long-term levodopa therapy. The reduced capacity for presynaptic storage of dopamine by nigral neurons is believed to be another important factor responsible for motor fluctuations (central pharmacokinetics). In addition, a mathematical model that was recently established based on the hypothesis that dopamine release is subject to probabilistic variations in the quantity of dopamine has indicated that motor fluctuations might be explained by presynaptic mechanisms. On the other hand, several studies demonstrated that changes in postsynaptic mechanisms (pharmacodynamics) play an important role in shortening the duration of levodopa action in advanced stages. In clinical practice therapeutic strategies for motor fluctuations are focused on continuous dopaminergic stimulation at postsynaptic dopamine receptors. Once motor fluctuations appear, therapeutic regimens should be individualized to retain optimal control of the symptoms based on accurate assessment of each patient's levodopa cycle and responses to drugs. Symptom diaries kept by patients or caregivers are useful for this purpose.