Motor fluctuations in Parkinson's disease: pathophysiology and treatment

At the initial stages of Parkinson's disease (PD), levodopa (LD) is able to reduce most motor symptoms and to significantly improve the patient's qual ity of Life. However, in the vast majority of patients with prolonged LD us age, some decline in efficacy occurs and motor complications eventually beg in to appear These complications consist not only of daily fluctuations in the voluntary motor performance often accompanied by involuntary movements, but also of fluctuations in cognitive, autonomic, and sensory functions. S everal recent studies on LD complications in PD have led to a better unders tanding of their pathophysiology and of the possible therapeutic interventi ons, and a summary of these findings is presented in this review Different observations now suggest that postsynaptic pharmacodynamic factors play a m ajor role in determining fluctuations in PD. Two explanations are given: ch ronic intermittent dopaminergic therapy may lead to postsynaptic receptor d ownregulation in PD; or, receptor changes in the striatum may occur indepen dently of treatment as a result of structural adaptation of the postsynapti c dopaminergic system to the progressive decline of the nigrostriatal pathw ay: The hypothesis of reversible postsynaptic changes as the main mechanism underlying a fluctuating response to LD lends itself to a possible pharmac ological manipulation of the dopaminergic response to reverse, or even avoi d, motor fluctuations (initial monotherapy with dopamine agonists and early combination LD/dopamine agonists). The role of peripheral pharmacokinetics factors is also critical and the use of controlled release LD formulations , of monoamine oxidase (MAO)-B and of catechol-O-methyltransferase (COMT) i nhibitors may all, to a different degree, improve such phenomena. In the la st decade, there has been a resurgence in surgical therapies in advanced PD , due to higher levels of accuracy and safety provided by the new surgical devices, and to a more precise localization of the target areas allowed by the neurophysiological mapping techniques. The surgical procedures currentl y used in advanced PD are stereotactic brain lesions (internal globus palli dus and subthalamic nucleus), chronic brain stimulation (of the same nuclei ) and striatal grafting of dopamine-producing cells. All these procedures h ave already shown their efficacy in the management of severe fluctuations i n PD, but their indications, and relative advantages and disadvantages, are still the subject of considerable debate and controversy. Eur J Neurol 6:1 -21 (C) 1999 Lippincott Williams & Wilkins.