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 quality of life. However, in the vast majority of patients with prolonged LD usage, some decline in efficacy occurs and motor complications eventually begin 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. Several recent studies on LD complications in PD have led to a better understanding of their pathophysiology and of the possible therapeutic interventions, and a summary of these findings is presented in this review. Different observations now suggest that postsynaptic pharmacodynamic factors play a major role in determining fluctuations in PD. Two explanations are given: chronic intermittent dopaminergic therapy may lead to postsynaptic receptor downregulation in PD; or, receptor changes in the striatum may occur independently of treatment as a result of structural adaptation of the postsynaptic dopaminergic system to the progressive decline of the nigrostriatal pathway. The hypothesis of reversible postsynaptic changes as the main mechanism underlying a fluctuating response to LD lends itself to a possible pharmacological manipulation of the dopaminergic response to reverse, or even avoid, 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) inhibitors may all, to a different degree, improve such phenomena. In the last 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 currently used in advanced PD are stereotactic brain lesions (internal globus pallidus and subthalamic nucleus), chronic brain stimulation (of the same nuclei) and striatal grafting of dopamine-producing cells. All these procedures have already shown their efficacy in the management of severe fluctuations in PD, but their indications, and relative advantages and disadvantages, are still the subject of considerable debate and controversy.