Pharmacological hypotheses and therapeutic strategies for gait disorders in Parkinson's disease

Gait disorders form part of the axial symptoms observed in Parkinson's disease (PD) and also represent a major source of therapeutic failure in the later stages of PD, with the appearance of freezing of gait (FOG) and falls. Double-blind clinical trials and, above all, clinical experience have demonstrated that L-DOPA is effective in reducing FOG. Dopaminergic agonists appear to be less effective than L-DOPA and lack formal proof of their efficacy. The enzyme inhibitors provide modest benefits, which need to be confirmed. Hence, these symptoms appear to be partially doparesistant and justify investigation of other major neurotrans mission systems. Of the various drugs with partial noradrenergic activity, methylphenidate may improve FOG and attention disorders. Memantine has shown some value in improving motor symptoms and gait in fluctuating parkinsonian patients - possibly by reducing the effect of glutamatergic hyperactivation of the subthalamic nucleus on the pedunculopontine nucleus (PPN). The PPN's dense cholinergic innervation also suggests that cholinesterase inhibitors may be of use, although any benefits must be set against a potential aggravation of rest tremor. The many interactions between the serotoninergic and dopaminergic systems require the implementation of clinical studies on the complex motor impact of serotoninergic treatments, which may aggravate the parkinsonian syndrome while improving gait (as is the case with paroxetine and ritanserin). This review seeks to develop the various pathophysiological hypotheses prompted by the results of fundamental studies and pilot clinical trials, with a view to justifying the implementation of confirmatory, double-blind, placebo-controlled therapeutic trials. (c) 2009 Elsevier Masson SAS. All rights reserved.