Is levodopa induced freezing of gait a paradox or an expected phenomenon?: a clinico-pathophysiological hypothesis.

BACKGROUND: Freezing of Gait (FOG) is the most disabling and puzzling symptom of Parkinson’s Disease (PD). FOG is strongly associated with increasing disease severity and longer duration of levodopa treatment. In addition to FOG in OFF states, there has been a characterization of ON-state freezing of gait (ON-FOG), often described as a “paradoxical” effect of dopaminergic therapy. METHODS: Literature review. RESULTS AND DISCUSSION: In this review, we propose, for the first time, levodopa-induced FOG to be an expected manifestation, rather than a paradox. We first clarify the clinical subtypes of FOG (OFF-FOG, levodopa unresponsive FOG, levodopa-induced FOG and biphasic FOG). We then examine the biomechanical, neurochemical, cognitive and sensori-motor mechanisms that differentiate limb movement from gait control, and explore their differing responses to chronic dopaminergic therapy, while discussing clinical implications of this hypothesis. CONCLUSION: This review provides a distinct phenotype of levodopa induced FOG and posits it to be secondary to expected non-uniform effects of levodopa therapy. The various mechanisms include levodopa-induced spatio-temporal dissociation of gait, disruption of multi-segment coordination and temporal coupling for execution of gait, negative influence on the striatal dopamine-cholinergic balance with maladaptive plasticity affecting the cognitive and sensorimotor networks. Identification of this phenotype is pivotal, since it requires optimal dopaminergic stimulation instead of maximisation, with alternative therapeutic strategies.