"On" state freezing of gait in Parkinson disease: a paradoxical levodopa-induced complication

Abstract

Objective: To describe the phenotype of levodopa-induced "on" freezing of gait (FOG) in Parkinson disease (PD).

Methods: We present a diagnostic approach to separate "on" FOG (deterioration during the "on state") from other FOG forms. Four patients with PD with suspected "on" FOG were examined in the "off state" (>12 hours after last medication intake), "on state" (peak effect of usual medication), and "supra-on" state (after intake of at least twice the usual dose).

Results: Patients showed clear "on" FOG, which worsened in a dose-dependent fashion from the "on" to the "supra-on" state. Two patients also demonstrated FOG during the "off state," of lesser magnitude than during "on." In addition, levodopa produced motor blocks in hand and feet movements, while other parkinsonian features improved. None of the patients had cognitive impairment or a predating "off" FOG.

Conclusions: True "on" FOG exists as a rare phenotype in PD, unassociated with cognitive impairment or a predating "off" FOG. Distinguishing the different FOG subtypes requires a comprehensive motor assessment in at least 3 medication states.

Figure 1. The 360-degree turn task

Subjects performed a 360-degree turn into each direction in each medication state. The figure shows the time normalized with respect to baseline performance (“off ”). For each subject, only the worst performance (with regard to the right/left direction) is displayed; case 1 was unable to complete the 360-degree-turn task and therefore the straight walking task is shown (the same subject was unable to complete the task in the “supra-on” condition).

Figure 2. Types of freezing of gait

The theoretical “threshold” (or rather, the dose range) for motor improvement (and also the threshold for improvement of “off” freezing of gait [FOG]) may be lower for appendicular manifestations of Parkinson disease (A) vs freezing of gait (B). “Off” state FOG occurs below the threshold for motor benefits. In this case a dose increase above such threshold is expected to eliminate the FOG. “Pseudo-on” FOG is an intermediate FOG level, occurring at doses where patients appear to otherwise respond well to medication. Although counterintuitive, a tolerable increase in the dose of antiparkinsonian medication in these patients is also expected to eliminate the FOG. Finally, “on” state FOG reported here may develop or worsen with higher l-dopa doses. For these patients, gait only improves after l-dopa dose reduction (adapted from Grimbergen et al.).