Practically Defined Off‐State Dyskinesia Following Repeated Intraputamenal Glial Cell Line–Derived Neurotrophic Factor Administration

ABSTRACT Background We recently showed that by employing an enhanced drug‐delivery approach, repeated administration of glial cell line–derived neurotrophic factor (GDNF) can produce a spatially distributed increased 18F‐DOPA positron emission tomography (PET) uptake, suggesting sprouting of dopaminergic terminals throughout the putamen structure. Despite this, we failed to prove a significant measurable clinical response. Since, however, we have identified a subject demonstrating a temporal relationship between repeated GDNF infusions and dyskinesia arising in the practically defined off (pracoff) state. Objectives To describe the development of pracoff dyskinesia across our study population and consider its utility as an indicator that trophic factor–induced terminal sprouting can affect enhanced endogenous dopamine levels. Methods This was a blinded retrospective analysis of videotaped motor assessments at eight weekly study visits. Dyskinesia in the pracoff and supramaximal on state were rated using the Clinical Dyskinesia Rating Scale. Logistic regression was employed to explore the predictors of pracoff dyskinesia. Generalized estimated equations were used to estimate the cumulative effect of repeated GDNF infusions. Results Mild–moderate choreiform dyskinesia in the pracoff state were seen in 47 assessments in 17 (n = 41) subjects. During the 18‐month timeframe, each subsequent 8‐week period of receiving GDNF increased the risk of demonstrating pracoff state dyskinesia by 34% (odds ratio [OR], 1.34 (95% confidence interval [CI], 1.20, 1.50); P