Dyskinesias and dopamine cell replacement in Parkinson's disease: a clinical perspective

Abstract

Both increased and decreased dyskinesias have been reported from open label clinical trials of transplantation of human embryonic dopamine rich tissue in Parkinson's disease patients. In the first double-blind clinical transplantation trial, 15% of the grafted patients developed severe postoperative dyskinesias in the “off” phase. Since then, postoperative off-medication dyskinesias have been reported from two additional series of grafted patients. However, such dyskinesias are probably not a novel phenomenon. These dyskinesias have shown a different temporal development postoperatively compared to the antiparkinsonian graft effects, and no significant relationship with the magnitude of graft-derived dopaminergic reinnervation or symptomatic relief. However, positron emission tomography studies have indicated that an unbalanced putaminal dopaminergic function may contribute to this postoperative complication. While there is little doubt that intrastriatal grafts can induce dyskinesias, these appear to differ from common drug-induced dyskinesias. The term graft-induced dyskinesias (GID) is therefore suggested to more clearly identify this complication. While GID bear some phenomenological resemblance to biphasic drug induced dyskinesias, the mechanism(s) behind this complication remains obscure. Available data are scarce but allow for hypotheses to be generated that could (and should) be addressed in experimental animals.

Introduction

For more than 20 years, intracerebral transplantation of embryonic ventral mesencephalic (VM) tissue, rich in dopamine (DA) neurons, has been looked upon as a particularly promising approach for the treatment of Parkinson's disease (PD). Hopes were fostered by the encouraging results produced by intrastriatal VM transplants both in animal models of PD [6], [46], [81] and in early open-label clinical trials [68], [69]. In a majority of transplanted patients the grafts were found to survive and ameliorate many of the symptoms of PD and to reduce the need for L-dopa. In response to the promising early findings, two double-blind randomized controlled trials (RCTs) of human embryonic VM grafts to patients with PD were initiated. After unblinding of the first of these, the previous enthusiasm was severely set back by reports that a subgroup of patients developed a severe and persistent form of dyskinesia at late postoperative periods [32], [37]. Other reports were soon to follow indicating that dyskinesias indeed can develop as a complication of intrastriatal VM grafting [40], [79]. These dyskinesias are a puzzling phenomenon that has not been foreseen by experimental studies of VM transplantation in animal models.