Levodopa–induced dyskinesias in the absence of nigrostriatal degeneration

Abstract

Levodopa (L-dopa)-induced dyskinesias (LIDs) are thought to occur in Parkinson’s disease (PD) patients as a consequence of nonphysiologic L-dopa replacement in patients with severe nigrostriatal terminal degeneration who lack the capacity to buffer fluctuating striatal dopamine levels. 1‐5 In this regard, disease severity has been considered to be a critical factor in the pathogenesis of dyskinesia. At odds with this concept, however, are recent findings suggesting that L-dopa dose, and not disease severity, is the key risk factor for the development of dyskinesia in PD patients. 6 Furthermore, in the current issue of Movement Disorders, Pons et al. describe the emergence of LID in patients with tyrosine hydroxylase (TH) deficiency who presumably have preserved dopamine terminals and striatal innervation. 7 Under normal circumstances (ie, in the unlesioned brain), L-dopa is thought to primarily be decarboxylated to dopamine in nigrostriatal terminals. However, the precise site and extent to which L-dopa is decarboxylated in the parkinsonian brain remains uncertain, as most striatal dopamine terminals have degenerated. While it has been traditionally assumed that L-dopa administration enhances dopamine synthesis and release in the surviving nigrostriatal neurons, it is also possible that exogenous L-dopa can be decarboxylated and released as dopamine by serotonin terminals, striatal capillaries, noradrenergic neurons, and monoaminergic striatal interneurons. 3,8 Indeed, Ldopa remains effective even in very advanced PD patients, where it is assumed that virtually all terminals in the dorsal striatum have undergone degeneration. Thus, it has been postulated that dysregulated release of dopamine from serotonin terminals and other sites also may be disruptive to striatal function and contribute to the development of dyskinesia. 8