Levodopa‐induced dyskinesia in Parkinson disease: Current and evolving concepts

Abstract

Levodopa-induced dyskinesia is a common complication in Parkinson disease. Pathogenic mechanisms include phasic stimulation of dopamine receptors, nonphysiological levodopa-to-dopamine conversion in serotonergic neurons, hyperactivity of corticostriatal glutamatergic transmission, and overstimulation of nicotinic acetylcholine receptors on dopamine-releasing axons. Delay in initiating levodopa is no longer recommended, as dyskinesia development is a function of disease duration rather than cumulative levodopa exposure. We review current and in-development treatments for peak-dose dyskinesia but suggest that improvements in levodopa delivery alone may reduce its future prevalence. ANN NEUROL 2018;84:797-811 D yskinesia, often referred to as L-dopa-induced dyskinesia (LID) to recognize L-dopa as the major contributor, is a motor complication arising in patients with Parkinson disease (PD) on chronic L-dopa treatment, largely in a dose-dependent fashion-except when given as an infusion, such as in L-dopa/carbidopa intestinal gel. 1 LID is phenomenologically recognized as chorea/choreoathetoid movements appearing initially on the more affected body side. LID occurs in 40% of patients after 4 years on L-dopa treatment, with risk especially high in younger patients treated with higher doses of L-dopa. 2 This review focuses on aspects of phenomenology, pathophysiology, and therapeutics that have undergone revisions or updates in recent years, emphasizing those of most relevance for modern clinical care and future research. We highlight the under-recognized diphasic dyskinesia, which is often mischaracterized as a peak-dose phenomenon and therefore mismanaged. We review evidence that corrects the misinterpretation of prior clinical trial data surmising LID as a function of duration of Ldopa exposure rather than duration of disease, justifying the inappropriate but still lingering recommendation to postpone L-dopa treatment as long as possible to "delay" the appearance of LID. 3 We also review the latest pathophysiologic concepts at the molecular, synaptic, and network levels, to provide the rationale for currently available as well as emerging treatments. Peak-Dose versus Diphasic DyskinesiaPeak-Dose Dyskinesia. Chorea that may be generalized or affect the more affected side or upper body often occurs during the therapeutic window of a L-dopa dose cycle View this article online at wileyonlinelibrary.com.

Diphasic Worsening of Freezing of Gait in Parkinson's Disease

“…Both patients experienced freezing during the off and on states, with significant worsening during the transition phase and notable improvement approximately 45 to 60 minutes after receiving a therapeutic dose of levodopa. This pattern seems similar to that observed in patients with diphasic dyskinesia …”

“…This pattern seems similar to that observed in patients with diphasic dyskinesia. 6 We note that all authors concurred that comparisons of changes in FOG observed in the videos with changes in the MDS-UPDRS-III item 11 scores gave the impression that the MDS-UPDRS-III scores were underrepresentative. More precise quantitative measures of FOG severity could potentially alleviate this.…”

Sex‐related pattern of intrinsic brain connectivity in drug‐naïve Parkinson's disease patients

“…However, this "native" pattern may become dysfunctional over the disease course and under chronic dopaminergic stimulation, potentially resulting in those changes in the oscillatory activity between the basal ganglia and motor cortex, which have been related to the development of treatment complications. 47,48 Interestingly, a PET [11]C-raclopride (a striatal post-synaptic ligand) study has demonstrated that PD patients who developed motor fluctuations after 3-years follow-up were presenting at baseline with greater binding potential decrease after a single L-dopa dosing, suggesting the presence of higher striatal synaptic dopaminergic level even before treatment initiation. 49 We acknowledge that, at this point, such hypothesis is merely speculative, given that we did not observe any motor complications in our sample at 2-year follow-up.…”

Neuroinflammation: Fanning the fire of l‐dopa‐induced dyskinesia

“…Although others remain in the pipeline, to this point, none of these novel treatment strategies have effectively translated to provide clear clinical benefit for the patient. In fact, approaches that have conveyed clinically relevant antidyskinetic efficacy are reformulated versions or alternative delivery systems for venerable but standard molecules . So, the question remains, is there a facet of LID that we have yet to fully understand, a common feature to the preclinical and clinical conditions that will open a new avenue for treatment approaches?…”

“…In fact, approaches that have conveyed clinically relevant antidyskinetic efficacy are reformulated versions or alternative delivery systems for venerable but standard molecules. 3 So, the question remains, is there a facet of LID that we have yet to fully understand, a common feature to the preclinical and clinical conditions that will open a new avenue for treatment approaches? The latest work by Boi et al in this current edition of Movement Disorders identifies just such a pathway forward by targeting neuroinflammation.…”