Levodopa-Induced Dyskinesias in Parkinson's Disease: An Overview on Pathophysiology, Clinical Manifestations, Therapy Management Strategies and Future Directions

Abstract

Since its first introduction, levodopa has become the cornerstone for the treatment of Parkinson's disease and remains the leading therapeutic choice for motor control therapy so far. Unfortunately, the subsequent appearance of abnormal involuntary movements, known as dyskinesias, is a frequent drawback. Despite the deep knowledge of this complication, in terms of clinical phenomenology and the temporal relationship during a levodopa regimen, less is clear about the pathophysiological mechanisms underpinning it. As the disease progresses, specific oscillatory activities of both motor cortical and basal ganglia neurons and variation in levodopa metabolism, in terms of the dopamine receptor stimulation pattern and turnover rate, underlie dyskinesia onset. This review aims to provide a global overview on levodopa-induced dyskinesias, focusing on pathophysiology, clinical manifestations, therapy management strategies and future directions.

Keywords: LIDs; Parkinson’s disease; clinical manifestations; levodopa-induced dyskinesias; motor complications; pathophysiology; therapy management.

Figure 1

Relationship between the incidence of levodopa-induced dyskinesias and levodopa exposure time. Data in the graph derive from the mean levodopa exposure time from each study reported in Table 2 expressed in years, the blue line represents the trend line for the reported data.

Figure 2

Levodopa-induced dyskinesia types. Legend: red line = plasma levodopa concentration [L-dopa] over time; lower dashed line = levodopa concentration threshold for OFF–ON transition; upper dashed line = levodopa concentration threshold for peak-dose dyskinesia transition; orange boxes = OFF dystonia periods; blue boxes = diphasic dyskinesia periods; yellow box = square-wave dyskinesia period; green box = peak-dose dyskinesia period.

Figure 3

LID and ON/OFF motor status recognition trough convolutional neural network. (Figure drawn by Dr. Pfister, reproduced, under the terms of the Creative Commons Attribution 4.0 License, from [78]).

Figure 4

LID neurophysiology findings at cortical and basal ganglia level (for whole description and references, see the corresponding paragraph: 2.7. Neurophysiology).

Figure 5

Nuclear neuroimaging ligands for Parkinson’s disease studies. Legend: DAT: Dopamine Transporter; PET: Positron Emission Tomography; SPECT: Single Photon Emission Computed Tomography; VMAT-2: Vesicular Monoamine Transporter 2. (The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license).

Figure 6

Upper graph: pharmacokinetic of 4 single doses of levodopa without the computation of the previous doses (Doses 1 to 4). Lower graph: real pharmacokinetic of the same 4 single doses of levodopa describing the net effect of the therapeutic scheme (the net dosing scheme is the result of the combination of Doses 1 to 4). Legend: lower dashed line = levodopa concentration threshold for OFF–ON transition; upper dashed line = levodopa concentration threshold for peak-dose dyskinesia transition.

Figure 7

Adaptive closed-loop therapy system for Parkinson’s disease patients. The four therapies, alone or in combination (deep brain stimulation, oral therapy, intestinal infusion therapy and subcutaneous infusion therapy) can be administered in adaptive controlled closed-loop way, through a multiparametric (LFP, biochemical and kinematic monitoring) sensing system. (Reproduced, under the terms of the Creative Commons Attribution 4.0 License, from [86]).