Levodopa-Induced Dyskinesia: Medical and Surgical Management

Although levodopa therapy remains the most effective symptomatic treatment for PD, its usefulness may be limited by these motor complications, which result in deterioration in quality of life. Levodopa-induced dyskinesia (LID) is characterized by a variety of hyperkinetic movements. Although chorea and dystonia are the most common manifestations of LID, stereotypies, tics, myoclonus, or ballism may occur. LID commonly starts in the lower extremity ipsilateral to the side first affected by PD, usually the most affected side. Early in LID, patients may not notice subtle hyperkinetic movements; however, as LID worsens it may interfere with activities of daily living, resulting in functional impairment, disability, and poor quality of life.2-5 LID occurs in 3 temporal patterns related to timing of levodopa dosing.1 Peak-dose dyskinesias are the most common and are characterized by the sequence of "improvement-dyskinesia-improvement." Diphasic dyskinesias are characterized by "dyskinesia-improvement-dyskinesia" and are often manifested clinically by dystonia and stereotypies.6 Diphasic dyskinesia accounts for 15% to 20% of LID.7 Some hyperkinetic movements occur in the functional off state in which patients may experience off dystonia characterized by painful sustained contractions. Off-dystonia occurs when plasma levodopa concentrations are low; therefore, off-dystonia frequently manifests itself before the first dose of levodopa is taken in the early morning on awakening, although it can occur during any off state.8 EPIDEMIOLOGY OF DYSKINESIA The risk of developing LID has been linked to disease severity, younger age at onset, female sex, duration of levodopa treatment, and total levodopa exposure.9,10 The use of different methods to recognize LID has resulted in variations in the frequency rate reported in the literature. A literature survey of more than 2000 publications identified LID in almost 40% of patients with PD treated with levodopa for 4 to 6 years.11 Another review found a prevalence of LID in up to 85% of patients with PD.3 In the DATATOP (Deprenyl and Tocopherol Antioxidative Therapy for Parkinson's Disease) study, LID was observed in almost 30% of patients after 20.5 months of levodopa therapy.12 In a community study, LID was present in 28% of patients with PD, with a mean time to onset of 6.7 years.13 PATHOGENESIS OF LID In the dopamine-denervated state, striatal dopamine levels depend on exogenously administered levodopa. With the short half-life of levodopa, fluctuating plasma and striatal dopamine concentrations and nonphysiological pulsatile striatal stimulation occur.14 The pulsatile stimulation results in abnormal basal ganglia firing patterns,15 altered striatal neurotransmitter receptors,16 abnormalities in neuropeptide levels,16 and immediate early gene expression.17 These alterations lead to functional changes in the basal ganglia input and output pathways. The direct striatal output pathway provides g-aminobutyric acidergic inhibitory input to the globus pallidus interna (GPi) and substantia nigra pars reticulata. Overactivity of the direct pathway drives the development of LID.18 The direct pathway is modulated by excitatory glutaminergic corticostriatal projections.19 In addition, serotonergic 5HT1A20 and 5HT2A α-receptors,21 and α2-adrenergic receptors19 influence the direct pathway. These provide potential targets for novel therapeutic discovery.