Levodopa-induced dyskinesias and their management

Abstract

This paper reviews the epidemiology, pathophysiology, clinical features and rationale for managing dyskinesias associated with Parkinson's disease. These are a common clinical problem occurring in up to 90% of patients and more frequently affect those with early-onset. Dyskinesias have a negative impact on quality of life and are an important cause of disability. Their precise etiology is still poorly understood, although it is recognized that dopaminergic pre-synaptic and post-synaptic mechanisms are involved together with extra-dopaminergic factors. The phenomenology of dyskinesias encompasses a variable mixture of two prevalent features: dystonia and chorea. We have studied their time course following a single acute levodopa challenge and have found that dystonia occurs throughout the duration of the on period, whereas choreiform movements occur only at the peak of therapeutic dopaminergic motor responses. This allows a schematic relationship to be drawn between a short duration motor response and the occurrence of dystonia and chorea. There is currently no satisfactory treatment for dyskinesias. Managing the therapeutic window does not provide an adequate solution due to the appearance of a dyskinesia threshold dose that narrows the therapeutic margin. High frequency stimulation of the subthalamic nucleus probably has some specific anti-dyskinetic action, but is limited by the small number of patients who are candidates for this treatment. Research efforts are currently focused on the development of specific anti-dyskinetic medications. Their availability will certainly change the current clinical practice and will widen again the therapeutic window of dopaminergic medications that has now become too narrow.

Breaking away from dopamine deficiency: an essential new direction for Parkinson’s disease

“…Although some cases of camptocormia and antecollis are due to focal myopathy of neck musculature (Lava and Factor , 2001 ;Kastrup et al , 2008 ), other suggest that they occur as a result of dystonia Savica et al , 2011 ) and this would account for reports of improvement with l -Dopa (Horiuchi et al , 2001 ;Song et al , 2008 ). However, dyskinesia and dystonia is also a common feature of DART overdosing (Del Sorbo and Albanese , 2008 ) and would account for the limited effi cacy of l -Dopa in relieving postural disorders of PD (Benatru et al , 2008 ) and would further explain how DART can precipitate or exacerbate antecollis and camptocormia (Fujimoto , 2006 ;Ho et al , 2007 ;Suzuki et al , 2008 ;Taguchi et al , 2008 ;Kataoka and Ueno , 2011 ). This again illustrates the delicate balance that needs to be achieved in the use of DART in treating PD as attributing deterioration of this symptom to disease progression alone may result in implementation of inappropriate DART regimens.…”

An Autoradiographic Study on the Pathogenesis of Levodopa-Induced Dyskinesia: Regulation of Dopamine Transporter by Levodopa in a Rat Model of Parkinson’s Disease

“…Although effective in the early stages of PD, this symptomatic therapy loses efficacy over time due to the development of severe side effects such as the on-off phenomenon, end-of-dose deterioration and dyskinesia. Clinical investigations indicate that these debilitating motor complications are observed in as many as approximately half of all PD patients after 5 years of L-DOPA therapy [27][28][29] . L-DOPA-induced dyskinesia occurring years after medication use is one of the common serious complications of PD treatment [9, 30] .…”

Evaluation of the Efficacy of Pramipexole for Treating Levodopa-induced Dyskinesia in Patients with Parkinson's Disease

“…Initially, dose reduction or discontinuation of levodopa should be considered. Unfortunately, this option is often difficult, because it causes worsening of the PD symptoms and decreases the patient's quality of life (QOL) (2,(6)(7)(8). More effective strategies for managing dyskinesias are needed that do not lead to a worsening of PD.…”

“…The oral administration of levodopa, a precursor for dopamine, is considered to be highly effective in the treatment of PD. However, the long-term use of levodopa is often complicated by the appearance of motor complications such as levodopa-induced dyskinesia (LID) (2). LID affects one-third of all patients with PD after two years of treatment and more than half of such patients after sustained exposure to levodopa for five years or longer (3)(4)(5).…”