Levodopa-induced dyskinesias in patients with Parkinson's disease: filling the bench-to-bedside gap

Summary

Levodopa is the most effective drug for the treatment of Parkinson's disease. However, the long-term use of this dopamine precursor is complicated by highly disabling fluctuations and dyskinesias. Although preclinical and clinical findings suggest pulsatile stimulation of striatal postsynaptic receptors as a key mechanism underlying levodopa-induced dyskinesias, their pathogenesis is still unclear. In recent years, evidence from animal models of Parkinson's disease has provided important information to understand the effect of specific receptor and post-receptor molecular mechanisms underlying the development of dyskinetic movements. Recent preclinical and clinical data from promising lines of research focus on the differential role of presynaptic versus postsynaptic mechanisms, dopamine receptor subtypes, ionotropic and metabotropic glutamate receptors, and non-dopaminergic neurotransmitter systems in the pathophysiology of levodopa-induced dyskinesias.

Introduction

Although the dopamine precursor levodopa is the most effective drug for the treatment of Parkinson's disease, long-term use of this drug is associated with disabling fluctuations and dyskinesias. These complications of levodopa have been recognised almost from the beginning of its pioneering use in patients by Cotzias.¹

The most common types of levodopa-induced dyskinesias in patients with Parkinson's disease are chorea and dystonia. These dyskinesias usually arise when brain concentrations of levodopa and dopamine reach the maximum dose concentration and are therefore called peak-dose dyskinesias. Chorea and dystonia are less common at the beginning and at the end of dosing; these events are called diphasic dyskinesias. However, dystonia can also occur when the levodopa concentration is very low (“off” dystonia; figure 1A).²

Among the various early descriptions of levodopa-induced dyskinesias, a simple but accurate clinical picture of this disorder was provided several years ago.³ These dyskinesias are most commonly seen in the facial muscles, jaw, tongue, and neck, and consist of irregular fast and slow movements, which can be categorised as a combination of choreiform movements, athetosis, and dystonia. These movements are irregular and occur at different times of the day. Levodopa-induced dyskinesias can appear as dystonic movements of the limbs and involuntary flexion of the toes, and can cause other abnormal movements of the trunk, with irregular hip or shoulder movements. Less common are abnormal respirations, such as panting or sighing respiration and forced inspiratory spasms and dyspnoea. Patients are frequently not aware of early minor facial dyskinesia, but these movements can later become embarrassing and cause severe disability.

Once levodopa-induced dyskinesias have developed in patients, they are difficult to treat. Young age of Parkinson's disease onset, disease severity, and high doses of levodopa increase the risk of development of these complications.⁴ Levodopa-induced dyskinesias negatively affect patients' quality of life and substantially augment the costs associated with their health care.⁵

Preclinical and clinical findings indicate that pulsatile stimulation of striatal postsynaptic receptors is a key mechanism underlying levodopa-induced dyskinesias;⁶ however, more work is needed to understand the pathogenesis of this clinical complication. Rodent models of levodopa-induced dyskinesia can help to understand the effect of specific receptor and post-receptor molecular mechanisms underlying the development and expression of dyskinetic movements.⁷ Moreover, non-human primates that have parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) provide a useful model as they share several clinical features with those presented in patients with Parkinson's disease and dyskinesia.⁸ Nevertheless, clinical studies designed to assess risk factors for the development of dyskinesias in patients with Parkinson's disease provide the most useful information towards understanding the pathophysiology of this disabling disorder.

In this Review, we discuss recent preclinical findings from rodent and primate models of levodopa-induced dyskinesia, as well as recent clinical data from patients with Parkinson's disease, focusing on dopaminergic and non-dopaminergic mechanisms underlying these involuntary movements. Moreover, we discuss possible reasons for the disappointing results from clinical studies designed to assess the efficacy of drugs targeting these mechanisms. Information emerging from these studies does not offer conclusive answers to questions such as what the key mechanism underlying levodopa-induced dyskinesias is or which treatment is the most effective to prevent and cure these dyskinesias. Accordingly, data from a recent experimental study showed that none of the parameters studied (such as genetic variations, delay of treatment onset after lesion, or time of day of the drug treatment) directly affected levodopa-induced dyskinesias, suggesting that a complex combination of individual factors are likely to interact to regulate the onset and development of abnormal movements in some patients, but not in others.⁹ Nevertheless, promising advances in experimental research focusing on levodopa-induced dyskinesias have recently emerged, including identification of the differential role of presynaptic versus postsynaptic mechanisms, the distinct role of dopamine receptors subtypes, and the role of ionotropic and metabotropic glutamate receptors and non-dopaminergic neurotransmitter systems. Moreover, new concepts are arising from clinical experience of deep brain stimulation and transplants in patients with Parkinson's disease. Thus, further characterisation of these promising areas of research could provide satisfactory answers to many crucial questions about dyskinesias.