Levodopa-induced Dyskinesia: Clinical Features, Pathophysiology, and Medical Management

Abstract

Levodopa-induced dyskinesia (LID) is commonly seen in Parkinson's disease patients treated with levodopa. This side effect is usually encountered after long duration of treatment, but occasionally, this may be seen even after few days or months of treatment. LID is broadly classified as peak-dose dyskinesia, wearing-off or off-period dyskinesia, and diphasic dyskinesia. Pathogenesis of LID is complex, and different neurotransmitters such as dopamine, glutamine, adenosine, and gamma-aminobutyric acid play important role altering the normal physiology of direct and indirect pathway of cortico-basal ganglia-thalamic loop responsible for fine motor control. Treatment of LID requires careful history taking and clinical examination to find the type of dyskinesia as different approach is required for different types. Changes in dopaminergic medication including continuous dopaminergic stimulation are very helpful in the management of peak-dose dyskinesia. Different types of surgical approaches including unilateral pallidotomy and deep brain stimulation have given very good result in patients, who cannot be managed by medications alone. The surgical management of LID is dealt with in detail in another review in this series.

Keywords: Dopamine; Parkinson's disease; dyskinesia; levodopa.

Figure 1

Time sequence of developing levodopa-induced dyskinesia in Parkinson's disease

Figure 2

The models of basal ganglia in normal condition, Parkinson's disease and Parkinson's disease with levodopa-induced dyskinesia. (a) The model of basal ganglia in normal condition. Normal dopaminergic input from substantia nigra pars compacta (SNc) influences the motor movement through dopaminergic receptors D1 (direct pathway) and D2 (indirect pathway). Basically, dopaminergic stimulation on D1 receptor facilitates motor movement while stimulation on D2 receptor inhibits motor movement. In addition, hyperdirect pathway may also inhibit motor movement. (b) In Parkinson's disease (PD), loss of dopaminergic input from SNc leads to underactivity of the direct pathway and overactivity of the indirect pathway. Finally, the glutamatergic output from thalamus is reduced and decreases the motor movement. In addition, the role of hyper-direct pathway in PD is still unknown; however, the hyperdirect pathway might increase its activity in PD. (c) After long-term administration of levodopa concomitant with more degree of loss of striatal dopamine, the interconnections within nigrostriatal circuit change in the opposite directions, overactivity of the direct pathway, and underactivity of the indirect pathway produces an excessive motor movement named “levodopa-induced dyskinesia.” In addition, the role of hyperdirect pathway in PD with LID is not exactly known; however, the hyperdirect pathway might decrease the activity in PD with LID stage. PD = Parkinson's disease; LID = levodopa-induced dyskinesia; GPe = Globus pallidus externa; GPi = Globus pallidus interna; SNc = substantia nigra pars compacta; SNr = substantia nigra pars reticulata; STN = Subthalamic nucleus; Green arrow = excitatory output; Red arrow with dashed line = inhibitory output

Figure 3

Possible pathophysiology of levodopa-induced dyskinesia. The pathophysiology of levodopa-induced dyskinesia could be classified into three levels. The first is cortical level, the second is presynapses within striatum, and the third is postsynapses within striatum. At the cortical level, it has an abnormal cortical plasticity resulting the abnormal of glutamatergic output to the striatum. Subsequently, at the presynaptic level, there are many alterations such as loss of striatal presynaptic dopaminergic terminal and increasing the role of presynaptic serotoninergic terminal. When these alterations are occurred coupling with administration of levodopa, the pulsatile release of the dopamine might occur. Another presynaptic alteration is the alteration of activity of endocannabinoid receptors that might increase the glutamatergic activity. According to the postsynaptic alterations, there is increased activity of dopaminergic receptor, especially on D1 receptor and increasing the activity of both metabotropic and ionotropic glutamatergic receptors. The result of the alterations of all levels is changing the intracellular signaling pathway leading to increase the phosphorylation that creates the abnormal synaptic plasticity in term of losing the ability to create the depotentiation. Finally, the onset of inappropriate control of motor function and the dyskinesia occurs