Levodopa-induced dyskinesia

Levodopa-induced dyskinesia is a form of dyskinesia associated with Levodopa used to treat Parkinson's disease. It often involves hyperkinetic movements, including chorea, dystonia, and athetosis.^[1]

Levodopa-induced dyskinesia has recently been suggested to be associated with cortical dysregulation of dopamine signaling,^[2] as well as being caused a disruption of the blood brain barrier, though not all evidence supports this later hypothesis.^[3]

Several mechanisms, of both central and peripheral origins, have been proposed to explain how L-DA might produce dyskinesia. It has been suggested that the non-physiological pulsatile stimulation of the post-synaptic receptors by dopamine (produced by intermittent doses via L-DA) ultimately creates alterations in the striatum of the basal ganglia, causing it to release abnormal motor outputs that result in the involuntary movements.^[4] It is thought that the stage of illness, the higher the dose and the frequency of L-Dopa treatment, and the younger the age of the patient at onset of symptoms, are considered to underlie the movements ^[5]

In the context of Parkinson's disease (PD), dyskinesia is often the result of chronic L-DOPA (Levodopa) therapy. These motor fluctuations occur in more than half of PD patients after 5–10 years of L-DOPA treatment, with the percentage of affected patients increasing over time.^[6] Based on the relationship with levodopa dosing, dyskinesia most commonly occurs at the time of peak L-DOPA plasma concentrations and is thus referred to as peak-dose dyskinesia (PDD). As patients advance, they may evidence diphasic dyskinesia (DD), which occur when the drug concentration rises or falls. If dyskinesia becomes too severe or impairs the patient's quality of life, a reduction in L-Dopa might be necessary, however this may be accompanied by a worsening of motor performance. Therefore, once established, LID is difficult to treat.^[5] Amongst pharmacological treatment, N-methyl-D-aspartate (NMDA) antagonist, (a glutamate receptor), amantadine, has been proven to be clinically effective in a small number of placebo controlled randomized controlled trials, while many others have only shown promise in animal models,.^[4][7] Attempts to moderate dyskinesia by the use of other treatments such as bromocriptine (Parlodel), a dopamine agonist, appears to be ineffective.^[8] In order to avoid dyskinesia, patients with the young-onset form of the disease or young-onset Parkinson's disease (YOPD) are often hesitant to commence L-DOPA therapy until absolutely necessary for fear of suffering severe dyskinesia later on. Alternatives include the use of DA agonists (i.e. ropinirole or pramipexole) in lieu of early L-DOPA use which delays the use of L-DOPA. Additionally, a review (Stocchi, F., Clin Neuropharmacol, 2010, 33, 198) shows that highly soluble L-DOPA prodrugs may be effective in avoiding the in vivo blood concentration swings that potentially lead to motor fluctuations and dyskinesia.

Patients with prominent dyskinesia resulting from high doses of antiparkinsonian medications may benefit from deep brain stimulation (DBS), which benefits the patient in two ways: 1) DBS allows a reduction in L-DOPA dosage of 50-60% (thus tackling the underlying cause); 2) DBS treatment itself (in the subthalamic nucleus or globus pallidus) can reduce dyskinesia.^[9]

The use of MDMA ("Ecstasy") has been shown to enhance the effects of L-DOPA while reducing the associated dyskinesia in primates with advanced PD.^[10] Its serotonergic actions may be responsible for this effect.

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