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]
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.[2] 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.[3] 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][5] Attempts to moderate dyskinesia by the use of other treatments such as bromocriptine (Parlodel), a dopamine agonist, appears to be ineffective.[6] 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.
Mechanism
Levodopa-induced dyskinesia (LID) have long been thought to arise through pathological alterations in pre-synaptic and post-synaptic signal transduction in the nigrostriatal pathway (dorsal striatum).[7] 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 severity of the involuntary movements [3]
In experiments employing real time electrophysiological recordings in awake and behaving animals, LIDs have recently been shown to be strongly associated with cortical gamma-oscillations with accompanying Δc-fos overexpression proposedly due to a dysregulation of dopamine signaling in the cortico-basal ganglia circuitry, concluded partially from reduced TH staining in cortex and the fact that a dopamine receptor 1 antagonist delivered exclusively to the cortex relieved the dyskinesias at the time point of peak-dyskinesias.[8]
ΔFosB overexpression in the dorsal striatum (nigrostriatal dopamine pathway) via viral vectors induces levodopa-induced dyskinesias in animal models of Parkinson's disease.[9][10] Dorsal striatal ΔFosB is overexpressed in rodents and primates with dyskinesias;[10] moreover, postmordem studies of individuals with Parkinson's disease that were treated with levodopa have also observed similar dorsal striatal ΔFosB overexpression.[10]
Treatment
Levetiracetam, an antiepileptic drug which has been demonstrated to reduce the severity of levodopa-induced dyskinesias, has been shown to dose-dependently decrease the induction of dorsal striatal ΔFosB expression in rats when co-administered with levodopa, although the signal transduction involved in this effect is unknown.[10]
Nicotine (administered by dermal adhesive patches) has also been shown to improve Levodopa-induced dyskinesia and other PD symptoms.[11][12]
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.[13]
Mavoglurant is also currently studied by Novartis for the treatment of this disease.
References
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- ↑ Obeso JA, et al. The evolution and origin of motor complications in Parkinson's disease. Neurology. 2000;55 (suppl 4):S13-S20.
- ↑ 3.0 3.1 Lua error in package.lua at line 80: module 'strict' not found.
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- ↑ van Hilten J, Ramaker C, Stowe R, Ives Nj., 2007. Bromocriptine/levodopa combined versus levodopa alone for early Parkinson's disease. Cochrane Database Syst Rev. 17 October 2007;(4):CD003634.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
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- ↑ Lua error in package.lua at line 80: module 'strict' not found.
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- ↑ Decamp E, Schneider JS. Brain Res. 2009 Mar 25;1262:109-14. Interaction between nicotinic and dopaminergic therapies on cognition in a chronic Parkinson model, |url=http://www.ncbi.nlm.nih.gov/pubmed/19368843
- ↑ Elan D. Louis, MD, MSc1, Julián Benito-León, MD, PhD2, and Félix Bermejo-Pareja, MD, PhD, Population-Based Prospective Study of Cigarette Smoking and Risk of Incident Essential Tremor, Neurology. 2008 May 6; 70(19): 1682–1687, url=http://www.neurology.org/content/70/19/1682
- ↑ Hiroki Toda, M.D., Ph.D.; Clement Hamani, M.D., Ph.D.; Andres Lozano, M.D., Ph.D., F.R.C.S. (C) 2004. Deep Brain Stimulation in the Treatment of Dyskinesia and Dystonia. Neurosurg Focus 17(1):9–13, 2004.
