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Levodopa-induced dyskinesia

Movement disorder

Field	Value
name	Levodopa-induced dyskinesia
field	Neurology

Levodopa-induced dyskinesia (LID) is a form of dyskinesia associated with levodopa (L-DOPA), used to treat Parkinson's disease. It often involves hyperkinetic movements, including chorea, dystonia, and athetosis.

In the context of Parkinson's disease (PD), dyskinesia is often the result of long-term dopamine therapy. These motor fluctuations occur in up to 80% of PD patients after 5–10 years of L-DOPA treatment, with the percentage of affected patients increasing over time. 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 present with symptoms of diphasic dyskinesia (DD), which occurs 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. Attempts to moderate dyskinesia by the use of other treatments such as bromocriptine (Parlodel), a dopamine agonist, appears to be ineffective. 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 dopamine agonists (e.g., ropinirole or pramipexole) in lieu of early L-DOPA treatment which delays the use of L-DOPA. Additionally, a review 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 has long been thought to arise through pathological alterations in pre-synaptic and post-synaptic signal transduction in the nigrostriatal pathway (dorsal striatum). It is thought that the stage of illness, dosage of L-DOPA, frequency of L-DOPA treatment and the youth of the patient at the onset of symptoms contribute to the severity of the involuntary movements associated with LID.

In experiments employing real-time electrophysiological recordings in awake and active animals, LIDs have 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. This was concluded partially from reduced tyrosine hydroxylase (TH) staining in the cortex – and the fact that a dopamine D1 receptor antagonist, delivered exclusively to the cortex, relieved the dyskinesia at its peak-time.

ΔFosB overexpression in the dorsal striatum (nigrostriatal dopamine pathway) via viral vectors generates levodopa-induced dyskinesia in animal models of Parkinson's disease. Dorsal striatal ΔFosB is overexpressed in rodents and primates with dyskinesias; moreover, postmortem studies of individuals with Parkinson's disease that were treated with levodopa have also observed similar dorsal striatal ΔFosB overexpression.

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 mechanism involved in this effect is unknown.

Nicotine (administered by dermal adhesive patches) has also been shown to improve levodopa-induced dyskinesia and other PD symptoms.

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

In 2017, the US Food and Drug Administration (FDA) approved the first treatment for levodopa-induced dyskinesia for Parkinson's patients: Gocovri (amantadine), manufactured by Adamas Pharmaceuticals. Mavoglurant and ketamine are also currently studied for the treatment of this disease.

Mesdopetam is under development for the treatment of levodopa-induced dyskinesia.

References

Gerlach, Manfred. (December 2011). "Mechanisms underlying and medical management of L-Dope-associated motor complications". Journal of Neural Transmission.
Ahlskog JE, Muenter MD. (2001). "Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature". Mov Disord.
Obeso JA. (2000). "The evolution and origin of motor complications in Parkinson's disease". Neurology.
Rascol, Olivier. (May 2002). "Treatment interventions for Parkinson's disease: an evidence based assessment". The Lancet.
Wolf, Elisabeth. (2010). "Long-term antidyskinetic efficacy of amantadine in Parkinson's Disease". Movement Disorders.
(2007). "Bromocriptine/levodopa combined versus levodopa alone for early Parkinson's disease". Cochrane Database Syst Rev.
(2010). "Factors associated with motor fluctuations and dyskinesia in Parkinson Disease: potential role of a new melevodopa plus carbidopa formulation (Sirio)". Clin Neuropharmacol.
(2014). "Presynaptic Mechanisms of l-DOPA-Induced Dyskinesia: The Findings, the Debate, and the Therapeutic Implications". Front Neurol.
Thanvi, Bhomraj. (2007). "Levodopa-induced dyskinesia in Parkinson's disease: clinical features, pathogenesis, prevention and treatment". Postgraduate Medical Journal.
(21 November 2012). "Levodopa-induced dyskinesia is strongly associated with resonant cortical oscillations.". The Journal of Neuroscience.
(May 2010). "Striatal overexpression of DeltaFosB reproduces chronic levodopa-induced involuntary movements". J. Neurosci..
(2015). "Levetiracetam Ameliorates L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats Inducing Critical Molecular Changes in the Striatum". Parkinson's Disease.
(2009). "Interaction between nicotinic and dopaminergic therapies on cognition in a chronic Parkinson model". Brain Res..
(2008). "Population-Based Prospective Study of Cigarette Smoking and Risk of Incident Essential Tremor". Neurology.
(2004). "Deep Brain Stimulation in the Treatment of Dyskinesia and Dystonia". Neurosurg Focus.
"Gocovri (Amantadine)".
PhD, Margarida Maia. (29 March 2022). "Ketamine Eases Parkinson's Patients' Levodopa-induced Dyskinesia".
(6 September 2024). "Mesdopetam - Integrative Research Laboratories".
(2024). "Levodopa-induced dyskinesia: do current clinical trials hold hope for future treatment?". Expert Opin Pharmacother.
(January 2021). "Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders". Biomolecules.

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