Levodopa-induced dyskinesia

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.[1]

Levodopa-induced dyskinesia
SpecialtyNeurology

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,[2] with the percentage of affected patients increasing over time.[3] 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.[4] Amongst pharmacological treatments, 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.[5][6] Attempts to moderate dyskinesia by the use of other treatments such as bromocriptine (Parlodel), a dopamine agonist, appears to be ineffective.[7] 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 treatment which delays the use of l-DOPA. Additionally, a review [8] 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).[9] 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; contributes to the severity of the involuntary movements associated with LID.[4]

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 receptor 1 antagonist, delivered exclusively to the cortex, relieved the dyskinesia at its peak-time.[10]

ΔFosB overexpression in the dorsal striatum (nigrostriatal dopamine pathway) via viral vectors generates levodopa-induced dyskinesia in animal models of Parkinson's disease.[11][12] Dorsal striatal ΔFosB is overexpressed in rodents and primates with dyskinesias;[12] moreover, postmortem studies of individuals with Parkinson's disease that were treated with levodopa have also observed similar dorsal striatal ΔFosB overexpression.[12]

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.[12]

Nicotine (administered by dermal adhesive patches) has also been shown to improve Levodopa-induced dyskinesia and other PD symptoms.[13][14]

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.[15]

Mavoglurant is also currently studied by Novartis for the treatment of this disease. On August 24, 2017 the FDA approved a drug to treat levodopa-induced dyskinesia for Parkinson's patients. The drug, Gocovri, is amantadine manufactured by Adamas Pharmaceuticals. It is the first FDA approved treatment for this condition.[16]

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References
  1. Gerlach, Manfred; Peter Riederer; Dieter Scheller (December 2011). "Mechanisms underlying and medical management of L-Dope-associated motor complications". Journal of Neural Transmission. 118 (12): 1659–1660. doi:10.1007/s00702-011-0728-0. PMID 22075781.
  2. Ahlskog JE, Muenter MD (2001). "Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature". Mov Disord. 16 (3): 448–458. doi:10.1002/mds.1090.
  3. Obeso JA; et al. (2000). "The evolution and origin of motor complications in Parkinson's disease". Neurology. 55 (S4): S13–S20. PMID 11147505.
  4. Thanvi, Bhomraj; Nelson Lo; Tom Robinson (2007). "Levodopa-induced dyskinesia in Parkinson's disease: clinical features, pathogenesis, prevention and treatment". Postgraduate Medical Journal. 83 (980): 384–388. doi:10.1136/pgmj.2006.054759. PMC 2600052. PMID 17551069.
  5. Rascol, Olivier; Goetz C.; Koller W.; Poewe W.; Sampaio C. (May 2002). "Treatment interventions for Parkinson's disease: an evidence based assessment". The Lancet. 359 (9317): 1589–1598. doi:10.1016/S0140-6736(02)08520-3. PMID 12047983.
  6. Wolf, Elisabeth; Seppi,K.; Katzenschlager, R.; Hochschorner, G.; Ransmayr, G.; Schwinenschuh, P.; Ott, E.; Kloiber, I.; Haubenberger, D.; Auff, E.; Poewe, W. (2010). "Long-term antidyskinetic efficacy of amantadine in Parkinson's Disease". Movement Disorders. 25 (10): 1357–1363. doi:10.1002/mds.23034. PMID 20198649.
  7. van Hilten J; Ramaker C; Stowe R; Nj Ives (2007). "Bromocriptine/levodopa combined versus levodopa alone for early Parkinson's disease". Cochrane Database Syst Rev. 4 (4): CD003634. doi:10.1002/14651858.cd003634.pub2. PMID 17943795.
  8. Stocchi F, Marconi S (2010). "Factors associated with motor fluctuations and dyskinesia in Parkinson Disease: potential role of a new melevodopa plus carbidopa formulation (Sirio)". Clin Neuropharmacol. 33 (4): 198–203. doi:10.1097/WNF.0b013e3181de8924. PMID 20414107.
  9. Cenci MA (2014). "Presynaptic Mechanisms of l-DOPA-Induced Dyskinesia: The Findings, the Debate, and the Therapeutic Implications". Front Neurol. 5: 242. doi:10.3389/fneur.2014.00242. PMC 4266027. PMID 25566170. The dopamine (DA) precursor l-DOPA has been the most effective treatment for Parkinson's disease (PD) for over 40 years. The response to this treatment changes with disease progression, and most patients develop dyskinesias (abnormal involuntary movements) and motor fluctuations within a few years of l-DOPA therapy. There is wide consensus that these motor complications depend on both pre- and post-synaptic disturbances of nigrostriatal DA transmission.
  10. Halje, P; Tamtè, M; Richter, U; Mohammed, M; Cenci, MA; Petersson, P (21 November 2012). "Levodopa-induced dyskinesia is strongly associated with resonant cortical oscillations" (PDF). The Journal of Neuroscience. 32 (47): 16541–51. doi:10.1523/jneurosci.3047-12.2012. PMC 6621755. PMID 23175810.
  11. Cao X, Yasuda T, Uthayathas S, Watts RL, Mouradian MM, Mochizuki H, Papa SM (May 2010). "Striatal overexpression of DeltaFosB reproduces chronic levodopa-induced involuntary movements". J. Neurosci. 30 (21): 7335–7343. doi:10.1523/JNEUROSCI.0252-10.2010. PMC 2888489. PMID 20505100.
  12. Du H, Nie S, Chen G, Ma K, Xu Y, Zhang Z, Papa SM, Cao X (2015). "Levetiracetam Ameliorates L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats Inducing Critical Molecular Changes in the Striatum". Parkinson's Disease. 2015: 1–9. doi:10.1155/2015/253878. PMC 4322303. PMID 25692070. Furthermore, the transgenic overexpression of ΔFosB reproduces AIMs in hemiparkinsonian rats without chronic exposure to L-DOPA [13]. ... FosB/ΔFosB immunoreactive neurons increased in the dorsolateral part of the striatum on the lesion side with the used antibody that recognizes all members of the FosB family. All doses of levetiracetam decreased the number of FosB/ΔFosB positive cells (from 88.7 ± 1.7/section in the control group to 65.7 ± 0.87, 42.3 ± 1.88, and 25.7 ± 1.2/section in the 15, 30, and 60 mg groups, resp.; Figure 2). These results indicate dose-dependent effects of levetiracetam on FosB/ΔFosB expression. ... In addition, transcription factors expressed with chronic events such as ΔFosB (a truncated splice variant of FosB) are overexpressed in the striatum of rodents and primates with dyskinesias [9, 10]. ... Furthermore, ΔFosB overexpression has been observed in postmortem striatal studies of Parkinsonian patients chronically treated with l-DOPA [26]. ... Of note, the most prominent effect of levetiracetam was the reduction of ΔFosB expression, which cannot be explained by any of its known actions on vesicular protein or ion channels. Therefore, the exact mechanism(s) underlying the antiepileptic effects of levetiracetam remains uncertain.
  13. Decamp E, Schneider JS (2009). "Interaction between nicotinic and dopaminergic therapies on cognition in a chronic Parkinson model". Brain Res. 1262: 109–14. doi:10.1016/j.brainres.2009.01.028. PMC 2706019. PMID 19368843.
  14. Louis Elan D.; Benito-León Julián; Bermejo-Pareja Félix (2008). "Population-Based Prospective Study of Cigarette Smoking and Risk of Incident Essential Tremor". Neurology. 70 (19): 1682–1687. doi:10.1212/01.wnl.0000311271.42596.32. PMC 2683619. PMID 18458228.
  15. Toda Hiroki; Hamani Clement; Lozano Andres (2004). "Deep Brain Stimulation in the Treatment of Dyskinesia and Dystonia". Neurosurg Focus. 17 (1): 9–13. doi:10.3171/foc.2004.17.1.2.
  16. "Gocovri (Amantadine)". Parkinson's News Today. Retrieved 4 February 2019.
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