Management of Dyskinesias in Parkinson Disease

Professor Yasser Metwally

November 19, 2008 — Dyskinesias, along with motor fluctuations, are the main motor complications of levodopa therapy. A retrospective analysis of studies investigating incidence of dyskinesias with levodopa treatment estimated that slightly more than one third of patients who had PD had dyskinesias after 4 to 6 years [1]. Early-onset PD and higher doses of levodopa are the biggest risk factors for the development of dyskinesias [2,3]. Dyskinesias may affect any part of the body and can be choreic or dystonic. They may manifest when plasma levodopa levels are at their peak (peak-dose dyskinesias), as plasma levodopa levels are rising and falling (diphasic dyskinesias), or when plasma levodopa levels are low (off-state dystonia). Dyskinesias typically are mild but may interfere with quality of life when painful or severe, as seen in advanced PD [4].

One way of treating dyskinesias is to modify the antiparkinsonian regimen. Peak-dose dyskinesias are related directly to the amount of levodopa given per dose, so decreasing individual doses generally reduces dyskinesias. The amount of clinical benefit to motor symptoms in PD may decline, however, and patients may experience increasing “off” periods. Thus, a decrease in individual doses of levodopa often has to be combined with more frequent administration, a practice termed dose fractionation. There are significant limitations to this approach, however, which are detailed in the article by Dewey elsewhere in this issue. Discontinuing catechol-O-methyltransferase (COMT) inhibitors or monoamine oxidase (MAO)-B inhibitors also may be helpful in reducing peak-dose dyskinesias.

Sustained-release formulations in theory could reduce dyskinesias, as they are released slowly throughout the day. In practice, however, they tend to prolong the duration of dyskinesias and increase the severity of dyskinesias in the late afternoon or early evening [5]. Patients who have dyskinesias and are on sustained-release levodopa formulations may benefit from switching to immediate-release levodopa.
Diphasic dyskinesias can be difficult to treat. The same strategies can be tried, but there are no data to support one strategy over the other. Other options include overlapping the doses of levodopa to prevent trough plasma levodopa levels until late in the evening or administering very small doses of levodopa frequently (such as 50 mg of levodopa given hourly while awake) [6].

Strategies for treating off-state dystonias are similar to strategies to reduce motor fluctuations in PD and may include changing the levodopa dosing schedule or adding dopamine agonists, COMT inhibitors, or MAO-B inhibitors.

Recent evidence-based reviews recommend amantadine for treating dyskinesias in PD [7,8]. Amantadine is believed to have an antidyskinetic effect through its action at the N-methyl-D-aspartate receptor. Amantadine can reduce dyskinesias between 24% and 60% [9,10,11,12,13]. In one study, the effect of amantadine was maintained for up to a year. Some patients, however, are reported to have had rebound dyskinesias when amantadine was discontinued [12]. Side effects include confusion, peripheral edema, and livedo reticularis.

A double-blind, placebo-controlled trial of clozapine demonstrates an increase in “on” time without dyskinesias with a corresponding decrease in “on” time with dyskinesias [14]. The potential for agranulocytosis and the frequent blood monitoring required make it an unattractive agent, however. Buspirone is reported effective in one small crossover trial of 10 patients [15], but only seven patients completed the trial, and there are no other large randomized studies. Clinical trials of other drugs reported to be helpful for treating dyskinesias were uncontrolled or failed to show efficacy in large double-blind trials [6,16].

Although pallidotomy commonly was used as a surgical intervention for dyskinesias with good results [8], most surgical centers have turned to deep brain stimulation (DBS) to treat patients who have motor fluctuations and dyskinesias. There are two main targets for DBS in patients who have PD: the globus pallidus interna (GPi) and the subthalamic nucleus (STN). Although DBS of the GPi reduces dyskinesias in open-label reports and blinded evaluations of patients on and off stimulation [17,18], a recent practice parameter determined that there was insufficient evidence to determine the efficacy of GPi DBS for dyskinesias [7]. Part of this lack of evidence is because most centers prefer to place electrodes in the STN DBS. In a meta-analysis of outcomes, STN DBS reduced dyskinesias in patients who had PD by an average of 69.1% [19]. This occurs along with a reduction in levodopa dosage, which is mainly responsible for the improvement in dyskinesias. Based on existing studies, STN DBS is considered possibly effective for reducing motor fluctuations, dyskinesias, and antiparkinsonian medications in PD [7]. Adverse effects from DBS surgery may include surgical complications, such as hemorrhage, stroke, infection of the device, seizures, delirium, and stimulation-related effects, such as dystonia, confusion, paresthesias, dysarthria, and diplopia, depending on the stimulation site.

References
1. Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord. 2001;16:448-458.
2. Schrag A, Schott JM. Epidemiological, clinical, and genetic characteristics of early-onset parkinsonism. Lancet Neurol. 2006;5:355-363.
3. Grandas F, Galiano ML, Tabernero C. Risk factors for levodopa-induced dyskinesias in Parkinson’s disease. J Neurol. 1999;246:1127-1133.
4. Pechevis M, Clarke CE, Vieregge P, et al. Effects of dyskinesias in Parkinson’s disease on quality of life and health-related costs: a prospective European study. Eur J Neurol. 2005;12:956-963.
5. Fabbrini G, Brotchie JM, Grandas F, et al. Levodopa-induced dyskinesias. Mov Disord. 2007;22:1379-1389quiz 1523.
6. Muenter MD. Patterns of dystonia in response to L-Dopa therapy for Parkinson’s disease. Mayo Clin Proc. 1977;52:163-174.
7. Pahwa R, Factor SA, Lyons KE, et al. Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;66:983-995.
8. Goetz CG, Poewe W, Rascol O, et al. Evidence-based medical review update: pharmacological and surgical treatments of Parkinson’s disease: 2001 to 2004. Mov Disord. 2005;20:523-539.
9. Luginger E, Wenning GK, Bosch S, et al. Beneficial effects of amantadine on L-dopa-induced dyskinesias in Parkinson’s disease. Mov Disord. 2000;15:873-878.
10. Metman LV, Del Dotto P, LePoole K, et al. Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study. Arch Neurol. 1999;56:1383-1386.
11. Snow BJ, Macdonald L, McAuley D, et al. The effect of amantadine on levodopa-induced dyskinesias in Parkinson’s disease: a double-blind, placebo-controlled study. Clin Neuropharmacol. 2000;23:82-85.
12. Thomas A, Iacono D, Luciano AL, et al. Duration of amantadine benefit on dyskinesia of severe Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2004;75:141-143.
13. Verhagen Metman L, Del Dotto P, van den Munckhof P, et al. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson’s disease. Neurology. 1998;50:1323-1326.
14. Durif F, Debilly B, Galitzky M, et al. Clozapine improves dyskinesias in Parkinson disease: a double-blind, placebo-controlled study. Neurology. 2004;62:381-388.
15. Bonifati V, Fabrizio E, Cipriani R, et al. Buspirone in levodopa-induced dyskinesias. Clin Neuropharmacol. 1994;17:73-82.
16. Goetz CG, Damier P, Hicking C, et al. Sarizotan as a treatment for dyskinesias in Parkinson’s disease: a double-blind placebo-controlled trial. Mov Disord. 2007;22:179-186.
17. Deep Brain Stimulation for Parkinson’s Disease Study Group . Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. N Engl J Med. 2001;345:956-963.
18. Visser-Vandewalle V, Van der Linden C, Temel Y, et al. Long-term motor effect of unilateral pallidal stimulation in 26 patients with advanced Parkinson disease. J Neurosurg. 2003;99:701-707.
19. Kleiner-Fisman G, Herzog J, Fisman DN, et al. Subthalamic nucleus deep brain stimulation: summary and meta-analysis of outcomes. Mov Disord. 2006;21(Suppl 14):S290-S304.