New Treatments for Chorea in Huntington’s Disease
Abstract & Commentary
Source: Metman LV, et al. A randomized, controlled trial using the NMDA-antagonist amantadine. Neurol. 2002;59: 694-699.
Metman and associates carried out a controlled trial using amantadine to determine whether they could ameliorate chorea. This was based on prior studies showing that N-methyl-D-aspartate antagonists such as dextrophan, dextromethorphan, and amantadine can alleviate levodopa-induced chorea inpatients with parkinsonism. It has been suggested that NMDA receptor sensitization contributes to the production of choreiform movements. Metman et al conducted a randomized, placebo-controlled crossover study of 24 patients with HD for 2 weeks. Patients were initially treated with amantadine at 100 mg 4 times per day vs placebo for 2 weeks and then were crossed over to the opposite regimen. All 24 patients completed this study but 2 were unevaluable. Metman et al demonstrated that chorea scores were lower with amantadine as compared to placebo. The median reduction in extremity chorea was 36% for the 22 evaluable patients and 56% in the 10 individuals with the highest plasma drug levels. Improvement correlated with plasma amantadine concentrations but did not correlate with the CAG repeat lengths of the patients. There was no worsening of parkinsonism scores. There was also no significant change in cognitive measures. There did not appear to be any significant adverse effects. Metman et al conclude that NMDA receptor supersenstivity contributes to choreiform dyskinesias in HD and that selective antagonists can confer palliative benefit.
Commentary
The development of an effective treatment for dyskinesias and chorea is a significant advance. Chorea in HD can usually be alleviated by drugs that inhibit dopaminergic neurotransmission. However, these drugs frequently cause untoward effects such as parkinsonism, akathisia, tardive dyskinesia, and sedation. The present results showing that amantadine significantly attenuates chorea in Huntington’s Disease patients are consistent with Metman et al’s prior results showing that amantadine attenuates dyskinesias in PD patients. They are also consistent with other studies showing that agents, which reduce glutamatergic neurotransmission significantly, attenuate hyperkinetic movements. For instance, we previously showed that riluzole significantly reduces choreic movements in HD patients. The NMDA receptor antagonist remacemide also has significant beneficial effects in animal models of PD.
Taken together, these observations implicate glutamatergic neurotransmission in the pathogenesis of hyperkinetic movement disorders. The evidence particularly implicates N-methyl-D-aspartate receptors, at which amantadine is a weak receptor antagonist.
The major question is whether this is a significant therapeutic advance. In early patients with predominant chorea, this well may be the case. In these patients, cognitive deficits and dystonia may be minimal. The social embarrassment of chorea may make treatment with amantadine extremely useful if it enables patients to resume a normal lifestyle for a few years (ie, the ability to go out in public without feeling socially ostracized). In the long run however, a treatment aimed solely at chorea is a temporary Band-Aid. The real cause of disability and inability of patients to function in either their jobs or social functions is cognitive dysfunction. This is most likely a consequence of neuronal degeneration in both frontal cortex and the basal ganglia. Until we have a treatment, which can effectively slow the neurodegenerative process, symptomatic treatment of chorea will remain a temporary solution. —M. Flint Beal
Dr. Beal, Professor and Chairman, Department of Neurology, Cornell University Medical College, New York, NY, is Editor of Neurology Alert.
Metman and associates carried out a controlled trial using amantadine to determine whether they could ameliorate chorea. This was based on prior studies showing that N-methyl-D-aspartate antagonists such as dextrophan, dextromethorphan, and amantadine can alleviate levodopa-induced chorea inpatients with parkinsonism.
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