Abstract
Pharmacological treatment of cerebellar ataxias and cerebellar nystagmus still remains difficult. The efficacy of most of the agents recommended in the past for symptomatic or even causative therapy could not be proven in larger state-of-the art clinical trials. Exceptions are (a) 4-aminopyridine (4-AP) for episodic ataxia type 2 (EA2): one observational and one randomized controlled trial showed a significant effect on the number of attacks of ataxia and quality of life; (b) aminopyridines in cerebellar downbeat nystagmus (DBN): two randomized controlled trials and several observational studies demonstrate a significant improvement of the intensity of DBN, visual acuity, and postural imbalance. In both diseases the sustained-release form is evidently also efficient; (c) 4-AP in cerebellar gait ataxia: evidence comes from two observational studies. (d) chlorzoxazone in DBN which, however, was so far demonstrated in only one observational study; (e) the modified amino acid acetyl-DL-leucine: evidently effective in cerebellar ataxias, shown in three observational studies, one on patients with Niemann-Pick type C; its mode of action has to be evaluated in animal models and on a cellular/electrophysiological level. There are ongoing randomized placebo-controlled trials on EA2 with 4-AP versus acetazolamide (EAT-2-TREAT), cerebellar gait ataxia with 4-AP (FACEG), and a multinational trial on cerebellar ataxia with acetyl-DL-leucine (ALCAT).
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References
Ilg W et al. Consensus paper: management of degenerative cerebellar disorders. Cerebellum. 2014;13(2):248–68.
Strupp M et al. Treatment of downbeat nystagmus with 3,4-diaminopyridine: a placebo-controlled study. Neurology. 2003;61(2):165–70.
Kalla R et al. 4-aminopyridine improves downbeat nystagmus, smooth pursuit, and VOR gain. Neurology. 2004;62(7):1228–9.
Claassen J, T.J., Kalla R, Spiegel R, Strupp M. Effects of dalfampridine on attacks in patients with episodic ataxia type 2—an observational study. J Neurol, 2012 (in press).
Schniepp R et al. 4-Aminopyridine improves gait variability in cerebellar ataxia due to CACNA 1A mutation. J Neurol. 2011;258(9):1708–11.
Schniepp R et al. 4-Aminopyridine and cerebellar gait: a retrospective case series. J Neurol. 2012;259(11):2491–3.
Strupp M et al. A randomized trial of 4-aminopyridine in EA2 and related familial episodic ataxias. Neurology. 2011;77(3):269–75.
Strupp M et al. Treatment of episodic ataxia type 2 with the potassium channel blocker 4-aminopyridine. Neurology. 2004;62(9):1623–5.
Alvina K, Khodakhah K. KCa channels as therapeutic targets in episodic ataxia type-2. J Neurosci. 2010;30(21):7249–57.
Feil K et al. Effect of chlorzoxazone in patients with downbeat nystagmus: a pilot trial. Neurology. 2013;81(13):1152–8.
Strupp M et al. Effects of acetyl-DL-leucine in patients with cerebellar ataxia: a case series. J Neurol. 2013;260(10):2556–61.
Etzion Y, Grossman Y. Highly 4-aminopyridine sensitive delayed rectifier current modulates the excitability of guinea pig cerebellar Purkinje cells. Exp Brain Res. 2001;139(4):419–25.
Hille B. Ionic channels of excitable membranes. 3dth ed. Sunderlang: Sinauer; 2001.
Alvina K, Khodakhah K. The therapeutic mode of action of 4-aminopyridine in cerebellar ataxia. J Neurosci. 2010;30(21):7258–68.
Weisz CJ et al. Potassium channel blockers inhibit the triggers of attacks in the calcium channel mouse mutant tottering. J Neurosci. 2005;25(16):4141–5.
Bense S et al. 18F-fluorodeoxyglucose hypometabolism in cerebellar tonsil and flocculus in downbeat nystagmus. Neuroreport. 2006;17(6):599–603.
Hourez R et al. Aminopyridines correct early dysfunction and delay neurodegeneration in a mouse model of spinocerebellar ataxia type 1. J Neurosci. 2011;31(33):11795–807.
Jen JC. Hereditary episodic ataxias. Ann N Y Acad Sci. 2008;1142:250–3.
Claassen J et al. Effects of dalfampridine on attacks in patients with episodic ataxia type 2: an observational study. J Neurol. 2013;260(2):668–9.
Baloh RW, Spooner JW. Downbeat nystagmus: a type of central vestibular nystagmus. Neurology. 1981;31(3):304–10.
Kalla R et al. Detection of floccular hypometabolism in downbeat nystagmus by fMRI. Neurology. 2006;66(2):281–3.
Kalla R et al. 4-Aminopyridine restores vertical and horizontal neural integrator function in downbeat nystagmus. Brain. 2007;130(Pt 9):2441–51.
Judge SI, Bever Jr CT. Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment. Pharmacol Ther. 2006;111(1):224–59.
Kalla R et al. Comparison of 10-mg doses of 4-aminopyridine and 3,4-diaminopyridine for the treatment of downbeat nystagmus. J Neuroophthalmol. 2011;31(4):320–5.
Claassen J et al. A randomised double-blind, cross-over trial of 4-aminopyridine for downbeat nystagmus—effects on slow phase eye velocity, postural stability, locomotion and symptoms. J Neurol Neurosurg Psychiatry. 2013;84(12):1392–9.
Claassen J et al. Dalfampridine in patients with downbeat nystagmus—an observational study. J Neurol. 2013;260(8):1992–6.
Kremmyda O et al. 4-Aminopyridine suppresses positional nystagmus caused by cerebellar vermis lesion. J Neurol. 2013;260(1):321–3.
Schniepp R et al. Increased gait variability is associated with the history of falls in patients with cerebellar ataxia. J Neurol. 2014;261(1):213–23.
Giordano I et al. Experience in a short-term trial with 4-aminopyridine in cerebellar ataxia. J Neurol. 2013;260(8):2175–6.
Becker-Bense S, F.R., Xiong G, Feil K, Bartenstein P, Strupp M, Dieterich M. Effects of acetyl-DLleucine on the cerebral activation pattern in cerebellar ataxia (FDG-PET study) - Oral Sessions No. O1201. Eur J Neurol. 2015; 22:21–117.
Bremova T, M.V., Amraoui Y, Mengel E, Reinke J, Kolníková M, Strupp M. Acetyl-DL-leucine in Niemann-Pick type C: a case series. Neurology. Neurology, 2015. In press.
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We thank Katie Ogston for copy-editing the manuscript.
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Some of the studies described are supported by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Vertigo and Balance Disorders (grant code 01 EO 0901).
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K. Feil, C. Muth, R. Schniepp, and J. Teufel report no disclosures. T. Bremova received speaker’s honoraria from Actelion. M. Strupp is Joint Chief Editor of the Journal of Neurology, editor in chief of Frontiers of Neuro-otology and section editor of F1000. He has received speaker’s honoraria from Abbott, UCB, GSK, TEVA, MSD, Heel, Biogen Idec, Pierre-Fabre, Eisai, and Hennig Pharma. He works as a consultant for Abbott.
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Feil, K., Bremova, T., Muth, C. et al. Update on the Pharmacotherapy of Cerebellar Ataxia and Nystagmus. Cerebellum 15, 38–42 (2016). https://doi.org/10.1007/s12311-015-0733-1
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DOI: https://doi.org/10.1007/s12311-015-0733-1