Treatment of downbeat nystagmus with 3,4-diaminopyridine: a placebo-controlled study

Abstract

Background: Several drugs that primarily act on gamma-aminobutyrate or muscarinic receptors have been used to treat downbeat nystagmus (DBN) syndrome despite their having only moderate success and causing several side effects that limit their effectiveness. These drugs were tested under the assumption that DBN was caused by a disinhibition of a physiologic inhibitory cerebellar input on vestibular nuclei.

Objective: To evaluate the effects of a single dose of the potassium channel blocker 3,4-diaminopyridine (3,4-DAP), which is known to increase the excitability of Purkinje cells, on DBN in a prospective, placebo-controlled, double-blind study with a crossover design.

Methods: Seventeen patients with DBN due to cerebellar atrophy (5), infarction (3), Arnold-Chiari malformation (1), or unknown etiology (8) were included in the study (1 of 18 patients had to be excluded). Mean peak slow-phase velocity (PSPV) was measured before and 30 minutes after randomized ingestion of 20 mg of 3,4-DAP or placebo orally; at least 1 week later, the treatments were switched.

Results: 3,4-DAP reduced mean PSPV of DBN from 7.2 +/- 4.2 degrees /s (mean +/- SD) before treatment to 3.1 +/- 2.5 degrees/s 30 minutes after ingestion of the 3,4-DAP (p < 0.001, two-way analysis of variance). Placebo had no measurable effect. In 10 of 17 subjects, the mean PSPV decreased by >50% and in 12 of 17 by >40%. In parallel, the subjects had less oscillopsia and felt more stable while standing and walking. Nine of the subjects continued to take the drug with success. Except for transient minor perioral or digital paresthesia reported by three subjects and nausea and headache reported by one, no other side effects were observed.

Conclusions: In this study, the authors demonstrated that a single dose of 3,4-DAP significantly improved DBN. In view of animal studies reporting that micromolar concentrations of 4-aminopyridine increased the excitability of Purkinje cells, it is suggested that the efficacy of 3,4-DAP may be due to an increase of the physiologic inhibitory influence of the vestibulocerebellum on the vestibular nuclei.