A randomized trial of 4-aminopyridine in EA2 and related familial episodic ataxias

Abstract

Objective: The therapeutic effects of 4-aminopyridine (4AP) were investigated in a randomized, double-blind, crossover trial in 10 subjects with familial episodic ataxia with nystagmus.

Methods: After randomization, placebo or 4AP (5 mg 3 times daily) was administered for 2 3-month-long treatment periods separated by a 1-month-long washout period. The primary outcome measure was the number of ataxia attacks per month; the secondary outcome measures were the attack duration and patient-reported quality of life (Vestibular Disorders Activities of Daily Living Scale [VDADL]). Nonparametric tests and a random-effects model were used for statistical analysis.

Results: The diagnosis of episodic ataxia type 2 (EA2) was genetically confirmed in 7 subjects. Patients receiving placebo had a median monthly attack frequency of 6.50, whereas patients taking 4AP had a frequency of 1.65 (p = 0.03). Median monthly attack duration decreased from 13.65 hours with placebo to 4.45 hours with 4AP (p = 0.08). The VDADL score decreased from 6.00 to 1.50 (p = 0.02). 4AP was well-tolerated.

Conclusions: This controlled trial on EA2 and familial episodic ataxia with nystagmus demonstrated that 4AP decreases attack frequency and improves quality of life.

Level of evidence: This crossover study provides Class II evidence that 4AP decreases attack frequency and improves the patient-reported quality of life in patients with episodic ataxia and related familial ataxias.

Figure 1. Participant flow

*Physical and neuro-ophthalmologic examinations, patient-reported event diary, and quality of life at the beginning and end of this period. 4AP = 4-aminopyridine.

Figure 2. Number of monthly ataxia attacks (primary outcome)

Number of attacks of ataxia per month (primary efficacy outcome measure) in the 2 treatment sequences (placebo/4-aminopyridine [4AP]; 4AP/placebo). The number was determined by the patient diary. (A, B) Trajectory plots for the 2 sequence groups (1-month baseline period [B], first 3-month treatment period [TP1], 1-month washout phase [WO], and second 3-month treatment period [TP2]). (C) Boxplots for outcome measured during the placebo and 4AP phases (box-and-whisker plot with 25% and 75% percentiles indicating the border of the box, the median [bold line], mean [asterisk], whiskers [extend to the most extreme data point, which is no more than 1.5 times the interquartile range from the box], and outliers). 4AP significantly reduced the number of attacks of ataxia per month (p = 0.03). Pat. = patient.

Figure 3. Burden of disease

Vestibular Disorders Activities of Daily Living Scale (VDADL) score as a measure of the burden of disease (secondary outcome). (A, B) Trajectory plots for the 2 sequence groups (1-month baseline period [B], first 3-month treatment period [TP1], 1-month washout phase [WO], and second 3-month treatment period [TP2]). (C) Boxplots for outcome measured during the placebo and the 4-aminopyridine (4AP) phases (box-and-whisker plot with 25% and 75% percentiles indicating the border of the box, the median [bold line], mean [asterisk]) and whiskers [extend to the most extreme data point, which is no more than 1.5 times the interquartile range from the box]). There are no outliers. 4AP significantly reduced the VDADL score (p = 0.022). Pat. = patient.