Vigabatrin retinal toxicity in children with infantile spasms: An observational cohort study

Abstract

Objectives: To determine time to vigabatrin (VGB, Sabril; Lundbeck, Deerfield, IL) induced retinal damage in children with infantile spasms (IS) and to identify risk factors for VGB-induced retinal damage (VGB-RD).

Methods: Observational cohort study including 146 participants (68 female, 81 male) with IS, an age-specific epilepsy syndrome of early infancy, treated with VGB. Participants ranged from 3 to 34.9 months of age (median 7.6 months). The median duration of VGB treatment was 16 months (range 4.6-78.5 months). Electroretinograms (ERGs) were performed according to the Standards of the International Society for Clinical Electrophysiology of Vision. Inclusion required baseline (pre-VGB or within 4 weeks of starting VGB treatment) and at least 2 follow-up ERGs. Significant reduction from baseline of the 30-Hz ERG flicker amplitude on 2 consecutive visits identified VGB-RD. Kaplan-Meier survival analyses depicted the effect of duration of VGB on VGB-RD.

Results: These data represent the largest survival analysis of children treated with VGB who did not succumb to retinal toxicity during the study. Thirty of the 146 participants (21%) showed VGB-RD. The ERG amplitude reduced with duration of VGB treatment (p = 0.0004) with no recovery after VGB cessation. With 6 and 12 months of VGB treatment, 5.3% and 13.3%, respectively, developed VGB-RD. There was neither effect of age of initiation of VGB treatment nor sex of the child on survival statistics and no significant effect of cumulative dosage on the occurrence of VGB-RD.

Conclusions: Minimizing VGB treatment to 6 months will reduce the prevalence of VGB-RD in patients with IS.

Figure 1. Raw ERG waveforms from a child who developed VGB-RD and one who did not

Light-adapted 2.29 flicker waveforms plotted against time (see insert for amplitude scale). (A) Male diagnosed with IS at 12 months of age and started VGB at 13 months of age. ERG waveforms are shown for the baseline test (top trace) and for 4 subsequent assessments at 3, 6, 10, and 13 months of VGB treatment. VGB-RD occurred after 3 months of VGB treatment. (B) Male diagnosed with IS at 4 months of age and started VGB at 7 months of age. ERG waveforms are shown for the baseline test (top trace) and for 4 follow-up assessments at 2, 6, 12, and 16 months of VGB treatment. There was no evidence of VGB-RD. ERG = electroretinogram; IS = infantile spasms; VGB = vigabatrin; VGB-RD = VGB-induced retinal damage.

Figure 2. Survival curve showing proportion of children without VGB-RD, according to duration of VGB treatment

The black solid line represents the Kaplan-Meier estimator of the survival function. Red lines represent 95% confidence limits. The small vertical tick-marks represent withdrawal from the study resulting in censoring of this participant from the sample. VGB = vigabatrin; VGB-RD = VGB-induced retinal damage.

Figure 3. Individual data points of age-adjusted LA 2.29 flicker amplitude plotted against time on VGB in months

Individual thin lines join data points from individual participants. The thick black line represents the median amplitude. The thick gray line represents the 95% confidence interval. Data plots in red represent cases in which VGB-RD had occurred during the testing period and blue plots represent absence of VGB-RD. Round symbols represent the data points when the child was still receiving VGB. VGB = vigabatrin; VGB-RD = VGB-induced retinal damage.

Figure 4. Boxplots showing effect of cumulative dosage on VGB-RD

The x-axis identifies time bin of drug treatment (time on VGB, months). The y-axis identifies cumulative dose of VGB (g/kg) and red/blue bars identify presence/absence of VGB-RD, respectively. Each individual box represents the range in cumulative dosage. The boxes represent the 25th and 75th percentiles of cumulative dosage and the band near the middle of the box is the median. The ends of the whiskers represent the 1.5th and 98.5th percentile. VGB = vigabatrin; VGB-RD = VGB-induced retinal damage.