Abstracts

Rationale: Although vigabatrin (VGB) is a first-line treatment for infantile spasms (IS) and particularly effective among children with tuberous sclerosis complex (TSC), the long-term cumulative risk of IS relapse approaches 50%. Despite consensus that VGB should be discontinued promptly in cases without efficacy, there is little guidance as to the ideal duration of VGB following successful elimination of hypsarrhythmia and IS. Practitioners must weigh the presumptive risk of relapse upon VGB withdrawal against the risk of VGB-associated visual field loss (VAVFL) and VGB-associated brain abnormalities on MRI (VABAM). Using a cohort of children with IS, TSC, and well-defined VGB exposure, we set out to evaluate the impact of post-response VGB treatment on the rate of IS relapse. Methods: Patients with IS and response to VGB were identified among participants in two concurrent multicenter, prospective observational studies. For each patient we tabulated dates of IS onset, response to VGB (based on seizure diaries and lack of hypsarrhythmia on study protocol EEGs), and relapse (if any). We quantified VGB exposure by calculating total duration of treatment, peak-dosage, and weighted-average dosage during the interval between response and either relapse or most recent study-follow-up. Time to relapse was evaluated using Kaplan-Meier plots and Cox proportional hazards regression. Results: Among 81 patients who developed IS, we identified 50 children who responded to VGB. During a median follow-up of 16.6 months (IQR 10.3 – 22.9), 12 (24%) patients subsequently relapsed after a median of 7.8 months (IQR 3.1 — 9.6). Relapse occurred after VGB discontinuation in 4 patients, and during continued VGB treatment in the remaining 8 cases. In survival analyses, risk of relapse was unaffected by the presence or absence of VGB treatment (HR 0.31, 95%CI 0.01 – 28.4). However, after adjustment for the duration of IS prior to response, risk of relapse was lower among patients with higher weighted-average VGB dosage (HR 0.33 [per 50mg/kg/d increment], 95%CI 0.13 – 0.83, p = 0.019) and higher peak VGB dosage (HR 0.49, 95%CI 0.25 – 0.94, p = 0.033). See Figure 1. In the first year after initial response, there were no relapses among patients with weighted average dose greater 125 mg/kg/day or peak dosage greater than 150 mg/kg/day. Conclusions: This study suggests that the risk of IS relapse in TSC may be reduced by aggressive VGB treatment, with high peak and/or weighted-average dosage. However, these results warrant replication, and it is not clear that the benefit of high-dose VGB treatment generalizes to patients without TSC, or patients who respond to other therapies (i.e. prednisolone, ACTH, or combination therapy). Further study is needed to better elucidate the role of VGB in the prevention of IS relapse, and to contrast this potential benefit with the competing risk of VAVFL and VABAM. Funding: Supported by the National Institute of Neurological Diseases and Stroke of the National Institutes of Health (U01-NS082320, P20-NS080199) and the Tuberous Sclerosis Alliance.