Abstracts

Rationale: Infantile spasms (IS) are the characteristic seizures of West syndrome that typically manifest in infants, have poor prognosis on neurodevelopmental milestones, epilepsy and early mortality. We used a multiple-hit rat model, which is a chronic model of medically refractory IS due to structural lesion, to test the efficacy of the potential drug with rapid onset of action on spasms, as early cessation of spasms may partially improve outcomes. In this study we aimed to determine efficacy and tolerability of a single injection of lacosamide (a known antiepileptic drug, used for treatment of seizures) on spasms and neurodevelopmental milestones in the multiple-hit rat model of IS. Methods: Spasms were induced in male Sprague-Dawley rats using intracerebral injections of doxorubicin and lipopolysaccharide on postnatal day (PN) 3 and intraperitoneal (i.p.) injection of p-chlorophenylalanine on PN5. A battery of neurodevelopmental tests was used for the daily milestones assessment. Rats were video-monitored on PN4 (1 hour pre-drug injection and 5 hours post-drug injection) and on PN5 (2 two-hour sessions). Lacosamide (10, 30 and 50 mg/kg) or vehicle was given in a single i.p. injection, after the onset of spasms on PN4 in a randomized, blinded, vehicle-controlled, dose-response study. Brain histology was performed on PN5 after the last monitoring session. A linear mixed model analysis of raw or normalized log-transformed spasm rates was used, considering the repeated observations on each individual animal. 12-15 rats per group were studied. Results: A single i.p. injection of lacosamide resulted in acute, dose-dependent spasm suppression within the first post-injection hour. The most significant differences in the efficacy of lacosamide were seen at the 4th hour (for 30 and 50 mg/kg/i.p. dose of lacosamide) and 5th hour (for 30mg/kg and borderline effect for 50mg/kg i.p. dose of lacosamide). Lacosamide did not affect neurodevelopmental milestones and was well tolerated. Conclusions: A single i.p. injection of lacosamide given after the onset of spasms can effectively suppress the spasms in the multiple-hit rat model of IS. Studies in progress include correlation analysis of the efficacy of lacosamide with its pharmacokinetics and video-EEG recordings analysis. In future we aim to determine efficacy of lacosamide on spasms, long-term neurodevelopmental, cognitive and epilepsy outcomes after repeat administration in the multiple-hit rat model of IS. Funding: Funded by the Department of Defense W81XWH-13-1-0180 grant, CURE (Infantile Spasms Initiative), NINDS NS091170, the Heffer family and Segal family foundations, and the Abbe Goldstein/Joshua Lurie and Laurie Marsh/ Dan Levitz families.