Abstracts

Rationale: Infantile spasms are the signature seizures of West syndrome, an epileptic encephalopathy of infancy. Its conventional treatments, adrenocorticotropin hormone (ACTH), steroids and vigabatrin, are not always effective, especially in symptomatic infantile spasms, and may produce adverse effects. Subsequent evolution to other epilepsies and poor developmental outcomes are also encountered in infants who do not respond to current therapies. Therefore, identification of more effective therapies for this syndrome is important. In this study, the efficacy of carisbamate, a novel broad spectrum anticonvulsive drug, was tested in the multiple-hit rat model of symptomatic infantile spasms (DLP model; AECOM patent #2080216183). In this model, spasms are ACTH-refractory and partially sensitive to vigabatrin. Methods: In the DLP model, spasms appear after a right intracerebral infusion of lipopolysaccharide and doxorubicin at postnatal day 3 (PN3) and p-chlorophenylalanine at PN5. To test the efficacy of carisbamate, we administered a single dose of carisbamate (10, 30, or 60 mg/kg/rat; groups CRS-10, -30 and -60 respectively; 10-13 rats/group) or its vehicle (group VEH; 10 rats) intraperitoneally in PN4 DLP male pups. Separate groups of DLP pups were implanted with epidural EEG electrodes at PN5-6 and injected with VEH (5 pups) or CRS-60 (7 pups) at PN6 or PN7. Rats were monitored before and after the injection using video (PN4) or video-EEG (PN6-7) recordings and the frequencies of clinical (PN4) or electroclinical spasms (PN6-7) were measured (spasms/hr; least square means SE). Results: At PN4, no significant differences in the frequency of spasms were seen prior to the injections: VEH: 5.91 1.1; CRS-10: 7.47 1.43; CRS-30: 6.53 0.8; CRS-60: 7.53 1.14. During the first 4 post-injection hours, however, spasms significantly decreased compared to VEH group (7.69 1.28), in a dose dependent manner, only in the CRS-30 (3.15 0.79; P<0.05) and CRS-60 (3.37 1.71; P<0.05) groups but not in CRS-10 (6.09 0.89) pups. No significant mortality was observed at least till PN5, as only 1 pup (group CRS-60) died by PN5. At PN6-7, no significant differences in the frequency of electroclinical spasms were seen before the injections: CRS-60= 12.8 1.82; VEH= 13.4 2.15. During the first two post-injection hours, the frequency of electroclinical spasms was however significantly suppressed in CRS-60 pups (3.5 1.54) compared to VEH treated pups (11.2 1.83) (P<0.01). Conclusions: Carisbamate displayed acute anticonvulsive effect on spasms after a single injection in an animal model of symptomatic infantile spasms. This acute suppressive effect of carisbamate would have an advantage in the treatment of infantile spasms because early response to spasms has been correlated with a favorable long-term outcome. Carisbamate may be a promising new therapy for symptomatic infantile spasms, including ACTH-refractory spasms. Funded by Johnson & Johnson, NINDS/NICHD (NS062947), NINDS (NS020253), IRSF and the Heffer Family Foundation.