Antiepileptogenic effects of rapamycin in a model of infantile spasms due to structural lesions

Objective: Infantile spasms may evolve into persistent epilepsies including Lennox-Gastaut syndrome. We compared adult epilepsy outcomes in models of infantile spasms due to structural etiology (multiple-hit model) or focal cortical inflammation and determined the anti-epileptogenic effects of pulse-rapamycin, previously shown to stop spasms in multiple-hit rats. Methods: Spasms were induced in 3-day-old male rats via right intracerebral doxorubicin/lipopolysaccharide (multiple-hit model) infusions. Controls and sham rats were used. Separate multiple-hit rats received pulse-rapamycin or vehicle intraperitoneally between postnatal days 4 and 6. In adult mice, video-EEG (electroencephalography) scoring for seizures and sleep and histology were done blinded to treatment. Results: Motor-type seizures developed in 66.7% of multiple-hit rats, usually from sleep, but were reduced in the pulse-rapamycin–treated group (20%, p =.043 vs multiple-hit) and rare in other groups (0–9.1%, p <.05 vs multiple-hit). Spike-and-wave bursts had a slower frequency in multiple-hit rats (5.4–5.8Hz) than in the other groups (7.6–8.3Hz) (p <.05); pulse rapamycin had no effect on the hourly spike-and-wave burst rates in adulthood. Rapamycin, however, reduced the time spent in slow-wave-sleep (17.2%), which was increased in multiple-hit rats (71.6%, p =.003). Sham rats spent more time in wakefulness (43.7%) compared to controls (30.6%, p =.043). Multiple-hit rats, with or without rapamycin treatment, had right more than left corticohippocampal, basal ganglia lesions. There was no macroscopic pathology in the other groups. Significance: Structural corticohippocampal/basal ganglia lesions increase the risk for post-infantile spasms epilepsy, Lennox-Gastaut syndrome features, and sleep dysregulation. Pulse rapamycin treatment for infantile spasms has anti-epileptogenic effects, despite the structural lesions, and decreases the time spent in slow wave sleep.