Abstracts

Rationale: Infantile spasms (IS) syndrome is a pediatric epilepsy syndrome manifesting with epileptic spasms in infancy and usually leads to other seizure types and epilepsy syndromes, including the Lennox-Gastaut Syndrome. IS due to structural/metabolic etiology are usually associated with worse prognosis. We previously characterized the early phenotype of a chronic rat model of IS due to structural lesion, the multiple hit rat model of IS, showing the presence of an early period with clusters of spasms and emergence of other types of seizures till postnatal day 21 (PN21). In this study, we evaluated whether the multiple-hit model of IS exhibits epilepsy in adulthood. Methods: Male Sprague-Dawley rats received right intracerebral infusions of doxorubicin and lipopolysaccharide at PN3 and intraperitaneal p-chlorophenylalanine at PN5. Epidural cortical EEG electrodes were placed between PN66-89 and long-term video-EEG records were recorded (XLTEK system) till PN150-306 and were reviewed by an observer blinded to treatment allocation. Rats were monitored in 24 hour epochs, 2-3 days per week, with video on between 9am-6pm, following a 12hr/12hr light/dark cycle. Results: Spontaneous motor seizures (stage 3-5) were detected in 3 out of 6 animals (50%) with younger age at occurrence PN127.5 ±4.1. All seizures started from the sleep state and had stereotypical appearance: initial flattening of the background with overlapping low amplitude 20-22.2 Hz fast activity, followed by rhythmic theta slowing at the right parietal area evolving into rhythmic sharp waveforms in the right parietal hemisphere and subsequent generalized 4-5 Hz continuous rhythmic spikes or spike and slow waves in the EEG. A postictal diffuse attenuation of the background was seen. In two seizure events, an initial burst of high amplitude rhythmic slowing intermixed with spike and slow waves preceded the onset. Average seizure duration was 41.6±3.7 seconds. The interictal background demonstrated excessive sleep patterns, continuous polymorphic slowing at the right parietal region and frequent right parietal spikes. In addition, bursts of spike and slow wave discharges (6 Hz) were detected in 1 out of 6 animals (% 16.6), which has not manifested motor seizures yet, with the first appearance at PN 87. Conclusions: Our results show that in the multiple-hit model of IS, 50% of the rats manifest epilepsy with motor seizures in adulthood, all of which arise from sleep and share electrographic similarities with the nocturnal tonic seizures seen in Lennox Gastaut syndrome. In addition, 1/6 rats with prior spasms manifested bursts of spike and slow wave complexes at a slower frequency range (6Hz) compared to the absence seizures seen in models of absence seizure (~8.5Hz). These slow spike and wave complexes are therefore reminiscent to the slow spike wave pattern of Lennox Gastaut syndrome. These findings indicate that the multiple-hit model of IS recapitulates the evolution of IS into other types of epilepsy syndromes, including Lennox-Gastaut syndrome. This study was funded by NINDS NS 20253, Autism Speaks, and the Heffer Family Foundation.