Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is a fatal complication of epilepsy and produces a significant public health burden.  Studies suggest that cardiorespiratory dysfunction is likely involved in the pathophysiology of SUDEP.  Clinical and animal studies show that seizures produce autonomic and respiratory dysfunction, leading to sympathetic hyperactivity and respiratory distress, including apnea.  While the heart is vulnerable to catecholamine surges and hypoxia, it remains unknown if repetitive seizures lead to cardiac damage and dysfunction, contributing to the pathogenesis of SUDEP.  In the current study, we repetitively induced generalized audiogenic seizures (AGSz) in DBA/1 mice and determined the effect of repeated seizures on cardiac histology. Methods: DBA/1 mice were subjected to daily acoustic stimulation (96 dB SPL) starting from postnatal day (PND) 28.  These mice started to exhibit AGSz-induced apnea and death from PND 30-32, which could be resuscitated using a rodent ventilator within 5 sec after respiratory gasp.  After ~9 continuous generalized AGSz and resuscitation, some DBA/1 mice became refractory to daily AGSz induction.  These mice were then given acoustic stimulation every 2-3 days.  At PND 88 (“treatment” for 2 months), these mice as well as age-matched control DBA/1 mice, never exposed to acoustic stimulation, were deeply anesthetized, and hearts were perfused with PBS, followed by 4% paraformaldehyde.  Serial 5-mm paraffin four-chamber sections (32 sections per heart) were collected for H & E, alizarin red or picrosirius red staining. Results: After repetitive induction of AGSz (18.4 ± 2.0 seizures; mean ± SEM), necrotic lesions (H & E staining) were observed in the ventricular walls in 61.5% of DBA/1 mice (2.3 ± 0.8 lesions/mouse) (n = 13).  A significantly smaller lesion in the left ventricle, possibly evoked by rare spontaneous seizures, was found in 2 of 11 (18.2%) control DBA/1 mice (0.2 ± 0.1 lesions/mouse).  The incidence of lesions and the amount of lesions were significantly greater in AGSz-induced DBA/1 mice than in control mice (p < 0.05).  The estimated size of lesions in AGSz-induced DBA/1 mice ranged from 20x20 to 600x200 mm2, and that in control DBA/1 mice was £ 40x40 mm2.  The incidence of severe lesions (>