Abstracts

Rationale: Status epilepticus (SE) is a prevalent disorder, which is associated with significant morbidity, including the development of epilepsy, and mortality. Studies indicate that lethal cardiac arrhythmias contribute to death following SE as well as sudden unexpected death in epilepsy (SUDEP). A wide range of potentially lethal cardiac arrhythmias (i.e. tachycardia, bradycardia, asystole, and atrioventricular blocks) is observed in patients and are indicative of underlying autonomic dysfunction. Tachycardia is the most commonly reported seizure related arrhythmia but asystole and bradycardia have also been observed and predominantly occur ictally in people with temporal lobe epilepsy (TLE). We sought to characterize cardiac arrhythmogenesis ictally and interictally using continuous electrocardiography (EKG) and video EEG (vEEG) recordings over 14 days following SE in a chemoconvulsant mouse model of TLE. Methods: Male C57BL6J mice were implanted with an intrahippocampal guide cannula and electrodes at 2-4 months of age. After a week of recovery, mice were recorded continuously for baseline EKG and vEEG activity. Subsequently, mice received saline (Veh) or kainate (SE) via the cannula and monitored for an additional two weeks. Investigators blinded to the group assignment reviewed EEG/EKG recordings at baseline and day 14 following SE. Electrographic seizures were defined as >10 s of continuous epileptiform discharges. Prolonged sinus pause was defined as longer than 2x the preceding RR interval. Sinus arrhythmia was defined as a sudden disruption in heart rate with a minimum 30 msec increase in RR₁-RR₂ intervals. Additionally, we calculated average hourly heart rate (HR) per animal. One-way and two-way analysis of variance was used to compare EKG variables between groups. Survival differences between Veh and SE mice were analyzed using Log-rank test. Results: Fifty percent of the SE mice had spontaneous seizures during the 14d monitoring period. SE mice were found to have an increased hourly HR when compared to Veh mice (p<0.01) at 14d post kainate administration. Additionally, there was significantly increased heart rhythm abnormalities 14d following SE (223.5 ± 69.57 vs 38.33 ± 14.28, SE vs Veh, p<0.05). Most notably there was an increased number of prolonged sinus pauses (79.5 ± 38.16 vs. 5.166 ± 2.54, SE vs Veh, p<0.01) and sinus arrhythmias (114.9 ± 35.67 vs 29.5 ± 12.36, SE vs Veh, p<0.01). Heart rate abnormalities most commonly occurred during the light cycle (sleep cycle) of the SE animals (174.40 ± 65.35 vs 32.16 ± 13.89, SE vs Veh, p<0.01). Lastly, SE mice had increased mortality with hazard ratio of 6.4 as compared with Veh mice. Conclusions: These findings suggest persistent cardiac autonomic dysfunction and instability following SE. Interestingly, the arrhythmias were observed most commonly during sleep. This raises the possibility that autonomic instability was worse during sleep, which may represent a candidate mechanism underlying SUDEP. Further research into the underlying mechanisms of cardiac dysfunction following SE may be fruitful in providing greater understanding as well as treatments to prevent future cases of SUDEP.  Funding: Not applicable