Abstracts

Rationale:
Approximately 30-50% of epilepsy patients fail to achieve seizure control with medical treatment, increasing their risk of sudden unexpected death in epilepsy (SUDEP). While the mechanisms underlying SUDEP are unclear, the current strategy for preventing SUDEP is to reduce seizure frequency. Seizure-induced respiratory arrest (S-IRA) is thought to be the terminal event preceding many cases of SUDEP. The ketogenic diet (KD) is a dietary therapy recommended for some epilepsy patients who fail trials of three anticonvulsant drugs. Recent work from our group found that a KD decreased mortality due to SUDEP in Scn1aR1407x/+ mice without affecting seizure frequency. The goal of the present study was to use DBA/1 mice, which have audiogenic seizures often followed by fatal S-IRA, to determine 1) the effect of a KD on S-IRA and 2) whether a KD affects male and female mice differently.
Method:
DBA/1 mice were primed upon weaning at P21 by exposing them to a loud alarm clock once per day for 60 seconds or until S-IRA occurred. If S-IRA occurred, the mouse was revived using a rodent ventilator. Priming was considered successful when animals had a tonic-clonic seizure that progressed to S-IRA on 3 consecutive days. Primed animals were randomly placed on a control diet (n=33) or a KD (Bio-Serv F3666, Frenchtown, NJ, U.S.A.) (n=32). Two cohorts of mice continued the same diet for 14 days (nKD= 14, nC= 7). Two other cohorts were placed on either diet for 7 days, after which they were crossed over to the other diet group (nKD= 20, nC= 16). The latency to S-IRA was reassessed in each group at the end of the period of time on the assigned diet (7 or 14 days). The latency to each S-IRA was recorded and expressed as the median value. Comparisons were made with a Mann-Whitney U test and a Wilcoxon test.
Results:
On a KD for 7 days, the median latency to S-IRA of 11 s was delayed compared to that on a control diet (7 s, p< 0.0001). Three mice on the KD did not have S-IRA on Day 7. When mice were crossed over from a control diet to a KD, their latency to S-IRA increased significantly to 15 s (p= 0.0078). When mice were switched from a KD to a control diet their latency to S-IRA decreased to 10 s (p= 0.0039). While on a control diet, the latency to S-IRA significantly decreased from 13 s on Day 0 to 7 s on Day 7 (p= 0.0002) and remained decreased to 8 s on Day 14 (p= 0.009). There was no significant difference in response to a KD between male and female DBA/1 mice. A KD for 14 days delayed the onset of S-IRA in males (n = 33) from 11 s compared to 7 s on a control diet (p= 0.0060), and also in females (n = 32) from 10 s on a KD compared to 6 s on a control diet (p= 0.0012). There was no difference in the latency to S-IRA in males and females or the effect of a KD.