Authors :
Presenting Author: Eduardo Bravo, PhD – University of iowa
Frida Teran, MD, PhD – Resident, Neurology, University of iowa; YuJaung Kim, PhD – University of Iowa; Angel Kelley, student – University of Iowa; Megan Crotts, student – University of Iowa; Claire Enyart, student – student, University of Iowa; Junko Kasuya, PhD – University of Iowa; Toshihiro Kitamoto, PhD – University of Iowa; George Richerson, MD, PhD – Chairman Neurology, Neurology, University of Iowa
Rationale: Patients with uncontrolled epilepsy have a high risk of sudden unexpected death in epilepsy (SUDEP), and seizure-induced respiratory arrest (S-IRA) is thought to be the determining cause of death in many cases. The goal of this study was to use
Scn1aR1407X/+ (Dravet Syndrome, DS) mice to determine how a diet containing whey (WD) affects (1) mortality; (2) seizures; (3) S-IRA, and; (4) autoresuscitation via gasping/sighs.
Methods: DS mice were fed a regular mouse diet or a diet supplemented with 13% whey (w/w) from the age they were weaned (P21) until P60. They were housed with littermates and video monitored to determine the rate of spontaneous death due to seizures.
A second cohort of mice was used to analyze ventilatory parameters. A temperature telemetry probe was implanted in the peritoneum at P21 in control and WD mice. The hypercapnic ventilatory response (HCVR) and the number of sighs in response to 10% hypoxia were evaluated a week later, before and after nonfatal generalized convulsive seizures were induced by hyperthermia.
A third cohort of mice was subjected to kindling by inducing modified Racine 4 (R4) seizures once per day for five days by gradually increasing electrical stimulation of the hippocampus, followed by five days of once-per-day stimulation of R5 seizures, or until animals died. Data was evaluated to determine the effect of a WD on the likelihood that R5 seizures result in death. Between times of seizure stimulation, mice were monitored in a mouse EMU for spontaneous seizures and death.
Results: A WD reduced death induced by spontaneous seizures in DS mice, increasing the survival rate at P60 from 34% in regular diet (n=66) to 58% in WD (n=69). A high number of deaths occurred during the transition from day to night on regular diet, but in mice on WD death was more random. Some mice on a WD were witnessed to have spontaneous R5 seizures with hindlimb extension, and yet recovered and survived, which had not been seen in DS mice previously. None of the interictal ventilatory parameters were affected by a WD, with similar values of ventilation, tidal volume and frequency, as well as the HCVR and the number of sighs in 10% O
2. During the electrical stimulation protocol, nine of twelve mice on control diet died after an average of 4.7±0.9 days of the protocol either during stimulation of seizures (n=7) or spontaneously while mice were monitored in the EMU (n=2). The five mice on WD survived until the tenth day at which time two died after a seizure was stimulated. During the five days that stimulation of R5 seizures was attempted, the 5 WD mice had 12 R5 seizures with hindlimb extension and ventilatory arrest, yet survived when apnea ended with recovery of normal breathing or in some cases with breaths that had some, but not all, features of gasping. Only one mouse on control diet survived a single R5 seizure with hindlimb extension and ventilatory arrest.
Conclusions: A WD decreased mortality of DS mice by preventing death from R5 seizures due to recovery from apnea, probably in some cases by recruitment of mechanisms involved in autoresuscitation.
Funding: NIH/NINDS U01-NS0904143 SUDEP Research Alliance
R01-NS123155
F31-NS110333