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(Abst. 3.364), 2015

Ventilatory arrest is the primary initiating event that leads to sudden death after heat-induced seizures in a Dravet mouse model.
Authors: E. Bravo, Y. Kim, G. Richerson
Content: Rationale: In patients with Dravet Syndrome (DS) and intractable epilepsy, Sudden Unexpected Death in Epilepsy (SUDEP) is the most common cause of death. Compared to the general population, DS patients are up to 40 times more likely to die from SUDEP. Several types of postictal arrhythmia have been associated with seizures, leading some investigators to conclude that cardiac arrest is the principal cause of SUDEP. However, in most documented cases of SUDEP there were no data available on respiratory function. The recent MORTality in Epilepsy Monitoring Unit Study (MORTEMUS) reported the largest series of SUDEP cases in epilepsy monitoring units (EMUs), and included video, EEG, and EKG. Respiratory activity was assessed indirectly by observing the video recording, but ventilation was not measured directly. In an animal model of DS (Kalume et al, J Clin Invest, 2013), heat induced seizures are followed by progressive bradycardia and death, which has been proposed to reproduce the events that occur in human DS patients with SUDEP. However, breathing was not measured in those experiments. Here we studied a mouse model of DS to determine the relationship between cardiac activity, respiratory output and death after heat-induced seizures.Methods: A mouse EMU was used to continuously record EEG, EMG, EKG, whole-body plethysmography (breathing), body temperature, room temperature, humidity and video. Heterozygous mice with a knockin mutation (R1407X) of SCN1A (Scn1aR1407X/+) and wild-type (WT) littermates on a C3H background were bred and genotyped as previously described (Auerbach et al, PLoS ONE, 2013). WT and Scn1aR1407X/+ mice were exposed to a heat lamp to cause a continuous increase in body temperature from 37°C to 43°C. For those mice that did not die on this first trial, a second trial was performed two days later.Results: In response to an increase in body temperature to 43°C, 100% of Scn1aR1407X/+ mice had at least one seizure on the first trial, with 84% of these mice having at least one convulsive seizure. 75% of Scn1aR1407X/+ mice died, and this always occurred after a convulsive seizure. Two days later, a second trial induced death in 100% of the remaining Scn1aR1407X/+ mice. In contrast, none of the WT mice had any seizures and 100% survived the two heating trials. In Scn1aR1407X/+ mice, when death occurred the first abnormality was always complete cessation of all respiratory effort that did not return. Heart rate remained normal for 20 seconds, and then subsequently began to decrease progressively over the next 3 minutes until asystole occurred.Conclusions: These results indicate that postictal death in Scn1aR1407X/+ mice is due to respiratory arrest, and that the subsequent bradycardia is likely secondary to an increase in parasympathetic output due to hypoxia. The combination of respiratory failure and bradycardia is likely more damaging than either one would be alone, since atropine can reduce postictal death in this model.