When Apnea Turns Terminal: When, How, Why?

Abstract

Objective: Sudden unexpected death in epilepsy (SUDEP) is an unpredictable and devastating comorbidity of epilepsy that is believed to be due to cardiorespiratory failure immediately after generalized convulsive seizures. Methods: We performed cardiorespiratory monitoring of seizure-induced death in mice carrying either a p.Arg1872Trp or p.Asn1768Asp mutation in a single Scn8a allele-mutations identified from patients who died from SUDEP-and of seizure-induced death in pentylenetetrazole-treated wild-type mice. Results: The primary cause of seizure-induced death for all mice was apnea, as (1) apnea began during a seizure and continued for tens of minutes until terminal asystole, and (2) death was prevented by mechanical ventilation. Fatal seizures always included a tonic phase that was coincident with apnea. This tonic phase apnea was not sufficient to produce death, as it also occurred during many nonfatal seizures; however, all seizures that were fatal had tonic phase apnea. We also made the novel observation that continuous tonic diaphragm contraction occurred during tonic phase apnea, which likely contributes to apnea by preventing exhalation, and this was only fatal when breathing did not resume after the tonic phase ended. Finally, recorded seizures from a patient with developmental epileptic encephalopathy with a previously undocumented SCN8A likely pathogenic variant (p.Leu257Val) revealed similarities to those of the mice, namely, an extended tonic phase that was accompanied by apnea. Interpretation: We conclude that apnea coincident with the tonic phase of a seizure, and subsequent failure to resume breathing, are the determining events that cause seizure-induced death in Scn8a mutant mice.

Sudden Unexpected Death in Epilepsy and Respiratory Defects in a Mouse Model of DEPDC5‐Related Epilepsy

“…For example, death could be prevented in a Dravet mouse model by mechanical ventilation and intracerebroventricular infusion of atropine, suggesting a central apnea mechanism of SUDEP. 5,52,53 Importantly, the tonic phase-related apnea has been observed in both Dravet mice and WT mice with chemically induced seizures, suggesting a possible common SUDEP mechanism independent of epilepsy etiology. 6 In agreement with these studies, Rbp4-Cre; Depdc5 F/F CKO mice developed ictal apnea before cardiac asystole during fatal seizures and, more interestingly, had baseline respiratory dysregulation.…”

“…Several animal models also recapitulated seizure‐induced respiratory arrest. For example, death could be prevented in a Dravet mouse model by mechanical ventilation and intra‐cerebroventricular infusion of atropine, suggesting a central apnea mechanism of SUDEP 5,52,53 . Importantly, the tonic phase‐related apnea has been observed in both Dravet mice and WT mice with chemically induced seizures, suggesting a possible common SUDEP mechanism independent of epilepsy etiology 6 .…”