Sudden unexpected death in epilepsy is prevented by blocking postictal hypoxia

Abstract

Epilepsy is at times a fatal disease. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in people with intractable epilepsy and is defined by exclusion; non-accidental, non-toxicologic, and non-anatomic causes of death. While SUDEP often follows a bilateral tonic-clonic seizure, the mechanisms that ultimately lead to terminal apnea and then asystole remain elusive and there is a lack preventative treatments. Based on the observation that discrete seizures lead to local vasoconstriction, resulting in hypoperfusion, hypoxia and behavioural disturbances in the forebrain (Farrell et al., 2016 eLife), we reasoned that similar mechanisms may play a role in SUDEP when seizures invade the brainstem. Here we tested this neurovascular-based hypothesis of SUDEP in awake non-anesthetized mice by pharmacologically preventing seizure-induced vasoconstriction, with cyclooxygenase-2 or L-type calcium channel antagonists. In both acute and chronic mouse models of SUDEP, ibuprofen and nicardipine extended life. We also examined the potential role of spreading depolarization in the acute model of SUDEP. These data provide a proof of principle for the neurovascular hypothesis of SUDEP and the use of currently available treatments to prevent it.

Fine Mapping and Candidate Gene Analysis of Dravet Syndrome Modifier Loci on Mouse Chromosomes 7 and 8

“…Dbx1 encodes Developing brain homeobox 1, a transcription factor critical for interneuron differentiation, including Cajal Retzius cells in the cortex and brainstem pre-Bötzinger complex interneurons (Akins et al 2017; Powers et al 2022; Vann et al 2018). Interestingly, the pre-Bötzinger complex is a critical nucleus for generating respiratory rhythms and has been implicated in SUDEP (Akins et al 2017; George et al 2023; Xia et al 2016).…”

SUDEP: A Local Low Pressure [pO2] System Makes It Hard to Breathe

“…It is in this context that George and colleagues 2 took a closer look at hypoxia in the brainstem and asked whether blocking vasoconstriction and subsequent hypoxia could postpone SUDEP in 2 preclinical models. For the acute model, a series of seizures were induced in control mice (ie, with no history of spontaneous recurrent seizures) via intrahippocampal kainate infusion, with the last seizure being terminal.…”

“…Brainstem spreading depolarization contributes to sudden death; however, it has been reported to occur both before hypoxia in anesthetized mice, and following hypoxia in both anesthetized and nonanesthetized mice. 2,9,10,12 Whether the varied sequence is a result of the anesthesia or specific to certain types of epilepsy requires further study.…”