Abstract
Sudden Unexpected Death in Epilepsy (SUDEP) causes significant mortality in epilepsy, affecting 1:1000 people every year. Preceding SUDEP, patients experienced a final GTC seizure, transient apneas and bradycardia, culminating in terminal apnea and asystole. Failure to recover from postictal hypercapnia and hypoxia (HH) is a critical risk factor for SUDEP. Central chemoreception initiates adaptive cardio-respiratory and autoresuscitation responses to HH changes, and is impaired in epilepsy and SUDEP. We have reported that the Kcna1-/- (KO) model of SUDEP, have increased GTCs, apnea, and chronic intermittent hypoxia (CIH) preceding SUDEP. We hypothesize that KO mice have impaired central chemoreception and autoresuscitation failure that contributes to their SUDEP susceptibility. We assessed the role of orexin antagonism and CIH in mitigating chemoreception dysfunction in preclinical SUDEP. Using non-invasive cardiorespiratory monitoring, we found that KO mice experienced increased apneas, intermittent bradycardia and hypoxia as they approached SUDEP. Using whole-body plethysmography, we found that high-risk KO mice had elevated ventilatory chemoresponses to a mild HH challenge (mimicking transient apnea) while 71% of KO mice failed to survive a severe HH challenge (mimicking terminal apnea). We next determined whether chemosensing orexin was involved in these responses. Orexin neurons exhibited exaggerated ex vivo chemosensitivity to low pH and may be upstream of the altered HH chemoresponses. Blocking orexin receptors improved cardio-respiration, oxygen saturation, and longevity of KO mice. It also rescued their in vivo ventilatory chemoresponses during mild and severe HH challenge and enabled survival. In response to a novel anoxia-autoresuscitation test (97% N₂, 3% CO₂), a majority of KO mice (~80%) had altered ventilatory chemoresponses and gasping parameters and succumbed to autoresuscitation failure and death. The risk of autoresuscitation failure increased with higher SUDEP risk. CIH pretreatment rescued ventilatory chemoresponses, improved gasping and enabled a majority of high-risk KO mice to autoresuscitate successfully and survive. Overall, these findings provide strong evidence that central chemoreception dysfunction contributes to autoresuscitation failure and death in a preclinical SUDEP model. We identified novel chemoreception-based cardiorespiratory biomarkers that may serve as predictors of SUDEP risk. This work highlights orexinergic pathway and CIH as promising targets for future SUDEP prevention studies.