Ictal activation of oxygen‐conserving reflexes as a mechanism for sudden death in epilepsy

• Published in: Epilepsia (Copenhagen) 2021-03, Vol.62 (3), p.752-764
• Main Authors: Biggs, Ethan N., Budde, Ryan, Jefferys, John G. R., Irazoqui, Pedro P.
• Format: Article
• Language: English
• Subjects: Animal models; Apnea; Blood pressure; Chemoreception (internal); Convulsions & seizures; Death; Diving; diving reflex; EKG; Epilepsy; Ethyl carbamate; Heart rate; Kainic acid; laryngeal chemoreflex; Oxygen; Reflexes; Respiration; Seizures; sudden unexpected death in epilepsy
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/epi.16831

Objective To test the hypothesis that death with physiological parallels to human cases of sudden unexpected death in epilepsy (SUDEP) can be induced in seizing rats by ictal activation of oxygen‐conserving reflexes (OCRs). Methods Urethane‐anesthetized female Long‐Evans rats were implanted with electrodes for electrocardiography (ECG), electrocorticography (ECoG), and respiratory thermocouple; venous and arterial cannulas; and a laryngoscope guide and cannula or nasal cannula for activation of the laryngeal chemoreflex (LCR) or mammalian diving reflex (MDR), respectively. Kainic acid injection, either systemic or into the ventral hippocampus, induced prolonged acute seizures. Results Reflex challenges during seizures caused sudden death in 18 of 20 rats—all MDR rats (10) and all but two LCR rats (8) failed to recover from ictal activation of OCRs and died within minutes of the reflexes. By comparison, 4 of 4 control (ie, nonseizing) rats recovered from 64 induced diving reflexes (16 per rat), and 4 of 4 controls recovered from 64 induced chemoreflexes (16 per rat). Multiple measures were consistent with reports of human SUDEP. Terminal central apnea preceded terminal asystole in all cases. Heart and respiratory rate fluctuations that paralleled those seen in human SUDEP occurred during OCR‐induced sudden death, and mean arterial pressure (MAP) was predictive of death, showing a 17 or 15 mm Hg drop (MDR and LCR, respectively) in the 20 s window centered on the time of brain death. OCR activation was never fatal in nonseizing rats. Significance These results present a method of inducing sudden death in two seizure models that show pathophysiology consistent with that observed in human cases of SUDEP. This proposed mechanism directly informs previous findings by our group and others in the field; provides a repeatable, inducible animal model for the study of sudden death; and offers a potential explanation for observations made in cases of human SUDEP.