Carotid body stimulation as a potential intervention in sudden death in epilepsy

Objective: To investigate carotid body (CB) mechanisms related to sudden death during seizure. Ictal activation of oxygen-conserving reflexes (OCRs) can trigger fatal cardiorespiratory collapse in seizing rats, which presents like human sudden unexpected death in epilepsy (SUDEP). The CB is strongly implicated in OCR pathways; we hypothesize that modulating CB activity will provide insight into these mechanisms of death.Methods: Long-Evans rats were anesthetized with urethane. Recordings included: electrocorticography, electrocardiography, respiration via nasal thermocouple, and blood pressure (BP). The mammalian diving reflex (MDR) was activated by cold water delivered through a nasal cannula. Reflex and stimulation trials were repeated up to 16 times (4 pre-intervention, 12 post-intervention) or until death. In some animals, one or both carotid bodies were denervated. In some animals, the CB was electrically stimulated, both with and without MDR. Seizures were induced with kainic acid (KA).Results: Animals without seizure and with no CB modulation survived all reflexes. Non-seizing animals with CB denervation survived 7.1 +/- 5.4 reflexes before death, and only 1 of 7 survived past the 12-trial threshold. Electrical CB stimulation without seizure and without reflex caused significant tachypnea and hypotension. Electrical CB stimulation with seizure and without reflex required higher amplitudes to replicate the physiological responses seen outside seizure. Seizing animals without CB intervention survived 3.2 +/- 3.6 trials (per-reflex survival rate 42.0% +/- 44.4%), and 0 of 7 survived past the 12-trial threshold. Seizing animals with electrical CB stimulation survived 10.5 +/- 4.7 ictal trials (per-reflex survival rate 86.3% +/- 35.0%), and 6 of 8 survived past the 12-trial threshold. Significance: These results suggest that, during seizure, the ability of the CB to stimulate a restart of respiration is impaired. The CB and its afferents may be relevant to fatal ictal apnea and SUDEP in humans, and CB stimulation may be a relevant intervention technique in these deaths. (c) 2022 Elsevier Inc. All rights reserved.