Abstracts

Rationale:
Sudden unexpected death in epilepsy (SUDEP) is a fatal complication of epilepsy which is poorly understood and difficult to study because it usually occurs unobserved. Patients with epilepsy have well-documented impairments in the autonomic nervous system (ANS), and autonomic instability has been implicated in SUDEP. The two pathways of the ANS typically operate in opposition; however, the mammalian diving reflex (MDR) and the laryngeal chemoreflex (LCR) strongly co-activate both pathways. These reflexes, and others, conserve oxygen by inducing bradycardia, apnea, and vasoconstriction. These oxygen-conserving reflexes (OCRs) have been implicated in SUDEP and other types of sudden death. In this study we present on data from over 30 rats in which we induce these reflexes during acute seizure, triggering sudden death.
Method:
In urethane-anesthetized female Long-Evans rats we recorded electrocardiography (ECG), electrocorticography (ECoG), respiratory, and blood pressure data. Kainic acid (KA) injection, either systemically or into the ventral hippocampus, induced acute seizures. After seizures developed, we used a nasal cannula to activate the MDR with cold mist in the nares or used a laryngoscope guide and cannula to activate the LCR with an acidic buffer applied to the larynx and observed the response. A minimum of five minutes between reflex challenges allowed the animal to fully recover prior to the next reflex challenge. Control animals were identical but given saline instead of KA. In selected animals we blocked conduction on the left vagus, surgically via vagotomy or electrically with a nerve cuff electrode, to determine the effect on the ictal reflex response.
Results:
Reflex challenges caused sudden death in 18 of 20 seizing rats within minutes of the reflexes, but never in 8 non-seizing rats. In all cases of death, terminal central apnea preceded terminal asystole. Significant ECoG suppression—analogous to generalized post-ictal EEG suppression—occurred following OCR activation. Heart and respiratory rate fluctuations that occurred during OCR-induced sudden death paralleled those seen in human SUDEP. Mean arterial pressure was found to be predictive of death, showing a 16 mmHg drop in the 20-second window around brain death. In fatal trials, terminal apnea occurred 64.1 ± 35.7 s after MDR challenges and 118.7 ± 44.7 s after LCR challenges. Preliminary results suggest that blocking conduction on the left vagus during seizure dramatically increases survival during these experiments.
Conclusion:
These results present a method of inducing sudden death in two epilepsy models that shows consistent pathophysiology to human cases of SUDEP. Preliminary results from blocking of left vagus conduction may provide further insight into a mechanism or therapy. This proposed mechanism provides a repeatable, inducible animal model for the study of sudden death during seizure and offers a potential explanation for observations made in cases of human SUDEP.
Funding:
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Funding:
: NIH OD023847.