CURE Epilepsy Discovery: When Does a Seizure Lead to SUDEP?

Key Points:

• CURE Epilepsy Taking Flight grantee Dr. Ian Wenker and colleagues used mouse models to determine the series of biological events underlying sudden expected death from epilepsy (SUDEP).
• Analysis of electrical activity from the brain and heart, along with breathing, revealed that the main cause of death was apnea (breathing cessation), which originated during the tonic phase of a seizure, the stage during which muscles stiffen.
• Restoration of breathing, either naturally or artificially, soon after the seizure had ended increased the rate of survival, thereby preventing SUDEP.
• The clinical relevance of these data was reflected in an epilepsy patient whose breathing disruptions were similar to those observed in the mice.

Deep Dive:

SUDEP is a devastating outcome for some people with epilepsy, and the most common cause of death among people with treatment-resistant epilepsy [1]. Despite significant research into the cause of SUDEP [2], including an implication of cardiorespiratory dysfunction [1,3], the precise series of biological events ultimately leading to death is not clear.

With the help of a CURE Epilepsy Taking Flight award, Dr. Ian Wenker and colleagues, working in the laboratory of Dr. Manoj Patel at the University of Virginia School of Medicine, sought to better understand these events. Specifically, they sought to determine the order in which physiological processes occur, the circumstances that lead to death, and what could be done during the seizure to prevent death [4]. The researchers used mouse models of epilepsy wherein seizures were induced either genetically or chemically. They measured breathing and monitored electrical activity from the brain and heart for both fatal and nonfatal seizures.

Dr. Wenker and colleagues found that during the tonic phase of a seizure, the phase in which muscles, including the primary breathing muscle known as the diaphragm, become rigid, breathing disruptions (apnea) were common. However, death only occurred if breathing did not promptly restart after the seizure. This conclusion was then tested by mechanically ventilating those mice whose breathing had not fully recovered after the seizure, and they survived.

To extend these exciting findings from mice to people with epilepsy, the researchers examined the corresponding data from a patient with a harmful genetic mutation similar to that in the mutant mice. The breathing patterns, frequency, and disruptions in this individual were comparable to those from seizure-susceptible mice, suggesting that treating any breathing disruptions in patients post-seizure may prevent SUDEP. Dr. Wenker plans to build on these data and hopes to contribute to the development of a protocol that may one day eliminate SUDEP completely.

Literature Cited

1. Ryvlin, P. et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol. 2013; 12(10): 966-977.
2. Jones, L.A. & Thomas, R.H. Sudden death in epilepsy: Insights from the last 25 years. Seizure 2017; 44: 232-236.
3. Stewart, M. et al. Causes and effects contributing to sudden death in epilepsy and the rationale for prevention and intervention. Neurol. 2020; 11: 765.
4. Wenker, I.C. et al. Postictal death is associated with tonic phase apnea in a mouse model of sudden expected death in epilepsy. Neurol. 2021; 89: 1023-1035.