What Are the Mechanisms of SUDEP?

KANSAS CITY, MO—Brain, cardiac, and respiratory dysfunctions may cause sudden unexpected death in epilepsy (SUDEP), according to an overview presented at the 46th Annual Meeting of the Child Neurology Society.

“In all likelihood, like the rest of medicine, [SUDEP] is not going to be as simple as one thing or the other. It will likely be a combination of multiple organs and susceptibilities and likely heterogeneous etiologies,” said Jeffrey Buchhalter, MD, PhD, Professor at the University of Calgary Cumming School of Medicine in Alberta.

Jeffrey Buchhalter, MD, PhD

SUDEP research publications have increased exponentially over the last two decades. Although the exact cause of SUDEP is unknown, understanding potential mechanisms and biomarkers may help researchers develop preventive strategies, said Dr. Buchhalter.

Brain Mechanisms

Studies have suggested that postictal generalized EEG suppression (PGES) is a risk factor and perhaps a biomarker for SUDEP. Lhatoo et al found that PGES lasting more than 80 seconds quadruples the risk of SUDEP. In addition, the postictal period is longer in adults than in children, said Dr. Buchhalter.

Freitas et al studied semiologic and EEG differences between generalized tonic-clonic seizures (GTCS) of adults and children. The researchers analyzed video-EEG data of 105 GTCS events in 61 consecutive patients (12 children, 23 seizure events; 49 adults, 82 seizure events) who were recruited from an epilepsy monitoring unit. They concluded that prolonged seizure phases and prolonged PGES duration might be electroclinical markers of SUDEP risk.

Seyal et al suggested that early administration of oxygen during a seizure may reduce risk of SUDEP. They concluded that a peri-ictal nursing intervention was associated with reduced duration of seizure-related respiratory dysfunction and reduced duration of PGES. The researchers added that these findings suggest the possibility that such interventions may be effective in reducing the risk of SUDEP in the outpatient setting. “This [research] changed my practice in terms of being willing to provide supplemental oxygen,” said Dr. Buchhalter.

A study by Walczak et al has indicated that one to three GTCS per year doubled the SUDEP risk, and more than three GTCS per year increase the risk of SUDEP eight times. “At face value, these numbers are powerful because so many of us see kids and adults who have a lot of GTCS,” said Dr. Buchhalter.

Cardiac and Respiratory Mechanisms

Seizure-related tachycardia and postictal ST-segment changes are common, and bradycardia and asystole have been observed in epilepsy units, said Dr. Buchhalter. Nevertheless, “phenomena associated with seizures are not always associated with SUDEP,” he said.

Central and obstructive apneas, desaturation, and hyperventilation may occur with generalized or focal seizures, and respiratory dysfunction may be a cause of SUDEP. In the MORTEMUS study, Ryvlin et al found that SUDEP in epilepsy monitoring units primarily follows an early postictal, centrally mediated, severe alteration of respiratory and cardiac function. Researchers examined data about patients’ respiration and cardiac function to determine when patients stopped breathing and when their hearts stopped beating. “In each instance, the lungs stopped first,” said Dr. Buchhalter. Despite the study’s ascertainment bias, MORTEMUS “is the best and only large series of this kind of data that has been presented,” he added.

The Role of Genetics

Bagnall et al searched for genetic risk factors in SUDEP cases. They performed an exome-based analysis of rare variants by collecting clinical information from 61 definite and probable SUDEP cases.

The researchers identified de novo mutations, previously reported pathogenic mutations, or candidate pathogenic variants in 46% of SUDEP cases. They concluded that a sizable proportion of SUDEP cases has clinically relevant mutations in cardiac arrhythmia and epilepsy genes and that understanding the genetic components of SUDEP can help to inform cascade testing of at-risk family members.

“I think this is a very hopeful set of experiments. This is the kind of [research] that can go from the lab to the bedside,” Dr. Buchhalter concluded.

—Erica Tricarico

Suggested Reading

Bagnall RD, Crompton DE, Petrovski S, et al. Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy. Ann Neurol. 2016;79(4):522-534.

Freitas J, Kaur G, Fernandez GB, et al. Age-specific periictal electroclinical features of generalized tonic-clonic seizures and potential risk of sudden unexpected death in epilepsy (SUDEP). Epilepsy Behav. 2013;29(2):289-294.

Goldman AM. Mechanisms of sudden unexplained death in epilepsy. Curr Opin Neurol. 2015;28(2):166-174.

Lhatoo SD, Faulkner HJ, Dembny K, et al. An electroclinical case-control study of sudden unexpected death in epilepsy. Ann Neurol. 2010;68(6):787-796.

Ryvlin P, Nashef L, Lhatoo SD, et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol. 2013;12(10):966-977.

Scorza FA, de Carmo AC, Scorza CA, Fiorini AC. SUDEP: A steep increase in publication since its definition. Epilepsy Behav. 2017;72:195-197.

Seyal M, Bateman LM, Li CS. Impact of periictal interventions on respiratory dysfunction, postictal EEG suppression, and postictal immobility. Epilepsia. 2013;54(2):377-382.

Shankar R, Cox D, Jalihal V, et al. Sudden unexpected death in epilepsy (SUDEP): Development of a safety checklist. Seizure. 2013;22(10):812-817.