Emerging Biomarkers of Sudden Unexpected Death in Epilepsy (SUDEP)

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with epilepsy. In fact, it has been estimated that a person with poorly controlled epilepsy has about a 35% lifetime risk of dying from SUDEP.

Even so, SUDEP remains poorly understood and therefore difficult to treat. There has been a surprising lack of awareness of SUDEP among epilepsy patients and even their doctors, but that may be changing.¹.

What Is SUDEP?

“SUDEP is an unexpected death from epilepsy in a person who was in otherwise good health. It is not caused by seizure-related injury or drowning. At autopsy, no cause for death can be identified. It affects young people disproportionately, and a recent study found that only stroke is responsible for more years of productive life lost among neurological diseases,” said Alica M. Goldman, MD, PhD, assistant professor of neurology at Baylor College of Medicine in Houston.²

In some cases seizure can trigger a cascade of cardiorespiratory events that result in death, clinical data indicate.^1,2 “Most frequently, SUDEP is not witnessed. It tends to occur at night and patients are frequently found lying facedown in bed. SUDEP has long been an understudied enigma. Our understanding of risk factors has been limited,” Goldman said.²

Clinical Risk Factors of SUDEP

A review of SUDEP risk factors that included data from four case-control studies identified statistically significant risk factors across all or some of the studies. The data was published in 2011 in the journal Epilepsia. The most significant risk factors were early onset of frequent and generalized tonic-clonic seizures (GTCS) that are difficult to control and antiepileptic drug (AED) polytherapy.³

Being male and taking lamotrigine (Lamactil, GlaxoSmithKline) were also identified as risk factors, and having epilepsy for 15 years or more was associated with almost double the risk of SUDEP. The link between lamotrigine therapy and SUDEP may be due to poor efficacy or to drug-induced cardiac arrhythmias. Although multiple use of AED was linked to SUDEP, the authors concluded that control of GTCS was more important than reducing AED use.³

“Understanding the epidemiological risk factors is important. Unfortunately, even patients at seemingly low risk may succumb to SUDEP. Research that enhances our understanding of SUDEP biology is critical in identification of clinical and molecular biomarkers that will help screening and identification of at-risk patients,” said Goldman.²

Emerging Biomarkers

Inherited or acquired defects in the 5-hydroxytryptamine (5-HT) serotonin system may play a role in decreased threshold for seizure and delayed respiratory recovery after seizure, both of which could contribute to SUDEP, clinical data and research in animal models suggest.⁴

This link could also explain an increased incidence in sleep apnea and depression in patients with epilepsy. The 5-HT link is also central to leading theories on sudden infant death syndrome (SIDS) that focus on cardiac and respiratory abnormalities associated with a defect in the 5-HT system.⁴

A 2014 article published in the journal Epilepsy & Behavior proposed nine neurocardiac genes that could be useful genetic biomarkers of SUDEP.⁵

“These are genes identified in mice and humans that have been linked to brain, heart, or autonomic nervous system dysfunction causing sudden death,” said Edward Glasscock, PhD, assistant professor in the Department of Cellular Biology and Anatomy at LSU Health Sciences Center in Shreveport, Louisiana.⁶

Complex combinations of single nucleotide polymorphisms and copy number variants in genes expressed in both respiratory and neurocardiac pathways include KCNA1 and SCN1A genes. These two genes have been identified in multiple studies as potential risk factors, because they are involved in neurocardiac and respiratory control pathways.^6,7

However, teasing out which genes are significant will not be easy. “There is a lot of genetic variation. We have identified many genes for epilepsy, but we have been surprised to find many people without epilepsy walking around with the same genes,” Glasscock said. “Finding the smoking gun is a dream we all have, but we are not there yet.”⁶

Using Biomarkers to Detect SUDEP Risk

“Currently, there are no definite guidelines for SUDEP screening. We can utilize sleep studies to uncover sleep apnea or other respiratory problems, routine electrocardiograms to detect cardiac arrhythmias, and combined cardiac and respiratory monitoring in epilepsy monitoring units to uncover seizure-related impaired ventilation or cardiac arrhythmias,” Goldman said. “If we find a coexisting cardiac arrhythmia or a respiratory disorder, often there are available therapies that could be lifesaving.”²

More research needs to be done to discover and better understand the optimal clinical and genetic biomarkers of SUDEP. There is now a national and international network of clinical and scientific investigators trying to unravel this complex condition. The National Institute of Neurological Disorders and Stroke (NINDS) is supporting much of the latest research.^2,8

Among them are Goldman and her colleagues at Baylor Medical College, which has a NINDS-funded program, called the Stop SUDEP Research Program. It includes a SUDEP case registry and genetic repository.

They are actively working with other researchers, patient-driven organizations, and families affected by SUDEP. The goal is to identify genetic risk factors, improve patient screening, and develop treatment and interventions that will prevent the condition. To learn more or get involved, email [email protected].^2,8

Chris Iliades, MD is a full-time freelance writer based in Cap Cod, Massachusetts.

This article was medically reviewed by Pat F. Bass III, MD, MS, MPH

References

1. Massey CA, Sowers LP, Dlouhy BJ, Richerson GB. Mechanisms of sudden unexpected death in epilepsy: the pathway to prevention. Nat Rev Neurol. 2014;10(5):271-82.
2. Hesdorffer DC, Tomson T, Benn E, et al. Combined analysis of risk factors for SUDEP. Epilepsia. 2011;52(6):1150-9.
3. Richerson GB, Buchanan GF. The serotonin axis: Shared mechanisms in seizures, depression, and SUDEP. Epilepsia. 2011;52 Suppl 1:28-38. Glasscock E. Genomic biomarkers of SUDEP in brain and heart. Epilepsy Behav. 2013; S1525-5050(13)00485-X
4. Klassen TL, Bomben VC, Patel A, et al. High-resolution molecular genomic autopsy reveals complex sudden unexpected death in epilepsy risk profile. Epilepsia. 2014;55(2):e6-12.
5. Stop SUDEP Research Program, Baylor College of Medicine, http://www.sudepaware.org/stop_sudep_research_program.html