Although people with refractory epilepsy, including some with frequent, ongoing convulsive seizures, are at high risk for sudden unexpected death in epilepsy (SUDEP), a large North American registry study reveals that even those with well-controlled and “benign” epilepsy also are at risk.
Investigators found that SUDEP occurred in patients who had not taken their last dose of epilepsy medication, those who were sleep deprived, and individuals who had not had a seizure in at least a year.
“What is really important is that SUDEP affects every segment of the epilepsy population,” Orrin Devinsky, MD, professor of neurology, neurosurgery, and psychiatry, chief of the NYU Epilepsy Service at NYU Langone Health in New York City, and a fellow of the American Academy of Neurology, told Medscape Medical News.
SUDEP can affect men, women, and children. It can affect “children diagnosed with benign epilepsies who are told they don’t need to be on medication, that they will outgrow the epilepsy. Unfortunately, [some] die before they have a chance to outgrow it,” Devinsky said. The severity of epilepsy cases in which SUDEP occurs varies widely, from cases characterized by centrotemporal spikes to epileptic encephalopathies and failed resective surgeries.
The study was published online June 19 in Neurology, the medical journal of the American Academy of Neurology.
Modifiable Risk Factors
It is estimated that about 1 in 1000 individuals with epilepsy die suddenly every year. During a 10-year period, there is a 1% risk for SUDEP; that risk is five times greater among those at highest risk.
SUDEP is not the only epilepsy-related cause of death — drowning, car accidents, falling down a flight of stairs, and severe burns also occur. Several risk factors are modifiable, so it is possible to lower the risk for SUDEP.
Combining one or more of these risk factors, such as drinking more alcohol than usual while sleep deprived, has a synergistic impact on risk.
Many previous population-based studies, medical examiner case-control series, and clinical case-control studies have focused on subgroups of epilepsy patients or patients whose condition was refractory to medication or surgery.
In contrast, Devinsky and colleagues evaluated a more general epilepsy population enrolled in a large international registry.
For the study, the investigators evaluated all enrollees in the North American SUDEP Registry (NASR) from October 2011 to June 2018. The registry includes patients with epilepsy who died; living first-degree relatives of people who died from presumed SUDEP; living control persons with epilepsy; and control persons with or without epilepsy who died.
The investigators classified cases as definite SUDEP, definite plus SUDEP (people with a secondary finding that may have contributed to death), or probable SUDEP.
Of the 331 individuals with epilepsy who died, 237 of these deaths were classified as SUDEP. This group included 135 individuals with definite SUDEP (57%), 25 with definite plus SUDEP (11%), and 77 who died from probable SUDEP (32%).
Most Die Alone, Asleep
There was a witness present for 7% of the SUDEP deaths in the study. In 10 of these 16 instances, the witness reported that a seizure immediately preceded death. Nine of these patients died while awake. The remaining seven were presumed to be asleep.
Overall, dying from SUDEP while asleep was much more likely than dying while awake. Among the 153 unwitnessed cases of SUDEP, 73% occurred during sleep.
The population included 203 individuals for whom there were sufficient registry data on medication prescription. Within this group, 89% were prescribed antiseizure medications, and 11% were never prescribed such agents.
Prior to their deaths, only 37% of 180 patients for whom dose information was available reportedly took their last prescribed antiseizure medication. Interviews with next of kin revealed that nonadherent individuals frequently forgot to take their medications, took subtherapeutic doses to minimize side effects, or intentionally avoided taking their medications.
Although information on alcohol intake just prior to death was unavailable for most registry enrollees, 15 patients were noted as having alcohol use disorder around their time of death. Four of these individuals were drinking the night they died, including three who had engaged in binge drinking.
The median age of the 237 patients with SUDEP was 26 years (range, 1–70 years); 38% were female. This group was 79% white, 11% Hispanic, 9% black, and 1% of other ethnicities.
For the 143 individuals for whom sufficient data were available for electroclinical diagnoses, 40% had generalized epilepsy, and 60% had focal epilepsy. There was also some crossover, with 10% having both generalized and focal epilepsy.
Regarding the frequency of seizures before death, 54% of patients had no generalized clonic tonic seizures in the prior month. In the year prior to death, 15% of 182 individuals who died were seizure free.
Start a Conversation
“The other finding from our paper, which has been identified before…is 84% of the family members we spoke to had never heard of SUDEP, and they believed their loved one had never been told about SUDEP,” Devinsky said.
Clinicians should discuss SUDEP with all patients with epilepsy for two reasons.
“First, some reassurance can be given to relieve anxiety for those at low risk (eg, focal aware or absence seizures only). Second and most important, patients and families must understand the critical — and potentially lifesaving — importance of seizure control,” he said.
“Someone might think: ‘If I have an occasional seizure because I missed a med, no big deal, I will be a little tired for an hour, and then I will be on my way.’ But if they understand there is a chance they could die from that seizure, one would hope they would be better about being fully adherent with their medication,” Devinsky added.
He acknowledged that neurologists might be reluctant to raise the specter of SUDEP.
“They don’t want to scare their patients, but they need to learn how to talk about it,” he said.
A conversation with a patient whose seizures are well controlled could start, for example, as follows: “Listen, I just want you to know you’re doing fantastic. There is a problem called SUDEP, or sudden death in epilepsy. Your chances of suffering it are extremely low; however, they do exist. If you can take your medications religiously and you can get good sleep and avoid excess alcohol, you will dramatically reduce your chances of getting this from very low to close to zero. But if you miss a single dose of medication, unfortunately, you could have a big seizure, and that big seizure could be deadly,’ ” said Devinsky.
Going forward, the investigators will evaluate individuals who experienced seizures that were recorded in an epilepsy unit. They plan to assess those who subsequently died in order to identify distinguishing factors in their clinical histories or diagnostic test findings in comparison with age- and sex-matched control persons who had a similar seizure but did not die from SUDEP.
“We hope studies like this will allow us to identify markers that more accurately identify patients at high risk for SUDEP and inform us about the mechanisms for SUDEP so we can more effectively prevent it,” he said.
“A Great Effort”
“There are many unknowns about SUDEP, and we do not talk about it with our patients, likely because of the lack of knowledge about the mechanism causing this condition, or the risk factors associated with it,” Jorge G. Burneo, MD, MSPH, FAAN, writes in an accompanying editorial.
The current study “represents a great effort, as it collected a substantial amount of data from different referral sources in the United States and Canada, and is the largest cohort of SUDEP cases so far,” writes Burneo, the Jack Cowin Chair in Epilepsy Research at Western University and coleader of EpLink, the epilepsy research program of the Ontario Brain Institute.
Burneo cautions about extrapolating the findings of the research to low- and middle-income countries.
“Knowledge about SUDEP in the developing world is scarce, likely related to a lack of resources necessary to establish and maintain surveillance tools or population databases. For that reason, a similar effort to the North American SUDEP registry should be replicated in other parts of the world,” he writes.
The study was supported by Finding a Cure for Epilepsy and Seizures at NYU Langone Health, Lundbeck, and the American Epilepsy Society. Devinsky is the principal investigator (uncompensated) for the NASR and the Sudden Unexplained Death in Childhood Registry and Research Collaborative. He receives grant support from the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, the Department of Defense, and the Centers for Disease Control and Prevention. Burneo receives funding from the Ontario Brain Institute, Western University, and the Rick Berg Legacy Fund.
Neurology. Published online June 19, 2019.