News from the American Epilepsy Society Annual Meeting
Genetic Variants Associated with Sudden Unexpected Death in Epilepsy
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Researchers reported that gene variants related to cardiac sudden death, long QT syndrome, and focal epilepsy were more prevalent in people who had died from sudden unexpected death in epilepsy than in a cohort of control patients.
Whole exome sequencing revealed that gene variants related to cardiac sudden death, long QT syndrome, and focal epilepsy were more prevalent in people who had died from sudden unexpected death in epilepsy (SUDEP) than in a cohort of control patients, Australian investigators reported earlier this month at the annual meeting of the American Epilepsy Society (AES) in Philadelphia.
The findings implicate cardiac rhythm defects in mortality in a percentage of SUDEP cases and suggest that for some patients, SUDEP could be prevented with appropriate drug therapy, Douglas Crompton, MD, PhD, a neurologist at the University of Melbourne, reported at the meeting.
Dr. Crompton and colleagues performed whole exome sequencing to identify genetic variants that were more prevalent in 62 people who had died from SUDEP at two major centers in Australia compared with 2,936 controls. Those in the SUDEP group had a mean age at epilepsy onset of 10.5 years, and the mean age at SUDEP was 28 years.
The researchers reported a higher prevalence of the cardiac sudden death-related gene NOSAP (p=0.00024), the long QT syndrome gene KCNH2 (p=0.0039), and the focal epilepsy gene DEPDC5 (p=0.00016) among the SUDEP patients. Six SUDEP cases (10 percent) had mutations in genes commonly responsible for long QT syndrome, eight (13 percent) had mutations in other cardiac arrhythmia genes, and 15 (24 percent) had mutations in known epilepsy genes, including six cases (10 percent) with mutations in DEPDC5.
“These findings raise the possibility that SUDEP might be prevented in some cases by avoiding the use of antiepileptic drugs known to alter the heart's electrical activity, such as prolonging the QT interval,” Dr. Crompton said in an AES news release ahead of the meeting. “In some cases, it may be advisable to recommend beta blockers, pacemakers, or implantable defibrillators.”
Dr. Crompton and colleagues also suggested that, based on their findings, patients with the focal epilepsy mutation DEPDC5 might have a predisposition to SUDEP, perhaps due to subtle cardiorespiratory abnormalities. However, they added, no single gene reached exome-wide significance in the study cohort, and analyses of larger SUDEP cohorts will be needed.
“The findings are definitely intriguing,” said Lara Jehi, MD, director of clinical research at the Cleveland Clinic Epilepsy Center and associate director of the clinic's Clinical Research Unit, who was not involved with the study. “The idea of looking for a gene that can predict SUDEP is very worthwhile.”
Dr. Jehi said “the findings linking [cardiac] genes like the long QT syndrome gene and the cardiac sudden death gene with SUDEP are essentially confirmatory, in the sense that it has long been known that patients with epilepsy who have long QT syndrome are at a higher risk for sudden death.”
However, she cautioned, “before we drive clinical judgment based on these findings or draw any mechanistic conclusions from them, it would be helpful to see how these results compare to [genetic studies] of patients who die from sudden death in general, and to patients who have epilepsy but survive,” she said.
That information will be key to determining “whether these genes are critical for the risk of SUDEP in patients with epilepsy in particular, or are a reflection of an increased risk of sudden death in the general population, or are a reflection of epilepsy,” she said.
Selim R. Benbadis, MD, a professor and director of the Comprehensive Epilepsy Program at the University of South Florida and Tampa General Hospital, said: “Those of us who take care of patients with epilepsy full time, especially at referral centers, lose one to two patients a year to SUDEP, on average. [Having] a way to identify patients who are at risk would be very helpful. And if we can identify them based on these genes, we can take measures like avoiding antiepileptic drugs that can cause arrhythmias or QT changes, and maybe even prophylactically putting these patients on beta blockers or installing pacemakers or implantable defibrillators.”
But he, too, emphasized that the research is still in its infancy. “We need to find out more about how sensitive and how specific these genetic changes are, how well they predict SUDEP, false positives and false negatives, and so forth,” he said.
It's not surprising that DEPDC5, which is associated with focal epilepsy, would be more common in patients who died from SUDEP, said Orrin Devinsky, MD, FAAN, a professor of neurology, neurosurgery, and psychiatry at New York University School of Medicine and director of the NYU Comprehensive Epilepsy Center, who was not involved in the study. Patients with treatment-resistant focal epilepsy are known to have a higher risk for SUDEP, “so we expect that a gene responsible for a certain percentage of treatment-resistant focal epilepsy is going to turn up in SUDEP patients,” he said.
Larger analyses of patients with similarly severe epilepsy who did not die from SUDEP could determine whether “DEPDC5 carries, in addition to the risk of epilepsy, an independent risk for SUDEP,” he added. “Notably, in a large multicenter EPGP-Epi4K study of localization-related epilepsy, DEPDC5 was a common epilepsy gene. However, this was not a SUDEP population but one that looked at families with at least two first-degree relatives with epilepsy. We need more data to better define a potential specific role of DEPDC5 in SUDEP.”
The finding that cardiac rhythm genes were more prevalent in the SUDEP patients was “novel and important,” said Dr. Devinsky, who also presented research at the AES meeting implicating certain cardiac genes in SUDEP.
Recent research suggests that “mechanisms of brain shutdown after a tonic-clonic seizure, as well as pulmonary dysfunction, are some of the major mechanisms responsible for SUDEP. But these cardiac genes may be the icing on the cake,” he said. “Maybe someone who has a seizure has post-ictal depressions in their brain, respiratory, and cardiac functions, and if it passes some critical window of time, the mutations in these genes rise from silent to deadly in such cases.”
As genetic research improves, Dr. Devinsky said, it may be possible to screen patients for these variants and initiate preventive treatment in patients determined to be at high risk for SUDEP. “I don't think we're there today,” he said, “but that may be where we're moving.”
EXPERTS: ON GENETIC VARIANTS ASSOCIATED WITH SUDEP