Literature Review

SUDEP Risk Decreases During Long-Term VNS Treatment

The data do not indicate which of several potential mechanisms explain the observed decline in risk.


For patients with refractory epilepsy who receive vagus nerve stimulation (VNS) therapy, the risk of sudden unexpected death in epilepsy (SUDEP) decreases significantly during long-term follow-up, according to research published online ahead of print January 16 in Epilepsia. This finding “has not been previously reported in the literature and would be of value for patients at risk of SUDEP,” said the authors.

Long-Term Data Are Lacking

Most epidemiologic studies of SUDEP have had cross-sectional designs. Consequently, neurologists have lacked information about potential changes in the rate of SUDEP over time. Cyberonics, a Houston-based company, records information about implantation of its VNS device when the implanting facilities provide this information to it. To understand the evolution of SUDEP risk over time, Philippe Ryvlin, MD, Head of the Department of Clinical Neurosciences at Vaud University Hospital in Lausanne, Switzerland, and colleagues analyzed information from the company’s database.

Philippe Ryvlin, MD

For their study, the authors examined patients who underwent device implantation for epilepsy between November 16, 1988, and December 31, 2012. Eligible participants were US citizens or residents at the time of implantation and had a Social Security Number and a known date of birth. To ascertain patients’ vital status and cause of death, Dr. Ryvlin and colleagues submitted data to the Centers for Disease Control and Prevention’s National Death Index (NDI). The NDI included an underlying cause and as many as 20 contributory causes for each death.

The investigators defined SUDEP according to the criteria published by Annegers in 1997. To adjudicate SUDEP, they examined NDI data and death reports that Cyberonics recorded in a subset of patients. For patients for whom a death report was unavailable, the investigators performed adjudication by extrapolation.

Rate of SUDEP Decreased by One-Fourth

According to the database, 57,551 patients underwent implantation with the VNS device during the study period. A total of 40,443 (70%) participants met the researchers’ inclusion criteria. Patients’ average age at implantation was 30.8, and 15% of patients were under age 12. Half of participants were male.

The median duration of follow-up was 7.6 years. In all, 2,864 (7%) participants underwent explantation or had their devices turned off before the cutoff date, and 3,689 (9%) patients died during the study period.

A total of 953 (25.8%) of the deaths were associated with underlying and contributory causes considered compatible with SUDEP. Adjudication per protocol resulted in 632 (66.3%) cases of definite, probable, and possible SUDEP. The consensus conclusion among investigators resulted in 638 (66.9%) SUDEP cases. Adjudication by extrapolation resulted in 667 (70.0%) SUDEP cases and 286 (30.0%) non-SUDEP cases.

The crude and age-adjusted rates of SUDEP during years 3 to 10 of follow-up (2.10/1,000 patient years and 1.68/1,000 patient years, respectively) were significantly lower than those observed during the first two years of follow-up (2.74/1,000 patient years and 2.47/1,000 patient years, respectively). The crude rate ratio of SUDEP was 0.77, and the age-adjusted rate ratio of SUDEP was 0.68.

Biomarkers of SUDEP Would Aid Research

Because the study did not include a control group, and the database did not have preimplantation baseline information or data about individual responses to VNS therapy, the analysis does not clarify the role of VNS in the rate of SUDEP. Factors such as attrition, natural evolution, aging, or changes in medications or medical practice over time could explain the study findings, said Dr. Ryvlin.

The reasons for which SUDEP risk decreases over time should be investigated further, said the authors. A three-year randomized controlled trial would require at least 28,000 patients in each arm to compare adjunctive VNS treatment and standard treatment, but this level of enrollment is not feasible. “Novel biomarkers highly predictive of SUDEP will be needed to make prospective studies of SUDEP prevention feasible in an enriched population,” said Dr. Ryvlin. “Until then, only large retrospective cohorts, such as the study presented here, can help us make progress in SUDEP prevention, an issue that one should acknowledge when weighing the limitations and value of currently available data.”

—Erik Greb

Suggested Reading

Ryvlin P, So EL, Gordon CM, et al. Long-term surveillance of SUDEP in drug-resistant epilepsy patients treated with VNS therapy. Epilepsia. 2018 Jan 16 [Epub ahead of print].

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