Thursday, October 20, 2016


Results of a large long-term study suggest that patients with drug-resistant epilepsy treated with vagus nerve stimulation (VNS) have a reduced risk of sudden unexpected death in epilepsy (SUDEP).

"It appears reasonable to conclude that VNS treatment in the long term significantly reduces the risk of SUDEP," said Philippe Ryvlin, MD, PhD, Department of Clinical Neurosciences, CHUV, Lausanne, Switzerland.

A study by Annegers and colleaguessuggested that SUDEP decreased with adjunctive VNS therapy, but this was not confirmed in another comparable study by Granbichler and colleagues.

The current study increased the power of these previous two studies "by 100-fold," said Dr Ryvlin. The new findings were reported here at the 2nd Congress of the European Academy of Neurology.

Dr Ryvlin and colleagues used a US database for their study. As he explained to meeting delegates, the US Food and Drug Administration requires all patients with drug-resistant epilepsy receiving VNS to be registered in a database and then followed…

Because SUDEP has not yet been included as an International Classification of Diseases code for cause of death, researchers developed an algorithm to determine deaths probably related to SUDEP. They had information on contributing factors and, in almost half the cases, on circumstances of death from families, physicians, and autopsies…

The other 30% of deaths were considered "potential" SUDEP. For example, when the cause of death was listed as epilepsy or convulsions, SUDEP might be "assumed" if the patient "was perfectly normal before and was found dead in bed in the morning," said Dr Ryvlin. 

In the study that included 40,443 patients, there were 3689 deaths after a mean follow up of 6.9 years. According to their algorithm, the researchers concluded that 22% of these were related to SUDEP.

The SUDEP rate was 2.9/1000 patient-years (95% CI 2.8 - 3.1). This compared with a rate of 4.1 in the Annegers study and 3.3 in the Granbichler study.

The SUDEP rate for the first 1 to 2 years of VNS treatment was 3.6 (95% CI 3.8 - 4.0), and after 2 years it was 2.7 (95% CI 2.5 - 2.9).

“It's not a huge difference ― the odds ratio is 0.7 (95% CI 0.6 - 0.9) ― but it's significant; the confidence intervals do not overlap,” said Dr Ryvlin.

The study also looked at the age-adjusted rate of SUDEP. "There is a clear trend to decreasing, especially for the first 2 or 3 years, and then it seems to stabilize," commented Dr Ryvlin.

To assess the potential impact of time and aging, researchers looked at the SUDEP rate in years 3 to 10 using data extrapolated from years 1 to 2. They came up with an overall SUDEP rate of 2.81, and 567.7 as the expected number of SUDEP cases.

The observed year 3 to 10 SUDEP rate was 2.10 and the number of observed cases was 423. So in the cohort of over 40,000 patients, there should have been 567 SUDEP cases, but there were only 423.

"We can assume that maybe we saved one in 40 patients from SUDEP," said Dr Ryvlin.

He acknowledged that during the period of observation ― 1988 to 2012 ― there might have been changes to physician practices or patient management that to some extent explained the reduction…
The study was limited by the quality of the available data. Whereas in the two previous studies there were only 12 or so SUDEP cases, here "we were dealing with big data and we probably underestimated the true rate of SUDEP," said Dr Ryvlin.

However, he added that this is unlikely to have affected the relationship between duration of patient follow up and reduction of SUDEP rates.

The authors concluded that the impact of aging and change of patient management over calendar years is unlikely to account for the reduction in SUDEP.

In contrast, the reduction "is likely to reflect the consequences of VNS treatment," said Dr Ryvlin.

This, he said, could be a direct result of, for example, less severe or less frequent generalized clonic-tonic seizures among the patient population, or a specific neuro-modulation effect on the brain-stem center. But it might also be an indirect effect, because of such things as changes in antiepileptic drug therapy after VNS.

2nd Congress of the European Academy of Neurology. Abstract #O1112. Presented May 28, 2016.

Dr Ryvlin has received consultant or speaker fees from Cyberonics, Eisai, and UCB Pharma.


  1. Granbichler CA, Nashef L, Selway R, Polkey CE. Mortality and SUDEP in epilepsy patients treated with vagus nerve stimulation. Epilepsia. 2015 Feb;56(2):291-6.

    The risk of premature death is increased in patients with intractable epilepsy. The effect of vagus nerve stimulation (VNS) on mortality remains unclear. In a previous study by Annegers et al., mortality was raised, comparable to similar intractable cohorts. Our aim was to calculate standardized mortality ratios (SMRs), identify epilepsy-related deaths, and estimate sudden unexpected death in epilepsy (SUDEP) rates in patients treated with VNS for epilepsy.
    All United Kingdom patients undergoing VNS between January 1, 1995 and December 31, 2010 at King's College Hospital, London were flagged through the national Medical Research Information Service. Analysis was performed in relation to all deaths occurring by December 31, 2010. Deceased patients were identified from the national death register, and additional information on cause and circumstances of death sought where appropriate to allow for classification of deaths.
    The cohort consisted of 466 patients, with 2993.83 person-years of follow-up and a median observation period of 5.9 years. Twenty-nine deaths occurred, 27 with the device active. SMR was 7.1 (95% confidence interval [CI] 4.8-10.3) for the active device; 12 deaths were considered epilepsy related, including 10 definite or probable SUDEP and one fatal near SUDEP. Definite/probable and fatal near SUDEP occurred at a rate of 3.7/1,000 person-years. SMRs decreased from 10.5 (5.6-19.5) in the first 2 years after implantation to 5.9 (3.7-9.5) thereafter, although CIs overlapped. SUDEP rates did not alter over time.
    SMRs and SUDEP rate in this study are comparable to other cohorts with intractable epilepsy, with SUDEP an important cause of death. VNS does not appear to lower the risk of premature death overall. There was a clear trend with lower SMR after 2 years of implantation, although CIs overlapped. SUDEP rates, however, did not change.

  2. Annegers JF, Coan SP, Hauser WA, Leestma J. Epilepsy, vagal nerve stimulation by the NCP system, all-cause mortality, and sudden, unexpected, unexplained death. Epilepsia. 2000 May;41(5):549-53.

    This report concerns the 2-year extension of the study of mortality and sudden, unexpected, unexplained death in epilepsy (SUDEP) in the cohort of patients receiving vagal nerve stimulation by the NCP System for the treatment of epilepsy.
    A cohort of 1,819 individuals was followed 3,176.3 person-years from implantation. The 25 deaths that occurred during NCP System activation were reviewed for SUDEP by a panel.
    The mortality rates were lower [standardized mortality ratio (SMR = 3.6)] with the extended follow-up compared to the previous finding (SMR = 5.3). The SUDEP rates (4.1 vs. 4.5 per 1,000 person-years) were similar to those in the previous study of this cohort. When the vagal nerve stimulation experience is stratified by duration of use, the rate of SUDEP was 5.5 per 1,000 over the first 2 years, but only 1.7 per 1,000 thereafter.
    The mortality and SUDEP rates are similar to those reported from clinical trials of new drugs and cohorts of severe epilepsy. The lower SUDEP rates after 2 years of follow-up are intriguing, but require further investigation.