Susan Jeffrey

April 24, 2017

BOSTON — A new practice guideline on sudden unexpected death in epilepsy (SUDEP) has been released by the American Academy of Neurology (AAN) and the American Epilepsy Society (AES).

For the document, the writing committee sought to establish incidence rates of SUDEP and identify any risk factors.

"We found that SUDEP is relatively rare in children, affecting 1 in 4500 children with epilepsy per year; that's according to moderate evidence," said coauthor Elizabeth Donner, MD, Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Ontario, Canada, and chair of the AES SUDEP Task Force.

SUDEP was more common in adults than in children, typically affecting 1 in 1000 adults living with epilepsy per year, Dr Donner said.

The major risk factor was generalized tonic-clonic seizures. "People with three or more of this type of seizure…were 15 times more likely to die suddenly than people who did not have this seizure type, so that's a very significant finding," Dr Donner said. "In total, this translates to up to 18 in 1000 deaths per year for people with epilepsy with frequent generalized tonic-clonic seizures."

"Our guideline brings clarity to the discussion, giving healthcare providers information they can use to help people with epilepsy reduce their risk," said lead author, Cynthia Harden, MD, Department of Neurology, Mount Sinai Health System, New York, New York, during a press conference here.

The guideline was co-developed by AAN and AES, and is endorsed by the International Child Neurology Association. It is published online April 24 in Neurology and was presented during a press conference here at the American Academy of Neurology 2017 Annual Meeting (AAN).

"Catastrophic" Risk

SUDEP is a "poorly understood and catastrophic risk of epilepsy," the authors write. "The sensitive nature of discussions of this infrequent but important risk with patients with epilepsy and their families has prompted the need for evidence-based information about SUDEP."

For this publication, the authors looked at the evidence on SUDEP incidence rates in different epilepsy populations and sought  any prognostic factors for SUDEP occurrence, they note. "This in turn will inform an honest and balanced discussion when clinicians counsel people about SUDEP, and provide insight into areas where more clinical research is needed."

To do this, they undertook a systematic review of the evidence, using a modified Grading Recommendations Assessment, Development and Evaluation process, with recommendations developed by consensus.

For the incidence rates, findings were based on 12 class I studies. "Imprecision in study findings resulted in moderate confidence in the evidence for SUDEP rates in childhood, and low confidence in the evidence for SUDEP rates in adulthood and overall," the authors note. 

Table 1. SUDEP Incidence    


SUDEP Incidence per 1000 Patient-Years (95% Confidence Interval)

Confidence Level


0.58 (0.31 - 1.08)



0.22 (0.16 - 0.31)



1.2 (0.64 - 2.32)



A previous study showed that patients and their families prefer to be informed of individual risk for an event like SUDEP, they note, but after being informed of an adverse event, they tend to overestimate the risk for that adverse event affecting them.

"Overestimation can be lessened by presenting the risk as a probability of both having and not having the event, and by using numbers in addition to words and frequencies rather than percentages to convey the risk," the authors write.

Accordingly, they suggest some language physicians may use to inform patients in a balanced way.

"Clinicians caring for young children with epilepsy should inform parents/guardians that in 1 year, SUDEP typically affects 1 in 4,500 children with epilepsy; therefore, annually 4,499 of 4,500 children will not be affected," they write (Level B). 

Similarly, "Clinicians should inform adult patients with epilepsy that SUDEP typically affects 1 in 1,000 adults with epilepsy per year; therefore, annually 999 of 1,000 adults will not be affected (Level B)."

Risk Factors

Looking at risk factors for SUDEP, the researchers included 6 class I studies and 16 class II studies.

The major risk factors they found were the presence and frequency of generalized tonic-clonic seizure (GTCS). People with three or more of these seizures per year had a 15-fold increased SUDEP risk.

"The large SUDEP risk increase from GTCS, coupled with epilepsy monitoring unit evidence demonstrating that a GTCS was always the precipitating event of SUDEP, strongly suggests that GTCS are not just associated with SUDEP but, rather, are in the causal path to SUDEP," the authors note. "From this, it seems reasonable to infer that improved control of an individual's GTCS will result in a reduced risk of SUDEP. Thus, a reduction in SUDEP risk is an additional benefit to the many benefits resulting from improved seizure control."

Other risk factors were associated with increased or decreased risk for SUDEP, but there wasn't enough evidence to make clear recommendations, the authors note.

Table 2. SUDEP Risk Factors


Odds Ratio (95% Confidence Interval)

Confidence Level


10 (17 - 14)


Frequency of GTCS    

  1 to 2 GTCS per year

5.07 (2.94 - 8.76)




  >3 GTCS per year

15.46 (9.92 - 24.10)


Not being seizure-free for 1 to 5 years

4.7 (1.4 - 16)


Not adding an AED when patient is medically refractory

6 (2 - 20)


Nocturnal supervision (risk reduction)

0.4 (0.2 - 0.8)


Use of nocturnal listening device (risk reduction)

0.1 (0 - 0.3)



In terms of recommendations, then, they suggest that for patients who continue to have GTCS, "clinicians should continue to actively manage epilepsy therapies to reduce seizures and SUDEP risk while incorporating patient preferences and weighing the risks and benefits of the new approach."

They also suggest that clinicians inform their patients that seizure freedom, "particularly freedom from GTCS (which is more likely to occur with medication adherence), is strongly associated with a decreased SUDEP risk."

Further research programs are underway, with the hope of expanding what's known about SUDEP and how often it occurs, the authors say.

"One is called the Center for SUDEP Research, which is funded by the National Institutes of Health," Dr Donner noted. Another is the North American SUDEP Registry, on which Dr Donner serves as a member of the executive board.

"One of the most grassroots approaches that we have right now is really the SUDEP registry, getting more detail on how many people have SUDEP, and getting I think the term SUDEP into the lexicon of medical examiners, because we're not really sure how many we're missing at that level," Dr Harden said. "We're providing the best evidence we have on incidence rates, but even that number could be refined just through greater awareness and greater collaboration with our medical examiner colleagues."


Putting SUDEP Into Perspective

In an editorial accompanying the publication, Barbara A. Dworetzky, MD, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, and Jaideep Kapur, MD, PhD, Department of Neurology, University of Virginia HSC, Charlottesville, call the guideline "an important first step for epilepsy practice."

"It begins to put the risk of SUDEP into perspective by challenging the strength of evidence for many of the risk factors reported in the literature," they write. "Patients and families may find this information reassuring as we look for ways to target specific subsets of patients at risk."

Among the strengths of the guideline are "the sound methodology, the large number of Class I and II studies, and the many practical consensus recommendations, such as informing patients and families about the risk of SUDEP and its low yearly risk (ie '999/1000 adults will not be affected': Level B)."

Clinicians should tell their patients that eliminating convulsions is strongly associated with a decreased risk for SUDEP, they add. "This may help some patients move on to the next treatment rather than remaining on one that is clearly no longer working as well as it should," they write.

Limitations of the guideline include the fact that the authors, "found insufficient evidence to determine many of the proposed risk factors, but this does not necessarily mean that they are not risk factors," Dr Dworetzky and Dr Kapur. "It is difficult to study SUDEP incidence and risk: this requires a great deal of effort to gather a large dataset, as this is an infrequent event that generally occurs out of the physician's purview."

A "key step" to reducing SUDEP incidence is to understand the pathophysiologic mechanisms, they write.   

"The authors propose that neuronal networks generating generalized tonic-clonic seizures compromise brainstem respiratory or autonomic control centers, leading to hypoventilation and autonomic dysregulation," they note. "In addition, normal arousal mechanisms may be compromised in these individuals."

Children with Dravet syndrome have an unusually high risk for SUDEP, they add. "Mutations in sodium channel gene SCN1A are the most common cause of Dravet syndrome and this gene is expressed in brain and heart. It is possible that these mutations render patients more susceptible to cardiac arrhythmias in the setting of a seizure.

"More research is needed to identify genetic and other risk factors, causes, and methods for preventing SUDEP," the editorialists conclude.

The guideline was developed with financial support from the American Academy of Neurology. Dr Harden reports she has received royalties from Wiley and UpToDate and has served as a contributing editor for Epilepsy Currents. Dr Donner has received research support from the Canadian Institutes of Health Research, Dravet Canada, and SUDEP Aware. Disclosures for coauthors appear in the paper. Dr Dworetzky has disclosed no relevant financial relationships. Dr Kapur receives National Institutes of Health funding for his research.

Neurology. Published online April 23, 2017. Abstract, Editorial

American Academy of Neurology 2017 Annual Meeting (AAN). 


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