Sudden unexpected death in epilepsy: Risk factors, biomarkers, and prevention

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Abstract

Sudden unexpected death in epilepsy (SUDEP) is one of the most important direct epilepsy-related causes of death, with an incidence in adults of 1.2 per 1000 person-years. Generalized tonic-clonic seizures have consistently emerged as the leading risk factor for SUDEP, particularly when such seizures are uncontrolled. High seizure burden, lack of antiepileptic drug (AED) treatment, polytherapy, intellectual disability, and prone position at the time of death are other key risk factors. Unfortunately, despite advances in treatment, overall mortality rates in epilepsy are rising. It is imperative that we learn more about SUDEP so that effective prevention strategies can be implemented. To help identify persons at greater risk of SUDEP and in need of closer monitoring, biomarkers are needed. Candidate biomarkers include electrocardiographic, electroencephalographic, and imaging abnormalities observed more frequently in those who have died suddenly and unexpectedly. As our knowledge of the pathophysiologic mechanisms behind SUDEP has increased, various preventative measures have been proposed. These include lattice pillows, postictal oxygen therapy, selective serotonin reuptake inhibitors, and inhibitors of opiate and adenosine receptors. Unfortunately, no randomized clinical trials are available to definitively conclude these measures are effective. Rather, gaining the best control of seizures possible (with AEDs, devices, and resective surgery) still remains the intervention with the best evidence to reduce the risk of SUDEP. In this evidence-based review, we explore the incidence of SUDEP and review the risk factors, biomarkers, and latest prevention strategies.

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Most cited references 54

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Jerome Engel, Michael McDermott, Samuel Wiebe … (2012)

Despite reported success, surgery for pharmacoresistant seizures is often seen as a last resort. Patients are typically referred for surgery after 20 years of seizures, often too late to avoid significant disability and premature death. We sought to determine whether surgery soon after failure of 2 antiepileptic drug (AED) trials is superior to continued medical management in controlling seizures and improving quality of life (QOL). The Early Randomized Surgical Epilepsy Trial (ERSET) is a multicenter, controlled, parallel-group clinical trial performed at 16 US epilepsy surgery centers. The 38 participants (18 men and 20 women; aged ≥12 years) had mesial temporal lobe epilepsy (MTLE) and disabling seizues for no more than 2 consecutive years following adequate trials of 2 brand-name AEDs. Eligibility for anteromesial temporal resection (AMTR) was based on a standardized presurgical evaluation protocol. Participants were randomized to continued AED treatment or AMTR 2003-2007, and observed for 2 years. Planned enrollment was 200, but the trial was halted prematurely due to slow accrual. Receipt of continued AED treatment (n = 23) or a standardized AMTR plus AED treatment (n = 15). In the medical group, 7 participants underwent AMTR prior to the end of follow-up and 1 participant in the surgical group never received surgery. The primary outcome variable was freedom from disabling seizures during year 2 of follow-up. Secondary outcome variables were health-related QOL (measured primarily by the 2-year change in the Quality of Life in Epilepsy 89 [QOLIE-89] overall T-score), cognitive function, and social adaptation. Zero of 23 participants in the medical group and 11 of 15 in the surgical group were seizure free during year 2 of follow-up (odds ratio = ∞; 95% CI, 11.8 to ∞; P < .001). In an intention-to-treat analysis, the mean improvement in QOLIE-89 overall T-score was higher in the surgical group than in the medical group but this difference was not statistically significant (12.6 vs 4.0 points; treatment effect = 8.5; 95% CI, -1.0 to 18.1; P = .08). When data obtained after surgery from participants in the medical group were excluded, the effect of surgery on QOL was significant (12.8 vs 2.8 points; treatment effect = 9.9; 95% CI, 2.2 to 17.7; P = .01). Memory decline (assessed using the Rey Auditory Verbal Learning Test) occurred in 4 participants (36%) after surgery, consistent with rates seen in the literature; but the sample was too small to permit definitive conclusions about treatment group differences in cognitive outcomes. Adverse events included a transient neurologic deficit attributed to a magnetic resonance imaging-identified postoperative stroke in a participant who had surgery and 3 cases of status epilepticus in the medical group. Among patients with newly intractable disabling MTLE, resective surgery plus AED treatment resulted in a lower probability of seizures during year 2 of follow-up than continued AED treatment alone. Given the premature termination of the trial, the results should be interpreted with appropriate caution. clinicaltrials.gov Identifier: NCT00040326.

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Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

Cynthia L Harden, Torbjörn Tomson, David Gloss … (2017)

To determine the incidence rates of sudden unexpected death in epilepsy (SUDEP) in different epilepsy populations and address the question of whether risk factors for SUDEP have been identified.