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Epilepsy Sudden Unexpected Death in Epilepsy – An Overview of Current Understanding and Future Perspectives Daniel Friedman 1 and Lawrence J Hirsch 2 1. Assistant Professor and Epileptologist, Comprehensive Epilepsy Center, Department of Neurology, New York University Langone Medical Center; 2. Professor of Neurology and Co-Director, Comprehensive Epilepsy Center, Department of Neurology, Yale University Abstract Sudden unexpected death in epilepsy (SUDEP) is likely to be the most common cause of disease-related mortality in people with epilepsy. The most commonly encountered scenario is that a previously healthy person is found dead in bed by family. Patients with frequent generalised tonic-clonic seizures are at highest risk but SUDEP can occur in patients who have never had convulsions. The mechanisms of SUDEP are poorly understood but seem to be related to seizure-related cardiac, respiratory or cerebral dysfunction. Seizure control is the only clear strategy to prevent SUDEP but that is not possible in the 30 % of patients with treatment-resistant epilepsy. Understanding the pathophysiology of SUDEP may lead to prevention strategies for patients who continue to have seizures despite maximal therapy. Keywords Epilepsy, sudden unexpected death in epilepsy, serotonin, adenosine, channelopathy Disclosure: Daniel Friedman receives salary support from The Epilepsy Study Consortium, a non-profit organisation dedicated to improving the lives of epilepsy patients, and devotes 10 % of his time to work done for the Consortium. The Consortium receives payments from a large number of pharmaceutical companies for consulting activities. All payments are made to The Consortium and not to Dr Friedman directly. Given that there are so many companies contributing, the amount contributed by each company towards Dr Friedman’s salary is minimal. Within the past year, the Epilepsy Study Consortium received payments from the 21 companies listed below. All payments are reported annually and reviewed by New York University’s Conflict of Interest Committee: Cyberonics, Cypress Biosience, Inc., Eisai Medical Research, Entra Pharmaceuticals, GlaxoSmithKline, Icagen, Inc., Intranasal/Ikano, Johnson & Johnson, Marinus, Neurotherapeutics, NeuroVista Corporation, Ono Pharma USA, Inc., Ovation/Lundbeck, Pfizer, Sepracor, SK Life Science, Supernus Pharmaceuticals, Taro, UCB Inc./Schwarz Pharma, Upsher-Smith and Valeant. Dr Friedman also receives royalties from the sale of What Do I Do Now: Epilepsy (Oxford University Press, 2011) and has served on an advisory board for GlaxoSmithKline. Lawrence J Hirsch has received research support from Eisai, Pfizer, UCB-Pharma, Upsher-Smith and Lundbeck; consultation fees from Lundbeck, Upsher-Smith and GlaxoSmithKline; and royalties for authoring chapters for UpToDate-Neurology and for co-authoring Atlas of EEG in Critical Care, by Hirsch and Brenner. Received: 13 December 2011 Accepted: 23 January 2012 Citation: European Neurological Review, 2012;7(1):67–71 Correspondence: Daniel Friedman, New York University Comprehensive Epilepsy Center, 223 E 34th Street, New York, NY 10016, US. E: daniel.friedman@nyumc.org People with epilepsy have a two- to threefold increased mortality 1 and are 24 times more likely to die of sudden death compared with the general population. 2 Although injuries associated with seizures, suicides, adverse effects of medications and the underlying aetiology of the epilepsy contribute to this increased mortality, sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. SUDEP is defined as a sudden and unexpected non-traumatic or non-drowning-related death in a patient with epilepsy that may or may not be due to a recent seizure. 3 On autopsy, there is no evidence of anatomical (e.g. myocardial infarction) or toxicological (e.g. drug overdose) cause of death. If no autopsy was performed, the death is called ‘probable’ SUDEP if there is no known alternative explanation for death (e.g. pre-existing heart disease) and ‘possible’ if there is a competing explanation for death. Most often, the death is unwitnessed and the patient is found in bed the following morning. 4 However, evidence suggests that the deaths are likely to be seizure-related. In a series of 15 witnessed SUDEP cases, all but one death occurred during or after a convulsive seizure; the remaining death occurred after a typical aura. 5 Pathological evidence also supports the role of terminal seizures; immunohistological examination of hippocampi of SUDEP cases has revealed elevated neuronal heat-shock protein 70 expression, a marker of acute © TOUCH BRIEFINGS 2012 neuronal injury that is often elevated after seizures, compared with non-SUDEP cases. 6 SUDEP is a categorical term and may have multiple aetiologies (see below). The incidence of SUDEP in the general epilepsy population has been reported to be 0.09–1.2/1,000 person-years. This incidence is higher, 1.1–5.9/1,000 person-years, in patients with medically refractory epilepsy and even higher, 6.3–9.3/1,000 person-years, in patients who have failed resective epilepsy surgery 7,8 (see Figure 1). In several case-control studies, the greatest risk factor for SUDEP was frequent seizures, especially generalised tonic-clonic seizures. 4,9–11 Other commonly identified risk factors were early age of epilepsy onset/long duration of epilepsy, young adult age (20–40 years old), male sex, variable anti-epileptic drug (AED) levels and AED polytherapy. 7,8 Some AEDs have been associated with elevated risk of SUDEP such as carbamazepine 12 and lamotrigine, 9,13 but this has not been found consistently. Some retrospective studies have identified factors associated with reduced risk of SUDEP such as having a roommate or other form of nocturnal supervision. 4,14 Factors that may modify SUDEP risk identified in case-control studies are summarised in Table 1. The mechanisms underlying SUDEP are unclear and it is likely to be the common endpoint for a variety of causes. Hypotheses, often 67