Sudden Unexpected Death in Epilepsy
Potential Role of Antiepileptic Drugs
First Online: 30 October 2012 DOI:
Cite this article as: Hesdorffer, D.C. & Tomson, T. CNS Drugs (2013) 27: 113. doi:10.1007/s40263-012-0006-1 Abstract
Among people with epilepsy, there is a 20-fold higher risk of dying suddenly and unexpectedly compared with the general population. This phenomenon is called sudden unexpected death in epilepsy (SUDEP) and the term is used when sudden death occurs in an otherwise reasonably healthy person with epilepsy and the autopsy is unrevealing. In most cases, SUDEP occurs during sleep and is unwitnessed. Risk factors for SUDEP include the presence or number of generalized tonic–clonic seizures (GTCS), nocturnal seizures, young age at epilepsy onset, longer duration of epilepsy, dementia, absence of cerebrovascular disease, asthma, male gender, symptomatic aetiology of epilepsy and alcohol abuse. Suggested factors predisposing to SUDEP have included long-QT-related mutations, impaired serotonergic brain stem control of respiration, altered autonomic control and seizures with a pronounced postictal suppression and respiratory compromise. Final events that may lead up to SUDEP are a postictal CNS shutdown with pronounced EEG suppression, ictal or postictal apnoea, and ictal cardiac arrhythmia. It is unknown whether antiepileptic drugs (AEDs) modify the risk for SUDEP. Studies have consistently found that the presence or number of GTCS is associated with an increased risk for SUDEP. Since continued presence of GTCS clearly necessitates the use of AEDs, both factors must be taken into account to determine whether one or both increases the risk for SUDEP. Some studies suggest that AEDs, such as lamotrigine and carbamazepine, may increase the risk of SUDEP, but rarely adjust for GTCS. Other studies, which have found that AEDs are associated with a decreased SUDEP risk, either adjust for the number of GTCS or are meta-analyses of randomized clinical trials. Studies assessing the impact of AEDs on the risk for SUDEP are limited because SUDEP is a rare event, making randomized clinical trials impossible to conduct. Observational studies focus on whether or not an AED was prescribed. When postmortem AED concentrations are assessed they are usually low or absent, perhaps due to sampling in deceased individuals, making it difficult to fully resolve whether AEDs increase or decrease SUDEP risk. Despite these caveats, the evidence suggests that AEDs are not associated with an increased risk for SUDEP on a population level, although some individuals may be susceptible to effects of AEDs. Recent evidence from a meta-analysis of randomized clinical trials of adjunctive AEDs at efficacious doses provides strong support for AED treatment as mono- or polytherapy to increase seizure control and protect against SUDEP in patients with refractory epilepsy. For patients for whom seizure control is unattainable, supervision or monitoring may prevent SUDEP, though this has never been formally tested.
Ficker DM, So EL, Annegers JF, et al. Population-based study of the incidence of sudden unexplained death in epilepsy. Neurology. 1998;51(5):1270–4.
Nashef L, So EL, Ryvlin P, Tomson T. Unifying the definitions of sudden unexpected death in epilepsy. Epilepsia. 2012;53(2):227–33.
Langan Y, Nashef L, Sander JW. Sudden unexpected death in epilepsy: a series of witnessed deaths. J Neurol Neurosurg Psychiatry. 2000;68(2):211–3.
Tomson T, Nashef L, Ryvlin P. Sudden unexpected death in epilepsy: current knowledge and future directions. Lancet Neurol. 2008;7(11):1021–31.
Sillanpää M, Shinnar S. Long-term mortality in childhood-onset epilepsy. N Engl J Med. 2010;363(26):2522–9.
First Seizure Trial Group (FIRST Group). Randomized clinical trial on the efficacy of antiepileptic drugs in reducing the risk of relapse after a first unprovoked tonic clonic seizure. Neurology 1993;43(3):478–483.
Marson A, Jacoby A, Johnson A, on behalf of the Medical Research Council MESS Study Group, et al. Immediate versus deferred antiepileptic drug treatment for early epilepsy and single seizures: a randomized controlled trial. Lancet. 2005;365(9476):2007–13.
Hesdorffer DC, Tomson T, Benn E, for the ILAE Commission on Epidemiology (Subcommission on Mortality), et al. Do antiepileptic drugs or generalized tonic-clonic seizure frequency increase SUDEP risk? A combined analysis. Epilepsia. 2012;53(2):249–52.
Aurlien D, Larsen JP, Gjerstad L, Taubøll E. Increased risk of sudden unexpected death in epilepsy in females using lamotrigine: a nested, case-control study. Epilepsia. 2012;53(2):258–66.
Nilsson L, Farahmand BY, Persson PG, et al. Risk factors for sudden unexpected death in epilepsy: a case-control study. Lancet. 1999;353(9156):888–93.
Walczak TS, Leppik IE, D’Amelio M, et al. Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study. Neurology. 2001;56(4):519–25.
Langan Y, Nashef L, Sander JW. Case-control study of SUDEP. Neurology. 2005;64(7):1131–3.
Hitiris N, Suratman S, Kelly K, et al. Sudden unexpected death in epilepsy: a search for risk factors. Epilepsy Behav. 2007;10(1):138–41.
Hesdorffer DC, Tomson T, Benn E, for the ILAE Commission on Epidemiology (Subcommission on Mortality), et al. Combined analysis of risk factors for SUDEP. Epilepsia. 2011;52(6):1150–9.
Lamberts RJ, Thijs RD, Laffan A, et al. Sudden unexpected death in epilepsy: people with nocturnal seizures may be at highest risk. Epilepsia. 2012;53(2):253–7.
Jick SS, Cole TB, Mesher RA, et al. Sudden unexpected death in young persons with primary epilepsy. Pharmacoepidemiol Drug Safety. 1992;1(2):59–64.
Nilsson L, Bergman U, Diwan VK, et al. Antiepileptic drug therapy and its management in sudden unexpected death in epilepsy: a case–control study. Epilepsia. 2001;42(5):667–73.
Tomson T, Beghi E, Sundqvist A, Johannessen SI. Medical risks in epilepsy: a review with focus on physical injuries, mortality, traffic accidents, and their prevention. Epilepsy Res. 2004;60(1):1–16.
Berg AT, Shinnar S, Levy FM, et al. Two-year remission and subsequent relapse in children with newly diagnosed epilepsy. Epilepsia. 2001;42(12):1553–62.
Tu E, Bagnall RD, Duflou J, Semsarian C. Post-mortem review and genetic analysis of sudden unexpected death in epilepsy (SUDEP) cases. Brain Pathol. 2011;21(2):201–8.
Tupal S, Faingold CL. Evidence supporting a role of serotonin in modulation of sudden death induced by seizures in DBA/2 mice. Epilepsia. 2005;47(1):21–6.
Surges R, Thijs RD, Tan HL, Sander JW. Sudden unexpected death in epilepsy: risk factors and potential pathomechanisms. Nat Rev Neurol. 2009;5(9):492–504.
Lhatoo SD, Faulkner HJ, Dembny K, et al. An electroclinical case-control study of sudden unexpected death in epilepsy. Ann Neurol. 2010;68(6):787–96.
So EL, Sam MC, Lagerlund TL. Postictal central apnea as a cause of SUDEP: evidence from near-SUDEP incident. Epilepsia. 2000;41(11):1494–7.
Espinosa PS, Lee JW, Tedrow UB, Bromfield EB, Dworetzky BA. Sudden unexpected near death in epilepsy: malignant arrhythmia from a partial seizure. Neurology. 2009;72(19):1702–3.
Aurlien D, Leren TP, Taubøll E, Gjerstad. New SCN5A mutation in a SUDEP victim with idiopathic epilepsy. Seizure. 2009;18(2):158–60.
Cantwell R, Clutton-Brock T, Cooper G, on behalf of the Centre for Maternal and Child Enquiries, et al. Saving mother’s lives: reviewing maternal deaths to make motherhood safer: 2006–2008. Br J Obstet Gyn. 2001;118(Suppl. 1):1–205.
Danielsson BR, Lansdell K, Patmore L, Tomson T. Effects of the antiepileptic drugs lamotrigine, topiramate and gabapentin on hERG potassium currents. Epilepsy Res. 2005;63(1):17–25.
Tran TA, Leppik IE, Blesi K, et al. Lamotrigine clearance during pregnancy. Neurology. 2002;59(2):251–5.
Ohman I, Beck O, Vitols S, Tomson T. Plasma concentrations of lamotrigine and its 2-N-glucuronide metabolite during pregnancy in women with epilepsy. Epilepsia. 2008;49(6):1075–80.
Herzog AG, Blum AS, Farina EL, et al. Valproate and lamotrigine level variation with menstrual cycle phase and oral contraceptive use. Neurology. 2009;72(10):911–4.
Tomson T, Kennebäck G. Arrhythmia, heart rate variability, and antiepileptic drugs. Epilepsia. 1997;38(Suppl. 11):S48–51.
Persson H, Ericson M, Tomson T. Carbamazepine affects autonomic cardiac control in patients with newly diagnosed epilepsy. Epilepsy Res. 2003;57(1):69–75.
Ryvlin P, Cucherat M, Rheims S. Risk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: a meta-analysis of placebo-controlled randomized trials. Lancet Neurol. 2011;10(11):961–8.
Faught E, Duh MS, Weiner JR, et al. Nonadherence to antiepileptic drugs and increased mortality: findings from the RANSOM study. Neurology. 2008;71(20):1572–8.
Ridsdale L, Charlton J, Ashworth M, et al. Epilepsy mortality and risk factors for death in epilepsy: a population-based study. Br J Gen Pract. 2011;61(586):e271–8.
Terrence CF Jr, Wisotzkey HM, Perper JA. Unexpected, unexplained death in epileptic patients. Neurology. 1975;25(6):594–8.
George JR, Davis GG. Comparison of anti-epileptic drug levels in different cases of sudden death. J Forensic Sci. 1998;43(3):598–603.
Leestma JE, Kalelkar MB, Teas SS, et al. Sudden unexpected death associated with seizures: analysis of 66 cases. Epilepsia. 1984;25(1):84–8.
Leestma JE, Walczak T, Hughes JR, et al. A prospective study on sudden unexpected death in epilepsy. Ann Neurol. 1989;26(2):195–203.
Lear-Kaul KC, Coughlin L, Dobersen MJ. Sudden unexpected death in epilepsy, a retrospective study. Am J Forensic Med Pathol. 2005;26(1):11–7.
Kloster R, Engelskjon T. Sudden unexpected death in epilepsy: a clinical perspective and a search for risk factors. J Neurol Neurosurg Psychiatry. 1999;67(4):439–44.
Opeskin K, Burke MP, Cordner SM, Berkovic SF. Comparison of antiepileptic drug levels in sudden unexpected death in epilepsy with death from other causes. Epilepsia. 1999;40(12):1795–8.
Tomson T, Skold AC, Holmgen P, et al. Postmortem changes in blood concentrations of phenytoin and carbamazepine: an experimental study. Ther Drug Monit. 1998;20(3):309–12.
Williams J, Lawthom C, Dunstan FD, et al. Variability of antiepileptic medication taking behaviour in sudden unexplained death in epilepsy: hair analysis at autopsy. J Neurol Neurosurg Psychiatry. 2006;77(4):481–4.
Cramer JA, Glassman M, Rienzi V. The relationship between poor medication compliance and seizures. Epilepsy Behav. 2002;3(4):338–42.
Kennebäck G, Ericson M, Tomson T, Bergfeldt L. Changes in arrhythmia profile and heart rate variability during abrupt withdrawal of antiepileptic drugs: implications for sudden death. Seizure. 1997;6:369–75.
Hennessy MJ, Tighe MG, Binnie CD, Nashef L. Sudden withdrawal of carbamazepine increases cardiac sympathetic activity in sleep. Neurology. 2001;57:1650–4.
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