Neuropathology of epilepsy: epilepsy-related deaths and SUDEP

  • Maria Thom
    Maria Thom BSc MB BS FRCPath MD Honorary Consultant in Neuropathology, Department of Neuropathology, UCL Institute of Neurology, London, UK. Conflict of interests: none
    Search for articles by this author
Published:November 29, 2018DOI:


      Most pathologists will encounter deaths in patients with epilepsy in their practice, including sudden deaths. A systematic approach to these post-mortem examinations is required, including gathering relevant clinical details and around the circumstances of death, in order to correctly categorise these cases. Macroscopic and histological examination of the brain can reveal (i) the underlying cause of the epilepsy, as cortical dysplasia or tumours, (ii) sequel of previous seizures, including hippocampal sclerosis and contusions and (iii) potentially the cause of death. Sudden and unexpected death in epilepsy (SUDEP) is still under-reported as a cause of death. Although by definition there is no structural or toxicological cause of death at post-mortem, clinical and experimental studies together with neuropathological findings are beginning to identify alterations in central autonomic regions, including the brainstem, critical for cardio-respiratory regulation. Neuropathology investigations following post-mortem examinations form an essential component in the identification of disease mechanisms in epilepsy-related deaths and their future prevention.


      To read this article in full you will need to make a payment


      Subscribe to Diagnostic Histopathology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Falco-Walter J.J.
        • Scheffer I.E.
        • Fisher R.S.
        The new definition and classification of seizures and epilepsy.
        Epilepsy Res. 2018; 139: 73-79
        • Vakharia V.N.
        • Duncan J.S.
        • Witt J.A.
        • Elger C.E.
        • Staba R.
        • Engel Jr., J.
        Getting the best outcomes from epilepsy surgery.
        Ann Neurol. 2018; 83: 676-690
        • Nashef L.
        • So E.L.
        • Ryvlin P.
        • Tomson T.
        Unifying the definitions of sudden unexpected death in epilepsy.
        Epilepsia. 2012; 53: 227-233
        • Harden 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.
        Neurology. 2017; 88: 1674-1680
        • Devinsky O.
        • Hesdorffer D.C.
        • Thurman D.J.
        • Lhatoo S.
        • Richerson G.
        Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention.
        Lancet Neurol. 2016; 15: 1075-1088
        • Ryvlin P.
        • Nashef L.
        • Lhatoo S.D.
        • et al.
        Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study.
        Lancet Neurol. 2013; 12: 966-977
        • Krohn W.
        Causes of death among epileptics.
        Epilepsia. 1963; 4: 315-322
        • Sommer W.
        Erkrankung des Ammonshorns als aetiologisches Moment der Epilepsie.
        Arch Psychiatr Nervenkr. 1880; 10: 631-675
        • Leestma J.E.
        • Kalelkar M.B.
        • Teas S.S.
        • Jay G.W.
        • Hughes J.R.
        Sudden unexpected death associated with seizures: analysis of 66 cases.
        Epilepsia. 1984; 25: 84-88
        • Hanna N.J.
        National sentinel clinical audit of epilepsy-related death: report 2002.
        Stationery Office, Norwich2002
        • Clark D.
        • Riney K.
        A population-based post mortem study of sudden unexpected death in epilepsy.
        J Clin Neurosci. 2016; 23: 58-62
        • Thom M.
        • Boldrini M.
        • Bundock E.
        • Sheppard M.N.
        • Devinsky O.
        Review: the past, present and future challenges in epilepsy-related and sudden deaths and biobanking.
        Neuropathol Appl Neurobiol. 2018; 44: 32-55
        • Blumcke I.
        • Spreafico R.
        • Haaker G.
        • et al.
        Histopathological findings in brain tissue obtained during epilepsy surgery.
        N Engl J Med. 2017; 377: 1648-1656
        • Black M.
        • Graham D.I.
        Sudden unexplained death in adults caused by intracranial pathology.
        J Clin Pathol. 2002; 55: 44-50
        • Thom M.
        • Michalak Z.
        • Wright G.
        • et al.
        Audit of practice in sudden unexpected death in epilepsy (SUDEP) post mortems and neuropathological findings.
        Neuropathol Appl Neurobiol. 2016; 42: 463-476
        • Blumcke I.
        • Aronica E.
        • Miyata H.
        • et al.
        International recommendation for a comprehensive neuropathologic workup of epilepsy surgery brain tissue: a consensus task force report from the ILAE Commission on Diagnostic Methods.
        Epilepsia. 2016; 57: 348-358
        • Blumcke I.
        • Thom M.
        • Aronica E.
        • et al.
        International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: a task force report from the ILAE Commission on Diagnostic Methods.
        Epilepsia. 2013; 54: 1315-1329
        • Blumcke I.
        • Thom M.
        • Aronica E.
        • et al.
        The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc task force of the ILAE Diagnostic Methods Commission.
        Epilepsia. 2011; 52: 158-174
        • Thom M.
        Review: hippocampal sclerosis in epilepsy: a neuropathology review.
        Neuropathol Appl Neurobiol. 2014; 40: 520-543
        • Kobow K.
        • Blumcke I.
        Epigenetics in epilepsy.
        Neurosci Lett. 2018; 667: 40-46
        • Kinney H.C.
        • Cryan J.B.
        • Haynes R.L.
        • et al.
        Dentate gyrus abnormalities in sudden unexplained death in infants: morphological marker of underlying brain vulnerability.
        Acta Neuropathol. 2015; 129: 65-80
        • Wandschneider B.
        • Koepp M.
        • Scott C.
        • et al.
        Structural imaging biomarkers of sudden unexpected death in epilepsy.
        Brain. 2015; 138: 2907-2919
        • Michalak Z.
        • Obari D.
        • Ellis M.
        • Thom M.
        • Sisodiya S.M.
        Neuropathology of SUDEP: role of inflammation, blood-brain barrier impairment, and hypoxia.
        Neurology. 2017; 88: 551-561
        • Blumcke I.
        • Aronica E.
        • Becker A.
        • et al.
        Low-grade epilepsy-associated neuroepithelial tumours – the 2016 WHO classification.
        Nat Rev Neurol. 2016; 12: 732-740
        • Patodia S.
        • Somani A.
        • O'Hare M.
        • et al.
        The ventrolateral medulla and medullary raphe in sudden unexpected death in epilepsy.
        Brain. 2018; 141: 1719-1733
        • Devinsky O.
        • Kim A.
        • Friedman D.
        • Bedigian A.
        • Moffatt E.
        • Tseng Z.H.
        Incidence of cardiac fibrosis in SUDEP and control cases.
        Neurology. 2018; 91: e55-e61
        • Nascimento F.A.
        • Tseng Z.H.
        • Palmiere C.
        • et al.
        Pulmonary and cardiac pathology in sudden unexpected death in epilepsy (SUDEP).
        Epilepsy Behav. 2017; 73: 119-125
        • Richerson G.B.
        • Boison D.
        • Faingold C.L.
        • Ryvlin P.
        From unwitnessed fatality to witnessed rescue: pharmacologic intervention in sudden unexpected death in epilepsy.
        Epilepsia. 2016; 57: 35-45
        • Hirsch L.J.
        • Donner E.J.
        • So E.L.
        • et al.
        Abbreviated report of the NIH/NINDS workshop on sudden unexpected death in epilepsy.
        Neurology. 2011; 76: 1932-1938
        • So E.L.
        • Bainbridge J.
        • Buchhalter J.R.
        • et al.
        Report of the American Epilepsy Society and the Epilepsy Foundation joint task force on sudden unexplained death in epilepsy.
        Epilepsia. 2009; 50: 917-922
        • Lhatoo S.
        • Noebels J.
        • Whittemore V.
        • Research NCfS.
        Sudden unexpected death in epilepsy: identifying risk and preventing mortality.
        Epilepsia. 2015; 56: 1700-1706