DeGiorgio, Christopher M.

Sperling, Michael R.

Surges, Rainer

English

Jefferson Digital Commons

Thomas Jefferson University Jefferson Digital Commons Department of Neurology Faculty Papers Department of Neurology 12-4-2019 Editorial: Sudden Unexpected Death in Epilepsy: Bio-markers, Mechanisms, Risk Identification and Prevention. Rainer Surges Michael R. Sperling Christopher M. DeGiorgio Follow this and additional works at: https://jdc.jefferson.edu/neurologyfp  Part of the Neurology Commons Let us know how access to this document benefits you This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Department of Neurology Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For more information, please contact: JeffersonDigitalCommons@jefferson.edu. EDITORIALpublished: 04 December 2019doi: 10.3389/fneur.2019.01277Frontiers in Neurology | www.frontiersin.org 1 December 2019 | Volume 10 | Article 1277Edited and reviewed by:Fernando Cendes,Campinas State University, Brazil*Correspondence:Rainer Surgesrainer.surges@ukbonn.deMichael R. Sperlingmichael.sperling@jefferson.eduChristopher M. DeGiorgiocmd@mednet.ucla.eduSpecialty section:This article was submitted toEpilepsy,a section of the journalFrontiers in NeurologyReceived: 18 October 2019Accepted: 18 November 2019Published: 04 December 2019Citation:Surges R, Sperling MR andDeGiorgio CM (2019) Editorial:Sudden Unexpected Death inEpilepsy: Bio-markers, Mechanisms,Risk Identification and Prevention.Front. Neurol. 10:1277.doi: 10.3389/fneur.2019.01277Editorial: Sudden Unexpected Deathin Epilepsy: Bio-markers,Mechanisms, Risk Identification andPreventionRainer Surges 1*, Michael R. Sperling 2* and Christopher M. DeGiorgio 3*1Department of Epileptology, University Hospital Bonn, Bonn, Germany, 2Department of Neurology, JeffersonComprehensive Epilepsy Center, Thomas Jefferson University, Philadelphia, PA, United States, 3Department of Neurology,David Geffen-UCLA School of Medicine, Sylmar, CA, United StatesKeywords: sudden death, blood pressure, apnea, sleep, ketogenic diet, epilepsy, seizures, mortalityEditorial on the Research TopicSudden Unexpected Death in Epilepsy: Bio-markers, Mechanisms, Risk Identificationand PreventionSudden unexpected death in epilepsy (SUDEP) is a common cause of epilepsy-related mortality,with an incidence of 1.2 per 1,000 persons (1). SUDEP causes 15–17% of all epilepsy-relateddeaths and carries a lifetime risk of 4–8% (1, 2). Reliable biomarkers and predictors are stilllacking, but the most important risk factors are nocturnal and frequent tonic-clonic seizures.Mechanisms include tachycardia and tachypnea followed by bradycardia, asystole, and apneain SUDEP cases documented in epilepsy monitoring units (3). The underlying neuronal andmolecular pathomechanisms that turn non-fatal into fatal seizures remain to be elucidated, butbrainstem dysfunction and spreading depression as well as defects in serotonin-related signalingappear to be involved. Comprehensive information about SUDEP is recommended and desired bymost patients, relatives, and caregivers. Improved seizure control by pharmacotherapy, epilepsysurgery, and neuromodulatory devices is key to SUDEP prevention. Nocturnal supervision isassociated with reduced SUDEP risk, and clinically tested seizure detection systems are available.CARDIORESPIRATORY MECHANISMSPostictal breathing disturbances are a hallmark of monitored SUDEP cases (3). In this ResearchTopic, Vilella et al. investigated the occurrence and influencing factors of seizure-related centralapnea in a prospective multicenter study. They found that postictal central apnea occurred in about20% of tonic-clonic seizures (generalized convulsive seizures) in 20% of the patients, its recurrencerisk amounted to about 50% in a given individual. Postictal central apnea was less frequent thanictal central apnea and seen in all epilepsy types, possibly indicating different pathomechanisms.In addition to respiratory dysfunction, recent studies described profound alterations of systemicarterial blood pressure and its regulation in association with seizures [e.g., (4, 5)], suggesting aSurges et al. Biomarkers and Mechanisms in SUDEPpossible role in SUDEP (6). Nass et al. summarize the currentknowledge on control of blood pressure in epilepsy, describethe relevant cerebral mechanisms and pathways and discusshow epilepsy- and seizure-related blood pressure alterations maycontribute to premature mortality and SUDEP.RISK FACTOR “NOCTURNAL SEIZURES”AND NUTRITIONSeizures arising from sleep or occurring during nighttime wereidentified as a risk factor for SUDEP (7). To date, it is stillunresolved whether this is predominantly due to the fact thatpeople are more often unsupervised or to distinct neuronalmechanisms and networks properties related to sleep. Purnell etal. review the possible factors contributing to the relationshipbetween sleep and SUDEP and explain potential molecular andneuronal mechanisms. In a mouse model of Dravet syndromewith high mortality, Teran et al. observed that SUDEP rates andseizure frequency were higher in the early evening and nighttime,suggesting that specific circadian or sleep-related neuronalmechanisms increase the risk of SUDEP. They also noted thatplacingmice on a ketogenic diet led to a considerable reduction inmortality. Importantly, the mice fed with ketogenic diet did nothave fewer seizures than control mice, indicating that nutritionaleffects on mortality and the SUDEP rate were independent ofseizure frequency. In another experimental study of this ResearchTopic, Taha et al. tested the effects of dietary measures on seizurethresholds in rat models of kindling and acute seizures. Theyfound that chronic dietary omega-3 polyunsaturated fatty aciddeficiency did not alter seizure thresholds, but impaired theeffects of acutely applied omega-3 docosahexaenoic acid (Tahaet al.) Altogether, the results of these two experimental studiesconfirm that nutrition has an impact on brain excitability andunderscore that more research should be performed on diet inthe context of epilepsy and maybe SUDEP.BIOMARKERS, RISK IDENTIFICATION,AND PREVENTIONThe search for reliable biomarkers and predictors of an elevatedSUDEP risk is of great importance for designing appropriatesafety measures and interventional studies to prevent SUDEP.An increasing number of studies deals with the question whetherbrain regions involved in the regulation of autonomic functiondisplay functional and structural alterations that are linked tothe SUDEP risk. If present, these alterations could serve asneuroimaging markers that would help to identify people athigher risk. In this Research Topic, Allen et al. have compiledrecent findings on resting-state functional and structural MRIstudies, strengthening the view that disturbed central autonomicand respiratory control contributes to the pathophysiology ofSUDEP. For instance, studies on morphometry and corticalthickness revealed reduced volume and cortical thinning in thethalamus, frontal cortex and at brainstem sites in patients withSUDEP and in those with tonic-clonic seizures. Importantly, theauthors point out that theMRI-based prediction of the individualSUDEP risk requires further studies. A personalized estimationof the danger, however, would be very helpful when counselingpeople with epilepsy and their relatives or caregivers. In thiscontext, Shankar et al. ask if “the time has come to stratifyand score SUDEP risk to inform people with epilepsy of theirchanges in safety”. The authors present work which identifiesthe need to improve communication at a primary care level.They suggest that regular reviews using a structured risk factorchecklist as a screening tool would help in earlier identificationof people whose health is worsening and to justify referralsto specialists.SUMMARYThis Research Topic compiles recent findings on seizure-relatedbreathing disturbances and blood pressure regulation, reviewsthe impact of sleep and nutrition on brain excitability and SUDEPand summarizes our current knowledge on neuroimagingmarkers. The variety of the contributions illustrates that anincreasing number of clinicians and researchers are committedto understand SUDEP, identify biomarkers and develop strategiesand interventions to mitigate the SUDEP risk. These worldwideefforts are also the success of tireless activities of patients, familiesand bereaved to promote awareness for premature mortality inepilepsy and SUDEP (8).AUTHOR CONTRIBUTIONSRS drafted the editorial. MS and CD critically revised the draft.REFERENCES1. Harden C, Tomson T, Gloss D, Buchhalter J, Cross JH, DonnerE, et al. Practice guideline summary: sudden unexpected death inepilepsy incidence rates and risk factors: Report of the GuidelineDevelopment, Dissemination, and Implementation Subcommittee ofthe American Academy of Neurology and the American EpilepsySociety. Neurology. (2017) 88:1674–80. doi: 10.1212/WNL.00000000000036852. DeGiorgio CM, Curtis A, Hertling D, Moseley BD. Suddenunexpected death in epilepsy: risk factors, biomarkers, andprevention. Acta Neurol Scand. (2019) 139:220–30. doi: 10.1111/ane.130493. Ryvlin P, Nashef L, Lhatoo SD, Bateman LM, Bird J, Bleasel A,et al. Incidence and mechanisms of cardiorespiratory arrests inepilepsy monitoring units (MORTEMUS): a retrospective study.Lancet Neurol. (2013) 12:966–77. doi: 10.1016/S1474-4422(13)70214-X4. Hampel KG, Jahanbekam A, Elger CE, Surges R. Seizure-related modulation of systemic arterial blood pressure infocal epilepsy. Epilepsia. (2016) 57:1709–18. doi: 10.1111/epi.135045. Hampel KG, Elger CE, Surges R. Impaired baroreflex sensitivityafter bilateral convulsive seizures in patients with focalepilepsy. Front Neurol. (2017) 8:210. doi: 10.3389/fneur.2017.00210Frontiers in Neurology | www.frontiersin.org 2 December 2019 | Volume 10 | Article 1277Surges et al. Biomarkers and Mechanisms in SUDEP6. Bozorgi A, Chung S, Kaffashi F, Loparo KA, Sahoo S, Zhang GQ, et al.Significant postictal hypotension: expanding the spectrum of seizure-inducedautonomic dysregulation. Epilepsia. (2013) 54:e127–30. doi: 10.1111/epi.122517. Lamberts RJ, Thijs RD, Laffan A, Langan Y, Sander JW. Suddenunexpected death in epilepsy: people with nocturnal seizures may be athighest risk. Epilepsia. (2012) 53:253–7. doi: 10.1111/j.1528-1167.2011.03360.x8. Panelli RJ. SUDEP: a global perspective. EpilepsyBehav. (2019) 106417. doi: 10.1016/j.yebeh.2019.07.018Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Copyright © 2019 Surges, Sperling and DeGiorgio. This is an open-access articledistributed under the terms of the Creative Commons Attribution License (CC BY).The use, distribution or reproduction in other forums is permitted, provided theoriginal author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Neurology | www.frontiersin.org 3 December 2019 | Volume 10 | Article 1277

Editorial: Sudden Unexpected Death in Epilepsy: Bio-markers, Mechanisms, Risk Identification and Prevention.

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Editorial: Sudden Unexpected Death in Epilepsy: Bio-markers, Mechanisms, Risk Identification and Prevention.

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