Nashef, L

Sander, JW

UCL Discovery

EDITORIALLina Nashef, FRCPJosemir W. Sander, FRCPCorrespondence toDr. Nashef:lina.nashef@nhs.netNeurology® 2016;87:1638–1639See page 1660Genes cut across systemsNeurologists should think “heart” and cardiologists “brain”Despite a strong association with a history of uncon-trolled convulsions, until recently, mystery surroundedsudden unexpected death in epilepsy (SUDEP). This iswhen a person with epilepsy, usually a young adult,dies suddenly without a structural or toxicologic causefor death identified.1 The Mortality in Epilepsy Mon-itoring Unit Study (MORTEMUS) has partially dis-pelled this mystery. Deaths occurred, in the absence oftimely assistance, in the aftermath of a convulsion withpostictal, centrally mediated severe respiratory and car-diac dysfunction. Hypoventilation and bradyarrhyth-mias were seen, with asystole usually occurring afterapnea.2 Much has been made of respiratory compro-mise in the context of postictal coma, usually in thesetting of generalized EEG suppression, when the indi-vidual has impaired ability to improve oxygenation bycorrecting position or enhancing respiration despitehypercapnia and hypoxia.3 This observation ties inwith conclusions of a recent review of arrhythmiasand seizures that found that postictal arrhythmiasmostly occurred following convulsions and often cor-related with (near) SUDEP.4 The MORTEMUSstudy showed a clear interrelation between respiratoryand cardiac dysfunction.3Genetic predisposition, particularly, but not exclu-sively, to sudden cardiac death, has long seemed plau-sible as a contributor in at least some SUDEP cases.Such predisposition not only accounts for disorderssuch as long QT syndrome (LQTS), with suddendeath presenting as early as in utero, but also someacquired disorders. Cardiac arrest following a first STelevation myocardial infarction, for example, is morecommon with a family history of sudden cardiac death,and genetic susceptibility is implicated in drug-inducedlong QT.5 A previous review explored the potential ofcoexisting genetic liability to cardiac arrhythmias asa factor in SUDEP, but lacked bridging clinical evi-dence between cardiac inherited gene determinantsand SUDEP.6 Recent studies have begun to fill thatgap, although more evidence is needed.In an Australian coronial study of 68 SUDEPcases, researchers identified previously reportedamino acid changing variants in the 3 most commonLQTS genes (LQTS1, KCNQ1 [KV7.1]; LQTS2,KCNH2 [HERG/KV11.1]; LQTS3, SCN5A [NaV1.5])in 6 (13%) cases, 2 in KCNH2 and 4 SCN5A.7 Morerecently, the group investigated 61 SUDEP cases.8 Theyperformed exome-based analysis of rare variants andscreened cardiac arrhythmia, respiratory control, and epi-lepsy genes for variants predicted to be pathogenic witha frequency of,0.1%. They found variants in 28 of the61 (46%), including known LQTSmutations in 4 (7%)and candidate variants in genes potentially predisposingto cardiac arrhythmia in 9 (15%), with 1 mutation eachin SCN5A and KCNQ1, and 2 mutations and 1 candi-date variant in KCNH2. Fifteen (25%) also had muta-tions in known epilepsy genes, 6 in DEPDC5. Thisstudy thus showed that a sizeable proportion of SUDEPcases had relevant mutations in cardiac arrhythmia andepilepsy genes. A comparator group of people with epi-lepsy in a similar age group dying of other causes wouldbe of interest.In this issue of Neurology®, Auerbach et al.9 reporton seizures, arrhythmias, and biomarkers using theirLQTS Registry in a large cohort of 965 geneticallyconfirmed LQTS cases (LQTS[1]) comparing themto those without genetic LQTS (LQTS[2]). This fol-lows from an earlier smaller study reporting more fre-quently reported seizures in LQTS2 than other LQTSsubtypes.10 Compared to LQTS(2), in the currentstudy, more LQTS1, LQTS2, and LQTS(1) partic-ipants were classified as having seizures. In LQTS(1)cases, a strong positive correlation was found betweenQTc duration and seizure history. Genotype influ-enced clinical presentation. LQTS2 mutations in theKCNH2 pore domain positively predicted both ar-rhythmias and seizures, while mutations in the cyclicnucleotide binding domain conferred a negative risk ofseizures, but not arrhythmias. LQTS2 and sex alsoboth predicted seizures independently. A history ofseizures was the strongest independent predictor ofarrhythmias.This study adds important observations on therelationship between seizures and LQTS and poten-tial overlap between genetic cardiac arrhythmias andepilepsy. Seizure manifestation, however, may stillFrom the Department of Neurology (L.N.), King’s College Hospital; UCL Institute of Neurology (J.W.S.), London, UK; and Stichting EpilepsieInstellingen Nederland (SEIN) (J.W.S.), Heemstede, the Netherlands.Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial.1638 © 2016 American Academy of Neurologyª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.have been a reflection of more severe arrhythmias ratherthan epilepsy. The authors defined a seizure history asa personal history of seizures or epilepsy or antiseizuremedication. Epilepsy phenotyping relied on self or phy-sician reporting and not on systemic ascertainment. Thecorrelation between seizure history and arrhythmias maybe explained by genetic factors causing both cardiacdisease and epilepsy but may also reflect a misdiagnosisof epilepsy. b-Blockers, however, reduced the risk ofarrhythmias in genotype-positive cases but not seizurerisk. This and the differing associations between gen-otypes and seizure risk strongly argue in favor of neu-rocardiac disease, at least in some cases.These and other studies provide accumulating evi-dence that in some who experience SUDEP, mutatedgenes coexpressed in the heart and the brain lead to epi-lepsy and arrhythmia. In others, however, there may becoincidental predisposition to cardiac death (whethermonogenic or polygenic), which may be more likelyto manifest in the context of uncontrolled convulsions.The Australian studies suggest these categories repre-sent an important minority of SUDEP cases.In addition to prevention of convulsions and assis-tance at the time of a seizure, we now have anotherpotential avenue for SUDEP prevention, one as yetunexplored. Genes do not recognize the arbitrary divi-sions of specialization today. Neurologists must considerthe heart and cardiologists the brain. Family studies,with a good yield in sudden cardiac death, are neededin SUDEP. We will need prolonged EEG recordingsof selected cases of LQTS to clarify with more cer-tainty when seizures in LQTS are due to epilepsyor epilepsy mimics. This chapter on genetic predis-position to SUDEP is not yet complete, but thisimportant study by Auerbach and colleagues addsnew insight to knowledge.STUDY FUNDINGNo targeted funding reported.DISCLOSUREL. Nashef in on the editorial board of Epilepsia and has served as a trusteeof Epilepsy Research UK. She has served on scientific advisory boards andas a speaker for Eisai and attended the American Epilepsy Society meetingas a guest of Bial. NeuroSigma has provided eTNS stimulators andelectrodes to her unit and UCB Pharma has sponsored departmentalmeetings. J.W. Sander has served on scientific advisory boards forUCB Pharma and Eisai; serves on the editorial board of LancetNeurology; has served on speaker’s bureaus for UCB Pharma, Eisai, Teva,and Lundbeck; has received research support from UCB Pharma, GSK,Eisai, The Marvin Weil Epilepsy Research Fund, and Nationaal EpilepsieFonds; and his current position is endowed by the UK Epilepsy Society.Go to Neurology.org for full disclosures.REFERENCES1. Surges R, Sander JW. Sudden unexpected death in epi-lepsy: mechanisms, prevalence, and prevention. Curr OpinNeurol 2012;25:201–207.2. Ryvlin P, Nashef L, Lhatoo SD, et al. Incidence andmechanisms of cardiorespiratory arrests in epilepsy moni-toring units (MORTEMUS): a retrospective study. LancetNeurol 2013;12:966–977.3. Sowers LP, Massey CA, Gehlbach BK, Granner MA,Richerson GB. Sudden unexpected death in epilepsy: fatalpost-ictal respiratory and arousal mechanisms. RespirPhysiol Neurobiol 2013;189:315–323.4. Van der Lende M, Surges R, Sander JW, Thijs RD. Car-diac arrhythmias during or after epileptic seizures. J NeurolNeurosurg Psychiatry 2016;87:69–74.5. Goldman AM, Behr ER, Semsarian C, Bagnall RD,Sisodiya S, Cooper PN. Sudden unexpected death in epi-lepsy genetics: molecular diagnostics and Prevention. Epi-lepsia 2016;57(suppl 1):17–25.6. Nashef L, Hindocha N, Makoff A. Risk factors in suddendeath in epilepsy (SUDEP): the quest for mechanisms.Epilepsia 2007;48:859–871.7. Tu E, Bagnall RD, Duflou J, Semsarian C. Post-mortemreview and genetic analysis of sudden unexpecteddeath in epilepsy (SUDEP) cases. Brain Pathol 2011;21:201–208.8. Bagnall RD, Crompton DE, Petrovski S, et al. Exome-based analysis of cardiac arrhythmia, respiratory control,and epilepsy genes in sudden unexpected death in epilepsy.Ann Neurol 2016;79:522–534.9. Auerbach DS, McNitt S, Gross RA, Zareba W,Dirksen RT, Moss AJ. Genetic biomarkers for the riskof seizures in long QT syndrome. Neurology 2016;87:1660–1668.10. Johnson JN, Hofman N, Haglund CM, Cascino GD,Wilde AA, Ackerman MJ. Identification of a possible path-ogenic link between congenital long QT syndrome andepilepsy. Neurology 2009;72:224–231.Neurology 87 October 18, 2016 1639ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.DOI 10.1212/WNL.00000000000030552016;87;1638-1639 Published Online before print July 27, 2016Neurology Lina Nashef and Josemir W. SanderGenes cut across systems: Neurologists should think ''heart'' and cardiologists ''brain''This information is current as of July 27, 2016ServicesUpdated Information & http://www.neurology.org/content/87/16/1638.full.htmlincluding high resolution figures, can be found at:References http://www.neurology.org/content/87/16/1638.full.html##ref-list-1This article cites 10 articles, 2 of which you can access for free at: Subspecialty Collections http://www.neurology.org//cgi/collection/prevalence_studiesPrevalence studies http://www.neurology.org//cgi/collection/ion_channel_gene_defectsIon channel gene defects disease-cardiachttp://www.neurology.org//cgi/collection/cardiac_see_cerebrovascular_Cardiac; see Cerebrovascular Disease/Cardiac http://www.neurology.org//cgi/collection/all_epilepsy_seizuresAll Epilepsy/Seizuresfollowing collection(s): This article, along with others on similar topics, appears in the  Permissions & Licensing http://www.neurology.org/misc/about.xhtml#permissionsits entirety can be found online at:Information about reproducing this article in parts (figures,tables) or in  Reprints http://www.neurology.org/misc/addir.xhtml#reprintsusInformation about ordering reprints can be found online:rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.1951, it is now a weekly with 48 issues per year. Copyright © 2016 American Academy of Neurology. All ® is the official journal of the American Academy of Neurology. Published continuously sinceNeurology 

Genes cut across systems: Neurologists should think "heart" and cardiologists "brain"

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Genes cut across systems: Neurologists should think "heart" and cardiologists "brain"

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