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The heart of epilepsy: Current views and future concepts

  • S. Shmuely
    Affiliations
    Stichting Epilepsie Instellingen Nederland—SEIN, Heemstede, The Netherlands

    NIHR University College London Hospitals Biomedical Research Centre, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
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  • M. van der Lende
    Affiliations
    Stichting Epilepsie Instellingen Nederland—SEIN, Heemstede, The Netherlands
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  • R.J. Lamberts
    Affiliations
    Stichting Epilepsie Instellingen Nederland—SEIN, Heemstede, The Netherlands
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  • J.W. Sander
    Affiliations
    Stichting Epilepsie Instellingen Nederland—SEIN, Heemstede, The Netherlands

    NIHR University College London Hospitals Biomedical Research Centre, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
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  • R.D. Thijs
    Correspondence
    Corresponding author at: Stichting Epilepsie Instellingen Nederland—SEIN, P.O. Box 540, 2130 AM Hoofddorp, The Netherlands. Fax: +31 23 558 8159.
    Affiliations
    Stichting Epilepsie Instellingen Nederland—SEIN, Heemstede, The Netherlands

    NIHR University College London Hospitals Biomedical Research Centre, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK

    Department of Neurology, LUMC Leiden University Medical Centre, Leiden, The Netherlands
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Open ArchivePublished:October 25, 2016DOI:https://doi.org/10.1016/j.seizure.2016.10.001

      Highlights

      • Cardiovascular (CV) comorbidities are common in people with epilepsy.
      • Epilepsy and CV disorders have a complex relationship.
      • Shared risk factors, causal and resultant mechanisms may play a role.
      • Great progress in clinical profiles has been made.
      • Further studies are needed to aid early identification of CV disorders in epilepsy.

      Abstract

      Cardiovascular (CV) comorbidities are common in people with epilepsy. Several mechanisms explain why these conditions tend to co-exist including causal associations, shared risk factors and those resulting from epilepsy or its treatment.
      Various arrhythmias occurring during and after seizures have been described. Ictal asystole is the most common cause. The converse phenomenon, arrhythmias causing seizures, appears extremely rare and has only been reported in children following cardioinihibitory syncope. Arrhythmias in epilepsy may not only result from seizure activity but also from a shared genetic susceptibility. Various cardiac and epilepsy genes could be implicated but firm evidence is still lacking. Several antiepileptic drugs (AEDs) triggering conduction abnormalities can also explain the co-existence of arrhythmias in epilepsy.
      Epidemiological studies have consistently shown that people with epilepsy have a higher prevalence of structural cardiac disease and a poorer CV risk profile than those without epilepsy. Shared CV risk factors, genetics and etiological factors can account for a significant part of the relationship between epilepsy and structural cardiac disease. Seizure activity may cause transient myocardial ischaemia and the Takotsubo syndrome. Additionally, certain AEDs may themselves negatively affect CV risk profile in epilepsy.
      Here we discuss the fascinating borderland of epilepsy and cardiovascular conditions. The review focuses on epidemiology, clinical presentations and possible mechanisms for shared pathophysiology. It concludes with a discussion of future developments and a call for validated screening instruments and guidelines aiding the early identification and treatment of CV comorbidity in epilepsy.

      Keywords

      1. Introduction

      Well over 100 years ago, the occurrence of asystole during the course of an epileptic seizure was described: “He uttered a cry and was seen to be rubbing his hands together. His pulse was immediately examined for but was not palpable” [
      • Russell A.E.
      Cessation of the pulse during the onset of epileptic fits, with remarks on the mechanism of fits.
      ]. Since then numerous associations between epilepsy and CV conditions have been identified, including this classical example of ictal asystole.
      Co-existing conditions form an important part of the overall burden of epilepsy [
      • Forsgren L.
      Prevalence of epilepsy in adults in northern Sweden.
      ,
      • Gaitatzis A.
      • Sisodiya S.M.
      • Sander J.W.
      The somatic comorbidity of epilepsy: a weighty but often unrecognized burden.
      ,
      • Kadima N.K.R.
      • Zack M.
      • Helmers S.
      Comorbidity in adults with epilepsy—United States, 2010.
      ,
      • Keezer M.R.
      • Sisodiya S.M.
      • Sander J.W.
      Comorbidities of epilepsy: current concepts and future perspectives.
      ]. Several mechanisms of association between epilepsy and comorbid conditions have been described: associations can be explained by cause or effect, a shared risk factor may cause both conditions, or the mechanism of the association is unknown or spurious (i.e. coincidental) (Fig. 1) [
      • Gaitatzis A.
      • Sisodiya S.M.
      • Sander J.W.
      The somatic comorbidity of epilepsy: a weighty but often unrecognized burden.
      ,
      • Keezer M.R.
      • Sisodiya S.M.
      • Sander J.W.
      Comorbidities of epilepsy: current concepts and future perspectives.
      ].
      Fig. 1
      Fig. 1Mechanisms of association between epilepsy and comorbid conditions. The dotted line indicates that an association does not really exist. Figure originates from Gaitatzis et al.
      [
      • Gaitatzis A.
      • Sisodiya S.M.
      • Sander J.W.
      The somatic comorbidity of epilepsy: a weighty but often unrecognized burden.
      ]
      , permission to reproduce copyrighted material granted by John Wiley & Sons.
      This review serves to discuss the fascinating borderland between epileptology and cardiology and focuses on the major developments over the last 25 years and on future developments. We use the comorbidity framework (Fig. 1) [
      • Gaitatzis A.
      • Sisodiya S.M.
      • Sander J.W.
      The somatic comorbidity of epilepsy: a weighty but often unrecognized burden.
      ] to review all cardiac conditions known, and alleged, to be linked to epilepsy. Associations with cardiac arrhythmias are discussed first, followed by an overview of all structural cardiac conditions related to epilepsy.

      2. Epilepsy and cardiac arrhythmias

      Various arrhythmias have been described, occurring during (ictal) or after (postictal) seizures. Sinus tachycardia is the most common ictal pattern, seen in up to 80% of all seizures [
      • Sevcencu C.
      • Struijk J.J.
      Autonomic alterations and cardiac changes in epilepsy.
      ] and in 82% of people with epilepsy [
      • Eggleston K.S.
      • Olin B.D.
      • Fisher R.S.
      Ictal tachycardia: the head-heart connection.
      ], but usually without symptoms. The most frequent clinically relevant arrhythmia is ictal asystole, occurring in 0.318% (95% CI 0.316–0.320%) of people with refractory focal epilepsy admitted for video-EEG [
      • van der Lende M.
      • Surges R.
      • Sander J.W.
      • Thijs R.D.
      Cardiac arrhythmias during or after epileptic seizures.
      ]. Ictal asystole, bradycardia and AV block predominantly occur in people with temporal lobe epilepsy (Table 1) [
      • van der Lende M.
      • Surges R.
      • Sander J.W.
      • Thijs R.D.
      Cardiac arrhythmias during or after epileptic seizures.
      ]. Clinically, ictal asystole is characterised by sudden loss of tone during a dyscognitive seizure [
      • Schuele S.U.
      • Bermeo A.C.
      • Alexopoulos A.V.
      • Locatelli E.R.
      • Burgess R.C.
      • Dinner D.S.
      • et al.
      Video-electrographic and clinical features in patients with ictal asystole.
      ]. The circulatory pattern resembles vasovagal syncope with a transient, progressive and self-limiting slowing of the heart rate and decrease of blood pressure [
      • Schuele S.U.
      • Bermeo A.C.
      • Alexopoulos A.V.
      • Locatelli E.R.
      • Burgess R.C.
      • Dinner D.S.
      • et al.
      Video-electrographic and clinical features in patients with ictal asystole.
      ,
      • Tinuper P.
      • Bisulli F.
      • Cerullo A.
      • Carcangiu R.
      • Marini C.
      • Pierangeli G.
      • et al.
      Ictal bradycardia in partial epileptic seizures: autonomic investigation in three cases and literature review.
      ,
      • van Dijk J.G.
      • Thijs R.D.
      • van Zwet E.
      • Tannemaat M.R.
      • van Niekerk J.
      • Benditt D.G.
      • et al.
      The semiology of tilt-induced reflex syncope in relation to electroencephalographic changes.
      ]. For many years, ictal asystole was thought to be a possible mechanism underlying sudden unexpected death in epilepsy (SUDEP). This appears to be unlikely: all but one reported case so far of ictal asystole were self-limiting [
      • van der Lende M.
      • Surges R.
      • Sander J.W.
      • Thijs R.D.
      Cardiac arrhythmias during or after epileptic seizures.
      ]. In this one case successful resuscitation was started after 44 s of asystole and the event was classified as near-SUDEP [
      • Lanz M.
      • Oehl B.
      • Brandt A.
      • Schulze-Bonhage A.
      Seizure induced cardiac asystole in epilepsy patients undergoing long term video-EEG monitoring.
      ]. The longest ictal asystole reported so far, however, lasted 96 s and appeared self-limiting [
      • Chaila E.B.J.
      • Tirupathi S.
      • Delanty N.
      Ictal bradycardia and asystole associated with intractable epilepsy: a case series.
      ]. Whether an event is classified as near-SUDEP or not will depend on interventions of medical personnel: prompt resuscitation in response to ictal asystole will likely lead to more classified as near-SUDEP cases. While there are no reports of fatal ictal asystole, it remains debatable whether ictal asystole can cause SUDEP.
      Table 1Reported (post)ictal cardiac arrhythmias. FDS—focal dyscognitive seizure; FAS—focal autonomic seizure; fbCS—focal seizure evolving to bilateral convulsive seizure; GTCS—generalised tonic clonic seizure; LT—left temporal; RT—right temporal; BT—bitemporal; Gen—generalised; Non loc—non-localising; PGES—postictal generalized EEG suppression; *in people with refractory focal epilepsy admitted for a vEEG recording. For more details see van der Lende et al.
      • van der Lende M.
      • Surges R.
      • Sander J.W.
      • Thijs R.D.
      Cardiac arrhythmias during or after epileptic seizures.
      .
      Seizure related arrhythmiaReported in n casesAssociated seizure typesReported in n casesEEG seizure onsetReported in n casesSUDEP association
      Ictal asystole10399% FDS9746% LT80Unlikely
      1% FAS31% RT
      13% BT
      10% other
      Postictal asystole1385% fbCS1320% LT10Very likely, accompanied or preceded by PGES/apnea
      15% FDS60% RT
      20% other
      Ictal bradycardia25100% FDS852% LT21Unlikely
      38% RT
      10% other
      Ictal AV block1190% FDS1073% LT11Unlikely
      10% FAS18% BT
      10% other
      Postictal AV block2100% fbCS2100% RT1Unlikely
      Atrial fibrillation1346% GTCS1333% LT3Unlikely
      46% fbCS33% Gen
      8% FDS33% Non loc
      (Post)ictal ventricular fibrillation3100% GTCS3Insufficient data0Probable, but in a minority of cases
      The precise mechanism of ictal asystole is unknown. It may result from epileptic activity directly stimulating the central autonomic networks [
      • Sevcencu C.
      • Struijk J.J.
      Autonomic alterations and cardiac changes in epilepsy.
      ,
      • Leung H.
      • Kwan P.
      • Elger C.E.
      Finding the missing link between ictal bradyarrhythmia, ictal asystole, and sudden unexpected death in epilepsy.
      ]. For example, focal stimulation of parts of the limbic system (i.e. amygdala, cingulate gyrus) may provoke asystole [
      • Sevcencu C.
      • Struijk J.J.
      Autonomic alterations and cardiac changes in epilepsy.
      ,
      • Altenmuller D.M.
      • Zehender M.
      • Schulze-Bonhage A.
      High-grade atrioventricular block triggered by spontaneous and stimulation-induced epileptic activity in the left temporal lobe.
      ,
      • Oppenheimer S.M.
      • Gelb A.
      • Girvin J.P.
      • Hachinski V.C.
      Cardiovascular effects of human insular cortex stimulation.
      ,
      • Pool J.L.
      • Ransohoff J.
      Autonomic effects on stimulating rostral portion of cingulate gyri in man.
      ]. Alternatively, seizure-induced fear and catecholamine release [
      • Simon R.P.
      • Aminoff M.J.
      • Benowitz N.L.
      Changes in plasma catecholamines after tonic-clonic seizures.
      ] may evoke a vasovagal response causing cardioinhibition and vasodilation [
      • Nilsson D.
      • Sutton R.
      • Melander O.
      • Fedorowski A.
      Spontaneous vs nitroglycerin-induced vasovagal reflex on head-up tilt: are there neuroendocrine differences?.
      ].
      Ictal asystole is assumed to be self-limiting, but may cause falls and injuries due to seizure-induced syncope [
      • Moseley B.D.
      • Ghearing G.R.
      • Munger T.M.
      • Britton J.W.
      The treatment of ictal asystole with cardiac pacing.
      ]. Proper trials are lacking but retrospective studies suggest that improving seizure control may prevent ictal asystole [
      • Bestawros M.
      • Darbar D.
      • Arain A.
      • Abou-Khalil B.
      • Plummer D.
      • Dupont W.D.
      • et al.
      Ictal asystole and ictal syncope: insights into clinical management.
      ,
      • Kohno R.
      • Abe H.
      • Akamatsu N.
      • Benditt D.G.
      Long-term follow-up of ictal asystole in temporal lobe epilepsy: is permanent pacemaker therapy needed?.
      ,
      • Strzelczyk A.
      • Cenusa M.
      • Bauer S.
      • Hamer H.M.
      • Mothersill I.W.
      • Grunwald T.
      • et al.
      Management and long-term outcome in patients presenting with ictal asystole or bradycardia.
      ]. It also seems advisable to withdraw negative inotropic drugs and to consider the implantation of a loop recorder to monitor possible future events in individuals in whom ictal asystole has been noted. If the asystolic episodes persist, cardiac pacemaker implantation should be considered to reduce the risk of trauma [
      • Moseley B.D.
      • Ghearing G.R.
      • Munger T.M.
      • Britton J.W.
      The treatment of ictal asystole with cardiac pacing.
      ,
      • Bestawros M.
      • Darbar D.
      • Arain A.
      • Abou-Khalil B.
      • Plummer D.
      • Dupont W.D.
      • et al.
      Ictal asystole and ictal syncope: insights into clinical management.
      ,
      • Strzelczyk A.
      • Cenusa M.
      • Bauer S.
      • Hamer H.M.
      • Mothersill I.W.
      • Grunwald T.
      • et al.
      Management and long-term outcome in patients presenting with ictal asystole or bradycardia.
      ,
      • Duplyakov D.
      • Golovina G.
      • Lyukshina N.
      • Surkova E.
      • Elger C.E.
      • Surges R.
      Syncope, seizure-induced bradycardia and asystole: two cases and review of clinical and pathophysiological features.
      ].
      In contrast to ictal asystole, postictal asystole is less common, associated with convulsive rather than focal (temporal lobe) seizures and has a higher fatality rate: 7 of 13 reported postictal asystole cases died from SUDEP [
      • van der Lende M.
      • Surges R.
      • Sander J.W.
      • Thijs R.D.
      Cardiac arrhythmias during or after epileptic seizures.
      ]. All fatal cases had a convulsive seizure with immediate postictal generalised EEG suppression and a stuttering course of transient apnoea and asystole resulting in a terminal apnoea followed by a terminal asystole [
      • Ryvlin P.
      • Nashef L.
      • Lhatoo S.D.
      • Bateman L.M.
      • Bird J.
      • Bleasel A.
      • et al.
      Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study.
      ].
      The mechanism underlying this sequence of postictal EEG suppression, apnoea, and terminal asystole has not yet been elucidated. Excessive inhibition causing brainstem depression might play a role [
      • Massey C.A.
      • Sowers L.P.
      • Dlouhy B.J.
      • Richerson G.B.
      Mechanisms of sudden unexpected death in epilepsy: the pathway to prevention.
      ]. Recent work in two animal models (mice carrying mutations in the KCNA1 gene or the SCN1A gene) demonstrated that seizures initiated by direct cortical stimulation may evoke a spreading depression causing brain stem inhibition and cardiorespiratory collapse [
      • Aiba I.
      • Noebels J.L.
      Spreading depolarization in the brainstem mediates sudden cardiorespiratory arrest in mouse SUDEP models.
      ].
      Another rare (post)ictal arrhythmia is ventricular tachycardia/ventricular fibrillation (VT/VF). So far three cases of postictal VT/VF leading to (near) SUDEP have been reported [
      • van der Lende M.
      • Surges R.
      • Sander J.W.
      • Thijs R.D.
      Cardiac arrhythmias during or after epileptic seizures.
      ]. All VT/VF occurred directly following a convulsive seizure. No cardiac lesions were found in the case reports. There may be a publication bias, however, as cases with seizure-triggered VT/VF and cardiac lesions may not qualify as SUDEP and thus may be less likely to be reported. The mechanism of seizure-induced VT/VF is unclear. Convulsive seizures may exert proarrhythmogenic effects by triggering the sympathetic nervous system, as reflected by the peak in catecholamines and electrodermal activity [
      • Simon R.P.
      • Aminoff M.J.
      • Benowitz N.L.
      Changes in plasma catecholamines after tonic-clonic seizures.
      ,
      • Poh M.Z.
      • Loddenkemper T.
      • Swenson N.C.
      • Goyal S.
      • Madsen J.R.
      • Picard R.W.
      Continuous monitoring of electrodermal activity during epileptic seizures using a wearable sensor.
      ]. At the same time, convulsive seizures may increase cardiac oxygen deprivation by inducing sinus tachycardia [
      • Eggleston K.S.
      • Olin B.D.
      • Fisher R.S.
      Ictal tachycardia: the head-heart connection.
      ] and respiratory impairment causing hypoxemia [
      • Bateman L.M.
      • Li C.S.
      • Seyal M.
      Ictal hypoxemia in localization-related epilepsy: analysis of incidence, severity and risk factors.
      ]. It has also been found that ECG-markers of sudden cardiac death such as QTc-lengthening and/or shortening [
      • Surges R.
      • Adjei P.
      • Kallis C.
      • Erhuero J.
      • Scott C.A.
      • Bell G.S.
      • et al.
      Pathologic cardiac repolarization in pharmacoresistant epilepsy and its potential role in sudden unexpected death in epilepsy: a case-control study.
      ,
      • Surges R.
      • Scott C.A.
      • Walker M.C.
      Enhanced QT shortening and persistent tachycardia after generalized seizures.
      ], and T-wave alternans are more prevalent [
      • Strzelczyk A.
      • Cenusa M.
      • Bauer S.
      • Hamer H.M.
      • Mothersill I.W.
      • Grunwald T.
      • et al.
      Management and long-term outcome in patients presenting with ictal asystole or bradycardia.
      ] during and after convulsive seizures. The various factors might interact as seizure-related cardiac repolarization abnormalities appeared more frequent in seizures with ictal hypoxemia compared to those without [
      • Seyal M.
      • Pascual F.
      • Lee C.Y.
      • Li C.S.
      • Bateman L.M.
      Seizure-related cardiac repolarization abnormalities are associated with ictal hypoxemia.
      ].
      Though seizure-induced VT/VF appears to be rare, a prospective community-based study of out-of-hospital cardiac arrests due to ECG-documented VT/VF showed that VT/VF risk in those with epilepsy was three times as high as the general population [
      • Bardai A.
      • Lamberts R.J.
      • Blom M.T.
      • Spanjaart A.M.
      • Berdowski J.
      • van der Staal S.R.
      • et al.
      Epilepsy is a risk factor for sudden cardiac arrest in the general population.
      ]. A further analysis of those cases with epilepsy and VT/VF showed that most were not seizure-related, but rather occurred in the context of either pre-existing heart disease or as the immediate result of an acute myocardial infarction [
      • Lamberts R.J.
      • Blom M.T.
      • Wassenaar M.
      • Bardai A.
      • Leijten F.S.
      • de Haan G.J.
      • et al.
      Sudden cardiac arrest in people with epilepsy in the community: circumstances and risk factors.
      ]. Pre-existing heart disease was a stronger predictor for VT/VF in people with epilepsy than markers of epilepsy severity. In a minority of cases, however, VT/VF was unexplained and a diagnosis of (near) SUDEP was established. It thus appears that sudden cardiac arrest and SUDEP are partially overlapping disease entities.
      The increased risk of non-seizure related VF/VT episodes in people epilepsy may be explained by high cardiovascular comorbidity [
      • Gaitatzis A.
      • Sisodiya S.M.
      • Sander J.W.
      The somatic comorbidity of epilepsy: a weighty but often unrecognized burden.
      ,
      • Gaitatzis A.
      • Carroll K.
      • Majeed A.
      • Sanders W J.
      The epidemiology of the comorbidity of epilepsy in the general population.
      ]. People with epilepsy may have a propensity for sudden cardiac death as reduced heart rate variability, a measure of cardiac sympathovagal balance that is also a risk marker of sudden cardiac death, progressively worsens over time in people with refractory, but not in those with well-controlled, epilepsy [
      • Suorsa E.
      • Korpelainen J.T.
      • Ansakorpi H.
      • Huikuri H.V.
      • Suorsa V.
      • Myllyla V.V.
      • et al.
      Heart rate dynamics in temporal lobe epilepsy—a long-term follow-up study.
      ]. In addition, other markers of sudden cardiac death such as early repolarization pattern and QTc-prolongation are more frequently found in the interictal ECGs of people with epilepsy than in those without epilepsy [
      • Lamberts R.J.
      • Blom M.T.
      • Novy J.
      • Belluzzo M.
      • Seldenrijk A.
      • Penninx B.W.
      • et al.
      Increased prevalence of ECG markers for sudden cardiac arrest in refractory epilepsy.
      ].
      Another mechanism explaining the association between arrhythmias and epilepsy is a shared genetic risk factor. A rapidly increasing number of genes potentially linking epilepsy to cardiac arrhythmias has been identified. Here we discuss some relevant examples; starting with the genes predominantly known for their cardiac functions and then the ‘epilepsy genes’.
      Several genetic ion channel mutations are thought to be expressed in the brain as well as in the heart, and might thus cause seizures and cardiac arrhythmias. The first reported genetic link between epilepsy and cardiac arrhythmias was the discovery of cardiac sodium channel gene SCN5A in the brain [
      • Hartmann H.A.
      • Colom L.V.
      • Sutherland M.L.
      • Noebels J.L.
      Selective localization of cardiac SCN5A sodium channels in limbic regions of rat brain.
      ]. Subsequently, more pathogenic variants in the long QT (LQT) gene family (i.e. KCNQ1, KCNH2 and SCN5A) were associated with a “seizure phenotype” (e.g. self-reported diagnosis of epilepsy and AED use) [
      • Anderson J.H.
      • Bos J.M.
      • Cascino G.D.
      • Ackerman M.J.
      Prevalence and spectrum of electroencephalogram-identified epileptiform activity among patients with long QT syndrome.
      ,
      • Auerbach D.S.
      • McNitt S.
      • Gross R.A.
      • Zareba W.
      • Dirksen R.T.
      • Moss A.J.
      Genetic biomarkers for the risk of seizures in long QT syndrome.
      ,
      • Aurlien D.
      • Leren T.P.
      • Tauboll E.
      • Gjerstad L.
      New SCN5A mutation in a SUDEP victim with idiopathic epilepsy.
      ,
      • Heron S.E.
      • Hernandez M.
      • Edwards C.
      • Edkins E.
      • Jansen F.E.
      • Scheffer I.E.
      • et al.
      Neonatal seizures and long QT syndrome: a cardiocerebral channelopathy?.
      ,
      • Keller D.I.
      • Grenier J.
      • Christe G.
      • Dubouloz F.
      • Osswald S.
      • Brink M.
      • et al.
      Characterization of novel KCNH2 mutations in type 2 long QT syndrome manifesting as seizures.
      ,
      • Partemi S.
      • Cestele S.
      • Pezzella M.
      • Campuzano O.
      • Paravidino R.
      • Pascali V.L.
      • et al.
      Loss-of-function KCNH2 mutation in a family with long QT syndrome, epilepsy, and sudden death.
      ]. Mice models indicated that other, non-LQT, cardiac channelopathy genes including RYR2 (associated with catecholaminergic polymorphic ventricular tachycardia) [
      • Lehnart S.E.
      • Mongillo M.
      • Bellinger A.
      • Lindegger N.
      • Chen B.X.
      • Hsueh W.
      • et al.
      Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice.
      ], and HCN1-4 [
      • Benarroch E.E.
      HCN channels: function and clinical implications.
      ,
      • Ludwig A.
      • Budde T.
      • Stieber J.
      • Moosmang S.
      • Wahl C.
      • Holthoff K.
      • et al.
      Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2.
      ] potentially predispose to epilepsy.
      Several postmortem studies suggest that the LQT and non-LQT cardiac gene mutations are more common in SUDEP victims [
      • Bagnall R.D.
      • Crompton D.E.
      • Petrovski S.
      • Lam L.
      • Cutmore C.
      • Garry S.I.
      • et al.
      Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy.
      ,
      • Leu C.
      • Balestrini S.
      • Maher B.
      • Hernandez-Hernandez L.
      • Gormley P.
      • Hamalainen E.
      • et al.
      Genome-wide polygenic burden of rare deleterious variants in sudden unexpected death in epilepsy.
      ,
      • Tu E.
      • Waterhouse L.
      • Duflou J.
      • Bagnall R.D.
      • Semsarian C.
      Genetic analysis of hyperpolarization-activated cyclic nucleotide-gated cation channels in sudden unexpected death in epilepsy cases.
      ]. As ictal recordings are lacking, it remains questionable whether the fatal events were caused by arrhythmias. The same applies to the identification of ‘epilepsy genes’ in the post-mortem cohorts [
      • Bagnall R.D.
      • Crompton D.E.
      • Petrovski S.
      • Lam L.
      • Cutmore C.
      • Garry S.I.
      • et al.
      Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy.
      ,
      • Leu C.
      • Balestrini S.
      • Maher B.
      • Hernandez-Hernandez L.
      • Gormley P.
      • Hamalainen E.
      • et al.
      Genome-wide polygenic burden of rare deleterious variants in sudden unexpected death in epilepsy.
      ]. These mutations could be markers explaining epilepsy severity or a genetically mediated liability to fatal seizures. In certain epilepsy syndromes, SUDEP risk seems particularly high.
      The most recognized example is the Dravet syndrome (DS), a severe epilepsy syndrome with high premature mortality, caused by SCN1A mutation [
      • Shmuely S.
      • Sisodiya S.M.
      • Gunning W.B.
      • Sander J.W.
      • Thijs R.D.
      Mortality in Dravet syndrome: a review.
      ]. In mutant SCN1A knock-out mice, postictal bradycardia and seizure-triggered ventricular fibrillation were recorded before a death resembling SUDEP [
      • Auerbach D.S.
      • Jones J.
      • Clawson B.C.
      • Offord J.
      • Lenk G.M.
      • Ogiwara I.
      • et al.
      Altered cardiac electrophysiology and SUDEP in a model of Dravet syndrome.
      ,
      • Kalume F.
      • Westenbroek R.E.
      • Cheah C.S.
      • Yu F.H.
      • Oakley J.C.
      • Scheuer T.
      • et al.
      Sudden unexpected death in a mouse model of Dravet syndrome.
      ]. In DS subjects, markers associated with the risk of sudden cardiac death (decreased HRV and increased QT-dispersion) have been found [
      • Delogu A.B.
      • Spinelli A.
      • Battaglia D.
      • Dravet C.
      • De Nisco A.
      • Saracino A.
      • et al.
      Electrical and autonomic cardiac function in patients with Dravet syndrome.
      ,
      • Ergul Y.
      • Ekici B.
      • Tatli B.
      • Nisli K.
      • Ozmen M.
      QT and P wave dispersion and heart rate variability in patients with Dravet syndrome.
      ]. Ictal proof is, however, lacking and is the subject of an ongoing study (ClinicalTrials.gov Identifier: NCT02415686).
      Other less well studied examples of ‘epilepsy genes’ possibly mediating SUDEP risk include KCNA1 and SCN8A. KCNA1 is expressed in the vagal nerve as well as in the brain, and is associated with seizures, cardiac arrhythmias, vagal hyperexcitability and premature death in KCNA1 null mice [
      • Glasscock E.
      • Yoo J.W.
      • Chen T.T.
      • Klassen T.L.
      • Noebels J.L.
      Kv1.1 potassium channel deficiency reveals brain-driven cardiac dysfunction as a candidate mechanism for sudden unexplained death in epilepsy.
      ]. Mutations in this gene were found in a SUDEP case with epileptic encephalopathy and suspected cardiac arrhythmias [
      • Klassen T.L.
      • Bomben V.C.
      • Patel A.
      • Drabek J.
      • Chen T.T.
      • Gu W.
      • et al.
      High-resolution molecular genomic autopsy reveals complex sudden unexpected death in epilepsy risk profile.
      ].
      A novel pathogenic SCN8A mutation was identified through whole-genome sequencing in a family affected by epileptic encephalopathy and SUDEP [
      • Veeramah K.R.
      • O'Brien J.E.
      • Meisler M.H.
      • Cheng X.
      • Dib-Hajj S.D.
      • Waxman S.G.
      • et al.
      De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP.
      ]. Before then, SCN8A mutations had only been linked to epilepsy in mice [
      • Papale L.A.
      • Beyer B.
      • Jones J.M.
      • Sharkey L.M.
      • Tufik S.
      • Epstein M.
      • et al.
      Heterozygous mutations of the voltage-gated sodium channel SCN8A are associated with spike-wave discharges and absence epilepsy in mice.
      ]. The SCN8A gene encodes a sodium channel that is expressed in heart and brain of mice and rats, and plays a role in excitation-contraction coupling, action potential propagation and pacemaking [
      • Du Y.
      • Huang X.
      • Wang T.
      • Han K.
      • Zhang J.
      • Xi Y.
      • et al.
      Downregulation of neuronal sodium channel subunits Nav1.1 and Nav1.6 in the sinoatrial node from volume-overloaded heart failure rat.
      ,
      • Noujaim S.F.
      • Kaur K.
      • Milstein M.
      • Jones J.M.
      • Furspan P.
      • Jiang D.
      • et al.
      A null mutation of the neuronal sodium channel NaV1.6 disrupts action potential propagation and excitation-contraction coupling in the mouse heart.
      ].
      We previously discussed how seizures may cause arrhythmias. Whether the converse phenomenon exists is a subject of controversy. The major complication is the fact that syncopal events are easily mistaken for epilepsy. Rates of misdiagnosis in epilepsy are high (up to 71%), and syncope is the commonest imitator [
      • Xu Y.
      • Nguyen D.
      • Mohamed A.
      • Carcel C.
      • Li Q.
      • Kutlubaev M.A.
      • et al.
      Frequency of a false positive diagnosis of epilepsy: a systematic review of observational studies.
      ]. This is understandable, as various symptoms and signs are seen in both conditions [
      • van Dijk J.G.
      • Thijs R.D.
      • van Zwet E.
      • Tannemaat M.R.
      • van Niekerk J.
      • Benditt D.G.
      • et al.
      The semiology of tilt-induced reflex syncope in relation to electroencephalographic changes.
      ,
      • Xu Y.
      • Nguyen D.
      • Mohamed A.
      • Carcel C.
      • Li Q.
      • Kutlubaev M.A.
      • et al.
      Frequency of a false positive diagnosis of epilepsy: a systematic review of observational studies.
      ,
      • Grubb B.P.
      • Gerard G.
      • Roush K.
      • Temesy-Armos P.
      • Elliott L.
      • Hahn H.
      • et al.
      Differentiation of convulsive syncope and epilepsy with head-up tilt testing.
      ,
      • Lempert T.
      • Bauer M.
      • Schmidt D.
      Syncope: a videometric analysis of 56 episodes of transient cerebral hypoxia.
      ]. Notably, jerking movements or signs indicative of cerebral standstill (complete flattening of the EEG) such as roving eye movements or stertorous breathing [
      • van Dijk J.G.
      • Thijs R.D.
      • van Zwet E.
      • Tannemaat M.R.
      • van Niekerk J.
      • Benditt D.G.
      • et al.
      The semiology of tilt-induced reflex syncope in relation to electroencephalographic changes.
      ] are often interpreted as signs specific to epilepsy. The true cause of these symptoms can only be determined with help of a detailed history (taking into account the circumstances and other diagnostic clues) or a proper investigation (e.g. ictal recording of video, heart rate, blood pressure and EEG) [
      • Wieling W.
      • van Dijk N.
      • de Lange F.J.
      • Olde Nordkamp L.R.
      • Thijs R.D.
      • van Dijk J.G.
      • et al.
      History taking as a diagnostic test in patients with syncope: developing expertise in syncope.
      ]. Two large scale surveys of up to 2000 tilt-table tests failed to identify any adult case with syncopal-induced seizures [
      • Blad H.
      • Lamberts R.J.
      • van Dijk G.J.
      • Thijs R.D.
      Tilt-induced vasovagal syncope and psychogenic pseudosyncope: overlapping clinical entities.
      ,
      • Mathias C.J.
      • Deguchi K.
      • Schatz I.
      Observations on recurrent syncope and presyncope in 641 patients.
      ]. In children, however, a few cases have been reported with a cardioinhibitory reflex syncope followed by video-EEG documented clonic seizures [
      • Battaglia A.
      • Guerrini R.
      • Gastaut H.
      Epileptic seizures induced by syncopal attacks.
      ,
      • Horrocks I.A.
      • Nechay A.
      • Stephenson J.B.
      • Zuberi S.M.
      Anoxic-epileptic seizures: observational study of epileptic seizures induced by syncopes.
      ,
      • Stephenson J.
      • Breningstall G.
      • Steer C.
      • Kirkpatrick M.
      • Horrocks I.
      • Nechay A.
      • et al.
      Anoxic-epileptic seizures: home video recordings of epileptic seizures induced by syncopes.
      ]. The reason why this phenomenon only appears to affect children is unknown. It may be that the seizure threshold is lower in children (paralleling febrile seizures that also peak in childhood). Alternatively, the depth of cerebral anoxia may be more profound in children as reflected by prolonged asystolic spells. For clinical management it is important to stress that syncope-induced seizures are extremely rare and probably only affect children. The diagnosis requires an ictal video-EEG recording.
      Several AEDs, particularly those with sodium blocking properties are known to trigger conduction abnormalities or arrhythmias [
      • Schuele S.U.
      Effects of seizures on cardiac function.
      ]. Atrioventricular (AV) conduction is the most frequent reported complication. ST changes, Brugada-like patterns, atrial fibrillation and QTc prolongation have also been reported but the association with AED treatment is less well established [
      • Al Aloul B.
      • Adabag A.S.
      • Houghland M.A.
      • Tholakanahalli V.
      Brugada pattern electrocardiogram associated with supratherapeutic phenytoin levels and the risk of sudden death.
      ,
      • DeGiorgio C.M.
      Atrial flutter/atrial fibrillation associated with lacosamide for partial seizures.
      ,
      • El-Menyar A.
      • Khan M.
      • Al Suwaidi J.
      • Eljerjawy E.
      • Asaad N.
      Oxcarbazepine-induced resistant ventricular fibrillation in an apparently healthy young man.
      ,
      • Feldman A.E.
      • Gidal B.E.
      QTc prolongation by antiepileptic drugs and the risk of torsade de pointes in patients with epilepsy.
      ,
      • Guldiken B.
      • Remi J.
      • Noachtar S.
      Cardiovascular adverse effects of phenytoin.
      ,
      • Ide A.
      • Kamijo Y.
      Intermittent complete atrioventricular block after long term low-dose carbamazepine therapy with a serum concentration less than the therapeutic level.
      ,
      • Ishizue N.
      • Niwano S.
      • Saito M.
      • Fukaya H.
      • Nakamura H.
      • Igarashi T.
      • et al.
      Polytherapy with sodium channel-blocking antiepileptic drugs is associated with arrhythmogenic ST-T abnormality in patients with epilepsy.
      ,
      • Kasarskis E.J.
      • Kuo C.S.
      • Berger R.
      • Nelson K.R.
      Carbamazepine-induced cardiac dysfunction: characterization of two distinct clinical syndromes.
      ,
      • Kaufman K.R.
      • Velez A.E.
      • Wong S.
      • Mani R.
      Low-dose lacosamide-induced atrial fibrillation: case analysis with literature review.
      ,
      • Krause L.U.
      • Brodowski K.O.
      • Kellinghaus C.
      Atrioventricular block following lacosamide intoxication.
      ,
      • Nizam A.
      • Mylavarapu K.
      • Thomas D.
      • Briskin K.
      • Wu B.
      • Saluja D.
      • et al.
      Lacosamide-induced second-degree atrioventricular block in a patient with partial epilepsy.
      ,
      • Randazzo D.N.
      • Ciccone A.
      • Schweitzer P.
      • Winters S.L.
      Complete atrioventricular block with ventricular asystole following infusion of intravenous phenytoin.
      ,
      • Strimel W.J.
      • Woodruff A.
      • Cheung P.
      • Kirmani B.F.
      Stephen Huang SK: Brugada-like electrocardiographic pattern induced by lamotrigine toxicity.
      ,
      • Swe T.
      • Bhattarai B.
      • Dufresne A.
      Type 1 Brugada pattern ECG due to supra-therapeutic phenytoin level.
      ,
      • Zoneraich S.
      • Zoneraich O.
      • Siegel J.
      Sudden death following intravenous sodium diphenylhydantoin.
      ]. Most clinically relevant arrhythmias were related to AED overdose. Carbamazepine is, however, known to cause AV conduction blocks at low levels; this is almost exclusively reported in elderly women [
      • Ide A.
      • Kamijo Y.
      Intermittent complete atrioventricular block after long term low-dose carbamazepine therapy with a serum concentration less than the therapeutic level.
      ,
      • Kasarskis E.J.
      • Kuo C.S.
      • Berger R.
      • Nelson K.R.
      Carbamazepine-induced cardiac dysfunction: characterization of two distinct clinical syndromes.
      ,
      • Takayanagi K.
      • Hisauchi I.
      • Watanabe J.
      • Maekawa Y.
      • Fujito T.
      • Sakai Y.
      • et al.
      Carbamazepine-induced sinus node dysfunction and atrioventricular block in elderly women.
      ]. Rapid administration of phenytoin may also cause sinus arrest and hypotension; elderly people and those with pre-existing heart disease seem most vulnerable to these adverse effects. IV administration should, therefore, be undertaken slowly, with continuous cardiac monitoring [
      • Guldiken B.
      • Remi J.
      • Noachtar S.
      Cardiovascular adverse effects of phenytoin.
      ,
      • Randazzo D.N.
      • Ciccone A.
      • Schweitzer P.
      • Winters S.L.
      Complete atrioventricular block with ventricular asystole following infusion of intravenous phenytoin.
      ,
      • Zoneraich S.
      • Zoneraich O.
      • Siegel J.
      Sudden death following intravenous sodium diphenylhydantoin.
      ,
      • DeToledo J.C.
      • Lowe M.R.
      • Rabinstein A.
      • Villaviza N.
      Cardiac arrest after fast intravenous infusion of phenytoin mistaken for fosphenytoin.
      ]. The above-mentioned AED effects do not seem to play a role in ictal arrhythmias. Nevertheless, it is important to take these effects into consideration in the selection of an AED and to monitor adverse effects closely especially in elderly people and those with cardiovascular comorbidities.

      3. Epilepsy and structural cardiac conditions

      Epidemiological studies have consistently shown that people with epilepsy have a higher prevalence of structural cardiac disease than those without epilepsy [
      • Kadima N.K.R.
      • Zack M.
      • Helmers S.
      Comorbidity in adults with epilepsy—United States, 2010.
      ,
      • Keezer M.R.
      • Sisodiya S.M.
      • Sander J.W.
      Comorbidities of epilepsy: current concepts and future perspectives.
      ,
      • Elliott J.O.
      • Lu B.
      • Shneker B.
      • Charyton C.
      • Layne Moore J.
      Comorbidity, health screening, and quality of life among persons with a history of epilepsy.
      ,
      • Kobau R.
      • Zahran H.
      • Thurman D.J.
      • Zack M.M.
      • Henry T.R.
      • Schachter S.C.
      • et al.
      Epilepsy surveillance among adults—19 States Behavioral Risk Factor Surveillance System, 2005.
      ,
      • Strine T.W.
      • Kobau R.
      • Chapman D.P.
      • Thurman D.J.
      • Price P.
      • Balluz L.S.
      Psychological distress, comorbidities, and health behaviors among U.S. adults with seizures: results from the 2002 National Health Interview Survey.
      ,
      • Tellez-Zenteno J.F.
      • Matijevic S.
      • Wiebe S.
      Somatic comorbidity of epilepsy in the general population in Canada.
      ]. Cardiovascular disease seems to be a significant contributor to the increased mortality in people with epilepsy, compared with the general population [
      • Ding D.
      • Wang W.
      • Wu J.
      • Ma G.
      • Dai X.
      • Yang B.
      • et al.
      Premature mortality in people with epilepsy in rural China: a prospective study.
      ,
      • Janszky I.
      • Hallqvist J.
      • Tomson T.
      • Ahlbom A.
      • Mukamal K.J.
      • Ahnve S.
      Increased risk and worse prognosis of myocardial infarction in patients with prior hospitalization for epilepsy—the Stockholm Heart Epidemiology Program.
      ,
      • Neligan A.
      • Bell G.S.
      • Johnson A.L.
      • Goodridge D.M.
      • Shorvon S.D.
      • Sander J.W.
      The long-term risk of premature mortality in people with epilepsy.
      ].
      Shared cardiovascular risk factors can account for the relationship between epilepsy and heart disease, in addition to shared genetics and etiological factors. People with a history of epilepsy are more likely to be obese, physically inactive, and current smokers [
      • Kobau R.
      • Zahran H.
      • Thurman D.J.
      • Zack M.M.
      • Henry T.R.
      • Schachter S.C.
      • et al.
      Epilepsy surveillance among adults—19 States Behavioral Risk Factor Surveillance System, 2005.
      ] and have a worse cardiovascular risk profile (i.e. hypertension, hypercholesterolemia, diabetes mellitus, stroke/TIA) than the general population [
      • Gaitatzis A.
      • Carroll K.
      • Majeed A.
      • Sanders W J.
      The epidemiology of the comorbidity of epilepsy in the general population.
      ,
      • Kobau R.
      • Zahran H.
      • Thurman D.J.
      • Zack M.M.
      • Henry T.R.
      • Schachter S.C.
      • et al.
      Epilepsy surveillance among adults—19 States Behavioral Risk Factor Surveillance System, 2005.
      ,
      • (CDC) CfDCaP
      Comorbidity in adults with epilepsy—United States, 2010.
      ,
      • Elliott J.O.
      • Moore J.L.
      • Lu B.
      Health status and behavioral risk factors among persons with epilepsy in Ohio based on the 2006 Behavioral Risk Factor Surveillance System.
      ]. Unsurprisingly, people with epilepsy have higher rates of fatal and nonfatal cardio- and cerebrovascular disease than controls (mortality ratios up to 5.3 and morbidity ratio up to 7) [
      • Gaitatzis A.
      • Carroll K.
      • Majeed A.
      • Sanders W J.
      The epidemiology of the comorbidity of epilepsy in the general population.
      ,
      • Cockerell O.C.
      • Johnson A.L.
      • Sander J.W.
      • Hart Y.M.
      • Goodridge D.M.
      • Shorvon S.D.
      Mortality from epilepsy: results from a prospective population-based study.
      ,
      • Nilsson L.
      • Tomson T.
      • Farahmand B.Y.
      • Diwan V.
      • Persson P.G.
      Cause-specific mortality in epilepsy: a cohort study of more than 9000 patients once hospitalized for epilepsy.
      ]. The presence of cardiovascular disease (e.g. congestive heart failure and cardiac arrhythmias) was also associated with higher mortality risk in people with epilepsy [
      • St Germaine-Smith C.
      • Liu M.
      • Quan H.
      • Wiebe S.
      • Jette N.
      Development of an epilepsy-specific risk adjustment comorbidity index.
      ].
      Epilepsy treatment can also contribute to a poorer cardiovascular risk profile in epilepsy. Use of the enzyme-inducing AEDs phenytoin or carbamazepine may lead to elevated serological vascular risk markers (e.g. total cholesterol, LDL, homocysteine), and, thus, result in accelerated atherosclerosis [
      • Brodie M.J.
      • Mintzer S.
      • Pack A.M.
      • Gidal B.E.
      • Vecht C.J.
      • Schmidt D.
      Enzyme induction with antiepileptic drugs: cause for concern?.
      ,
      • Katsiki N.
      • Mikhailidis D.P.
      • Nair D.R.
      The effects of antiepileptic drugs on vascular risk factors: a narrative review.
      ,
      • Lopinto-Khoury C.
      • Mintzer S.
      Antiepileptic drugs and markers of vascular risk.
      ,
      • Mintzer S.
      • Skidmore C.T.
      • Abidin C.J.
      • Morales M.C.
      • Chervoneva I.
      • Capuzzi D.M.
      • et al.
      Effects of antiepileptic drugs on lipids, homocysteine, and C-reactive protein.
      ]. Certain AEDs (e.g. valproic acid, carbamazepine) are also known to cause weight gain and increase the risk of developing non-alcoholic fatty liver disease and metabolic syndrome, leading to further deterioration of the cardiovascular risk profile [
      • Katsiki N.
      • Mikhailidis D.P.
      • Nair D.R.
      The effects of antiepileptic drugs on vascular risk factors: a narrative review.
      ].
      The co-occurrence of epilepsy and (congenital) heart disease, often accompanied by intellectual disability, may result from a multiple malformation syndrome: genetic defects may affect the development of both heart and brain, or abnormal cardiovascular function may lead to poor (intrauterine) brain growth [
      • Miller G.
      • Vogel H.
      Structural evidence of injury or malformation in the brains of children with congenital heart disease.
      ].
      CV disease can sometimes (indirectly) cause epilepsy through a predisposition to stroke [
      • Attar H.
      • Sachdeva A.
      • Sundararajan S.
      Cardioembolic stroke in adults with a history of congenital heart disease.
      ,
      • Ferlazzo E.
      • Gasparini S.
      • Beghi E.
      • Sueri C.
      • Russo E.
      • Leo A.
      • et al.
      Epilepsy in cerebrovascular diseases: Review of experimental and clinical data with meta-analysis of risk factors.
      ]. Stroke is a common risk factor for epilepsy and accounts for about a third of newly diagnosed seizures in people over the age of 60 years [
      • Ferlazzo E.
      • Gasparini S.
      • Beghi E.
      • Sueri C.
      • Russo E.
      • Leo A.
      • et al.
      Epilepsy in cerebrovascular diseases: Review of experimental and clinical data with meta-analysis of risk factors.
      ,
      • Camilo O.
      • Goldstein L.B.
      Seizures and epilepsy after ischemic stroke.
      ,
      • Forsgren L.
      • Bucht G.
      • Eriksson S.
      • Bergmark L.
      Incidence and clinical characterization of unprovoked seizures in adults: a prospective population-based study.
      ,
      • Hauser W.A.
      • Annegers J.F.
      • Kurland L.T.
      Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984.
      ]. In particular, those with ischemic events with cortical involvement, cerebral hemorrhage (i.e. primary hemorrhage or hemorrhagic transformation of ischemic stroke) and early post-stroke seizures, have an increased risk of post-stroke epilepsy [
      • Ferlazzo E.
      • Gasparini S.
      • Beghi E.
      • Sueri C.
      • Russo E.
      • Leo A.
      • et al.
      Epilepsy in cerebrovascular diseases: Review of experimental and clinical data with meta-analysis of risk factors.
      ].
      Seizure activity may not only induce arrhythmias but may also lead to structural cardiac changes [
      • Schuele S.U.
      Effects of seizures on cardiac function.
      ,
      • Natelson B.H.
      • Suarez R.V.
      • Terrence C.F.
      • Turizo R.
      Patients with epilepsy who die suddenly have cardiac disease.
      ,
      • Nei M.
      • Sperling M.R.
      • Mintzer S.
      • Ho R.T.
      Long-term cardiac rhythm and repolarization abnormalities in refractory focal and generalized epilepsy.
      ,
      • Tigaran S.
      • Molgaard H.
      • McClelland R.
      • Dam M.
      • Jaffe A.S.
      Evidence of cardiac ischemia during seizures in drug refractory epilepsy patients.
      ]. Epileptic seizures have been reported to provoke cardiac ischaemia via both acute and chronic effects on the heart (e.g. impaired heart rate variability, cardiac fibrosis, ST-segment depression and increased heart rate) [
      • Schuele S.U.
      Effects of seizures on cardiac function.
      ,
      • P-Codrea Tigaran S.
      • Dalager-Pedersen S.
      • Baandrup U.
      • Dam M.
      • Vesterby-Charles A.
      Sudden unexpected death in epilepsy: is death by seizures a cardiac disease?.
      ]. Transient myocardial ischaemia as indicated by ST-segment depression, was reported in a small-scale study in 40% of all 15 seizures [
      • P-Codrea Tigaran S.
      • Dalager-Pedersen S.
      • Baandrup U.
      • Dam M.
      • Vesterby-Charles A.
      Sudden unexpected death in epilepsy: is death by seizures a cardiac disease?.
      ]. Another study, however, failed to demonstrate troponin increases, suggesting that the reported ST changes do not usually cause myocardial damage [
      • Woodruff B.K.
      • Britton J.W.
      • Tigaran S.
      • Cascino G.D.
      • Burritt M.F.
      • McConnell J.P.
      • et al.
      Cardiac troponin levels following monitored epileptic seizures.
      ].
      Seizures are the second most frequent CNS condition known to induce the cardiomyopathy known as Takotsubo syndrome (TTS) [
      • Finsterer J.
      • Wahbi K.
      CNS disease triggering Takotsubo stress cardiomyopathy.
      ]. TTS mimics myocardial infarction clinically, electrocardiographically and chemically [
      • Finsterer J.
      • Bersano A.
      Seizure-triggered Takotsubo syndrome rarely causes SUDEP.
      ]. It is characterized by acute onset of chest pain and dyspnoea, sometimes concomitant with palpitations, tiredness, oedema, fever, syncope, anxiety, nausea or vomiting [
      • Finsterer J.
      • Wahbi K.
      CNS disease triggering Takotsubo stress cardiomyopathy.
      ]. The seizure type that most frequently causes TTS is the generalized tonic-clonic seizure [
      • Le Ven F.
      • Pennec P.Y.
      • Timsit S.
      • Blanc J.J.
      Takotsubo syndrome associated with seizures: an underestimated cause of sudden death in epilepsy?.
      ,
      • Lemke D.M.
      • Hussain S.I.
      • Wolfe T.J.
      • Torbey M.A.
      • Lynch J.R.
      • Carlin A.
      • et al.
      Takotsubo cardiomyopathy associated with seizures.
      ]. Seizures most likely trigger TTS by the stress-induced release of catecholamines [
      • Szardien S.
      • Mollmann H.
      • Willmer M.
      • Akashi Y.J.
      • Hamm C.W.
      • Nef H.M.
      Mechanisms of stress (takotsubo) cardiomyopathy.
      ]. This abundant catecholamine release may be a contributing factor in fatal status epilepticus [
      • Manno E.M.
      • Pfeifer E.A.
      • Cascino G.D.
      • Noe K.H.
      • Wijdicks E.F.
      Cardiac pathology in status epilepticus.
      ]. A relationship between TTS and SUDEP, however, does not appear likely [
      • Finsterer J.
      • Wahbi K.
      CNS disease triggering Takotsubo stress cardiomyopathy.
      ].

      4. Future concepts

      Significant progress has been made since the publication of Russel’s case history: the complex interrelationship between epilepsy and cardiac conditions has been explored widely and this review aimed to capture all major discoveries made in this field (Table 2, Table 3). Many discoveries of coexisting conditions were made by serendipity, and underlying mechanisms are yet to be uncovered. Treatment regimens are consequently often speculative and lack a personalized approach involving all comorbid conditions. As comorbidity gains recognition we now need to become better at noticing these symptom patterns. Today a substantial gap still remains between the specialties, but as we are now becoming aware of all overlapping syndromes epileptologists will increasingly need to improve their cardiac skills. Pattern recognition can be fostered by incorporating validated screening instruments and guidelines, aiding the early identification and treatment of cardiovascular comorbidity in epilepsy. Concomitantly, a fundamental change in the way clinicians think of epilepsy is crucial.
      Table 2Putative mechanisms of associations between epilepsy and cardiac arrhythmias. HRV—heart rate variability; VT—ventricular tachycardia; VF—ventricular fibrillation; AED—antiepileptic drugs.
      Putative mechanisms of associations between epilepsy and cardiac arrhythmias
      Mechanisms of associationConditions
      Direct causalArrhythmias → seizures
      Shared risk factorGenetics → epilepsy and arrhythmias
      • -
        Important ‘heart genes’: KCNQ1, KCNH2, SCN5A, RYR2
      • -
        Important ‘epilepsy genes’: SCN1A, KCNA1, SCN8A
      ResultantAED → arrhythmias
      • -
        Particularly carbamazepine, phenytoin and lacosamide
      Seizures → arrhythmias
      • -
        Ictal: tachycardia, asystole, bradycardia and AV block
      • -
        Postictal: asystole, AV block, atrial flutter or fibrillation and ventricular fibrillation
      Table 3Putative mechanisms of associations between epilepsy and structural cardiac disease. AED—antiepileptic drugs; TTS—Takotsubo syndrome.
      Putative mechanisms of associations between epilepsy and structural cardiac disease
      Mechanisms of associationConditions
      Indirect causalCardiac condition → stroke → epilepsy
      Shared risk factorGenetic → malformation of cortical and cardiac development → epilepsy and cardiovascular comorbidity
      Increased prevalence of cardiovascular risk factors in epilepsy → stroke/cardiac disease
      ResultantAED → poorer cardiovascular risk profile (e.g. arteriosclerosis, weight gain, non alcoholic fatty liver disease and metabolic syndrome)
      Seizures → transient myocardial ischaemia and seizure-triggered Takotsubo syndrome (TTS)
      Epilepsy will soon be viewed as a collection of individual disorders that share a phenotype of an abnormal tendency for unprovoked epileptic seizures. The number of rare epilepsy syndromes with cardiac phenotypes will increase substantially. Epilepsy will be seen as a symptom-complex, and all comorbidities, even the most inconspicuous, should be considered as part of the stratification and phenotyping in people with epilepsy. Cardiovascular comorbidities will provide insight into common mechanisms for epilepsy and give a window into common genetic predispositions. They may also provide important diagnostic clues. Channelopathies, for example, are increasingly identified in people with epilepsy. Genetic factors may explain both the epilepsy and the comorbid disorder(s), even in people with sporadic epilepsies [
      • Kasperaviciute D.
      • Catarino C.B.
      • Chinthapalli K.
      • Clayton L.M.
      • Thom M.
      • Martinian L.
      • et al.
      Uncovering genomic causes of co-morbidity in epilepsy: gene-driven phenotypic characterization of rare microdeletions.
      ]. Genome wide scanning will be widely available and drive the paradigm shift in epilepsy. Certain genes might be identified as contributing to SUDEP [
      • Bagnall R.D.
      • Crompton D.E.
      • Petrovski S.
      • Lam L.
      • Cutmore C.
      • Garry S.I.
      • et al.
      Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy.
      ,
      • Leu C.
      • Balestrini S.
      • Maher B.
      • Hernandez-Hernandez L.
      • Gormley P.
      • Hamalainen E.
      • et al.
      Genome-wide polygenic burden of rare deleterious variants in sudden unexpected death in epilepsy.
      ], potentially allowing the development of individualised risk prevention strategies. Another major contributor to early identification of overlapping syndromes will be the development of new non-invasive tools to record heart function at home. The miniaturisation of sensors will favour long-term home-based recordings thus aiding the early identification of cardiac arrhythmias.
      Advances in seizure detection will likely take off. ECG alone will help to detect a wide variety of seizures but lacks specificity. Combining ECG with other modalities including an accelerometry and electrodermal activity will likely improve accuracy and facilitate the widespread use of seizure detection devices in those with refractory epilepsy [
      • Ulate-Campos A.
      • Coughlin F.
      • Gainza-Lein M.
      • Fernandez I.S.
      • Pearl P.L.
      • Loddenkemper T.
      Automated seizure detection systems and their effectiveness for each type of seizure.
      ,
      • van Andel J.
      • Thijs R.D.
      • de Weerd A.
      • Arends J.
      • Leijten F.
      Non-EEG based ambulatory seizure detection designed for home use: What is available and how will it influence epilepsy care.
      ].
      Another unmet need relates to the treatment of epilepsy: many AEDs have proarrhythmogenic and arteriosclerogenic effects. Though non-pharmacological options exist, drug therapy is still the mainstay of epilepsy treatment and other options are usually only explored after AEDs have failed to successfully control seizures [
      • Duncan J.S.
      • Sander J.W.
      • Sisodiya S.M.
      • Walker M.C.
      Adult epilepsy.
      ]. Many new AEDs have been launched in the last two decades, but have failed to improve the burden of side effects or substantially change prognosis for seizure control [
      • Loscher W.
      • Schmidt D.
      Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma.
      ,
      • Wassenaar M.
      • van Heijl I.
      • Leijten F.S.
      • van der Linden P.
      • Uijl S.G.
      • Egberts A.C.
      • et al.
      Treatment of epilepsy in daily clinical practice: have outcomes improved over the past 10 years?.
      ]. With improved understanding of epileptogenesis, epigenetic determinants and pharmacogenomics comes the hope for better, disease-modifying or even curative pharmacological and non-pharmacological treatment strategies. Until then, comorbidity should be considered when prescribing AEDs.
      The incorporation of neurocardiology into the paroxysmal spectrum will require a critical review of the epilepsy services. We need to validate new instruments to screen for cardiovascular conditions. Modern non-invasive long-term ECG devices may help screen for cardiac conditions and a cardiologist should review any relevant abnormalities. In cases where there is a relevant family history or abnormal ECG findings, a specialist cardiac assessment should be done. Identification and adequate treatment of cardiovascular disorders in epilepsy should therefore be an important part of epilepsy management.
      Particular attention should be given to modifiable risk factors such as smoking, obesity, sedentary lifestyle, high cholesterol and hypertension. Physicians should screen for these risk factors in people with epilepsy, provide general health information and if necessary adjust AED treatment. Further studies are needed to improve risk profiling, thus allowing for screening in high risk individuals (with, for example, implantable loop recorders) and targeted interventions (e.g. defibrillators).

      Conflict of interest statement

      SS, MvdL and RJL report no conflict of interest. JWS reports personal fees from Lundbeck and Teva, grants and personal fees from UCB, Eisai, grants from GSK, WHO and Dutch National Epilepsy Fund, outside the submitted work; his current position is endowed by the Epilepsy Society, he is a member of the Editorial Board of the Lancet Neurology, and receives research support from the Marvin Weil Epilepsy Research Fund. RDT receives research support from the Dutch National Epilepsy Fund, NUTS Ohra Fund, Medtronic, and AC Thomson Foundation, and has received fees for lectures from Medtronic, UCB and GSK.

      Funding

      This work was supported by the Dutch National Epilepsy Fund [project number 15-10]; and Christelijke Vereniging voor de Verpleging van Lijders aan Epilepsie (the Netherlands) .

      Acknowledgements

      This work was partly done at the UCLH/UCL Comprehensive Bio-Medical Research Centre which received a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres funding scheme. We are grateful to Dr. GS Bell, for critically reviewing the manuscript.

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