Review ArticleCardiorespiratory abnormalities during epileptic seizuresSanjeev V.Kothare a ,1,*,Kanwaljit Singh a ,b ,1a Comprehensive Epilepsy Center,Department of Neurology,New York University Langone Medical Center,New York,NY,USA bDepartment of Pediatrics (Neurology),University of Massachusetts Medical School,Worcester,MA,USAA R T I C L E I N F O Article history:Received 31May 2014Received in revised form 17July 2014Accepted 22August 2014Available online 3September 2014Keywords:EpilepsySudden death in epilepsy Cardiac abnormalities Respiratory abnormalities EEGA B S T R A C TSudden unexpected death in epilepsy (SUDEP)is a leading cause of death in young and otherwise healthy patients with epilepsy,and sudden death is at least 20times more common in epilepsy patients as com-pared to patients without epilepsy.A significant proportion of patients with epilepsy experience cardiac and respiratory complications during seizures.These cardiorespiratory complications are suspected to be a significant risk factor for SUDEP.Sleep physicians are increasingly involved in the care of epilepsy patients and a recognition of these changes in relation to seizures while a patient is under their care may improve their awareness of these potentially life-threatening complications that may occur during sleep studies.This paper details these cardiopulmonary changes that take place in relation to epileptic seizures and how these changes may relate to the occurrence of SUDEP.©2014Elsevier B.V.All rights reserved.1.IntroductionEpilepsy affects nearly 1%of the general population [1,2].Epi-lepsy can be classified by seizure type,underlying causes,epilepsy syndromes,and by events taking place during the seizures.Seizure types are broadly classified by whether the source of seizures is lo-calized (focal or partial seizures)or diffusely distributed (generalized seizures)in the brain.Generalized seizures can be further classi-fied according to their effects (tonic–clonic seizures,absence seizures,myoclonic seizures,clonic seizures,tonic seizures,and atonic seizures).Focal or partial seizures can be further classified into simple partial (where only a small part of the lobe is affected and the person does not lose awareness of the surrounding)or complex partial (a larger part of the hemisphere is affected and the person loses con-sciousness and awareness)seizures.Approximately 35%of individuals with epilepsy do not ade-quately respond to medications and are thus considered “medication resistant.”[3]Sudden death is 20–40times more common in people with epilepsy (and especially so in poorly controlled seizures)as compared to people without epilepsy.Sudden unexpected death in epilepsy (SUDEP)is one of the leading causes of death in young and otherwise healthy adults with epilepsy (see below for furtherdetails)[4,5].SUDEP is much less frequently seen in children [6].Epileptiform discharges are often activated by sleep and tend to occur 14times more frequently in non-rapid eye movement (NREM)sleep than in wakefulness [7]and,therefore,sleep stage and sleep/wake state may influence the likelihood for a seizure to occur,with seizures occurring most frequently in NREM sleep,followed by wakefulness,and less likely during rapid eye movement (REM)sleep [8].As such,the deleterious effects of seizures and SUDEP are more likely to occur when patients emerge from the sleep state [9].A significant proportion of patients experience cardiac/or pul-monary dysfunction due to seizures (details follow).These changes may worsen the seizure prognosis/outcome and are believed to be related to,at least in part,the occurrence of SUDEP.This paper details these cardiopulmonary changes that take place in relation to epi-leptic seizures and how these changes may relate to the occurrence of SUDEP.Sleep physicians are often involved in the care of epi-lepsy patients on an increasing frequency and a recognition of these changes in relation to seizures may improve their awareness of these potentially life-threatening complications that occur during sleep studies.2.Respiratory changes during seizuresThe respiratory center [10](Fig.1)consists of four nuclei located in the medulla oblongata and pons of the brainstem.The inspira-tory center (also known as the dorsal respiratory group)is located in the dorsal portion of the medulla oblongata and causes*Corresponding prehensive Epilepsy Center,Department of Neurology,NYU Langone Medical Center,New York,NY,USA.Tel.:+6465580806;fax:+6463857164.E-mail address:Sanjeev.Kothare@ (S.V.Kothare).1Drs.Singh and Kothare contributed equally and are co-first authors./10.1016/j.sleep.2014.08.0051389-9457/©2014Elsevier B.V.All rights reserved.Sleep Medicine 15(2014)1433–1439Contents lists available at ScienceDirectSleep Medicinejournal homepage:/locate/sleepinspiration when stimulated.The expiratory center (ventral respi-ratory group)is located in the anterolateral part of medulla oblongata,anterolateral to the inspiratory center.The pneumo-taxic center is located in the upper part of pons and it controls the rate and pattern of breathing.This center is inhibited by impulses from the ventral respiratory group.The apneustic center is located in the lower part of pons.This center discharges stimulatory im-pulses to the dorsal respiratory group to stimulate inspiration,discharges inhibitory impulses to the ventral respiratory group to inhibit expiration,and receives inhibitory impulses from the pneu-motaxic center and from the lung stretch receptors –thus in turn limiting inspiration.An abnormal input to these respiratory centers during seizure-associated neuronal activation leads to many of the respiratory changes observed with seizures.Respiratory changes occurring in relation to seizures are seen with generalized as well as focal seizures,especially those arising from the mesial temporal structures.These changes have been re-peatedly demonstrated in numerous studies and include central and obstructive apneas,hypoventilation,hypercapnia,and desaturation with acidosis,bradypnea,and tachypnea [11].Most important of these changes is the respiratory depression causing central apnea.Figure 2depicts tachypnea accompanying a tonic seizure followed by postictal central apnea,which could be a mechanism for SUDEP,especially if the patient was in prone position and the apnea was prolonged.Much of the research evaluating the occurrence of respiratory changes in seizures has been done in adults.Bateman et al.(2008)prospectively analyzed the occurrence of ictal hypoxemia in localization-related epilepsy in 56patients with 304seizures [13].They found that ictal hypoxemia was associated with seizure lo-calization (temporal seizures),lateralization (right-sided seizures),male gender,longer seizure duration,and contralateral spread of seizures.Tezer et al.(2009)in a case–control study on two pa-tients reported that apneas were associated in patients with right temporal and paracentral epilepsy [14].Seyal et al.(2010)re-ported a severe and prolonged increase of ictal andpostictalFig.1.Respiratory centers of the brain.Figure sourced from Wikimedia commons and republished under the Creative Commons Attribution 3.0Unported license.(/wiki/File:2327_Respiratory_Centers_of_the_Brain.jpg ).1434S.V.Kothare,K.Singh/Sleep Medicine 15(2014)1433–1439expiratory carbon dioxide (ETCO2)in 187seizures in 33patients [15].Seyal et al.(2012)also evaluated the occurrence of postictal generalized electroencephalography suppression (PGES)(cerebral shutdown)with respiratory abnormalities and found no associa-tion of PGES with postictal central apnea in 102patients with localization-related epilepsy [16](see below for more on PGES).In children,the weight of literature evaluating the occurrence of cardiopulmonary abnormalities with seizures is rather limited,with most studies being of a descriptive nature.Southall et al.(1987)re-ported the occurrence of apnea and hypoxemia in one pediatric patient with complex partial seizures [17].Hewertson et al.(1994)reported the occurrence of hypoxemic apparent life-threatening events in 17infants with partial seizures [18].Hewertson et al.(1996)dem-onstrated the occurrence of hypoxemia/desaturation,apnea,and sinus tachycardia in the majority of 53seizures in 10children [19].O’Regan and Brown (2005)demonstrated the occurrence of tachypnea,apnea,and hypoxemia in 101seizures in 37children [20].Moseley et al.(2010)demonstrated the presence of ictal hypoxemia in general-ized as compared to non-generalized seizures [21].Singh et al.(2013)analyzed 101seizures in 26children and found an association of ictal apnea,bradycardia,and desaturation with younger age,male gender,and symptomatic generalized,left temporal longer-duration sei-zures [22].Pavlova et al.(2013)compared 101seizures in 26children and 55seizures in 22adults and found that ictal apnea and brady-cardia occurred more often in children with PGES occurred more often in adult seizures as compared to children [23].Serotonin and breathing:Serotonin,a neurotransmitter,has been shown to affect brainstem respiratory center excitability.Changes in serotonin levels have been reported in patients with sudden infant death syndrome (SIDS)[24].Mouse models of epilepsy have shown that selective serotonin reuptake inhibitors (SSRIs)(fluoxetine)re-verses respiratory arrest in those animals [25].Subsequently,a retrospective human study showed that medically refractory epi-lepsy patients taking SSRIs had reduced chances of ictal desaturation as compared to patients not on SSRIs [26].The serotonin raphe-hippocampal pathway may be impaired in epilepsy as shown in a rat model of epilepsy [27]and it has been hypothesized that SSRI usage in epilepsy may help by enhancing the excitability of the brain respiratory centers.In summary,several respiratory changes occur during seizures as a result of abnormal neuronal activation of the respiratory center in the brain.The most serious of these changes are those associ-ated with respiratory depression (such as hypoxemias and central apneas)most commonly observed in young men with symptom-atic generalized,contralaterally spreading,left or right temporal,longer-duration seizures.3.Cardiac changes during seizuresIctal autonomic changes can also cause cardiovascular manifes-tations [28].Sympathetic responses are common during most seizures,causing tachycardia,and hypertension.Tonic–clonicFig.2.Tonic seizure with hyperventilation and CO 2washout with central apnea at seizure termination in stage-2sleep.Tonic seizure (solid arrow)with accompanying hyperventilation and CO 2washout (dashed arrow),with a central apnea at the termination of the tonic seizure in stage-2sleep.Results suggest that patient lying prone and presenting with prolonged apnea after a seizure may be at an increased risk for SUDEP [12].This modified montage could be used in the future to further assess the degree of hyper/hypoventilation during seizures.1435S.V.Kothare,K.Singh/Sleep Medicine 15(2014)1433–1439seizures and complex partial seizures of temporal or extratemporal origin often lead to sympathetic activation.However,ictal para-sympathetic activity or sympathetic inhibition can also occur,causing bradycardia and hypotension [29,30].Combinations of sympathet-ic and parasympathetic activation and inhibition may occur simultaneously or sequentially during individual seizures.As with the research studies exploring cardiac changes in association with seizures,most have been done in adults.Figure 3shows how the interaction of sympathetic and parasympathetic centers results in various cardiovascular manifestations during seizures.Moseley et al.(2011)analyzed autonomic changes in 218sei-zures from 76patients and reported the occurrence of ictal sinus tachycardia in 57%of seizures,who were on >3antiepileptic drugs (AEDs)and experienced generalized seizures that had normal brain magnetic resonance imagings (MRIs)[31].Ictal bradycardia was less common,occurring in 2%of seizures and was associated with seizure clustering,and a history of >50seizures/month was reported.Surges et al.(2009)followed 74subclinical seizures (electrographic sei-zures without clinical accompaniment)in 26patients and reported insignificant changes in cardiac function during localized electrographic seizures [32].Nilsen et al.(2010)on the other hand reported that pre-ictal tachycardia was associated with secondary generalization of seizures in 38patients with partial epilepsy [33].Surges et al.(2010)found an association with ictal and postictal tachycardia,postictal heart rate variability,and abnormal QTc short-ening with secondary generalization in 25patients with medically refractory temporal lobe epilepsy [34].In children,Hewertson et al.(1996)demonstrated the occurrence of ictal tachycardia in the ma-jority of 53seizures recorded in 10patients [19].Singh et al.(2013)reported the occurrence of ictal bradycardia in association with younger age,male gender,and symptomatic generalized,left temporal-onset longer-duration seizures [22].Pavlova et al.(2013)reported that ictal bradycardia occurred more commonly in sei-zures in children as compared to adults [23].3.1.Other cardiac changes during seizuresOther cardiac abnormalities that may occur include asystole,re-polarization anomalies (prolonged or shortened QTc interval),and atrial fibrillation.These possibly may arise from seizures arising from the insular cortex.Seizure-induced cardiac asystole has been reported in some studies.Sehuele et al.(2007)assessed 6827patients undergoing long-term video-EEG monitoring and ictal asystole was recorded in 10patients (0.27%),the majority of them (8/10)occurring in temporal lobe epilepsy patients [35].Lanz et al.(2011)retrospectively ana-lyzed the occurrence of cardiac asystole in 2003epilepsy patients undergoing long-term EEG monitoring.Out of 2003patients,only seven patients experienced asystole,all of them occurring in tem-poral lobe epilepsy patients [36].Pathogenic cardiac repolarization has been described in epilepsy patients.Electrocardiography (EKG)indicators of abnormal cardiac repolarization during seizures (such as prolonged or shortened QTc interval)are risk factors for life-threatening tachyarrhythmia and sudden cardiac death.Several studies have indicated the occurrence of peri-ictal QTc interval prolonga-tion in >10%patients of epilepsy [34,37–39].The co-occurrence of ictal hypoxemia has especially been shown to be a risk factor for pro-longed QTc interval [40].Peri-ictal shortening of QTc interval has also been reported,especially in relation to generalized tonic clonic sei-zures (GTCS)(Surges et.al 2010)[41].Peri-ictal changes in heart rate variability have been described in relation to seizures and SUDEP.A recent case report of an epilepsy patient who died of SUDEP de-scribed the occurrence of a marked increase of pre-ictal parasympathetic activity and shortened QTc interval followed by a cluster of GTCS,PGES,asystole,and cardiac arrhythmias [42].Com-plicating this picture,several antiepileptic medications can also lead to QTc interval abnormalities (QTc prolongation:pregabelin,lamotrigine,valproate,stiripentol,and ketogenic diet;QTc shorten-ing:rufinamide,primidone,phenytoin,and carbamazepine)[43].Fig.3.Interaction of sympathetic or parasympathetic systems causing cardiovascular manifestations during seizures.1436S.V.Kothare,K.Singh/Sleep Medicine 15(2014)1433–1439In summary,several cardiac changes occur during seizures as a result of ictal autonomic dysfunction.Sympathetic responses(causing tachycardia and hypertension)are more common as compared to parasympathetic responses(causing bradycardia and hypoten-sion).Younger age,male gender,multiple AEDs,and generalized, temporal lobe,and longer-duration seizures predispose patients to experiencing these cardiac alterations.3.2.Genetic basis of cardiopulmonary changes in associationwith seizuresA few studies have shown that mutations in genes could lead to predisposition to cardiopulmonary complications during sei-zures.For example,in mice models and in a human cohort study, mutations in potassium channel-coding genes(KCNQ1,KCNH2,and SCN5A)have been found to predispose a severe form of pro-longed QTc interval,thus potentially predisposing the subjects to sudden death in epilepsy.KCNQ1gene encodes for the cardiac KvLQT1delayed rectifier channel.In mice,this channel is present in neurons of certain regions of the forebrain and brainstem.Sei-zures in this model might predispose cardiac arrhythmia[44]. Another study in mice has shown that mutations in Kv1.1potas-sium channel-coding genes predisposed mice to early onset of epilepsy,fivefold increase in AV conduction blocks,bradycardia and premature ventricular contraction,and sudden death[45].3.3.Sudden unexpected death in epilepsySUDEP refers to the sudden unexpected death of a seemingly healthy individual with epilepsy.SUDEP is defined as a“sudden,un-expected,witnessed or unwitnessed,non-traumatic and non-drowning death,occurring in benign circumstances,in an individual with epilepsy,with or without evidence for a seizure and exclud-ing documented status epilepticus(seizure duration>30minutes or seizures without recovery in between)in which postmortem ex-amination does not reveal a cause of death.”SUDEP is the most common cause of death that can be directly attributable to epilep-sy[46].SUDEP most often occurs at night,possibly during sleep[47]. The incidence of SUDEP is1in1000with epilepsy(general popu-lation1in40,000),and1in100–200with refractory epilepsy,but is four times more likely in adults as compared to children[48].While potential mechanisms have been postulated,a high seizure frequency remains the biggest conclusively substantiated under-lying risk factor.Cardiac arrhythmias[49],respiratory abnormalities [50],or a combination[9,51,52]have been postulated in the causation of SUDEP[53].The role of breathing in the mechanisms of SUDEP has been understudied and is probably underestimated.Studies have shown age to have a strong effect on the rate and severity of respiratory abnormalities with obstructive sleep apnea syndrome being more common in older individuals[7,54],and more severe after the age of50[7].The peak age for SUDEP in adults, however,is between20and40years[55].Given the increased in-cidence of obstructive sleep abnormalities with age,we believe that the seizure-related breathing disturbances also differ by age group. The interaction between seizures,sleep,and cardiopulmonary func-tion is an important,yet understudied area of investigation and is a growing area of research in epilepsy.A better understanding of mechanisms and association of these cardiorespiratory abnormali-ties in seizures may offer better insights to causes and,potentially, a better prediction of patients who might experience SUDEP.A recent study[56]collected data from four case–control studies to increase the power to identify risk factors for SUDEP[57–60]. The following risk factors for SUDEP(in289cases and958living controls)with epilepsy were identified:1)Multiple(more than three)GTCS per year,2)multiple AEDs,3)epilepsy duration,4) childhood onset of epilepsy,5)male gender,and6)symptomatic epilepsy.The risk for SUDEP was37times greater in persons with early onset of epilepsy(younger than age16)and eight times in those whose epilepsy began at age16or older compared to healthy controls.Although the peak incidence of SUDEP is between ages 20and40years,the study implied that it is those patients who had early onset of epilepsy are more susceptible to developing SUDEP later on in their life.A reanalysis of the data used in the abovementioned study showed that of these six risk factors,the effect of allfive tended to decrease once the effect of GTCS frequen-cy was taken into account,meaning that GTCS frequency remained the most important risk factor for SUDEP[61].Another recently published,large,multicenter study(the Mechanisms of Cardiore-spiratory Arrests in Epilepsy Monitoring Units(MORTEMUS)study) performed a comprehensive evaluation of cardiorespiratory arrests in29epilepsy patients who died subsequent to an admission to epilepsy monitoring units[62].This study showed that patients who had subsequently died due to cardiorespiratory arrest had an early postictal tachypnea induced by a generalized tonic clonic seizure followed within3min by transient or terminal cardiopul-monary dysfunction(apnea and/or bradycardia culminating in asystole).Where transient,this dysfunction later recurred with ter-minal apnea and cardiac arrest within11min of the end of seizure.There is not a single mechanism to explain the mechanisms of SUDEP.Potential mechanisms may include:1)cardiac arrhyth-mias(possibly related to the cardiovascular effects of insular cortex), 2)ventilatory impairment,prolonged apneas,or oxyhemoglobin desaturations triggered by seizures,3)impaired righting re-sponses leading to suffocation(most patients with SUDEP have been found to be in the prone position),4)autonomic instability during or after a seizure,and/or5)postictal serotonin(5-HT)neuronal dys-function causing depression of breathing,impaired arousal,and repositioning reflexes.Cerebral shutdown is a yet another putative mechanism causing SUDEP that has been put forward.PGES(Fig.4),which is a hall-mark of cerebral shutdown,is defined as the immediate postictal (within30s),generalized absence of electroencephalographic ac-tivity>10μV in amplitude,allowing for muscle,movement, breathing,and electrode artifacts[63].Prolonged PGES may be an independent risk marker for SUDEP.Lhatoo et al.(2010)showed that PGES>50s increased the risk for SUDEP by a significant margin,and each1-s increase in PGES duration increased the risk for PGES by 1.7%[63].It is however not clear whether PGES is an indirect or direct marker of cerebral dysregulation.A recent study examined the relationship between sympathetic and parasympathetic changes(as measured by electrodermal activity and heart rate variability)and PGES in seizure patients,and found that the increase in electro-dermal activity response amplitude and decreased parasympathetic modulated power of heart rate variability were directly correlated to prolonged PGES[64].Therefore,it may be presumed that PGES may serve as a marker of postictal autonomic dysregulation.In another study,13patients with PGES and GTCS were compared to 12random controls,and it was found that patients with PGES were more likely to be motionless postictally and were more likely to have resuscitative interventions(such as suction,oxygen administra-tion,and position altered)performed.PGES in these patients may be a sign of deeper coma,delayed arousal,and a predisposition to SUDEP[65].Another study compared secondarily generalized con-vulsive seizures with and without PGES,and found that oxygen desaturation duration and extent as well as peak end-tidal CO2el-evation was greater in patients with PGES[16].A recent study however failed tofind an association between PGES and SUDEP, where they found no significant differences in the presence or du-ration of PGES between17SUDEP cases and matched controls[66]. Several studies have shown that PGES occurs less frequently in pe-diatric[23,67]as compared to adult seizures[63].This association of age with PGES may indicate that a developing pediatric brain is1437S.V.Kothare,K.Singh/Sleep Medicine15(2014)1433–1439less likely to manifest PGES than the mature adult brain,and it may also indicate that to the extent that PGES plays a role in causing SUDEP,it may not be due to “cerebral exhaustion”but due to the existence of a possible “controlling network”inside the brain stem that is activated by seizure activation [23,66].4.ConclusionIn this paper,we have detailed the type of cardiorespiratory changes that take place in patients with epilepsy in relation to sei-zures,and how these changes may relate to an increased risk of sudden death in epilepsy.When indicated,patients undergoing sleep studies in patients with epilepsy should have additional EEG elec-trodes to localize and lateralize seizures,and assess the effect of these seizures on cardiorespiratory functions,including oxygenation and end-tidal CO 2.Similarly,in patients undergoing video-EEG moni-toring in the epilepsy telemetry unit,additional channels may be supplemented to assess their oxygenation and respiratory effort during and after seizures,especially when these patients experi-ence apneas,or prolonged desaturation during or after their seizures.In those patients who have obstructive apneas,appropriate inter-ventions such as the use of continuous positive airway pressure (CPAP)could be carried out and those who have significant desaturations or central apnea could benefit from a trial of SSRIs.These patients also need more careful monitoring such as the in-sertion of pacemaker for any possible cardiac asystole,home monitoring in bed,checking for supine position,and maintaining an elevated head position during sleep.4.1.Practice points for the clinician1.Sleep physicians need to be aware of potential cardiopulmo-nary complications in their epilepsy patients when they come for sleep studies.2.Certain types of patients are potentially more likely to experi-ence these cardiopulmonary complications –those of youngerage,of the male gender,on multiple AEDs,and who have longer-duration,temporal lobe,symptomatic generalized seizures.3.These patients may need additional monitoring,such as addi-tional EEG electrodes,a more careful assessment of their O 2and end-tidal CO 2levels,and EKG monitoring.Conflict of interestThe ICMJE Uniform Disclosure Form for Potential Conflicts of In-terest associated with this article can be viewed by clicking on the following link:/10.1016/j.sleep.2014.08.005.References[1]ILAE.Proposal for revised clinical and electroencephalographic classi-fication of epileptic seizures.From the commission on classification and terminology of the international league against epilepsy.Epilepsia 1981;22(4):489–501.[2]ILAE.Proposal for revised classification of epilepsies and epileptic syndromes.Commission on classification and terminology of the international league against epilepsy.Epilepsia 1989;30(4):389–99.[3]Kwan P,Brodie MJ.Definition of refractory epilepsy:defining the indefinable?Lancet Neurol 2010;9(1):27–9.[4]Dasheiff RM.Sudden unexpected death in epilepsy:a series from an epilepsysurgery program and speculation on the relationship to sudden cardiac death.J Clin Neurophysiol 1991;8(2):216–22.[5]Nilsson L,Ahlbom A,Farahmand BY,Tomson T.Mortality in a population-basedcohort of epilepsy surgery patients.Epilepsia 2003;44(4):575–81.[6]Weber P,Bubl R,Blauenstein U,Tillmann BU,Lutschg J.Sudden unexplaineddeath in children with epilepsy:a cohort study with an eighteen-year follow-up.Acta Paediatr 2005;94(5):564–7.[7]Pavlova MK,Duffy JF,Shea SA.Polysomnographic respiratory abnormalities inasymptomatic individuals.Sleep 2008;31(2):241–8.[8]Herman ST,Walczak TS,Bazil CW.Distribution of partial seizures duringthe sleep–wake cycle:differences by seizure onset site.Neurology 2001;56(11):1453–9.[9]Langan Y,Nashef L,Sander JW.Case-control study of SUDEP.Neurology2005;64(7):1131–3.[10]Urfy MZ,Suarez JI.Breathing and the nervous system.Handb Clin Neurol2014;119:241–50.Fig.4.Postictal Generalized EEG Suppression (PGES).This figure shows an example of suppression of EEG activity immediately following the ending of a seizure.1438S.V.Kothare,K.Singh/Sleep Medicine 15(2014)1433–1439[11]Blum AS.Respiratory physiology of seizures.J Clin Neurophysiol2009;26(5):309–15.[12]Grigg-Damberger MM.Sudden unexpected death in epilepsy:what does sleephave to do with it?Sleep Med Clin2012;7(1):157–70.[13]Bateman LM,Li CS,Seyal M.Ictal hypoxemia in localization-relatedepilepsy:analysis of incidence,severity and risk factors.Brain2008;131(Pt12):3239–45.[14]Tezer FI,Remi J,Noachtar S.Ictal apnea of epileptic origin.Neurology2009;72(9):855–7.[15]Seyal M,Bateman LM,Albertson TE,Lin TC,Li CS.Respiratory changes withseizures in localization-related epilepsy:analysis of periictal hypercapnia and airflow patterns.Epilepsia2010;51(8):1359–64.[16]Seyal M,Hardin KA,Bateman LM.Postictal generalized EEG suppression is linkedto seizure-associated respiratory dysfunction but not postictal apnea.Epilepsia 2012;53:825–31.[17]Southall DP,Stebbens V,Abraham N,Abraham L.Prolonged apnoea with severearterial hypoxaemia resulting from complex partial seizures.Dev Med Child Neurol1987;29(6):784–9.[18]Hewertson J,Poets CF,Samuels MP,Boyd SG,Neville BG,Southall DP.Epilepticseizure-induced hypoxemia in infants with apparent life-threatening events.Pediatrics1994;94(2Pt1):148–56.[19]Hewertson J,Boyd SG,Samuels MP,Neville BG,Southall DP.Hypoxaemia andcardiorespiratory changes during epileptic seizures in young children.Dev Med Child Neurol1996;38(6):511–22.[20]O’Regan ME,Brown JK.Abnormalities in cardiac and respiratory functionobserved during seizures in childhood.Dev Med Child Neurol2005;47(1):4–9.[21]Moseley BD,Nickels K,Britton J,Wirrell E.How common is ictal hypoxemiaand bradycardia in children with partial complex and generalized convulsive seizures?Epilepsia2010;51(20067502):1219–24.[22]Singh K,Katz ES,Zarowski M,Loddenkemper T,Llewellyn N,Manganaro S,et al.Cardiopulmonary complications during pediatric seizures:a prelude to understanding SUDEP.Epilepsia2013;54(6):1083–91.[23]Pavlova M,Singh K,Abdennadher M,Katz ES,Dworetzky BA,White DP,et al.Comparison of cardiorespiratory and EEG abnormalities with seizures in adults and children.Epilepsy Behav2013;29(3):537–41.[24]Duncan JR,Paterson DS,Hoffman JM,Mokler DJ,Borenstein NS,Belliveau RA,et al.Brainstem serotonergic deficiency in sudden infant death syndrome.JAMA 2010;303(5):430–7.[25]Tupal S,Faingold CL.Evidence supporting a role of serotonin in modulationof sudden death induced by seizures in DBA/2mice.Epilepsia2006;47(1):21–6.[26]Bateman LM,Li CS,Lin TC,Seyal M.Serotonin reuptake inhibitors are associatedwith reduced severity of ictal hypoxemia in medically refractory partial epilepsy.Epilepsia2010;51(10):2211–14.[27]Mazarati AM,Pineda E,Shin D,Tio D,Taylor AN,Sankar orbidity betweenepilepsy and depression:role of hippocampal interleukin-1beta.Neurobiol Dis 2010;37(2):461–7.[28]Sevcencu C,Struijk JJ.Autonomic alterations and cardiac changes in epilepsy.Epilepsia2010;51(5):725–37.[29]Van Buren JM.Some autonomic concomitants of ictal automatism;a study oftemporal lobe attacks.Brain1958;81(4):505–28.[30]Devinsky O.Effects of seizures on autonomic and cardiovascular function.Epilepsy Curr2004;4(15562299):43–6.[31]Moseley BD,Wirrell EC,Nickels K,Johnson JN,Ackerman MJ,Britton J.Electrocardiographic and oximetric changes during partial complex and generalized seizures.Epilepsy Res2011;95(3):237–45.[32]Surges R,Henneberger C,Adjei P,Scott CA,Sander JW,Walker MC.Do alterationsin inter-ictal heart rate variability predict sudden unexpected death in epilepsy?Epilepsy Res2009;87(2–3):277–80.[33]Nilsen KB,Haram M,Tangedal S,Sand T,Brodtkorb E.Is elevated pre-ictal heartrate associated with secondary generalization in partial epilepsy?Seizure 2010;19(5):291–5.[34]Surges R,Adjei P,Kallis C,Erhuero J,Scott CA,Bell GS,et al.Pathologic cardiacrepolarization in pharmacoresistant epilepsy and its potential role in sudden unexpected death in epilepsy:a case-control study.Epilepsia 2010;51(19817816):233–42.[35]Schuele SU,Bermeo AC,Alexopoulos AV,Locatelli ER,Burgess RC,Dinner DS,et al.Video-electrographic and clinical features in patients with ictal asystole.Neurology2007;69(5):434–41.[36]Lanz M,Oehl B,Brandt A,Schulze-Bonhage A.Seizure induced cardiac asystolein epilepsy patients undergoing long term video-EEG monitoring.Seizure 2011;20(2):167–72.[37]Tavernor SJ,Brown SW,Tavernor RM,Gifford C.Electrocardiograph QTlengthening associated with epileptiform EEG discharges–a role in sudden unexplained death in epilepsy?Seizure1996;5(1):79–83.[38]Kandler L,Fiedler A,Scheer K,Wild F,Frick U,Schneider P.Early post-convulsiveprolongation of QT time in children.Acta Paediatr2005;94(16278992): 1243–7.[39]Brotherstone R,Blackhall B,McLellan A.Lengthening of corrected QT duringepileptic seizures.Epilepsia2010;51(19732135):221–32.[40]Seyal M,Pascual F,Lee CY,Li CS,Bateman LM.Seizure-related cardiacrepolarization abnormalities are associated with ictal hypoxemia.Epilepsia 2011;52(11):2105–11.[41]Surges R,Scott CA,Walker MC.Enhanced QT shortening and persistenttachycardia after generalized seizures.Neurology2010;74(20124208):421–6.[42]Jeppesen J,Fuglsang-Frederiksen A,Brugada R,Pedersen B,Rubboli G,Johansen P,et al.Heart rate variability analysis indicates preictal parasympathetic overdrive preceding seizure-induced cardiac dysrhythmias leading to sudden unexpected death in a patient with epilepsy.Epilepsia 2014;55:e67–71.[43]Surges R,Taggart P,Sander JW,Walker MC.Too long or too short?New insightsinto abnormal cardiac repolarization in people with chronic epilepsy and its potential role in sudden unexpected death.Epilepsia2010;51(5):738–44. [44]Goldman AM,Glasscock E,Yoo J,Chen TT,Klassen TL,Noebels JL.Arrhythmiain heart and brain:KCNQ1mutations link epilepsy and sudden unexplained death.Sci Transl Med2009;1(2):2ra6.[45]Glasscock E,Yoo JW,Chen TT,Klassen TL,Noebels JL.Kv1.1potassiumchannel deficiency reveals brain-driven cardiac dysfunction as a can-didate mechanism for sudden unexplained death in epilepsy.J Neurosci 2010;30(15):5167–75.[46]Nashef L,So EL,Ryvlin P,Tomson T.Unifying the definitions of suddenunexpected death in epilepsy.Epilepsia2012;53(22191982):227–33.[47]Nashef L,Shorvon SD.Mortality in epilepsy.Epilepsia1997;38(9579950):1059–61.[48]Neligan A,Hauser WA,Sander JW.The epidemiology of the epilepsies.HandbClin Neurol2012;107:113–33.[49]Espinosa PS,Lee JW,Tedrow UB,Bromfield EB,Dworetzky BA.Suddenunexpected near death in epilepsy:malignant arrhythmia from a partial seizure.Neurology2009;72(19):1702–3.[50]Johnston SC,Horn JK,Valente J,Simon RP.The role of hypoventilation in a sheepmodel of epileptic sudden death.Ann Neurol1995;37(4):531–7.[51]Langan Y,Nashef L,Sander JW.Sudden unexpected death in epilepsy:a seriesof witnessed deaths.J Neurol Neurosurg Psychiatry2000;68(2):211–13. [52]Walczak T.Do antiepileptic drugs play a role in sudden unexpected death inepilepsy?Drug Saf2003;26(10):673–83.[53]Tomson T,Walczak T,Sillanpaa M,Sander JW.Sudden unexpected death inepilepsy:a review of incidence and risk factors.Epilepsia2005;46(Suppl.11):54–61.[54]Young T,Palta M,Dempsey J,Skatrud J,Weber S,Badr S.The occurrence ofsleep-disordered breathing among middle-aged adults.N Engl J Med 1993;328(17):1230–5.[55]Asadi-Pooya AA,Sperling MR.Clinical features of sudden unexpected death inepilepsy.J Clin Neurophysiol2009;26(5):297–301.[56]Hesdorffer DC,Tomson T,Benn E,Sander JW,Nilsson L,Langan Y,et al.Combined analysis of risk factors for SUDEP.Epilepsia2011;52(6):1150–9. [57]Nilsson L,Farahmand BY,Persson PG,Thiblin I,Tomson T.Risk factors forsudden unexpected death in epilepsy:a case-control ncet 1999;353(10093982):888–93.[58]Walczak TS,Leppik IE,D’Amelio M,Rarick J,So E,Ahman P,et al.Incidenceand risk factors in sudden unexpected death in epilepsy:a prospective cohort study.Neurology2001;56(11222798):519–25.[59]Hitiris N,Suratman S,Kelly K,Stephen LJ,Sills GJ,Brodie MJ.Sudden un-expected death in epilepsy:a search for risk factors.Epilepsy Behav 2007;10(17196884):138–41.[60]Langan Y,Nashef L,Sander JW.Case-control study of SUDEP.Neurology2005;64(15824334):1131–3.[61]Hesdorffer DC,Tomson T,Benn E,Sander JW,Nilsson L,Langan Y,et al.Doantiepileptic drugs or generalized tonic-clonic seizure frequency increase SUDEP risk?A combined analysis.Epilepsia2012;53(2):249–52.[62]Ryvlin P,Nashef L,Lhatoo SD,Bateman LM,Bird J,Bleasel A,et al.Incidenceand mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS):a retrospective ncet Neurol2013;12(10):966–77. [63]Lhatoo SD,Faulkner HJ,Dembny K,Trippick K,Johnson C,Bird JM.Anelectroclinical case-control study of sudden unexpected death in epilepsy.Ann Neurol2010;68(20882604):787–96.[64]Poh MZ,Loddenkemper T,Reinsberger C,Swenson NC,Goyal S,Madsen JR,et al.Autonomic changes with seizures correlate with postictal EEG suppression.Neurology2012;78(23):1868–76.[65]Semmelroch M,Elwes RD,Lozsadi DA,Nashef L.Retrospective audit of postictalgeneralized EEG suppression in telemetry.Epilepsia2012;53(2):e21–4. [66]Surges R,Strzelczyk A,Scott CA,Walker MC,Sander JW.Postictal generalizedelectroencephalographic suppression is associated with generalized seizures.Epilepsy Behav2011;21(3):271–4.[67]Kim AJ,Kuroda MM,Nordli DR Jr.Abruptly attenuated terminal ictal patternin pediatrics.J Clin Neurophysiol2006;23(6):532–50.1439S.V.Kothare,K.Singh/Sleep Medicine15(2014)1433–1439。
