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Sudden death in epilepsy: Insights from the last 25 years

  • Lliwen A. Jones
    Affiliations
    Department of Neurology, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, United Kingdom
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  • Rhys H. Thomas
    Correspondence
    Corresponding author at: Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, United Kingdom.
    Affiliations
    Department of Neurology, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, United Kingdom

    Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, United Kingdom
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Open ArchivePublished:October 14, 2016DOI:https://doi.org/10.1016/j.seizure.2016.10.002

      Highlights

      • SUDEP is the leading cause of mortality in chronic refractory epilepsy.
      • Pathophysiology remains poorly understood but risk factors identified.
      • No proven intervention for its prevention.
      • Increasing awareness and research in the last 25 years.
      • Several promising future research avenues to minimise SUDEP impact.

      Abstract

      Sudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in patients with refractory epilepsy, and as such has been a major research focus over the last 25 years. The earliest SUDEP research papers were published in Seizure, as have scores of SUDEP papers since. In this review we discuss the efforts to try and describe the pathophysiological basis of SUDEP, the drive to discover the clinical risk factors that increase the likelihood of SUDEP, and the motivation to increase awareness of SUDEP. These three areas are the prime factors that, when answered, will allow us to better mitigate against SUDEP and help individuals monitor their personal risk. The field has benefited from strong definitions, multinational collaboration, the use of cutting edge genetic analysis, and ensuring that bereaved families are able to take part in research when this is appropriate. Clearly there is much that we do not know and yet, has any area of epilepsy research come so far in the last 25 years?

      Abbreviations:

      SUDEP (sudden unexpected death in epilepsy), MORTEMUS (Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units), GTCS (generalised tonic-clonic seizure), PGES (postictal generalised EEG suppression), AED (antiepileptic drug), NICE (National Institute for Health and Care Excellence), LQTS (long QT syndrome), SSRI (selective serotonin reuptake inhibitors), ICD (implantable cardiac defibrillators)

      Keywords

      1. Introduction

      Epilepsy, unfortunately, is associated with a reduction in life-expectancy. Genetic and acquired epilepsies can be associated with life-limiting disorders, such as inborn-errors of metabolism syndromes, or primary brain tumours. People with epilepsy as part of a neurodevelopmental disorder, often comorbid with autism and physical impairment also have reduced longevity. It is now well recognised that the suicide rate in people with epilepsy in greatly elevated above the population means. The focus of this review however is of the peculiar apparently idiopathic deaths that occur in both sexes, people of all ages and with little or no precipitant. Cruelly it is most common in young adults and strikes when people are alone. We will discuss that some groups are at greater risk, but everyone with convulsive seizures appears to be at some risk.
      For over a century, it has been recognised that patients with epilepsy are at risk of death from epilepsy itself [
      • Nashef L.
      • Sander J.W.
      Sudden unexpected death in epilepsy—where are we now?.
      ]. Studies have consistently reported an increased mortality rate in epilepsy of two to four times that of the general population [
      • Shankar R.
      • Cox D.
      • Jalihal V.
      • Brown S.
      • Hanna J.
      • McLean B.
      Sudden unexpected death in epilepsy (SUDEP): development of a safety checklist.
      ]. It has long been recognised that death may occur due to the underlying disease, as a result of a prolonged seizure or through injury. In the late twentieth century, it became apparent that there is an excess mortality in patients with chronic epilepsy that cannot be attributed to these mechanisms, with many deaths occurring unexpectedly and in benign circumstances [
      • Nashef L.
      • Sander J.W.
      Sudden unexpected death in epilepsy—where are we now?.
      ]. Termed as Sudden Unexpected Death in Epilepsy (SUDEP), this was defined in 1997 by Nashef [
      • Nashef L.
      Sudden unexpected death in epilepsy: terminology and definitions.
      ]:“Sudden, unexpected, witnessed or unwitnessed, non-traumatic and non-drowning death in patients with epilepsy, with or without evidence of a seizure and excluding documented status epilepticus, in which post-mortem examination does not reveal a toxicologic or anatomic cause for death.”
      SUDEP is the leading cause of mortality in patients with chronic refractory epilepsy, estimated to cause 10–50% of deaths [
      • Shorvon S.
      • Tomson T.
      Sudden unexpected death in epilepsy.
      ,
      • Tomson T.
      • Nashef L.
      • Ryvlin P.
      Sudden unexpected death in epilepsy: current knowledge and future directions.
      ,
      • Surges R.
      • Thijs R.D.
      • Tan H.L.
      • Sander J.W.
      Sudden unexpected death in epilepsy: risk factors and potential pathomechanisms.
      ]. The topic has attracted increasing amounts of interest from both the scientific and epilepsy community since its definition. Given the sudden and devastating nature of SUDEP, most often affecting young people between the ages of 20 and 40, better knowledge of its pathophysiology and associated risk factors is crucial so that attempts at treatment and prevention can be made [
      • Langan Y.
      Sudden unexpected death in epilepsy (SUDEP): risk factors and case control series.
      ]. We will discuss the key developments in the field over the last 25 years before commenting on future clinical and research priorities.

      2. Pathophysiology

      Despite vigorous efforts, the pathophysiology of SUDEP today remains little better understood than when first described in the literature. The publication of several SUDEP epidemiological studies, case series of witnessed and monitored SUDEP and human and animal epilepsy research however, have provided data from which possible SUDEP mechanisms have been proposed [
      • Dlouhy B.J.
      • Gehlbach B.K.
      • Rickerson G.B.
      Sudden unexpected death in epilepsy: basic mechanisms and clinical implications for prevention.
      ].
      The 2013 MORTEMUS study was a milestone in SUDEP research; a multi-centre retrospective study examining SUDEP cases in epilepsy monitoring units. The 16 SUDEP cases and nine near SUDEP described offer a unique opportunity to better understand the mechanism underlying SUDEP as they occurred in monitored units. The study concluded that in the cases examined, a generalised tonic-clonic seizure (GTCS) led to early post-ictal, central-induced alteration of respiratory and cardiac function. This led either to immediate death or to a period of restored cardiorespiratory function before terminal apnoea causing cardiac arrest. The majority of patients remained in the prone position following seizure termination until death, with no attempt made to optimise their position. This may promote hypoxia, although it is noted that not all patients were in the prone position. As has been noted both anecdotally and in the literature, the majority of SUDEP cases occurred at night [
      • Opeskin K.
      • Berkovic S.F.
      Risk factors for sudden unexpected death in epilepsy: a controlled prospective study based on coroners cases.
      ]. This may reflect decreased nocturnal supervision of epilepsy patients or may be suggestive that the circadian rhythm plays a role in SUDEP. The study reported that postictal generalised EEG suppression (PGES) was found to be more common at night, possibly promoting postictal central apnoea and 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.
      ]. Two other studies published failed to replicate this finding [
      • Lee A.
      • Wu S.
      • Zhou X.
      • Liebenthal J.
      • Rose S.
      • Tao J.X.
      Periictal autonomic dysfunction and generalized postictal EEG suppression in convulsive seizures arising from sleep and wakefulness.
      ,
      • Moseley B.D.
      • So E.
      • Wirrell E.C.
      • Nelson C.
      • Lee R.W.
      • Mandrekar J.
      • et al.
      Characteristics of postictal generalized EEG suppression in children.
      ].
      The most common proposed mechanism reported in other studies is that of seizure-induced respiratory dysfunction [
      • Swallow R.A.
      • Hillier C.E.
      • Smith P.E.
      Sudden unexplained death in epilepsy (SUDEP) following previous seizure-related pulmonary oedema: case report and review of possible preventative treatment.
      ]. Although the majority of patients are found in the prone position, the face is usually tilted to one side and the airway is not completely obstructed. A case series of witnessed deaths reported that most patients experienced breathing difficulties before death [
      • Lee A.
      • Wu S.
      • Zhou X.
      • Liebenthal J.
      • Rose S.
      • Tao J.X.
      Periictal autonomic dysfunction and generalized postictal EEG suppression in convulsive seizures arising from sleep and wakefulness.
      ]. This may be due to a combination of obstructive and central apnoea ultimately leading to asystole. The persistence of hypoxia and hypercapnia after respiratory effort has been restored or increased has suggested the possibility of intrinsic pulmonary dysfunction. The evidence remains circumstantial with post-mortem examination showing pulmonary oedema in many SUDEP cases but not significant enough to cause death [
      • 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.
      ].
      Another proposed mechanism is that of seizure related cardiac arrhythmia. There are many case reports of patients receiving cardiac pacemakers as a result of postictal bradycardia and asystole. Genetic mutations in ion channels have also been studied as a potential cause for SUDEP, particularly long QT syndrome (LQTS) [
      • Dlouhy B.J.
      • Gehlbach B.K.
      • Rickerson G.B.
      Sudden unexpected death in epilepsy: basic mechanisms and clinical implications for prevention.
      ]. A study of 61 people with SUDEP (the majority with definite SUDEP) were studied with exome sequencing and four had mutations in genes known to contribute to LQTS; two with KCNH2, one KCNQ1 and a fourth with SCN5A. A further nine had variants in candidate genes for cardiac arrhythmia; that is to say genes coding for ion channels that may contribute to LQTS, Brugada syndrome or catecholaminergic polymorphic ventricular tachycardia [
      • 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.
      ]. An ultra-rare variant in SCN5A has previously been identified in in a young woman with SUDEP [
      • Aurlien D.
      • Leren T.P.
      • Taubøll E.
      • Gjerstad L.
      New SCN5A mutation in a SUDEP victim with idiopathic epilepsy.
      ]. It remains unclear whether patients with LQTS and epilepsy are at increased risk of SUDEP, and this mechanism is unlikely to be the primary cause of SUDEP in the majority of patients.
      Other proposed mechanisms include that prolonged PGES leads to electrocerebral shutdown, leading to cardiorespiratory dysfunction. This was proposed in the MORTEMUS study, but studies have been inconsistent in determining the role played by PGES in SUDEP [
      • Dlouhy B.J.
      • Gehlbach B.K.
      • Rickerson G.B.
      Sudden unexpected death in epilepsy: basic mechanisms and clinical implications for prevention.
      ]. A study by Shen et al. explored the possibility that adenosine may play a role in centrally-induced cardiorespiratory dysfunction, suggesting that adenosine receptor antagonists such as caffeine may have a protective effect against SUDEP when given at seizure onset [
      • Shen H.Y.
      • Li T.
      • Boison D.
      A novel mouse model for sudden unexpected death in epilepsy (SUDEP): role of impaired adenosine clearance.
      ].

      3. Risk factors

      Since its definition, there have been numerous studies to attempt to define and assess the impact of individual patient risk factors that may increase the likelihood of SUDEP. There are several fixed, non-modifiable risk factors but of more interest are those significant but modifiable risk factors that patients and healthcare professionals can together attempt to address in order to reduce the risk of SUDEP.
      The significant but non-modifiable risk factors for SUDEP appear to be male sex [
      • Nilsson L.
      • Farahmand B.Y.
      • Persson P.-G.
      • Thiblin I.
      • Tomson T.
      Risk factors for sudden unexpected death in epilepsy: a case-control study.
      ,
      • Annegers J.F.
      • Coan S.P.
      SUDEP: overview of definitions and review of incidence data.
      ], history of GTCS [
      • Nilsson L.
      • Farahmand B.Y.
      • Persson P.-G.
      • Thiblin I.
      • Tomson T.
      Risk factors for sudden unexpected death in epilepsy: a case-control study.
      ,
      • Tomson T.
      • Walczak T.
      • Sillanpaa M.
      • Sander J.W.
      Sudden unexpected death in epilepsy: a review of incidence and risk factors.
      ,
      • Sperling M.R.
      Sudden unexpected death in epilepsy.
      ,
      • McGugan E.A.
      Sudden unexpected deaths in epileptics—a literature review.
      ,
      • Ficker D.M.
      Sudden unexpected death and injury in epilepsy.
      ], younger age of onset [
      • Nilsson L.
      • Farahmand B.Y.
      • Persson P.-G.
      • Thiblin I.
      • Tomson T.
      Risk factors for sudden unexpected death in epilepsy: a case-control study.
      ,
      • Annegers J.F.
      • Coan S.P.
      SUDEP: overview of definitions and review of incidence data.
      ,
      • Tomson T.
      • Walczak T.
      • Sillanpaa M.
      • Sander J.W.
      Sudden unexpected death in epilepsy: a review of incidence and risk factors.
      ,
      • Ficker D.M.
      Sudden unexpected death and injury in epilepsy.
      ,
      • Hitris N.
      • Suratman S.
      • Kelly K.
      • Stephen L.J.
      • Sills G.J.
      • Brodie M.J.
      Sudden unexpected death in epilepsy: a search for risk factors.
      ], longer duration of epilepsy [
      • Tomson T.
      • Walczak T.
      • Sillanpaa M.
      • Sander J.W.
      Sudden unexpected death in epilepsy: a review of incidence and risk factors.
      ,
      • McGugan E.A.
      Sudden unexpected deaths in epileptics—a literature review.
      ,
      • Hitris N.
      • Suratman S.
      • Kelly K.
      • Stephen L.J.
      • Sills G.J.
      • Brodie M.J.
      Sudden unexpected death in epilepsy: a search for risk factors.
      ,
      • Téllez-Zenteno J.F.
      • Hernández Ronquillo L.
      • Wiebe S.
      Sudden unexpected death in epilepsy: evidence-based analysis of incidence and risk factors.
      ,
      • Walczak T.S.
      • Leppik I.E.
      • D’Amelio M.
      • Rarick J.
      • So E.
      • Ahman P.
      • et al.
      Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study.
      ], symptomatic aetiology [
      • Annegers J.F.
      • Coan S.P.
      SUDEP: overview of definitions and review of incidence data.
      ,
      • Hesdorffer D.C.
      • Tomson T.
      • Benn E.
      • Sander J.W.
      • Nilsson L.
      • Langan Y.
      • et al.
      Combined analysis of risk factors for SUDEP.
      ], and associated learning disability [
      • Walczak T.S.
      • Leppik I.E.
      • D’Amelio M.
      • Rarick J.
      • So E.
      • Ahman P.
      • et al.
      Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study.
      ,
      • Hesdorffer D.C.
      • Tomson T.
      • Benn E.
      • Sander J.W.
      • Nilsson L.
      • Langan Y.
      • et al.
      Combined analysis of risk factors for SUDEP.
      ,
      • Young C.
      • Shankar R.
      • Palmer J.
      • Craig J.
      • Hargreaves C.
      • McLean B.
      • et al.
      Does intellectual disability increase sudden unexpected death in epilepsy (SUDEP) risk?.
      ]. Although fixed, the knowledge of these risk factors are useful for clinicians when counselling patients for SUDEP. More importantly for the drive to minimise the risk of SUDEP, several modifiable risk factors have also been identified. Consistently reported are higher frequency of GTCS [
      • Langan Y.
      Sudden unexpected death in epilepsy (SUDEP): risk factors and case control series.
      ,
      • Tomson T.
      • Walczak T.
      • Sillanpaa M.
      • Sander J.W.
      Sudden unexpected death in epilepsy: a review of incidence and risk factors.
      ,
      • Sperling M.R.
      Sudden unexpected death in epilepsy.
      ,
      • Ficker D.M.
      Sudden unexpected death and injury in epilepsy.
      ,
      • Téllez-Zenteno J.F.
      • Hernández Ronquillo L.
      • Wiebe S.
      Sudden unexpected death in epilepsy: evidence-based analysis of incidence and risk factors.
      ,
      • Langan Y.
      • Nashef L.
      • Sander J.W.
      Case-control study of SUDEP.
      ], and antiepileptic drug (AED) polytherapy [
      • Nilsson L.
      • Farahmand B.Y.
      • Persson P.-G.
      • Thiblin I.
      • Tomson T.
      Risk factors for sudden unexpected death in epilepsy: a case-control study.
      ,
      • Tomson T.
      • Walczak T.
      • Sillanpaa M.
      • Sander J.W.
      Sudden unexpected death in epilepsy: a review of incidence and risk factors.
      ,
      • Sperling M.R.
      Sudden unexpected death in epilepsy.
      ,
      • McGugan E.A.
      Sudden unexpected deaths in epileptics—a literature review.
      ,
      • Téllez-Zenteno J.F.
      • Hernández Ronquillo L.
      • Wiebe S.
      Sudden unexpected death in epilepsy: evidence-based analysis of incidence and risk factors.
      ,
      • Walczak T.S.
      • Leppik I.E.
      • D’Amelio M.
      • Rarick J.
      • So E.
      • Ahman P.
      • et al.
      Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study.
      ,
      • Lhatoo S.D.
      • Sander J.W.
      Cause-specific mortality in epilepsy.
      ], although it is recognised that AED polytherapy may be a surrogate for seizure frequency. Identification that the seizure frequency may increase in the months prior to a SUDEP has implications for SUDEP surveillance and healthcare system delivery [
      • Shankar R.
      • Jalihal V.
      • Walker M.
      • Laugharne R.
      • McLean B.
      • Carlyon E.
      • et al.
      A community study in Cornwall UK of sudden unexpected death in epilepsy (SUDEP) in a 9-year population sample.
      ]. The majority of SUDEP cases occur at night and several studies have reported that a lack of night-time surveillance as a risk factor for SUDEP [
      • Shankar R.
      • Cox D.
      • Jalihal V.
      • Brown S.
      • Hanna J.
      • McLean B.
      Sudden unexpected death in epilepsy (SUDEP): development of a safety checklist.
      ]. Inconsistently reported is the use of lamotrigine and carbamazepine; further research is required to establish their roles as potential SUDEP risk factors [
      • Shankar R.
      • Cox D.
      • Jalihal V.
      • Brown S.
      • Hanna J.
      • McLean B.
      Sudden unexpected death in epilepsy (SUDEP): development of a safety checklist.
      ,
      • Hesdorffer D.C.
      • Tomson T.
      • Benn E.
      • Sander J.W.
      • Nilsson L.
      • Langan Y.
      • et al.
      Combined analysis of risk factors for SUDEP.
      ,
      • Timmings P.L.
      Sudden unexpected death in epilepsy: is carbamazepine implicated?.
      ].

      4. SUDEP awareness

      Despite sudden deaths in people with epilepsy being reported for over a century, the concept of SUDEP only gained recognition just over two decades ago. Until the 1990s, there was almost no public awareness of its potential impact on people with epilepsy and very little in the medical literature. In the early 1995, the charity Epilepsy Bereaved was founded by families who had been affected by SUDEP in order to raise awareness amongst the public and medical community [

      SUDEP Action. Breaking the SUDEP taboo 1992–1995. Available at: https://sudep.org/breaking-sudep-taboo-1992-1995 [accessed 21.08.16].

      ]. The first international conference was held in 1996 which led to the first international publication on SUDEP [

      SUDEP Action. Grabbing international attention on SUDEP. Available at: https://sudep.org/grabbing-international-attention-sudep [accessed 21.08.16].

      ]. Following the landmark paper by Nashef in the same year which standardised the definition of SUDEP, research into SUDEP gained huge momentum. This is shown by the frequency of research using the word ‘SUDEP’ since the first instance in 1993 (Fig. 1), note the peak in 1997. It is worth noting that these first two papers were published in Seizure [
      • Drake M.E.
      • Reider C.R.
      • Kay A.
      Electrocardiography in epilepsy patients without cardiac symptoms.
      ,
      • Coyle H.P.
      • Baker-Brian N.
      • Brown S.W.
      Coroners’ autopsy reporting of sudden unexplained death in epilepsy (SUDEP) in the UK.
      ].
      Fig. 1
      Fig. 1The exponential growth in SUDEP research as measured by the use of the word ‘SUDEP’ in PubMed. The first instance is in 1993. The 2016 figures are for the year up to and including August.
      Increased awareness of SUDEP amongst the medical community has been vital in ensuring that cases of possible SUDEP are referred to the coroner for investigation. All cases should receive a tailored SUDEP autopsy in order to exclude other causes of death. There have been many reports of likely SUDEP cases being issued another cause of death, such as status epilepticus, or accidental death, by medical professionals and coroners despite there being no evidence for this. SUDEP may therefore be under-reported and the inaccurate classification of these deaths may skew epidemiological studies aiming to identify relevant risk factors.
      The discussion of SUDEP with patients and their caregivers has always been a controversial topic. The National Institute for Health and Care Excellence (NICE) updated their guidelines on epilepsy management in 2004 to include SUDEP [

      National Institute for Health and Care Excellence (NICE). Epilepsies: diagnosis and management [CG137]; 2012. Available at: www.nice.org.uk/guidance/cg137/chapter/1-guidance?unlid=107164064020164914651 [accessed 21.08.16].

      ]. They advise that giving patients tailored information about their risk of SUDEP should be done as part of a counselling checklist for children, young people and adults with epilepsy and their families.
      Several papers have been published that suggest that this is not routinely done in epilepsy clinics, with rates of clinicians routinely discussing SUDEP ranging from 4 to 6.8% [
      • Miller W.R.
      • Young N.
      • Friedman D.
      • Buelow J.M.
      • Devinsky O.
      Discussing sudden unexpected death in epilepsy (SUDEP) with patients: practices of health-care providers.
      ,
      • Waddell B.
      • McColl K.
      • Turner C.
      • Norman A.
      • Coker A.
      • White K.
      Are we discussing SUDEP? A retrospective case note analysis.
      ,
      • Friedman D.
      • Donner E.J.
      • Stephens D.
      • Wright C.
      • Devinsky O.
      Sudden unexpected death in epilepsy: knowledge and experience among U.S. and Canadian neurologists.
      ]. The most common reasons given for not discussing SUDEP are that neurologists feel that their patients are at low risk and the fear of a negative reaction [
      • Friedman D.
      • Donner E.J.
      • Stephens D.
      • Wright C.
      • Devinsky O.
      Sudden unexpected death in epilepsy: knowledge and experience among U.S. and Canadian neurologists.
      ]. The commonest reasons given for discussing SUDEP were the patient enquiring about it and the neurologist counselling someone with known SUDEP risk factors [
      • Morton B.
      • Richardson A.
      • Duncan S.
      Sudden unexpected death in epilepsy (SUDEP): don’t ask, don’t tell?.
      ]. Beran et al. reported in 2004 that to disclose the risk of SUDEP when not sought by the patient may in fact be unethical and transgress the basic principle to “do no harm”, as there is no proven intervention to minimise SUDEP and that knowledge of the condition may negatively impact quality of life [
      • Beran R.G.
      • Weber S.
      • Sungaran R.
      • Venn N.
      • Hung A.
      Review of the legal obligations of the doctor to discuss Sudden Unexplained Death in Epilepsy (SUDEP)—a cohort controlled comparative cross-matched study in an outpatient epilepsy clinic.
      ]. It was also reported that doctors are unlikely to be found negligent for not discussing SUDEP as, unlike the ‘back to sleep’ campaign for lessening sudden infant death, there is no proven treatment or intervention [
      • Beran R.G.
      • Weber S.
      • Sungaran R.
      • Venn N.
      • Hung A.
      Review of the legal obligations of the doctor to discuss Sudden Unexplained Death in Epilepsy (SUDEP)—a cohort controlled comparative cross-matched study in an outpatient epilepsy clinic.
      ,
      • Beran R.G.
      SUDEP revisited—a decade on: have circumstances changed?.
      ]. However, there is mounting evidence that patients and their families do wish to be informed of the risk of SUDEP, both within the paediatric and adult population [
      • Gayatri N.A.
      • Morrall M.C.H.J.
      • Jain V.
      • Kashyape P.
      • Pysden K.
      • Ferrie C.
      Parental and physician beliefs regarding the provision and content of written sudden unexpected death in epilepsy (SUDEP) information.
      ,
      • Ramachandrannair R.
      • Jack S.M.
      • Meaney B.K.
      • Ronen G.M.
      SUDEP: what do parents want to know?.
      ,
      • Tonberg A.
      • Harden J.
      • McLellan A.
      • Chin R.F.
      • Duncan S.
      A qualitative study of the reactions of young adults with epilepsy to SUDEP disclosure, perceptions of risks, views on the timing of disclosure, and behavioural change.
      ]. Despite not routinely being informed of the risk, this does not mean that patients are ignorant of SUDEP and they may resort to inaccurate and unreliable information sources that do not take into account their personal risk of SUDEP [
      • Morton B.
      • Richardson A.
      • Duncan S.
      Sudden unexpected death in epilepsy (SUDEP): don’t ask, don’t tell?.
      ]. Given that the majority of reported patient reactions by physicians are negative following these conversations, further research is required to determine the best way of delivering the information to patients and their families [
      • Friedman D.
      • Donner E.J.
      • Stephens D.
      • Wright C.
      • Devinsky O.
      Sudden unexpected death in epilepsy: knowledge and experience among U.S. and Canadian neurologists.
      ].

      5. Treatment and prevention

      There remains no effective evidence-based treatment or prevention against SUDEP. The mainstay of management has been in addressing the modifiable risk factors to reduce SUDEP risk. This includes promoting AED compliance to reduce the incidence of GTCS and making patients and families aware of the potential consequences of uncontrolled nocturnal seizures [

      National Institute for Health and Care Excellence (NICE). Epilepsies: diagnosis and management [CG137]; 2012. Available at: www.nice.org.uk/guidance/cg137/chapter/1-guidance?unlid=107164064020164914651 [accessed 21.08.16].

      ]. The use of a safety checklist has gained interest since it was first proposed and has subsequently been developed in to a smart-phone app [
      • Shankar R.
      • Cox D.
      • Jalihal V.
      • Brown S.
      • Hanna J.
      • McLean B.
      Sudden unexpected death in epilepsy (SUDEP): development of a safety checklist.
      ]. Patient education is important in promoting adherence to AEDs, avoiding factors that may trigger seizures, appropriately reacting to clusters of seizures and being aware of the interaction of other drugs with AEDs [
      • Ryvlin P.
      • Nashef L.
      • Tomson T.
      Prevention of sudden unexpected death in epilepsy: a realistic goal?.
      ]. Lattice pillows have been proposed as an intervention to reduce the risk of airway obstruction [
      • Ryvlin P.
      • Nashef L.
      • Tomson T.
      Prevention of sudden unexpected death in epilepsy: a realistic goal?.
      ,
      • Devinsky O.
      Sudden, unexpected death in epilepsy.
      ,
      • Rugg-Gunn F.
      • Duncan J.
      • Hjalgrim H.
      • Seyal M.
      • Bateman L.
      From unwitnessed fatality to witnessed rescue: nonpharmacologic interventions in sudden unexpected death in epilepsy.
      ], but there have been no studies to evaluate their use in epilepsy. Nocturnal supervision has been found to be protective against SUDEP in one study [
      • Langan Y.
      • Nashef L.
      • Sander J.W.
      Case-control study of SUDEP.
      ], possibly suggesting that nocturnal seizure alarms may have a role in improving night-time supervision [
      • Ryvlin P.
      • Nashef L.
      • Tomson T.
      Prevention of sudden unexpected death in epilepsy: a realistic goal?.
      ,
      • Rugg-Gunn F.
      • Duncan J.
      • Hjalgrim H.
      • Seyal M.
      • Bateman L.
      From unwitnessed fatality to witnessed rescue: nonpharmacologic interventions in sudden unexpected death in epilepsy.
      ]. The use of selective serotonin reuptake inhibitors (SSRI), opiate receptor inhibitors, adenosine receptor inhibitors, cardiac pacemakers and implantable cardiac defibrillators (ICD) have also been proposed as future targets for SUDEP prevention but there have been no trials examining the benefits of these in the prevention of SUDEP [
      • Ryvlin P.
      • Nashef L.
      • Tomson T.
      Prevention of sudden unexpected death in epilepsy: a realistic goal?.
      ].
      Within the hospital setting, several interventions are recommended to reduce the duration of seizures, respiratory dysfunction and EEG suppression. These include repositioning of the patient, oral suctioning and oxygen administration as well as prompt administration of AED if indicated [
      • Rugg-Gunn F.
      • Duncan J.
      • Hjalgrim H.
      • Seyal M.
      • Bateman L.
      From unwitnessed fatality to witnessed rescue: nonpharmacologic interventions in sudden unexpected death in epilepsy.
      ]. The MORTEMUS study also showed that in near-SUDEP cases, resuscitation was prompt whereas in the SUDEP cases it was delayed suggesting that close monitoring of patients in hospital with the use of direct supervision, ECG, EEG and oxygen saturations may reduce the risk of SUDEP [
      • 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.
      ,
      • Rugg-Gunn F.
      • Duncan J.
      • Hjalgrim H.
      • Seyal M.
      • Bateman L.
      From unwitnessed fatality to witnessed rescue: nonpharmacologic interventions in sudden unexpected death in epilepsy.
      ].
      Ultimately there remains no consistently proven preventative strategy or treatment for SUDEP [
      • Maguire M.J.
      • Jackson C.F.
      • Marson A.G.
      • Nolan S.J.
      Treatments for the prevention of Sudden Unexpected Death in Epilepsy (SUDEP).
      ], although several of those described show promise and deserve further research to determine their effectiveness.

      6. The next 25 years

      There are several key challenges that we face over the next 25 years in improving epilepsy care provided to patients and minimising the devastating impact of SUDEP. More research is required into the pathophysiology of SUDEP which may ultimately lead to the development of preventative strategies. It is quite plausible that just as we consider ‘epilepsy’ to be a collection of disparate epilepsies, we may need to identify the pathophysiologies of SUDEP. The reliance of EEG as a key biomarker for determining PGES currently limits all studies of SUDEP in the community. The identification of biomarkers for SUDEP that go beyond electrophysiological measures may help this.
      As discussed, many significant risk factors have been identified that place patients with epilepsy at increased risk of SUDEP. Whilst some of these are not modifiable, those that are must be addressed with each patient. In particular, seizure control must be optimised and nocturnal seizures minimised. Clinicians can focus on communicating the benefits of medication adherence and tailoring the medication regimen to the person with the use of longer-acting agents where indicated. Sleep-related convulsions may not always be recognised by the patient and when they do occur, they may be perversely considered to be benign as they may not necessarily affect driving status [
      • Thomas R.H.
      • King W.H.
      • Johnston J.A.
      • Smith P.E.
      Awake seizures after pure sleep-related epilepsy: a systematic review and implications for driving law.
      ] and they occur in a place of perceived safety.
      There needs to be increased awareness of SUDEP both by healthcare professionals and by patients as it is only by doing this that patient risk factors for SUDEP can be addressed. Whilst there are many studies reporting the lack of discussion of SUDEP with patients and the fact that patients and their caregivers wish to receive such information, there is further work required to identify the best way in which to divulge this information whilst minimising patient anxiety and distress. Increased awareness of SUDEP within the wider medical community beyond the specialty of neurology is also required, to encourage the reporting of sudden epilepsy deaths to the coroner and for adequate SUDEP post mortem examinations to be undertaken. This may lead to better appreciation of the pathophysiology of SUDEP and the identification of more modifiable risk factors.
      Through the above, a better understanding of SUDEP may lead to effective prevention strategies. It is chilling to recognise that most people with epilepsy who die a SUDEP death, die alone. More research is required particularly for the role of nocturnal supervision of epilepsy patients, as though it is currently suggested in the literature that supervision is protective, to routinely advise this could have a deleterious effect on the quality of life of epilepsy patients and should not be undertaken lightly without substantive evidence for its recommendation. Nocturnal seizure alarms appear to be a promising alternative and these warrant further research to determine whether offer any protection against SUDEP. Further research is also required to determine the effectiveness of SSRIs, opiate and adenosine receptor inhibitors, cardiac pacemakers and ICDs in the prevention of SUDEP. We hope that reducing the treatment gap and ensuring the highest quality epilepsy care for everyone may reduce SUDEP rates; already there is evidence that successful epilepsy surgery reduces mortality, in part, by lowering SUDEP rates [
      • Sperling M.R.
      • Barshow S.
      • Nei M.
      • Asadi-Pooya A.A.
      A reappraisal of mortality after epilepsy surgery.
      ].
      The aim in 25 years is to reduce the incidence of SUDEP and the anxiety that the threat of SUDEP has on patients and their families. The ultimate goal is to find a treatment or prevention so effective that it is abolished. Hopefully through continued high quality research as has been the case over the last two decades, this is an attainable goal.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Conflict of interest statement

      We have no relevant conflicts of interest to RHT has received research support from Epilepsy Research UK, Action Medical Research, Epilepsy Action and the Dravet Society; he is the web editor of Seizure; he has received honoraria from Eisai, Sanofi and UCB.

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