Summary of the 2016 Partners Against Mortality in Epilepsy (PAME) Conference.

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Summary of the 2016 Partners Against Mortality in Epilepsy (PAME) Conference

Abstract Authors: Kevin D Graber, MD, Jeffrey Buchhalter, MD, PhD, Elson So, MD, Rainer Surges, MD, Detlev Boison, PhD, Franck Kalume, PhD, Cyndi Wright, Brian Gehlbach, MD, Jeff Noebels, MD, PhD, Vicky Whittemore, PhD, Elizabeth J. Donner, MD, MSc, Tom Stanton, MPP, Henry Smithson, MD, Jane Hanna, Masud Seyal, MD, PhD, Philippe Ryvlin, MD, PhD

The third biannual Partners Against Mortality in Epilepsy (PAME) conference was held in Alexandria, VA from June 2326, 2016. This was an intimate meeting of clinical and basic scientists, clinicians, people affected by Sudden Unexpected Death in Epilepsy Patients (SUDEP) in a loved one, people living with epilepsy and patient advocate organizations. Plenary sessions have been summarized by moderators, including: 1) Mortality in people with epilepsy: epidemiology and surveillance. 2) Mortality in children. 3) What do we know about the factors that predispose certain people to die from a seizure? 4) What are the events that occur during and after a seizure that cause a death in SUDEP? 5) What are the options for prevention now and in the future? 6) Advocacy perspectives: how can we speed up awareness and prevention? 7) Updates and discussion on select programs in mortality research. Breakout sessions allowed for a more focused audience. Those summarized here are: Frequent non-SUDEP causes of mortality in people with epilepsy; Mechanisms of SUDEP; Lessons learned in grief and how to better support families; Future directions for research to impact prevention; and How do we improve SUDEP risk disclosure? While significant progress has been made with review of human mortality in epilepsy and study of animal models, this meeting emphasized the need for: better understandings of the epidemiology of SUDEP, advances in the understandings of mechanisms, continued search for biomarkers and preventative measures, patient education, increased awareness, continued advocacy for patient and family support and research funding.

Introduction to Moderator Summaries Kevin Graber, MD, Enduring Materials Committee

The third biannual PAME conference occurred in Alexandria, VA from June 23-26, 2016, an intimate meeting of scientists, clinicians and patient advocates—families and friends of those affected by epilepsy and mortality. Walter Koroshetz, MD, director of the National Institute of Neurological Disease and Stroke (NINDS) welcomed the group, acknowledged the importance of issue and interest in continued funding of projects. The term “unexplained” has been retired and the “U” in the acronym is sudden unexpected death in epilepsy patients (SUDEP); evidence supports seizures as the proximate cause. A recent overall incidence estimate is 1.11 per 1,000 annually in the United States (1), but this varies considerably in specific circumstances. Annual epilepsy related mortality in children is generally lower, ~0.36 per 1,000 with uncomplicated epilepsy cases, but up to 7.43 per 1,000 in those with underlying Epilepsy Currents, Vol. 16, No. 6 Supplement 2016 pp. 1–17 © American Epilepsy Society

additional neurological disability (2). Notable additional risk factors for mortality include increased frequency of seizures, nocturnal seizures, adults under 40 years old, prone position, occurrence of generalized convulsive seizures with a true tonic phase, and generalized post ictal generalized EEG suppression (3). The reasons for generally higher adult than pediatric risk are unclear, but hypotheses are that factors predisposing to autonomic dysfunction (e.g. 4,5) may take time to develop, or children might be better able to withstand autonomic fluctuations during seizure (6). Another hypothesis is that this is due to more supervision in children; nocturnal monitoring might be protective (3,7). One speaker suggested that avoidance of sleeping prone might help, while other speakers noted that significant movement occurs during seizures; currently there isn’t evidence that avoiding the prone position when falling asleep is protective. Among potentially sufficient mechanisms, respiratory dysfunction appears to be somewhat more common than cardiac dysrhythmia or electrocerebral suppression in examples in humans and animal models (3,8-10), however, there is an interplay between these processes. It is notable that supplemental oxygenation administration alone would not be expected to compensate for respiratory failure. Emerging data suggest that some drugs that inhibit serotonin reuptake reduce respiratory arrest in some SUDEP animal models as well

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2016 Partners Against Mortality in Epilepsy Conference

as seizure-related oxygen desaturations in humans (at least in complex partial seizures) (see 11 for review). Suggested additional potential protective interventions might also include nocturnal supervision, seizure-alarm devices, anti-suffocation pillows, and methods to avoid missed medications. Although promising recent progress has been made, data remain insufficient to create accurate individualized patient risk calculators. This is one goal of the Center for SUDEP Research (CSR) (12). Unfortunately, there remains a considerable variation in risk disclosure by clinicians, despite the clear desire of patients/families to receive this information. Practitioners with less experience in care of epilepsy, no experience in SUDEP, and fatalistic views are less likely to discuss SUDEP with their patients (13,14). The inclusion of patient advocates and bereaved families at this meeting focused the need for better education of practitioners and medical examiners, better family support mechanisms, the search for antemortem biomarkers and implementation of preventative measures. There were plenary sessions addressing epidemiology and surveillance, mortality in children, predisposing factors, events during and after seizures leading to death, prevention, advocacy perspectives, and updates on select research programs. Breakout sessions allowed discussion among a more targeted audience; summaries included here are those on non-SUDEP epilepsy related mortality, in depth exploration of SUDEP mechanisms, lessons learned with advocacy efforts, future research efforts in prevention, and better risk disclosure. Links to the program including supporters and partners (15) and plenary handouts (16) are available online. Overall, this meeting stressed the need for: better understandings of the epidemiology of SUDEP; advances in the understandings of mechanisms; continued search for biomarkers; patient education; increased awareness and disclosure by providers; continued advocacy for patient and family support and research funding. References 1. Thurman DJ, Hesdorffer DC, French JA. Sudden unexpected death in epilepsy: assessing the public health burden. Epilepsia 2014;55:1479– 1485. 2. Berg AT, Nickels K, Wirrell EC, Geerts AT, Callenbach PM, Arts WF, Rios C, Camfield PR, Camfield CS. Mortality risks in new-onset childhood epilepsy. Pediatrics 2013;132:124–131. 3. Ryvlin P, Nashef L, Lhatoo SD, Bateman LM, Bird J, Bleasel A, Boon P, Crespel A, Dworetzky BA, Høgenhaven H, Lerche H, Maillard L, Malter MP, Marchal C, Murthy JM, Nitsche M, Pataraia E, Rabben T, Rheims S, Sadzot B, Schulze-Bonhage A, Seyal M, So EL, Spitz M, Szucs A, Tan M, Tao JX, Tomson T. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurology 2013;12:966–977. 4. Mueller SG, Bateman LM, Laxer KD. Evidence for brainstem network disruption in temporal lobe epilepsy and sudden unexplained death in epilepsy. Neuroimage Clin 2014;9:208–216. 5. Lacuey N, Zonjy B, Theerannaew W, Loparo KA, Tatsuoka C, Sahadevan J, Lhatoo SD. Left-insular damage, autonomic instability, and sudden unexpected death in epilepsy. Epilepsy Behav 2016;55:170– 173. 6. Sarkis RA, Thome-Souza S, Poh MZ, Llewellyn N, Klehm J, Madsen JR, Picard R, Pennell PB, Dworetzky BA, Loddenkemper T, Reinsberger C.. Autonomic changes following generalized tonic clonic seizures:

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An analysis of adult and pediatric patients with epilepsy. Epilepsy Res 2015;115:113–118. Nashef L, Fish DR, Garner S, Sander JW, Shorvon SD. Sudden death in epilepsy: a study of incidence in a young cohort with epilepsy and learning difficulty. Epilepsia 1995;36:1187–1194. Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, Julius D. Eating disorder and epilepsy in mice lacking 5‑HT2C serotonin receptors. Nature 1995;374:542–546. Faingold CL, Randall M, Tupal S. DBA/1 mice exhibit chronic susceptibility to audiogenic seizures followed by sudden death associated with respiratory arrest. Epilepsy Behav 2010;17:436–440. Buchanan GF, Murray NM, Hajek MA, Richerson GB. Serotonin neurones have anti-convulsant effects and reduce seizure-induced mortality. J Physiol 2014;592:4395–4410. Goldman AM, Behr ER, Semsarian C, Bagnall RD, Sisodiya S, Cooper PN. Sudden unexpected death in epilepsy genetics: Molecular diagnostics and prevention. Epilepsia 2016;57(Suppl 1):17–25. Source: www.sudepresearch.org. Accessed September 2016. Donner EJ, Waddell B, Osland K, Leach JP, Duncan S, Nashef L, Picot MC. After sudden unexpected death in epilepsy: Lessons learned and the road forward. Epilepsia 2016;57(Suppl 1):46–53. Strzelczyk A, Zschebek G, Bauer S, Baumgartner C, Grond M, Hermsen A, Kieslich M, Krämer G, Kurlemann G, May TW, Mayer T, Neubauer BA, Pfäfflin M, Plecko B, Ryvlin P, Schubert-Bast S, Stefan H, Trinka E, Knake S, Seifart C, Rosenow F. Predictors of and attitudes toward counseling about SUDEP and other epilepsy risk factors among Austrian, German, and Swiss neurologists and neuropediatricians. Epilepsia 2016;57:612–620. Source: http://pame.aesnet.org/sites/default/files/PAME-PROGRAM-2016.pdf. Accessed September 2016. Source: http://pame.aesnet.org/?q=node/26. Accessed September 2016.

Session Summary: Mortality in People with Epilepsy: Epidemiology and Surveillance Moderator: Vicky Whittemore, PhD

This session explored the epidemiology of epilepsy-related mortality, suicide, and case registries. A panel discussed how to get correct data, ensure that all populations are being explored, and how to improve case ascertainment. Epidemiology of epilepsy-related mortality Presented by Dale C. Hesdorffer, PhD

The new classifications of status epilepticus (SE) put forward by the International League Against Epilepsy (ILAE) provide for better representation of seizure types in the new classification which may lead to better therapeutic interventions (1). For those with Prolonged Refractory Status Epilepticus (PRSE), there is a 66% survival to discharge from the hospital and good outcome for 22% at 6 months post PRSE (2). Almost half of the Individuals with New-onset Refractory Status Epilepticus (NORSE) have an autoimmune or paraneoplastic etiology after investigation. Many individuals survive and do well, despite NORSE, and epilepsy develops in 57% (3). The age-adjusted incidence of sudden unexpected death in epilepsy (SUDEP) in the United States (US) is 1.11 SUDEPs per 1,000 people with epilepsy (adjusted for the 2000 standard


population) (4). Using the US and European population estimates in 2013, there were an estimated 2,750 SUDEPs per year in the US, and 3,994 SUDEPs per year in the 28 nations of the European Union. Dr. Hesdorffer made the point that the exclusion of drowning from cases of SUDEP may be inappropriate since changes are seen in the autonomic nervous system with water emersion in normal populations and in those with epilepsy. Aberrant control of cardiac or respiratory function may occur more in individuals with epilepsy as demonstrated in SUDEP and drowning, and similar findings are seen in individuals with SE. She concluded that drowning, SUDEP and SE all share an aberrant control of cardiac and respiratory function that lead to death. Suicide among people with epilepsy Presented by Niu Tan, MD, PhD

Patients with epilepsy may have a stronger tendency toward suicide than healthy controls (5). Dr. Tan, from the Centers for Disease Control and Prevention, discussed a populationbased study using the U.S National Violent Death Reporting System (NVDRS) from 17 states, from 2003 – 2011 (6). Annual suicide mortality rate in epilepsy averaged 16.89 (range 13.01- 23.20)/100,000, which was 22% higher than the general population. Of total suicide deaths in the population, 1.2% were in people with epilepsy. Those with epilepsy were more likely to complete suicide in their place of residence, and twice as likely to poison themselves as suicides in those without epilepsy (38% vs 17%). Those 40-49 years of age and being unmarried were risk factors. Family/social support may be crucial in prevention of suicide among people with epilepsy. To help prevent suicide, people with epilepsy may benefit from having caregivers, relatives, and friends supervise the availability of potentially harmful materials including drugs. Case ascertainment and registries: what information is currently being collected in the US/UK/Australia? Presented by Heather MacLeod, MS, CGC

The Program Manager for The Sudden Death in the Young (SDY) Case Registry for the Data Coordinating Center described the goals of the Registry. The SDY is working to count, understand and prevent sudden death in the young. The project is funded by the National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC). The SDY Data Coordinating Center, located in Michigan, is working to implement the SDY Case Registry. Ten states are currently funded to compile data and collect samples for DNA extraction on SDY cases. The Registry is compiling information from autopsies, death scene investigations, family and medical history and DNA samples obtained at the time of autopsy. The National Heart, Lung, and Blood Institute (NHLBI) has funded 3 researchers to study the consented DNA samples and information compiled on cases. NHLBI-funded researchers will collaborate with the National Institute of Neurological Disease and Stroke (NINDS)-funded Center for SUDEP Research investigators on SUDEP (7).

Challenges and opportunities to understand sudden unexpected death in epilepsy (SUDEP) using death certificate data Presented by Margaret Warner, MPH

This talk discussed issues surrounding the death certificate and death scene investigations as they related to mortality in epilepsy. There is not a consensus on the use of SUDEP on the death certificate, so cause of death may be recorded in many different ways making use of death certificate information a less reliable way in which to determine the numbers of deaths. Overall, it was agreed that there is a need for increased and ongoing surveillance of mortality in epilepsy, as well as for research to understand the underlying causes of death associated with epilepsy. References 1. Trinka E, Cock H, Hesdorffer D, Rossetti AO, Scheffer IE, Shinnar S, Shorvon S, Lowenstein DH. A definition and classification of status epilepticus – Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia 2015;56:1515–1523. 2. Kilbride RD, Reynolds AS, Szaflarski JP, Hirsch LJ. Clinical outcomes following prolonged refractory status epilepticus (PRSE). Neurocrit Care 2013;18:374–385. 3. Gaspard N, Foreman BP, Alvarez V, Cabrera Kang C, Probasco JC, Jongeling AC, Meyers E, Espinera A, Haas KF, Schmitt SE, Gerard EE, Gofton T, Kaplan PW, Lee JW, Legros B, Szaflarski JP, Westover BM, LaRoche SM, Hirsch LJ; Critical Care EEG Monitoring Research Consortium (CCEMRC). New-onset refractory status epilepticus: Etiology, clinical features, and outcome. Neurology 2015;85:1604–1613. 4. Thurman DJ, Hesdorffer DC, French JA. Sudden unexpected death in epilepsy: assessing the public health burden. Epilepsia 2014;55:1479– 1485. 5. CDC, Morbidity and Mortality Weekly Report (MMWR), 2014;63:1–33; contact [email protected] for more information. 6. Bell GS, Gaitatzis A, Bell CL, Johnson AL, Sander JW. Epilepsia 2009;50:1993–1942. 7. Source: http://www.nhlbi.nih.gov/news/spotlight/fact-sheet/frequently-asked-questions-about-sudden-death-young-case-registry. Accessed September 2016.

Session Summary: Mortality in Children Moderator: Elizabeth J. Donner, MD, MSc, FRCPC

This session started with advocate/parent speakers, Shannon Bursick, MD and Joe Bursick. The session focused on the data available about mortality in children with epilepsy, with comparison to the SUDEP literature in adults. Advocacy groups ask for increased awareness and research efforts to translate into prevention. A panel discussed why overall numbers are a bit less than adults. The reasons are unknown and more research is necessary, but hypotheses include potentially differences in seizure types, resilience of youth (stronger bodies?), and possibly parental supervision. The facts about mortality in pediatric epilepsy Presented by Anne Berg, PhD

Children with epilepsy have a significantly elevated risk of premature mortality compared to the general population. In a

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study of mortality in 4 cohorts on newly diagnosed childhood epilepsy, the mortality rate was 260 per 100 000 per year, up to 10 times higher than mortality in children without epilepsy. What these authors demonstrated, however, is that the majority of deaths were in children with significant neurodisability. Mortality rates in children with complicated epilepsy, defined as epilepsy associated with neurodisability or an underlying brain condition, was 743 per 100,000 per year in contrast to only 36 per 100,000 per year in uncomplicated epilepsy (1). Most excess death in young people with epilepsy is not seizure-related and is most often related to acute or chronic respiratory conditions. In the 4 combined cohorts, the seizure-related death rates were 43 per 100,000 per year, again more common in complicated epilepsy at 122 per 100,000 per year in contrast to 14 per 100,000 per year in uncomplicated epilepsy. Seizurerelated deaths accounted for 19% of all deaths and included 10 cases of SUDEP and 3 due to other seizure-related causes. In uncomplicated epilepsy, sudden and seizure-related death rates were similar to rates for other common causes of death in young people such as accidents, suicides and homicides. Based on our current understanding of mortality in children with epilepsy it is possible to identify low, moderate and high-risk categories by type of epilepsy. The literature suggests that children at the highest risk include those with epileptic encephalopathies, such as Dravet and Lennox Gastaut Syndromes. In these children, most mortality is not seizure-related and most often is related to aspiration or non-aspiration pneumonia. Children at moderate risk include those with non-syndromic epilepsies. In this group, mortality risk is modified by the presence of neurodisability and other comorbidities. Finally, the group at lowest risk appears to be children with childhood epilepsy syndromes such as Juvenile Myoclonic Epilepsy and the Benign Partial Epilepsies of Childhood. Mortality rates are very low in these populations and based on current literature there is no measurable risk of seizure-related deaths. While it is important to recognize that all people with epilepsy are at risk, the children in this group are by far at the lowest risk. Children with epilepsy and their families are confronted by the possibility of seizure-related deaths and premature mortality. This data may be helpful to inform families and stratify risk. Relating the risk of death in epilepsy to familiar risks may facilitate discussions of seizure-related mortality with children and families. SUDEP in children: compare and contrast with adult literature Presented by Sanjeev Kothare, MD

While SUDEP does occur in children, it is noted to be up to 10 times less common. (2) Several hypotheses exist for the decreased risk of sudden death in children, related to the known risk factors for SUDEP and potential biomarkers. First, it is possible that nocturnal and daytime supervision of children with epilepsy results in more frequent ictal interventions that reduce deaths. This may be supported by the MORTEMUS Project in which deaths in the epilepsy monitoring unit occurred more in individuals who did not receive prompt peri- or post-ictal care and by earlier work suggesting that nocturnal supervision is protective for SUDEP (3,4).

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It is also hypothesized that better cardiopulmonary reserve may allow children to easier tolerate periods of apnea and hypoventilation. A study of cardiopulmonary complications associated with seizures in children found patterns associated with ictal bradycardia, apnea, and hypoxemia related to age, gender, side of the epileptogenic zone and seizure type and duration. The authors concluded that potentially life-threatening cardiopulmonary abnormalities are associated with predictable patient and seizure characteristics (5). Further, children may be better able to tolerate the physical effects of seizures and be less prone to autonomic shutdown and postictal generalized EEG suppression (PGES) as seen in adult cases of SUDEP. This was explored in a study of postictal autonomic changes in children and adults. In a sample of 20 people with epilepsy of varied ages, age was strongly correlated with both durations of PGES and electrodermal activity. Children had greater sympathetic activation and higher vagal suppression (6). These finding may provide clues about the variable age effects of seizures on the autonomic nervous system Further study of SUDEP in children is needed. By focusing study on children with epilepsy and SUDEP in children, we may be able to identify protective features that can be translated to preventative strategies for all people living with epilepsy. Lessons learned in sudden unexpected death in childhood Presented by Laura Crandall, MA

Sudden Unexpected Death in Childhood (SUDC) is the sudden death of a child older than one year of age, which remains unexplained after a thorough case investigation (7). The incidence of SUDC among children 1-18 years of age is approximately 344 deaths per year in the US, making it the 5th leading cause of death in children aged 1-4 years. In contrast to Sudden Infant Death Syndrome (SIDS), where genetic discoveries and extensive risk reduction public awareness programs have decreased rates by 50% over the past two decades, very little progress has been made towards understanding the pathogenesis of SUDC and rates of SUDC have doubled during this period. The absence of standards for post mortem examinations and infrequent organ retention and genetic specimen availability significantly hamper meaningful research. Furthermore, in contrast to SIDS research, which has received greater than $500 million in funding over the last 20 years, SUDC research funding has totaled less than 10 million over the same time period. The SUDC Foundation is the only organization worldwide that is dedicated to increasing awareness of sudden unexpected deaths in childhood, funding crucial research into the causes and prevention of SUDC, and advocating for the needs of families affected by these tragedies. The Foundation was founded by parents struggling to understand the unexplained deaths of their own children and has grown into a powerful research and lobby organization. The Foundation was instrumental in bringing forward the Sudden Unexpended Death Data Enhancement and Awareness Act, signed by President Obama in 2014. From 2011 to 2014, the SUDC had reported 123 cases of SUDC. These were predominantly males, most born singleton


at term and most often found prone from sleep. It was noted that 32% had a history of febrile seizures, suggesting a possible link to SUDEP (7,8). The SUDC Registry and Research Collaborative has been formed at NYU to study the risk that lead to SUDC. Cases are reviewed, genetic testing is performed when able and families are provided with a study report. The goal is to identify at risk individuals and establish prevention strategies. Researchers working in the field of epilepsy mortality will benefit from the experience of the SUDC Foundation, which has brought forward the need for standardized death evaluation and research. References 1. Berg AT, Nickels K, Wirrell EC, Geerts AT, Callenbach PM, Arts WF, Rios C, Camfield PR, Camfield CS. Mortality risks in new-onset childhood epilepsy. Pediatrics 2013;132:124–131. 2. Donner EJ, Smith CR, Snead OC, 3rd. Sudden unexplained death in children with epilepsy. Neurology 2001;57:430–434. 3. Ryvlin P, Nashef L, Lhatoo SD, Bateman LM, Bird J, Bleasel A, Boon P, Crespel A, Dworetzky BA, Høgenhaven H, Lerche H, Maillard L, Malter MP, Marchal C, Murthy JM, Nitsche M, Pataraia E, Rabben T, Rheims S, Sadzot B, Schulze-Bonhage A, Seyal M, So EL, Spitz M, Szucs A, Tan M, Tao JX, Tomson T. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurology 2013;12:966–977. 4. Nashef L, Fish DR, Garner S, Sander JW, Shorvon SD. Sudden death in epilepsy: a study of incidence in a young cohort with epilepsy and learning difficulty. Epilepsia 1995;36:1187–1194. 5. Singh K, Katz ES, Zarowski M, Loddenkemper T, Llewellyn N, Manganaro S, Gregas M, Pavlova M, Kothare SV. Cardiopulmonary complications during pediatric seizures: a prelude to understanding SUDEP. Epilepsia 2013;54:1083–1091. 6. Sarkis RA, Thome-Souza S, Poh MZ, Llewellyn N, Klehm J, Madsen JR, Picard R, Pennell PB, Dworetzky BA, Loddenkemper T, Reinsberger C.. Autonomic changes following generalized tonic clonic seizures: An analysis of adult and pediatric patients with epilepsy. Epilepsy Res 2015;115:113–118. 7. Krous HF, Chadwick AE, Crandall L, Nadeau-Manning JM. Sudden unexpected death in childhood: a report of 50 cases. Pediatr Dev Pathol 2005;8:307–319. 8. Hesdorffer DC, Crandall LA, Friedman D, Devinsky O. Sudden unexplained death in childhood: A comparison of cases with and without a febrile seizure history. Epilepsia 2015;56:1294–1300.

Session Summary: What Do We Know About the Factors that Predispose Certain People to Die from a Seizure? Moderators: Rainer Surges, MD and Elson So, MD

This session focused factors that predispose patients to SUDEP, and started with a parent story by Trish Barns. The session continued with a discussion of the autonomic nervous system and the potential role in SUDEP, and explored potential genetic factors. Seizure type and sleep are also important factors. Secondarily tonic clonic seizures with a true tonic phase appear to convey elevated risk. Although the prone position is a risk factor, patients move during seizures and there likely is little role in encouraging a specific sleep position. Issues of medication non-compliance and traumatic injuries from seizures were also discussed.

How does a disturbed autonomic nervous system facilitate SUDEP? Presented by Brian Moseley, MD

Dr. Moseley (University of Cincinnati) pointed out that various disturbances of autonomic functions occur in people with epilepsy and in association with epileptic seizures that may lead to or facilitate SUDEP. Cardiac dysfunction includes sinus tachycardia (which occurs with the majority of seizures and which can be prominent and long-lasting especially in the context of generalized tonic-clonic seizures, GTCS), stressinduced cardiomyopathy, bradycardia (occurring in up to 4% of seizures) and asystole (occurring in up to 0.5% of patients), abnormalities of cardiac repolarization (peri-ictal prolongation or shortening of QT intervals, potentially triggering the onset of ventricular tachyarrhythmias) and decreased heart rate variability (which is associated with an increased risk of sudden cardiac death (1,2). Seizures also induce transitory hypoventilation (especially due to central apnea) in up to one third of seizures, leading to hypoxemia and hypercapnia (3). Seizurerelated respiratory dysfunction may be caused by disrupted activity of brainstem respiratory centers, seizure-induced pulmonary right-to-left shunt, and/or neurogenic pulmonary edema. Which genes could play a role in SUDEP? Presented by Alicia Goldman, MD, PhD

Dr. Goldman (Baylor College of Medicine, Houston) explained that research in animal models and in people with epilepsy has led to the identification of candidate SUDEP genes important for cardio-autonomic and respiratory functions as well as for arousal from sleep. For instance, serotoninreceptor (5HT2C) knock-out mice as well mice lacking serotonin neurons are susceptible to convulsive seizures and premature mortality. Similarly, serotonin neurons and 5-HT2A receptors, are especially important for arousal from sleep due to rising CO2. Interestingly, treatment with antidepressants that inhibit serotonin reuptake reduced lethal respiratory arrest in animal models and seizure-related desaturations in humans. An increasing number of studies making use of transgenic animal models revealed that genes and mutations typically causing cardiac arrhythmias are also expressed in the brain (e.g. KCNQ1, SCN5A); and animals in the different models displayed epileptic seizures, cardiac arrhythmias and sudden death. Conversely, some mutations in selected genes with primary association to epilepsy exert effects on cardiac function (e.g. KCNA1, SCN1A), thereby linking disturbed cardiac and brain function to a fatal cascade leading to SUDEP (4). Recent findings in patients who have died of SUDEP strengthen these assumptions as about 20 % of SUDEP cases carried various mutations linked to cardiac arrhythmias (5). Still, there is the emerging evidence that genes influencing cardio-respiratory processes linked to SUDEP may operate in combination with molecular mechanisms triggering spreading depolarization that was initially described in hemiplegic migraine (6). Two independent genetic models demonstrated susceptibility to brain stem shutdown due to spreading depolarization that in turn resulted in cardio-respiratory

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collapse and sudden death. In summary, ongoing human studies and research on animal models remain critical for discoveries and validation of genes predisposing to sudden death in epilepsy since it is now evident that there is no single common SUDEP gene and that the genetic landscape of SUDEP is heterogeneous and complex. Are there dangerous and harmless seizures? Presented by Philippe Ryvlin, MD, PhD

Dr. Ryvlin (University of Lausanne, Switzerland) stressed that, in spite of the above described pathophysiological and genetic considerations, there is no clearly identified biomarker of an increased risk of SUDEP so far (7). Epidemiological studies, however, have revealed that the seizure type and seizure features matter. The most important risk factors for SUDEP are the occurrence of GTCS (odds ratio 19.6 for people with 3 or more GTCS per year) and nocturnal seizures (odds ratio 2.6). These findings are also supported by the MORTEMUS study investigating SUDEP or near-SUDEP cases during video-EEG monitoring (8). Other seizure characteristics may also be linked with an increased SUDEP risk, such as seizure-onset zone (e.g. bilateral onset, localized onset in insula or extra-temporal regions) and seizure-related effects on cardiorespiratory function. In contrast, SUDEP has never been reported in childhood absence epilepsy. Why do people die during sleep? Presented by James Tao, MD, PhD

The relationship between SUDEP and sleep was emphasized by Dr. Tao (University of Chicago Medical Center), who identified from his systematic review of the literature 114 SUDEP cases whose state of wakefulness was known (unpublished data). Eighty-five percent (95/114) of these SUDEP cases occurred during sleep. Hypotheses attempting to explain this relationship include: 1) nocturnal seizures are associated with more prominent autonomic dysfunction than diurnal seizures; 2) nocturnal seizures are associated with prolonged postictal generalized EEG suppression (PGES) leading to central apnea (9); 3) impaired postictal arousal and prone position lead to asphyxia. The role of autonomic dysfunction was strongly implicated by the cascading cardiorespiratory events observed in the video-EEG recordings of the 14 SUDEP and 9 near SUDEP cases in the MORTEMUS study, which depicted neurovegetative breakdown with lethal consequences unless resuscitative interventions were employed within 3 minutes of seizure termination. As has been pointed out in other sessions, longer PGES is associated with higher SUDEP risk, and GTCS during sleep appears to have longer PGES than GTCS during wake (9). The fact that a majority (73 %) of SUDEP were found in the prone position also raised the possibility of the role of asphyxiation in causing death (10). In addition to optimizing seizure control, Dr. Tao discussed the nuances of studying the following measures for mitigating SUDEP risk: nocturnal supervision, seizure-alarming devices, anti-suffocation pillows, and avoidance of prone position when sleeping.

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Why don’t people take their medicines and the effect on SUDEP risk? Presented by Edward Faught, MD

Dr. Faught (Emory University) pointed out that electronic monitoring that tracks opening of pill bottles revealed that average doses of medications were not taken about 20% of the time (11). The RANSOM (Research on Antiepileptic Nonadherence and Selected Outcomes in Medicaid) study conducted by Dr. Faught showed that nonadherence occurred about 25% of the time, measured in quarters (three-month periods) (12). Comparing nonadherent with adherent quarters, mortality was three times higher, fractures were 21% higher and motor vehicle accidents were 108% higher. There were also 86% more hospitalizations and 50% more emergency room visits. Although we do not know how nonadherence specifically relates to the increased mortality and morbidities, the increase in hospital and emergency room encounters suggests that the mediating factor is increased seizures. Attempts to assess the role of medication compliance by measuring postmortem serum AED concentrations have yielded mixed results. Measurement of AED concentrations in hair samples, which reflect the degree of consistency of AED intake over weeks, has shown greater variability in AED levels in SUDEP vs. non-SUDEP persons (13). Dr. Faught pointed out that the most common reason for nonadherence is simply forgetting to take the medicines. Health care providers should strive to improve adherence by: 1) inquiring and assessing medication intake in a nonjudgmental way 2) suggesting memory aids such as pill boxes, cell phone reminders, family assistance or supervision, and pharmacy alerts, and 3) educating patients about potentially serious consequences of irregular medication compliance. Who is at risk for seizure-related injuries and deaths? Presented by Elaine Wirrell, MD

Dr. Wirrell showed that the risk of injuries in persons with epilepsy (PWE) varies according to the population studied. The prospective multicenter European study, which resembled a population-based group of patients with epilepsy, showed that the hazard ratio for injuries was 1.6 in PWE compared with the control group (14), but the rate was not significantly higher for non-seizure related injuries. However, injury risk is higher with greater epilepsy severity (4 fold higher in an epilepsy clinic population) and other co-existent neurological disability (100 fold greater in multihandicapped PWE) (15). Likewise, rates of accidental death were higher in hospital-based cohorts than in population-based cohorts (16). Potential factors leading to increased risk for seizure-related injuries include abrupt falls, lack of aura, loss of awareness, and high seizure frequency. AED side effects should also be considered when evaluating for causes of injuries in PWE. Drowning is the injury most likely to result in death in PWE. It happens when bathing or swimming, especially if unsupervised. Risk factors for drowning include high seizure frequency, greater number of AED adverse effects, generalized tonic-clonic seizure type, and intellectual or motor handicaps (17).


Evidence-based reviews of the literature on motor vehicular accidents (MVA) in PWE shows inconsistent findings. Data from crash and casualty databases showed that MVA were less when the required seizure-free period is longer (i.e. 3 months vs. 12 months) (18). Based on self-reported data, the following appear to reduce risk of MVA: epilepsy surgery, longer required seizure-free period (6 to 12 months), few prior non-seizure related crashes, and regular AED adjustments. It should be noted that mandatory reporting by care providers does reduce MVA in PWE. References 1. Surges R, Scott CA, Walker MC. Enhanced QT shortening and persistent tachycardia after generalized seizures. Neurology 2010;74:421– 426. 2. Moseley B, Wirrell E, Nickels K, Johnson J, Ackerman M, Britton J.Electrocardiographic and oximetric changes during partial complex and generalized seizures. Epilepsy Res 2011;95:237–245. 3. Bateman L, Li S, Seyal M.Ictal hypoxemia in localization-related epilepsy: analysis of incidence, severity and risk factors. Brain 2008;131:3239–3245. 4. Goldman AM, Behr ER, Semsarian C, Bagnall RD, Sisodiya S, Cooper PN. Sudden unexpected death in epilepsy genetics: Molecular diagnostics and prevention. Epilepsia 2016;57(Suppl 1):17–25. 5. Bagnall RD, Crompton DE, Petrovski S, Lam L, Cutmore C, Garry SI, Sadleir LG, Dibbens LM, Cairns A, Kivity S, Afawi Z, Regan BM, Duflou J, Berkovic SF, Scheffer IE, Semsarian C. Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy. Ann Neurol 2016;79: 522–534. 6. Aiba I, Noebels J. Spreading depolarization in the brainstem mediates sudden cardiorespiratory arrest in mouse SUDEP models. Sci Transl Med 2015;7:ra46. 7. Tomson T, Surges R, Delamont R, Haywood S, Hesdorffer D. Who to target in sudden unexpected death in epilepsy prevention and how? Risk factors, biomarkers, and intervention study designs. Epilepsia 2016;57(Suppl 1): 4–16. 8. Ryvlin P, Nashef L, Lhatoo SD, Bateman LM, Bird J, Bleasel A, Boon P, Crespel A, Dworetzky BA, Høgenhaven H, Lerche H, Maillard L, Malter MP, Marchal C, Murthy JM, Nitsche M, Pataraia E, Rabben T, Rheims S, Sadzot B, Schulze-Bonhage A, Seyal M, So EL, Spitz M, Szucs A, Tan M, Tao JX, Tomson T. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurology 2013;12: 966–977. 9. Lamberts RJ, Gaitatzis A, Sander JW, Elger CE, Surges R, Thijs RD. Postictal generalized EEG suppression: an inconsistent finding in people with multiple seizures. Neurology 2013;81: 1252–1256. 10. Liebenthal J, Wu S, Rose S, Ebersole J, Tao J, Association of prone position with sudden unexpected death in epilepsy. Neurology 2015;84: 703–709. 11. McAuley J, McFadden L, Elliot J, Shneker B. An evaluation of selfmanagement and medication adherence in persons with epilepsy. Epilepsy & Behavior 2008;13: 634–641. 12. Faught E, Duh MS, Weiner JR, Guérin A, Cunnington MC. Nonadherence to antiepileptic drugs and increased mortality: Findings from the RANSOM study. Neurology 2008;71: 572–1578. 13. Williams J, Lawthom C, Dunstan FD, Dawson TP, Kerr MP, Wilson JF, Smith PE. Variability of antiepileptic medication taking behaviour in sudden unexplained death in epilepsy: hair analysis at autopsy. Journal of Neurology, Neurosurgery & Psychiatry 2006;77:481–484.

14. Beghi E, Cornaggia C, RESt-1 Group. Morbidity and accidents in patients with epilepsy: results of a European cohort study. Epilepsia 2002;43:1076–1083. 15. Nakken KO, Lossius R. Seizure-related injuries in multihandicapped patients with therapy-resistant epilepsy. Epilepsia 1993;34:836–840. 16. Shackleton DP, Westendorp RG, Kasteleijn-Nolst DG, de Craen AJ, Vandenbroucke JP. Survival of patients with epilepsy: as estimate of the mortality risk. Epilepsia 2002;43:445–450. 17. Kemp AM, Sibert JR. Epilepsy in children and the risk of drowning. Arch Dis Child 1993;68:684–685. 18. Classen S, Crizzle AM, Winter SM, Silver W, Eisenschenk S, Evidencebased review on epilepsy and driving. Epilepsy Behav 2012;23:103– 112.

Session Summary: What Are the Events that Occur During and After a Seizure that Cause a Death in SUDEP? Moderators: Rainer Surges, MD and Elson So, MD

What have MORTEMUS and investigations of actual SUDEP cases taught us about pathophysiological mechanisms of death Presented by Philippe Ryvlin, MD, PhD

The MORTEMUS study (1) has allowed us to collate 13 SUDEP (including two fatal near-SUDEP) and seven non-fatal nearSUDEP in patients undergoing video-EEG monitoring. Regarding SUDEP, 85% occurred at night and 70% during sleep without preferential sleep stage. All SUDEP occurred following a generalized tonic-clonic seizure (GTCS), which fulfilled type-1 GTCS criteria (2) whenever assessable. At the time of SUDEP, 90% of patients were prone, but only 40% were already sleeping prone before the fatal seizure occurred. In 58% of cases, a complete withdrawal of AEDs was performed, which appears likely to have promoted an otherwise unusual GTCS in the majority of patients. Finally, in SUDEP cases, cardiorespiratory resuscitation (CPR) was not performed before 13 minutes post-ictally. These findings are in sharp contrast with those observed in near-SUDEP, where only 14% of which occurred at night, never in the prone position, with CPR was always started within three minutes post-ictally. In SUDEP, patients always demonstrated tachypnea and tachycardia at the end of the fatal GTCS. Respiratory arrest, often associated with asystole, occurred within 30 seconds to three minutes postictally in all patients. In one third, this evolved into terminal cardiorespiratory arrest, while in the remaining two-thirds, irregular and possibly ineffective respiration and heart beat resumed for some minutes before terminal apnea followed by terminal asystole. Overall, the data suggest a post-ictal abrupt alteration of brainstem centers controlling cardiorespiratory activity, with hypoxemia and altered breathing possibly predominating over cardiac dysfunction, at least in the earlier phase of SUDEP. More recently, a monitored SUDEP was reported in three patients without evidence of a preceding GTCS. In two of these patients, however, a brain surgery was recently performed (callosotomy or intracranial EEG recording), raising the possibility of an alternative cause of death (3). Overall, data from monitored SUDEP cases suggest that such deaths might be prevented by reducing the frequency of GTCS, especially type-1, and counteracting the mechanisms

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responsible for brainstem dysfunction during the immediate post-ictal period. New insights into seizure-related changes in cardiovascular and autonomic function Presented by Roland Thijs, MD, PhD

The clinically relevant effects of seizures on cardiovascular autonomic control were reviewed. Peri-ictally there is a shift towards sympathetic dominance with sinus tachycardia, blood pressure increase, pupillary dilatation and increases in norepinephrine and adrenaline (4). These changes are most pronounced with generalized tonic clonic seizures (GTCS). Evidence for changes in heart rate and blood pressure induced by electrical stimulation of various cortical and subcortical structures were discussed (4). The most commonly seen peri-ictal cardiac arrhythmias are ictal and postictal asystole, and ictal bradycardia (5,6). Less commonly occurring are ictal and postictal AV block, atrial fibrillation and ventricular fibrillation. In epilepsy monitoring units (EMU), the prevalence of ictal asystole is around 0.318% seen predominantly with complex partial seizures in temporal lobe epilepsy (6). Ictal asystole may be a seizure terminating mechanism and is likely self-limiting. Postictal asystole occurs less frequently but has a substantially higher association with SUDEP (7,8). The prevalence of ventricular fibrillation/tachycardia (VF/VT) in the EMU is extremely rare and all 3 reported cases were preceded by GTCS with no risk factors identified. All 3 cases were associated with near-SUDEP or SUDEP. VF/VT had an oddsratio of 2.9 in patients with epilepsy relative to non-epilepsy patients identified from a general population database (6). Cardiovascular disease rather than epilepsy characteristics is the main determinant of VT/VF in people with epilepsy in the community (9,10). The prevalence of peri-ictal hypotension is unknown as continuous blood pressure pressures are typically not obtained in the EMU. Available data indicates that peri-ictal hypotension may coincide with bradycardia/asystole or occur in isolation and be associated with postictal generalized EEG suppression (4). However, available data on peri-ictal blood pressure changes are sparse and require further study (11). Changes in respiratory control induced by seizures Presented by George Richerson, MD, PhD

The importance of respiratory control in the mechanisms of death after seizures were discussed. Data from the MORTEMUS study of SUDEP recorded in epilepsy monitoring units (EMU’s) showed that postictal changes in breathing and heart rate were not consistent with sudden cardiac death (1). Some cases of SUDEP are likely due to primary respiratory arrest. Mouse models of SUDEP indicate that animals die from respiratory arrest (12-14). In a mouse model of Dravet syndrome, homologous to the human condition, ventilatory arrest occurred immediately following heat induced seizures (15). In these Dravet mice, respiratory arrest occurred before asystole and mechanical ventilation rescued the mice. High dose atropine prevents death in these mice. It has been suggested that death in these animals is prevented by atropine blocking the increased peri-

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ictal vagal output to the heart (16). However, atropine crosses the blood-brain barrier. Current data suggests that atropine may prevent death by stimulation of a respiratory control network in the brainstem that has muscarinic receptors affected by atropine. Studies are needed to demonstrate that these mice do indeed have peri-ictal apnea. Spreading depression in the brainstem: the storm before the quiet Presented by Jeff Noebels, MD, PhD

A number of SUDEP genes have been validated in mouse models, most of which were also reported in human SUDEP cases, such as KCNQ1, KCNH2, SCN5a, SCN1A, RYR2, and SCN8a (17). The first four of these genes are also responsible for long QT syndromes. Other genes associated with SUDEP in mice include Scnb1, Kcna1 and Senp2. In contrast, loss of function mutation of other genes might be protective against SUDEP such as Cacna1a P/Q calcium channel and Tau microtubule binding protein (18). In two mouse SUDEP models (i.e. Kv1.1-/and Scn1a -/-), a spreading depression (SD) in the brainstem was linked to the cardiorespiratory collapse leading to SUDEP and flattened cortical EEG (19). These mouse models also demonstrated a lower threshold for SD (19). The latter, described by Leão in 1944 (20), remains the hallmark of migrainous aura when occurring in the cortex, and consists in a large, prolonged depolarizing wave affecting both neurons and glia triggered by hypoxia, stimulation, or KCl that generates a massive ion translocation into extracellular space with outpouring of extracellular potassium and glutamate, slow DC potential shift, loss of membrane potential, synaptic failure, axon conduction block, and dendritic swelling. At the brainstem level, SD might be responsible for a vicious circle through aggravated central respiratory dysfunction. Interestingly, P/Q and Tau modifiers restore SD threshold in the mouse SUDEP models, a mechanism that might account for their anti-SUDEP effect (21). These observations suggest a role for genes involved in familial hemiplegic migraine (ATP1A2 ) or alternating hemiplegia (ATP1A3). Role of postictal generalized EEG suppression (PGES) Presented by Samden Lhatoo, MD

The relationship between PGES and SUDEP remains a matter of debate. While some groups suggested that PGES was a direct or surrogate risk marker for SUDEP, others failed to replicate this finding (22-24). What is clear however is that PGES typically occurs after a generalized tonic-clonic seizures (GTCS) in about 27% to 82% of cases (24). This large variability might reflect the fact that not all GTCS are the same and that PGES seems more likely to be associated with those GTCS demonstrating a clear symmetrical arm extension tonic phase (2). Furthermore, interpretation of both video and EEG data remain subjective and vulnerable to bias, hampering comparability between series using different criteria to qualify GTCS and PGES. More objective metrics using signal processing algorithm based tools and machine learning, as well as consensus guidelines are needed to progress in the field. Investigating the intracerebral correlates of PGES may also help to better


understand the pathophysiology (potentially neuronal exhaustion, hypoxia, hypoperfusion, neuronal inhibition, and/or diencephalic switch?) and define more appropriate diagnostic criteria. Indeed, it appears that not all intra-cerebral leads demonstrate PGES when the latter is concomitantly recorded with scalp-EEG (25). Despite the above limitations, PGES appears to be systematically observed during SUDEP, and more frequent during sleep and seizures associated with ictal hypoxemia and hypercapnia (26). Prospective studies are now needed to firmly establish the predictive value of PGES for SUDEP. The role of sleep wakefulness in SUDEP

3.

4. 5.

6.

Presented by Gordon Buchanan, MD, PhD

The association between sleep state and/or time of day to SUDEP was discussed. Most reported SUDEP cases occur during sleep (27). However, only a minority of these cases were witnessed. In the MORTEMUS study, in cases captured in the EMU, most SUDEP occurred in NREM sleep (1). In seizures occurring during sleep, stimulation of the patient may be sufficient to restore normal cardiorespiratory function (27, 28). In the EMU, earlier nursing intervention reduces the duration of peri-ictal hypoxemia (29). Seizures are much less likely to occur during REM sleep than during NREM sleep or wakefulness (30). Mice lacking 5-HT neurons in the CNS have a lower seizure threshold and increased seizure-induced mortality. In these mice, breathing ceased during most seizures without recovery. In contrast, cardiac activity persisted for many minutes before terminal arrest. The mortality rate of mice was reduced by mechanical ventilation during the seizure or 5-HT2A receptor agonist pretreatment. Death in this animal model ensued from respiratory failure, followed by terminal asystole. Unlike wild type mice, in 5-HT deficient mice, CO2 was ineffective in promoting arousal (14). It is possible that mechanisms causing death in these 5-HT deficient models might be shared with those leading to SUDEP. In adult mice there is more profound respiratory suppression and mice were more likely to die when seizures were induced using maximal electroshock during sleep rather than during wakefulness. REM sleep appeared to be a particularly vulnerable period. Mice that died had increased baseline respiratory rate variability compared with those that did not die (31). These data suggest the possibility that, in humans, there may be baseline respiratory abnormalities that can predict which individuals have higher risk for seizure-induced death. References 1. Ryvlin P, Nashef L, Lhatoo SD, Bateman LM, Bird J, Bleasel A, Boon P, Crespel A, Dworetzky BA, Høgenhaven H, Lerche H, Maillard L, Malter MP, Marchal C, Murthy JM, Nitsche M, Pataraia E, Rabben T, Rheims S, Sadzot B, Schulze-Bonhage A, Seyal M, So EL, Spitz M, Szucs A, Tan M, Tao JX, Tomson T. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol 2013;12:966–977. 2. Alexandre V, Mercedes B, Valton L, Maillard L, Bartolomei F, Szurhaj W, Hirsch E, Marchal C, Chassoux F, Petit J, Crespel A, Nica A, Navarro V, Kahane P, De Toffol B, Thomas P, Rosenberg S, Denuelle M, Jonas J, Ryvlin P, Rheims S; REPO2MSE study group. Risk factors of postictal

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

generalized EEG suppression in generalized convulsive seizures. Neurology 2015;85:1598–1603. Lhatoo SD, Nei M, Raghavan M, Sperling M, Zonjy B, Lacuey N, Devinsky O. Nonseizure SUDEP: Sudden unexpected death in epilepsy without preceding epileptic seizures. Epilepsia 2016;57:1161–1168. Sevcencu C, Struijk JJ. Autonomic alterations and cardiac changes in epilepsy. Epilepsia 2010;51:725–737. Tinuper P, Bisulli F, Cerullo A, Carcangiu R, Marini C, Pierangeli G, Cortelli P. Ictal bradycardia in partial epileptic seizures: Autonomic investigation in three cases and literature review. Brain 2001;124:2361– 2371. van der Lende M, Surges R, Sander JW, Thijs RD. Cardiac arrhythmias during or after epileptic seizures. J Neurol Neurosurg Psychiatry 2015;87:69–74. Rugg-Gunn FJ, Simister RJ, Squirrell M, Holdright DR, Duncan JS. Cardiac arrhythmias in focal epilepsy: a prospective long-term study. Lancet 2004;364:2212–2219. Nei M, Sperling MR, Mintzer S, Ho RT. Long-term cardiac rhythm and repolarization abnormalities in refractory focal and generalized epilepsy. Epilepsia 2012;53:e137–40 Bardai A, Lamberts RJ, Blom MT, Spanjaart AM, Berdowski J, van der Staal SR, Brouwer HJ, Koster RW, Sander JW, Thijs RD, Tan HL. Epilepsy is a risk factor for sudden cardiac arrest in the general population. PLoS One 2012;7:e42749. Lamberts RJ, Blom MT, Wassenaar M, Bardai A, Leijten FS, de Haan GJ, Sander JW, Thijs RD, Tan HL. Sudden cardiac arrest in people with epilepsy in the community: Circumstances and risk factors. Neurology 2015 21;85:212–218. Bozorgi A, Chung S, Kaffashi F, Loparo KA, Sahoo S, Zhang GQ, Kaiboriboon K, Lhatoo SD. Significant postictal hypotension: expanding the spectrum of seizure-induced autonomic dysregulation. Epilepsia 2013;54:e127–130. Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, Julius D. Eating disorder and epilepsy in mice lacking 5‑HT2C serotonin receptors. Nature 1995;374:542–546. Faingold CL, Randall M, Tupal S. DBA/1 mice exhibit chronic susceptibility to audiogenic seizures followed by sudden death associated with respiratory arrest. Epilepsy Behav 2010;17:436–440. Buchanan GF, Murray NM, Hajek MA, Richerson GB. Serotonin neurones have anti-convulsant effects and reduce seizure-induced mortality. J Physiol 2014;592:4395–4410. Auerbach DS1, Jones J, Clawson BC, Offord J, Lenk GM, Ogiwara I, Yamakawa K, Meisler MH, Parent JM, Isom LL. Altered cardiac electrophysiology and SUDEP in a model of Dravet syndrome. PLoS One 2013;8:e77843. Massey CA, Sowers LP, Dlouhy BJ, Richerson GB. Mechanisms of sudden unexpected death in epilepsy: the pathway to prevention. Nature Reviews Neurology 2014;10:271–282. Klassen TL, Bomben VC, Patel A, Drabek J, Chen TT, Gu W, Zhang F, Chapman K, Lupski JR, Noebels JL, Goldman AM.. High-resolution molecular genomic autopsy reveals complex sudden unexpected death in epilepsy risk profile. Epilepsia 2014;55:e6–12. Ayata C, Shimizu-Sasamata M, Lo EH, Noebels JL, Moskowitz MA. Impaired neurotransmitter release and elevated threshold for cortical spreading depression in mice with mutations in the alpha1A subunit of P/Q type calcium channels. Neuroscience 2000;95:639–645. Aiba I, Noebels JL. Spreading depolarization in the brainstem mediates sudden cardiorespiratory arrest in mouse SUDEP models. Sci Transl Med 2015;8;7:282ra46.

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20. Leão AAP. Spreading depression of activity in the cerebral cortex. J Neurophysiol 1944;7:359–390. 21. Aiba I, Wehrens XH, Noebels JL. Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death. Proc Natl Acad Sci USA 2016;113:E4895–4903. 22. Lhatoo SD, Faulkner HJ, Dembny K, Trippick K, Johnson C, Bird JM. An electroclinical case-control study of sudden unexpected death in epilepsy. Ann Neurol 2010;68:787–796. 23. Lamberts RJ, Gaitatzis A, Sander JW, Elger CE, Surges R, Thijs RD. Postictal generalized EEG suppression: an inconsistent finding in people with multiple seizures. Neurology 2013;81:1252–1256. 24. Surges R, Strzelczyk A, Scott CA, Walker MC, Sander JW. Postictal generalized electroencephalographic suppression is associated with generalized seizures. Epilepsy Behav 2011;21:271–274. 25. Altenmüller DM, Schulze-Bonhage A, Elger CE, Surges R. Local brain activity persists during apparently generalized postictal EEG suppression. Epilepsy Behav 2016;62:218–224. 26. Seyal M, Hardin KA, Bateman LM. Postictal generalized EEG suppression is linked to seizure-associated respiratory dysfunction but not postictal apnea. Epilepsia 2012;53: 825–831 27. Lamberts RJ, Thijs RD, Laffan A, Langan Y, Sander JW. Sudden unexpected death in epilepsy: people with nocturnal seizures may be at highest risk. Epilepsia 2012;53:253–257. 28. Shorvon S, Tomson T. Sudden unexpected death in epilepsy. Lancet 2011;10;378:2028–2038. 29. Seyal M, Bateman LM, Li CS. Impact of periictal interventions on respiratory dysfunction, postictal EEG suppression, and postictal immobility. Epilepsia 2013;54:377–382. 30. Ng M, Pavlova M. Why are seizures rare in rapid eye movement sleep? Review of the frequency of seizures in different sleep stages. Epilepsy Res Treat 2013;2013:932790. 31. Hajek MA, Buchanan GF. Influence of vigilance state on physiological consequences of seizures and seizure-induced death in mice. J Neurophysiol 2016;115:2286–2293.

Session Summary: What are the Options for Prevention Now and in the Future? Moderators: Tom Stanton, MPP and Henry Smithson, MD

Co-moderators Dr. Henry Smithson and Tom Stanton described the questions to be addressed in the session: Where are the gaps in SUDEP prevention? Are there clear opportunities for engagement between groups on the needs that are identified from this session? Is there a place for families and generalists to discuss the best way to provide this information and how it can be used at an epilepsy review to reduce future personal risk? What can families do now to engage? Are any technologies and device interventions ready for primetime? They expressed that doctor-patient dialogue about the risks of mortality is a key piece to the equation when seeking better outcomes. The session started with family advocate Margaret Storey, who shared the story of her daughter Josie, who has Aicardi Syndrome. She challenged epilepsy advocates and medical professionals to change the standard of care and to reframe our notions of how to achieve wellness in epilepsy. She expressed that it is unacceptable to send caretakers home from a hospital to care for their refractory child without any information or resources to monitor that child, when they had just been so intensely monitored within the hospital setting.

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Seizure monitoring devices Presented by Tobias Loddenkemper, MD

Dr. Loddenkemper presented an overview of the seizure monitoring and device resources that are in the marketplace, as well as resources that are in the pipeline. He overviewed a range of current monitoring options, and indicated that multimodule resources that monitor for more than one type of seizure measure will become the norm in the future, versus the mostly uni-module systems that exist today to measure only movement. Although not FDA-proven to reduce risk, there are on the market or in development devices that employ body sensors for electromyography, electroencephalography, electrodermal responses, electrocardiography, accelerometry, and oxygenation. There are video detection systems, mattress sensors and systems using near infrared spectrometry (1-15). Dr. Loddenkemper believes it is important for medical professionals to be informed about monitoring options so they can provide informed guidance to their patients. Disclosing and managing risk Presented by Jane Hanna

Ms. Hanna (SUDEP Action) spoke on the topic of disclosing and managing the risk of SUDEP. She shared that while risk information has been available since 2002, much has changed in how it can be presented. She cited the new EpSMon-self-monitor App (16) as one example. She encourages medical professionals to couch the risk of SUDEP within the doctor-patient conversation that gives the entire spectrum of epilepsy-related risks. She said it is important to enable patients and caretakers to make fully informed choices about their treatment. Tools not rules for discussing SUDEP Presented by Jeffrey Buchhalter, MD, PhD

Dr. Buchhalter presented “tools not rules” for medical professionals who are discussing SUDEP. He advocates for medical professionals to present the risk of SUDEP within the context of other epilepsy-related risks. He discussed the importance of “tailored risk”: giving a patient (or their caretaker) an assessment of their risk level that is specific to their medical history. He cited the forthcoming SUDEP guidelines from the American Academy of Neurology (17) as a resource that he expects to improve the communication about SUDEP. Living with and managing epilepsy Presented by Barbara Jobst, MD

Dr. Jobst emphasized the importance of patient self-management and resources available to patients. Studies suggest that factors associated with patients seeking information include being female and having higher income while those who have suffered from epilepsy longer report more stigma management behaviors (18). She highlighted the Managing Epilepsy Well (MEW) Network, created by the Centers for Disease Control and Prevention’s (CDC) Prevention Research Centers and Epilepsy Program, to foster research in self-management and quality of life improvement (19). Dr. Jobst and her team at


Dartmouth developed HOBSCOTCH (HOme Based Self-management & COgnitive Training CHanges lives), a program that uses self-management strategies to improve subjective and objective memory function in patients with epilepsy (20,21). References 1. Carlson C, Arnedo V, Cahill M, Devinsky O. Detecting nocturnal convulsions: efficacy of the MP5 monitor. Seizure 2009;18:225–227. 2. Pediaditis M, Tsiknakis M, Leitgeb N. Vision-based motion detection, analysis and recognition of epileptic seizures--a systematic review. Comput Methods Programs Biomed 2012;108:1133–1148. 3. Lu H, Pan Y, Mandal B, Eng HL, Guan C, Chan DW. Quantifying limb movements in epileptic seizures through color-based video analysis. IEEE Trans Biomed Eng 2013;60:461–469. 4. Cook MJ, O’Brien TJ, Berkovic SF, Murphy M, Morokoff A, Fabinyi G, D’Souza W, Yerra R, Archer J, Litewka L, Hosking S, Lightfoot P, Ruedebusch V, Sheffield WD, Snyder D, Leyde K, Himes D. Prediction of seizure likelihood with a long-term, implanted seizure advisory system in patients with drug-resistant epilepsy: a first-in-man study. Lancet Neurol 2013;12:563–571. 5. Milosevic M, Van de Vel A, Bonroy B, Ceulemans B, Lagae L, VanRumste B, Van Huffel S. Automated Detection of Tonic-Clonic Seizures using 3D Accelerometry and Surface Electromyography in Pediatric Patients. IEEE J Biomed Health Inform 2016;20:1333–1341. 6. Source: http://hellothread.com/understanding-epilepsy-withresearchkit-epiwatch-app. Accessed September 2016. 7. Becq G, Kahane P, Minotti L, Bonnet S, Guillemaud R. Classification of epileptic motor manifestations and detection of tonic-clonic seizures with acceleration norm entropy. IEEE Trans Biomed Eng 2013;60:2080– 2088. 8. Van de Vel A, Verhaert K, Ceulemans B. Critical evaluation of four different seizure detection systems tested on one patient with focal and generalized tonic and clonic seizures. Epilepsy Behav 2014;37:91–94. 9. Conradsen I, Beniczky S, Wolf P, Terney D, Sams T, Sorensen HB. Multimodal intelligent seizure acquisition (MISA) system--a new approach towards seizure detection based on full body motion measures. Conf Proc IEEE Eng Med Biol Soc 2009 2009;2591–2595. 10. Shoeb A, Pang T, Guttag J, Schachter S. Non-invasive computerized system for automatically initiating vagus nerve stimulation following patient-specific detection of seizures or epileptiform discharges. Int J Neural Syst 2009;19:157–172. 11. Source: http://www.samialert.com/sami-3/. Accessed September 2016. 12. Poh MZ, Loddenkemper T, Reinsberger C, Swenson NC, Goyal S, Sabtala MC, Madsen JR, Picard RW. Convulsive seizure detection using a wrist-worn electrodermal activity and accelerometry biosensor. Epilepsia 2012;53:e93–97 13. Source: www.empatica.com/product-embrace. Accessed September 2016. 14. Dolgin E. Technology: Dressed to detect. Nature 2014;511:S16–17. 15. Ulate-Campos A, Coughlin F, Gaínza-Lein M, Fernández IS, Pearl PL, Loddenkemper T. Automated seizure detection systems and their effectiveness for each type of seizure. Seizure 2016;40:88–101. 16. Source: https://sudep.org/epilepsy-self-monitor. Accessed September 2016. 17. Source: https://www.aan.com/Guidelines/home/UnderDevelopment. Accessed September 2016. 18. Escoffery C, Bamps Y, LaFrance WC Jr, Stoll S, Shegog R, Buelow J, Shafer P, Thompson NJ, McGee RE, Hatfield K. Development of

the Adult Epilepsy Self-Management Measurement Instrument (AESMMI). Epilepsy Behav 2015;50:172–183. 19. DiIorio CK, Bamps YA, Edwards AL, Escoffery C, Thompson NJ, Begley CE, Shegog R, Clark NM, Selwa L, Stoll SC, Fraser RT, Ciechanowski P, Johnson EK, Kobau R, Price PH; Managing Epilepsy Well Network. The prevention research centers’ managing epilepsy well network. Epilepsy Behav 2010;19:218–224. 20. Source: http://www.dartmouth-hitchcock.org/epilepsy/hobscotch. html. Accessed September 2016. 21. Caller TA, Ferguson RJ, Roth RM, Secore KL, Alexandre FP, Zhao W, Tosteson TD, Henegan PL, Birney K, Jobst BC. A cognitive behavioral intervention (HOBSCOTCH) improves quality of life and attention in epilepsy. Epilepsy Behav 2016;57:111–117.

Session Summary: Advocacy Perspectives: How Can We Speed Up Awareness and Prevention? Moderator: Jane Hanna, OBE, CEO SUDEP Action Presented by Mark Stevenson, Karen Osland, Cyndi Wright, Rosemary Panelli, MHP, PhD, Samuel Weibe, MSc, MD

This session started with a family presentation by Mark Stevenson, who told the heart wrenching story of his college son’s death from epilepsy (1,2). He exemplified how advocates can increase SUDEP awareness as he has started a college scholarship for patients with epilepsy, joined the local Epilepsy Foundation board, and promoted state legislation to have the Colorado chief medical officer establish a SUDEP Awareness Program to educate medical examiners and coroners. Karen Osland (Deputy CEO SUDEP Action) provided a UK advocacy perspective from Epilepsy Bereaved (today known as SUDEP Action) founded by families to support and empower their work with professional champions to spread awareness and drive action to tackle deaths. Many have wanted to turn private pain into public purpose with powerful collaborations between families and clinical teams helping to tackle barriers to advocacy and prevention. Recent examples include the development of the SUDEP and Seizure Safety Health Checklist and EpsMon self-monitor App, both good practice tools supporting clinical and patient engagement and given clinical backing by the British Medical Journal and UK Patient Safety Awards in 2016 (3). Families not only have a track record as powerful advocates but provide motivation, participation in research, and a major source of funding when national funding streams are not available. Yet, in the aftermath of an epilepsy-related death which are usually sudden, families are traumatized. Common experiences from many of the 500 families reporting to the Epilepsy Deaths Register are gaps in epilepsy services and opportunities missed to communicate and reduce risk (4). Most want someone to talk to, to find answers to their individual questions, and to understand investigations of death. Common needs also include learning more about epilepsy related death, the opportunity to meet experts, as well as contact with other bereaved families and counselling. Families value a specialist service tailored to their journey following a death (5). Signposting of bereaved families to specialist services where these exist can help and empower families and help speed advocacy and change. Cyndi Wright spoke about how the narratives of the families not only inspired the launch of the Epilepsy Foundation

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SUDEP Institute in 2013 but motivate all working in the field. She encouraged participants to imagine the experiences of families before and after SUDEP. She talked about daily struggles that many faced to manage often without any communication about risk. Sadly, the overwhelming number of medical providers are not advising people of their risk. In the aftermath of a sudden unexpected death, families are left with no idea about why their loved one has died. For some, the medical examiner may use the term SUDEP. Others may come to this discovery by searching the web. Traditional research and awareness efforts were not driving progress fast enough. She discussed the SUDEP Challenge Initiatives (6). These challenges set and awarded by epilepsy and SUDEP experts enabled the best and most valuable solutions to be identified. The first was empowering patients, and the winner was initiative “Aim for Zero:” meaning working toward zero seizures, zero missed medications, zero instances of excess alcohol and zero missed physician visits. The second challenge was preventing epileptic seizures, and the winner was EpsMon, an epilepsy self-monitor app designed to monitor epilepsy activity between medical visits and empower people to decrease risk. The current challenge is to identify predictive biomarkers. Dr. Rosey Panelli presented perspectives from Australia, highlighting the need for an uplift in awareness and communication of ways to reduce risk in the community (7). This would not only help the case for development of quality epilepsy services but would also better position services to ensure the delivery of research findings in relation to the reduction of risk and prevention of death (8). She suggested that educating primary care physicians may be a critical step to avoid premature death in epilepsy and discussed strategies for successful engagement with primary care (9,10). She encouraged the importance of international collaboration through epilepsy death registers, the SUDEP global conversation, and SUDEP Awareness Day which attracts unity and participation from a wide range of organizations across the world (October 23rd; 11). Dr. Wiebe discussed a global perspective on challenges of health related mortality, and how this relates to epilepsy. He noted that a third world primary care physician may see 80 patients a day at the rate of seven minutes per patient, and need to address competing risks such as access to food or malaria. He contrasted epilepsy-related mortality with the 1.2 million motor vehicle-related deaths in India from 2006-2015, the number one cause in those age 14-49 (12). World poverty has a major impact on the ability to pay for medications. For example, in the third world, the numbers of days one must work to afford drugs are on average 7.8 for valproate, 2.7 for carbamazepine, 1.05 for phenytoin and 0.9 for phenobarbital (13). Thus, addressing poverty and overall health care access are critically important to reduce epilepsy-related mortality globally. References 1. Stevenson M, Stanton T. Knowing the risk of SUDEP. Two family’s perspective and the Danny Did Foundation. Epilepsia 2014;55:1495– 1500. 2. Source: http://www.sudepglobalconversation.com/#!tyler/c1el7. Accessed September 2016.

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3. Source: https://sudep.org/article/sudep-action-and-partners-win-hsjaward. Accessed September 2016. 4. Source: https://epilepsydeathsregister.org/en/reports-research. Accessed September 2016. 5. Donner EJ, Waddell B, Osland K, Leach JP, Duncan S, Nashef L, Picot MC. After sudden unexpected death in epilepsy: Lessons learned and the road forward. Epilepsia 2016;57(Suppl 1):46–53. 6. Source: http://www.epilepsy.com/get-help/sudep-institute/sudepchallenge-initiative. Accessed September 2016. 7. Hanna N J, Black M, Sander JW, Smithson WH, Appleton R, Brown S, Fish DR. The National Sentinel Clinical Audit of Epilepsy-Related Death: Epilepsy – death in the shadows. The Stationery Office. 2002. Source: https://sudep.org/sites/default/files/national-sentinelclinical-audit-of-epilepsy-related-death-2002-summary.pdf. Accessed September 2016. 8. Ridsdale L. Avoiding premature death in epilepsy. BMJ 2015; doi: 10.1136/bmj.h718. 9. Source: www.epilepsyingeneralpracticec.com.au. Accessed September 2016. 10. Source: http://elearning.rcgp.org.uk/course/info. php?popup=0&id=176. Accessed September 2016. 11. Source: http://www.sudepawarenessday.org/. Accessed September 2016. 12. Source: http://www.nytimes.com/2016/06/21/opinion/campaigningto-make-indias-roads-safer.html. Accessed September 2016. 13. Cameron A, Bansal A, Dua T, Hill SR, Moshe SL, Mantel-Teeuwisse AK, Saxena S. Mapping the availability, price, and affordability of antiepileptic drugs in 46 countries. Epilepsia 2012;53:962–969.

Session Summary: Updates and Discussion on Select Programs in Mortality Research Moderator Maggie Moore, MPH (summarized by Kevin Graber, MD) Presented by Maggie Moore, MPH, Samden Lhatoo, MD, Brandy Fureman, PhD, Tracy Dixon-Salazar, PhD, Samuel Wiebe, MSc, MD

The objectives of this session were to discuss organizations working in epilepsy mortality research, and to describe resources, programs and gaps. Dr. Lhatoo (Case Western Reserve University and Center for SUDEP Research) highlighted numerous ongoing projects in SUDEP research. He highlighted the American Epilepsy Society and the Epilepsy Foundation Joint Task Force on SUDEP (1) and the Center for SUDEP Research (CSR) (2). The CSR is a National Institute for Neurological Disorders and Stroke (NINDS) funded Center Without Walls for Collaborative Research in the Epilepsies, and is comprised of researchers from 14 institutions across the US and Europe. It has four different cores: Administrative, Informatics and Data Analytics, Morphometric Analysis, and Molecular Diagnostics. Current projects include 1) autonomic and imaging biomarkers, 2) cardiac gene and circuit mechanisms, 3) neuropathology, 4) respiratory and arousal mechanisms, and 5) iPSC and mouse neurocardiac models. There is data sharing, and a program for pilot awards and mentorship (2). While information may be a bit insufficient at the moment, goals of the program include creation of an individualized patient SUDEP index risk calculator tool. Additional goals include understanding mechanisms


to pave the way for SUDEP prevention, and creation of a large SUDEP research database—for example the Multi-Modality Epilepsy Data Capture and Integration System (MEDCIS) (3). The goals of the Molecular Diagnostic Core under the direction of Alicia Goldman at Baylor College of Medicine, are to create a SUDEP gene variant research data base to identify novel genes and molecular biomarkers and a SUDEP genetics clinic. The morphometric analytical network is to facilitate a SUDEP brain collection to correlate brain morphometric studies with clinical electrophysiological and autonomic investigations. For example, patients with temporal lobe epilepsy have volume loss in autonomic brainstem regions, which might increase risk for fatal dysregulation after severe seizures (4). Insular damage may also increase autonomic instability and SUDEP risk (5). Studies and projects of brainstem spreading depression, cardiac gene mechanisms, respiratory and arousal mechanisms, and iPSC and mouse neurocardiogenic models were also highlighted (6-10). Dr. Lhatoo noted an exponential rise in SUDEP publications over the past 5 decades (1,319 PubMed “hits”) as of the meeting, and that the CSR alone was responsible for almost 20% of all SUDEP-related publications from 2014-2015. Dr. Fureman highlighted funding from the Epilepsy Foundation Targeted Program in Morbidity and Mortality, currently funding studies on brainstem atrophy as a potential SUDEP marker (4) and the role of norepinephrine and serotonin in seizure-induced respiratory arrest and death (11). The SUEDP Institute Challenge Initiative is to identify human biomarkers that can predict and allow development of interventions. CURE funding has contributed to 1) finding that respiratory arrest is the leading cause of SUDEP, 2) discovery of a link between SUDEP and cardiac genes, 3) funding of SUDEP registries in Canada, Sweden and the US, 4) the development of six animal models of SUDEP, 5) understanding that generalized tonic clonic seizures are a clear risk for death, and 6) increased SUDEP awareness. Dr. Salazar-Dixon noted that 5-10% of Citizens United for Research in Epilepsy (CURE) funds go directly to SUDEP research. CURE also separately funds additional studies of epilepsy syndromes in which SUDEP risk is particularly high (such as Dravet syndrome and others) (12). CURE has funded $3.6 million in projects in 8 different countries. She noted that this is on the order of NIH funding for SUDEP, which has increased over the past half a decade from minimal funding to $7-8 million per year (13). Dr. Weibe, treasurer of the International League Against Epilepsy, discussed the burden of mortality in epilepsy globally, and lost years due to death and disability. Although this may be 275 years /100,000 individuals in some African countries (14). Globally, epilepsy-related deaths are a higher percentage of neurologically-related deaths among those with lower compared to higher incomes (15). A portion of this discrepancy is that overall percentages of total deaths attributed to neurological causes, are larger in higher income populations, as individuals tend to live longer and have more chance for late in life disease. For example, earlier-life communicable, nutritional and perinatal deaths are more common in low income countries. Outside of the United States and Europe, the

largest concentration of SUDEP research is currently underway in Australia, China and Brazil; unfortunately, very little SUDEP research is underway in the third world. References 1. So EL, Bainbridge J, Buchhalter JR, Donalty J, Donner EJ, Finucane A, Graves NM, Hirsch LJ, Montouris GD, Temkin NR, Wiebe S, Sierzant TL. Report of the American Epilepsy Society and the Epilepsy Foundation joint task force on sudden unexplained death in epilepsy. Epilepsia 2009;50:917–922. 2. Source: www.sudepresearch.org. Accessed September 2016. 3. Zhang GQ, Cui L, Lhatoo S, Schuele SU, Sahoo SS. MEDCIS: MultiModality Epilepsy Data Capture and Integration System. AMIA Annu Symp Proc 2014 2014:1248–1257. 4. Mueller SG, Bateman LM, Laxer KD. Evidence for brainstem network disruption in temporal lobe epilepsy and sudden unexplained death in epilepsy. Neuroimage Clin 2014;9:208–216. 5. Lacuey N, Zonjy B, Theerannaew W, Loparo KA, Tatsuoka C, Sahadevan J, Lhatoo SD. Left-insular damage, autonomic instability, and sudden unexpected death in epilepsy. Epilepsy Behav 2016;55:170– 173. 6. Aiba I, Noebels J. Spreading depolarization in the brainstem mediates sudden cardiorespiratory arrest in mouse SUDEP models. Sci Transl Med 2015;7:ra46. 7. Glasscock E, Yoo JW, Chen TT, Klassen TL, Noebels JL. Kv1.1 potassium channel deficiency reveals brain-driven cardiac dysfunction as a candidate mechanism for sudden unexplained death in epilepsy. J Neurosci 2010;30:5167–5175. 8. Goldman AM, Glasscock E, Yoo J, Chen TT, Klassen TL, Noebels JL. Arrhythmia in heart and brain: KCNQ1 mutations link epilepsy and sudden unexplained death. Sci Transl Med 2009;1:2ra6. 9. Sowers LP, Massey CA, Gehlbach BK, Granner MA, Richerson GB. Sudden unexpected death in epilepsy: fatal post-ictal respiratory and arousal mechanisms. Respir Physiol Neurobiol 2013;189:315–323. 10. Liu Y, Lopez-Santiago LF, Yuan Y, Jones JM, Zhang H, O’Malley HA, Patino GA, O’Brien JE, Rusconi R, Gupta A, Thompson RC, Natowicz MR, Meisler MH, Isom LL, Parent JM. Dravet syndrome patientderived neurons suggest a novel epilepsy mechanism. Ann Neurol 2013;74:128–139. 11. Zhan Q, Buchanan GF, Motelow JE, Andrews J, Vitkovskiy P, Chen WC, Serout F, Gummadavelli A, Kundishora A, Furman M, Li W, Bo X, Richerson GB, Blumenfeld H. Impaired Serotonergic Brainstem Function during and after Seizures. J Neurosci 2016;36:2711–2722. 12. Source: http://www.cureepilepsy.org/research/. Accessed September 2016. 13. Source: gathered from https://projectreporter.nih.gov/reporter.cfm. Accessed June 2016. 14. Source: www.who.int/healthinfo/global_burden_disease/GHE_ DALY_2012_country.xls. Accessed June 2016. 15. Source: www.who.int/healthinfo/global_burden_disease/GHE_DthWBInc_2000_2012.xls. Accessed June 2016

Session Summary: Frequent Non-SUDEP Causes of Mortality in People with Epilepsy Moderators: Rainer Surges, MD and Elson So, MD

Breakout sessions allowed for content aimed at a more limited audience. Drs. Surges and So moderated a scientific session discussing non-SUDEP causes of death in epilepsy patients.

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Talks focused on immune system dysfunction, tumors, atherosclerosis and depression/suicide. Why do a disturbed immune system and non-CNS tumors cause premature death in epilepsy? Presented by Orrin Devinsky, MD

Dr. Devinsky (New York University) explained that people with chronic epilepsy have a higher risk of premature death when compared to the general population. The major causes include pneumonia and tumors other than brain tumors (1), suggesting significant epilepsy-related alterations of the immune system. Emerging evidence supports the role of immunemediated mechanisms. People suffering from any autoimmune-diseases appear to have a significantly increased risk of developing epilepsy, possibly via inflammatory mechanisms (involving e.g. cytokines, antibodies or immune-complexes) and secondary to vascular disease and stroke (2). These findings prompt the question of whether regular screening examinations and possibly immune-modulatory treatments may be beneficial in people with epilepsy. Which factors enhance the occlusion of blood vessels of the heart and brain in epilepsy? Presented by Stephan Schuele, MD, MPH

Dr. Schuele (Northwestern University, Chicago) pointed out that cardiovascular morbidity and mortality due to myocardial infarction and ischemic stroke are increased in people with chronic epilepsy as compared to the general population, especially in younger patients (1). As in other populations, established cardiovascular risk factors such as arterial hypertension and disturbed lipid blood profiles are likely to play an important role. For instance, sympathetic autonomic tone is enhanced in epilepsy, favoring onset of arterial hypertension. Furthermore, enzyme-inducing anticonvulsant drugs have detrimental effects on lipid profile, thereby favoring atherosclerosis (3). Importantly, sudden cardiac death appears to be more frequently encountered in epilepsy patients and especially in those taking anticonvulsant drugs targeting sodium channel blockers. Another study has found that epilepsy patients who experienced ventricular tachyarrhythmias had more frequently concomitant cardiac diseases than epilepsy patients without ventricular tachyarrhythmias (4). These observations suggest that monitoring of cardiovascular risk factors in epilepsy patient is warranted, and that the selection of anticonvulsant drugs should take into account comorbidities aside from efficacy and other criteria. What increases the risk of suicide and depression in people with epilepsy? Presented by Elson So, MD

Evidence discussed by Dr. So showed the incidence of depression is increased by about 2 times before epilepsy onset, and also after the onset (5). Moreover, older adults with major depression have a four-fold risk of developing an unprovoked seizure (6). Evidence for the role of anti-depressants in causing the increased seizure risk is not strong.

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Data derived from Food and Drug Administration (FDA)approved anti-depressant drug trials revealed that subjects who took placebo had twice the risk of developing seizures as those who took SSRIs (7). It would seem that SSRIs are “seizure-protective”, with the exception of immediate-release bupropion, which was shown to be associated with increased seizure risk. A finding that may explain the bidirectional relationship between depression and epilepsy is diminished serotonin receptor activity in the limbic system, which has been observed in persons with epilepsy (PWE) and in persons with depression (8). The incidence of suicidality is increased by about two-fold, both before and after epilepsy onset (5). A population-based study in Denmark revealed that in PWE with major psychiatric disorder, suicide risk is increased nearly 30 times during the first 6 months following epilepsy diagnosis (9). The FDA had cautioned about increased suicidality associated with antiepileptic drug (AED) use. However, the absolute rate of suicidality is only 0.43% with AED intake and 0.22% with placebo intake. The increased risk was based on pooled data derived from many types of AEDs. However, it is well-known that some AEDs such as levetiracetam can be associated with new-onset or exacerbated depression. Therefore, the overall benefit-to-risk balance should be carefully assessed in each patient when using an AED. Given the higher risk for depression and suicidality in PWE, patients should be periodically screened for depression by using validated brief questionnaires such as the PHQ-9 or the NDDI-E (10). Detection of depression or suicidality would permit prompt intervention or referral to psychiatric specialists for management of the condition. References 1. Neligan A, Bell GS, Johnson AL, Goodridge DM, Shorvon SD, Sander JW. The long-term risk of premature mortality in people with epilepsy. Brain 2011;134:388–395. 2. Ong MS, Kohane IS, Cai T, Gorman MP, Mandl KD. Population-level evidence for an autoimmune etiology of epilepsy. JAMA Neurol 2014; 71:569–574. 3. Mintzer S, Skidmore CT, Abidin CJ, Morales MC, Chervoneva I, Capuzzi DM, Sperling MR. Effects of antiepileptic drugs on lipids, homocysteine, and C-reactive protein. Annals of Neurology 2009;65:448–456. 4. Lamberts RJ, Blom MT, Wassenaar M, Bardai A, Leijten FS, de Haan GJ, Sander JW, Thijs RD, Tan HL. Sudden cardiac arrest in people with epilepsy in the community: Circumstances and risk factors. Neurology 2015;85:212–218. 5. Hesdorffer DC, Ishihara L, Mynepalli L, Webb DJ, Weil J, Hauser WA. Epilepsy, Suicidality, and Psychiatric Disorders: A Bidirectional Association. Ann Neurol 2012;72:184–191. 6. Hesdorffer DC, Hauser WA, Annegers JF, Cascino G. Major depression is a risk factor for seizures in older adults. Ann Neurol 2000;47:246– 249. 7. Alper K, Schwartz KA, Kolts RL, Khan A. Seizure incidence in psychopharmacological clinical trials: An analysis of Food and Drug Administration (FDA) summary of approval reports. Biol Psychiatry 2007;62:345–354. 8. Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ, Huang Y, Gautier C, Mathis C. PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 1999;46:1375–1387.


9. Christensen J, Vestergaard M, Mortensen PB, Sidenius P, Agerbo E. Epilepsy and risk of suicide: a population-based case-control study. Lancet Neurology 2007;6:693–698. 10. Gilliam FG, Barry JJ, Hermann BP, Meador KJ, Vahle V, Kanner AM. Rapid detection of major depression in epilepsy: a multicentre study. Lancet Neurology, 2006;5:399–405.

Session Summary: Mechanisms of SUDEP Moderators: Detlev Boison, PhD, Franck Kalume, PhD

The goal of this breakout session was to highlight the role of respiratory mechanisms implicated in SUDEP and their control by the endogenous modulators adenosine and serotonin. New findings suggest that SUDEP-like events might be more prevalent than previously thought. The first presentations focused on respiratory abnormalities mediated by seizure-spread to the amygdala and postictal pulmonary edema as possible precipitators of SUDEP. Provocative findings were presented suggesting that SUDEP-like events also occur in Alzheimer’s disease. The final presentations discussed the SUDEP-promoting and SUDEP-preventing roles of adenosine and serotonin, respectively. The identification of molecular mechanisms implicated in respiratory failure might have implications for sudden death not only in persons with epilepsy but also beyond the epilepsy population. How do seizures in the forebrain influence cardiorespiratory control? Presented by Brian J. Dlouhy, MD

Eyewitness accounts and SUDEP cases in epilepsy monitoring units suggest the inciting event leading to SUDEP may be respiratory depression induced by seizures. A research participant with intractable epilepsy was monitored during seizures recorded by intracranial electrodes and mapped by high-resolution brain imaging (1). Central apnea and O2 desaturation occurred when seizures spread to the amygdala. Importantly, focal electrical stimulation of the amygdala reproduced the apnea and O2 desaturation. Similar effects of amygdala stimulation were observed in two additional subjects, including one without a seizure disorder. All participants were unaware of the apnea evoked by the stimulation and expressed no dyspnea, despite being awake and vigilant. In contrast, voluntary breath holding caused severe dyspnea. These findings suggest that seizure spread to the amygdala may cause loss of spontaneous breathing of which patients are unaware, and thus has potential to contribute to SUDEP. Postictal pulmonary edema Presented by Masud Seyal, MD, PhD

The relevance of postictal pulmonary edema (PPE) to SUDEP remains controversial. Case reports of seizure-related pulmonary edema including recurrent pulmonary edema and SUDEP suggest that PPE is more common than previously thought. 24 consecutive patients who had a bedside chest x-ray (CXR) following a generalized tonic-clonic seizure (GTCS) were studied in an epilepsy monitoring unit (2). Eleven patients had at least one abnormal CXR. Seven of these had PPE on at least

one CXR. Four patients had focal infiltrates or atelectasis alone. Two of the seven patients with PPE also had evidence for a focal CXR abnormality. The mean duration of the preceding seizure was significantly longer (250 seconds) in the group of GTCS with postictal CXR abnormalities compared to the group with normal CXRs (101 seconds) (p=0.002). Severe, untreated postictal PPE may thus be relevant in the pathophysiology of SUDEP. Sudden death in mouse models of Alzheimer’s disease neuropathology Presented by Helen E. Scharfman, PhD

There is growing interest in the overlap between Alzheimer’s disease (AD) and epilepsy. It is commonly believed that plaques and tangles cause AD but there are other hypotheses, such as the idea that seizures cause or contribute to AD. Strikingly, sudden unexplained death also occurs in mouse models of AD. In the Tg2576 mouse model of AD convulsive seizures occur early in life (3) and animals often die shortly afterwards. Alternatively, animals are found to suddenly die but were normal the day before. In mouse models of AD seizures can occur prior to the onset of cognitive decline when the animals are young. Seizures as well as SUDEP emerge in sleep. Clinical information about SUDEP in patients with AD is still lacking because aging is accompanied by increased death of all types so there could be elevated risk of SUDEP in AD simply because of aging. Mechanisms of SUDEP: purines and the control of breathing Presented by Haiying Shen, MD, PhD

The adenosine hypothesis of SUDEP (4) predicts that a seizure-induced adenosine surge in combination with impaired metabolic clearance can trigger lethal apnea or cardiac arrest. If excessive adenosine triggers SUDEP, then adenosine receptor antagonists, such as caffeine or theophylline, might prevent SUDEP. The challenge therapeutically is that the components of the purinergic system that protect against respiratory depression also promote seizures, and vice versa. Purinergic therapies must exploit mechanisms that will either enhance respiratory activity without affecting cortical excitability, or preferentially, enhance respiratory activity and at the same time reduce cortical excitability. 5-HT2c receptor: implications for SUDEP Presented by Chen Liu, PhD

Depletion of serotonin (5-HT) in the brain produces proconvulsant effects, whereas 5-HT has antiepileptic effects. At the same time dysfunction of 5-HT neurotransmission has been implicated in SUDEP. Mice lacking the 5-HT 2c receptor (Htr2c) (5) demonstrated a global increase in seizure susceptibility in multiple seizure paradigms. At the same time these Htr2c null mice suffered from SUDEP-like events with a high incidence of mortality. Pretreatment with an Htr2c agonist effectively reduced the incidence of seizures and seizure-induced death in DBA/2J mice, but not in Htr2c null mice. Advanced molecular tools have been

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developed that include a reactivate-able Htr2c null allele for the neuron specific restoration of Htr2c, a floxed Htr2c allele for the neuron specific ablation of Htr2c, and a Htr2c-Cre knock-in model for ontogenetic and chemogenic manipulations. Recent findings suggest that Htr2c acts on GABAergic neurons to modulate seizure vulnerability and susceptibility. References 1. Dlouhy BJ, Gehlbach BK, Kreple CJ, Kawasaki H, Oya H, Buzza C, Granner MA, Welsh MJ, Howard MA, Wemmie JA, Richerson GB. Breathing Inhibited When Seizures Spread to the Amygdala and upon Amygdala Stimulation. J Neurosci 2015;35:10281–10289. 2. Kennedy JD, Seyal M. Respiratory pathophysiology with seizures and implications for sudden unexpected death in epilepsy. J Clin Neurophysiol 2015;32:10–13. 3. Kam K, Duffy AM, Moretto J, LaFrancois JJ, Scharfman HE. Interictal spikes during sleep are an early defect in the Tg2576 mouse model of beta-amyloid neuropathology. Sci Rep 2016;6:20119. 4. Shen HY, Li T, Boison D. A novel mouse model for sudden unexpected death in epilepsy (SUDEP): role of impaired adenosine clearance. Epilepsia 2010;51:465–468. 5. Berglund ED, Liu C, Sohn JW, Liu T, Kim MH, Lee CE, Vianna CR, Williams KW, Xu Y, Elmquist JK. Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis. J Clin Invest 2013;123:5061–5070.

Session Summary: Lessons Learned in Grief and How to Better Support Families Moderator: Cyndi Wright, SUDEP Institute

This session was a panel discussion of the lessons learned from research studies, support organizations and families on how we can better support those bereaved by epilepsy. Presented by Rajesh Ramachandran Nair, MD, Karen Osland, Rosemary Panelli, MPH, PhD, Henry Smithson, MD, Linda Coughlin Brooks, RN, BSN, Jennifer Murphy, MS

The session began with Dr. Nair (McMaster University) describing the findings from several of his research studies that demonstrated families want to be informed of the risk of SUDEP and the majority want to know soon after the diagnosis. According to his research, the best way to provide information on SUDEP is in a face-to-face conversation between the person with epilepsy (or a caregiver if a minor) and their neurologist. Ms. Osland (SUDEP Action) discussed how we are all experts in our own grief and people grieve differently. It is important for families to get continued support through trained support professionals whose role it is to listen, help families understand SUDEP, support families through the death investigation and to connect the bereaved with other families. When they are ready, families should be provided with opportunities and support to participate in research and to become advocates. Dr. Panelli (SUDEP Action) discussed the power of the bereaved in effecting political change. Family stories have incredible impact in raising awareness and changing behavior. Dr. Smithson (University College Cork) discussed the important of registries including the Epilepsy Deaths Register (1) and the North American SUDEP Registry (2).

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Ms. Coughlin Brooks (Epilepsy Foundation SUDEP Institute) discussed how not being informed of the risk of death complicates the grieving process after a loved one dies. She emphasized the importance of families working with medical examiners to ensure epilepsy appeared as a cause of death on the death certificate. She also explained the importance of contacting healthcare providers of the death to help them become aware of deaths in epilepsy and also so they can help families answer questions or maybe even review the death certificate. Ms. Murphy (Patrick Ring Foundation) discussed the importance of partnerships with fellow bereaved families as well as between organizations so together we can make more resources available to increase awareness, support and ultimately save lives. The summary message from the session was for families to continue to connect, register with a registry, share SUDEP materials and information, and most importantly to share their stories to help drive change and save lives. References 1. Source: https://epilepsydeathsregister.org/. Accessed September 2016. 2. Source: http://sudep-registry.org/. Accessed September 2016.

Session Summary: Future Directions for Research to Impact Prevention Moderators: Brian Gehlbach, MD, Jeff Noebels, MD, PhD

In the future, the prevention of SUDEP may involve the use of biomarkers to identify high-risk individuals for the purpose of receiving targeted interventions. These biomarkers may derive from neuroimaging, genetic, or cardiorespiratory data obtained during the ictal or inter-ictal period. In order to be clinically useful, these biomarkers will need to be accurate, reproducible, easy to obtain, and sensitive to changes in risk. Ideally, these biomarkers would also lie within the causal pathway and therefore lead to targeted interventions. It is likely that no one biomarker will suffice to denote SUDEP risk, and that panels of biomarkers targeted to specific populations and contexts will be required. Is there an antemortem imaging biomarker of SUDEP? Presented by Susanne Mueller, MD

Quantitative neuroimaging performed in patients suffering from epilepsy has revealed widespread structural abnormalities beyond the presumed seizure focus (1-3). These abnormalities are often not detected by conventional visual analysis of brain MRIs. In some patients, these abnormalities extend to cortical and brainstem regions involved in central autonomic and respiratory control. It is possible that abnormalities in these critical regions develop and progress over time in patients with poorly controlled epilepsy, placing them at increased risk for fatal breakdown of the cardiorespiratory system in situations of heightened demand, as during a generalized seizure. This hypothesis is supported by the finding of severe brainstem damage in several autonomic control regions in a small series of patients who later died of SUDEP (4).


Cardiac biomarkers for SUDEP risk Presented by Stephan Schuele, MD

Potential cardiac biomarkers of SUDEP risk include ictal and inter-ictal electrocardiographic abnormalities, tests of autonomic function (e.g. analysis of heart rate variability), and functional/structural imaging modalities including echocardiography. For many years, SUDEP was felt to be principally a cardiovascular event. An increasing awareness of the effects of seizures on breathing, combined with the temporal sequence of cardiorespiratory failure described in the MORTEMUS study, have tempered this view (5). Overall, the most common cardiac abnormality found in epilepsy is sinus tachycardia, which is not itself a lethal rhythm (6). In addition, while underlying cardiovascular disease and various long QT syndromes both likely increase the risk of sudden cardiovascular death in patients with epilepsy, these conditions may only explain a small subset of SUDEP cases. The role of cardiac biomarkers may need to be re-thought. Conceivably, postictal cardiac changes may not be the primary mechanism for SUDEP but could serve as cardiac biomarkers to distinguish benign versus potentially fatal post-ictal EEG suppression or respiratory abnormalities.

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Respiratory biomarkers for SUDEP risk Presented by Lisa Bateman, MD

Respiratory mechanisms are likely to play an important role in SUDEP, based on accumulating data from monitored human SUDEP cases and animal models of epileptic death (7,8). Periictal respiratory alterations, such as hypoxemia, hypercapnia, apnea, or even neurogenic pulmonary edema, occur far too commonly, and typically recover too quickly, to be considered alone as meaningful biomarkers of SUDEP risk. Universal recommendations for specific respiratory interventions (e.g. home oxygen or resuscitative equipment) cannot be made for the general epilepsy population without a better understanding of the critical peri-ictal respiratory patterns that portend the highest risk of SUDEP. Contribution of genetics in SUDEP diagnostics and prediction Presented by Alica Goldman, MD, PhD

SUDEP gene profiling in humans is centered either on 1) case control gene profiling in a population of SUDEP cases vs matched living epilepsy patients, or 2) patient-centric genetic analysis in the families of individuals who died of SUDEP. It is evident that there is no one common SUDEP gene or gene family that can explain all cases of SUDEP, and that the genetics of sudden death in epilepsy is complex (9). Genetic model systems continue to be critical in discovery, validation, and pathophysiological understanding of the established and emerging SUDEP genes (10,11). References 1. Bernhardt BC, Worsley KJ, Besson P, Concha L, Lerch JP, Evans AC, Bernasconi N. Mapping limbic network organization in temporal lobe epilepsy using morphometric correlations: Insights on the relation

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between mesiotemporal connectivity and cortical atrophy. Neuroimage 2008;42:515–524. Mueller SG, Laxer KD, Barakos J, Cheong I, Garcia P, Weiner MW. Subfield atrophy pattern in temporal lobe epilepsy with and without mesial sclerosis detected by high-resolution MRI at 4 Tesla: Preliminary results. Epilepsia 2009;50:1474–1483. Wandschneider B, Koepp M, Scott C, Micallef C, Balestrini S, Sisodiya SM, Thom M, Harper RM, Sander JW, Vos SB, Duncan JS, Lhatoo S, Diehl B. Structural imaging biomarkers of sudden unexpected death in epilepsy. Brain 2015;138:2907–2919. Mueller SG, Bateman LM, and Laxerc KD. Evidence for brainstem network disruption in temporal lobe epilepsy and sudden unexplained death in epilepsy. Neuroimage Clin 2014;5:208–216. Ryvlin P, Nashef L, Lhatoo SD, et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol 2013;12:966–77. Bermeo-Ovalle AC, Kennedy JD, Schuele SU. Cardiac and autonomic mechanisms contributing to SUDEP. J Clin Neurophysiol 2015;32(1):21–29. Bateman LM, Li CS, Seyal M. Ictal hypoxemia in localization-related epilepsy: analysis of incidence, severity and risk factors. Brain 2008;131:3239–3245. Massey CA, Sowers LP, Dlouhy BJ, Richerson GB. Mechanisms of sudden unexpected death in epilepsy: the pathway to prevention. Nat Rev Neurol 2014;10(5):271–282. Goldman AM, Behr ER, Semsarian C, Bagnall RD, Sisodiya S, Cooper PN. Sudden unexpected death in epilepsy genetics: Molecular diagnostics and prevention. Epilepsia 2016;57(Suppl 1):17–25. Goldman AM, Glasscock E, Yoo J, et al. Arrhythmia in heart and brain: KCNQ1 mutations link epilepsy and sudden unexplained death. Sci Transl Med 2009;1:2ra6. Aiba I, Wehrens XH, Noebels JL. Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death. Proc Natl Acad Sci USA 2016. pii: 201605216. [Epub ahead of print]

Session Summary: How Do We Improve SUDEP Risk Disclosure Moderator and Presenter: Henry Smithson.

This breakout session was an open floor discussion about improving information provision about SUDEP risk. There were about 90 participants, mostly patient advocates, along with some clinicians from Canada, the USA and Europe. Field notes were collected and discussion was around the need for information and the concern that there was still a lack of knowledge provision. Disclosure of risk was important but as part of a broader discussion about how to reduce the risk and reduce the impact of the condition. Bereaved families feel unsupported and would encourage the development of support groups with expertise in epilepsy and epilepsy risk. There was much enthusiasm to learn from a UK charity that had been offering support for families for 20 years and to develop links between groups across state and national borders. Several families of SUDEP victims expressed anger and disappointment about non-disclosure of risk prior to loss of a loved one. Information about SUDEP risk can help patients and families make educated decision, and can help to mitigate pain of the survivors.

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