partners against mortality in epilepsy conference summary · 2015-01-13 · and research...

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Epilepsy Currents, Vol. 14, No. 6 Supplement 2014 pp. 14–31 © American Epilepsy Society

It’s CurrentEpilepsy Resources and Updates

Summary Session: Overview of Mortality in Epilepsy Including SUDEP

Moderator: David J. Thurman, MD, MPH

Overview of Short- and Long-Term Mortality in EpilepsyOn average, the overall risk of premature mortality among people with epilepsy, measured by the standardized mortality ratio (SMR), appears to be 2–3 times higher than that of the general population. This risk varies greatly among subgroups with epilepsy, depending on several factors such as the cause of epilepsy. In defining “epilepsy-related” deaths, it is important

to separate those attributable directly to epilepsy or seizures from those attributable to underlying neurologic diseases causing epilepsy.

Deaths attributable directly to epilepsy include sudden unexpected death in epilepsy (SUDEP) as well as some cases of fatal status epilepticus. The true incidence of epilepsy-caused mortality is unknown, as national mortality records provide inaccurate data on epilepsy. Therefore, estimates must rely on extrapolations from studies of limited populations, popula-tion- or clinic-based, with substantial potential for error. Com-bined data from a few prospective population-based studies conducted by medical examiners yield an estimated annual rate of SUDEP of 1.22 cases per 1,000 people with epilepsy, a rate corresponding to nearly 2,800 deaths from SUDEP in the United States each year (1). SUDEP incidence varies by age: much lower among young children, higher among adoles-

Moderator Summaries

Jeffrey Buchhalter MD, PhD, Gardiner Lapham RN, MPH

The second Partners Against Mortality in Epilepsy conference occurred in Minneapolis, MN, from June19–22, 2014. This conference, as well as the one in 2012 (1), grew out of the desire to provide a forum in which the most recent informa-tion regarding mortality in epilepsy, especially Sudden Unexpected Death in Epilepsy (SUDEP), could be shared by all stakeholders: the bereaved, people living with epilepsy, families, basic scientists, clinical scientists, and advocacy and research organizations. To this end, the conference was built around plenary sessions so that all could and would attend presentations that were designed to be accessible to multiple levels of scientific and clinical backgrounds. The speakers did an outstanding job in this regard. The topics were expanded from the 2012 conference focus on SUDEP to include: other important causes of mortality in epilepsy (e.g., suicide, accidents), the process of grief related to epilepsy, upcoming epilepsy mortality surveillance efforts and provider guidelines. Potential mechanisms underlying SUDEP (genetic, respiratory, cardiac, and autonomic) were discussed in detail by some of the most prominent scientists in the field. In addition to the more didactic plenary sessions, attendees were provided the opportunity to participate in smaller discussion groups intended to provide a more in-depth review of scientific topics for those interested.

As for the first meeting, this conference was accomplished by the hard work of volunteers of our “partner” organiza-tions, including the American Epilepsy Society, Epilepsy Foundation, Citizens United for Research in Epilepsy, Finding a Cure for Epilepsy and Seizures, Danny Did Foundation, and the National Institute of Neurological Disorders and Stroke. The essential contributions of Ms. Cyndi Wright (SUDEP Institute/Epilepsy Foundation) and Mr. Jeffrey Melin (American Epilepsy Society) must be gratefully acknowledged. Similarly, thanks go to all the speakers and moderators who so graciously gave their time and knowledge to make this such a successful and meaningful meeting. A complete list of the generous sponsors and slides presented at the conference are available online (2).

References1. Buchhalter J, So EL, Berg AT, Kanner AM, Hessdorffer DC, Mintzer S, Hirsch LJ, Thurman DJ, Sierzant T, Nashef L, Donner EJ, Bateman LM,

Tomson T, Devinsky O, Pollanen M, Jeffs T, Goldman AM, Hanna J, Bauer C, Richerson G, Parent J, Faingold CL, Buchanan GF, Kinney H, Bealer SL, Schuele S, Surges R, Nair RR, Collins N, Devinsky O, Hesdorffer D, Chong D, Friedman D, Panelli R, Noebels J, Vatta M, Mulkey D, Anderson A, Buchhalter J, Whittemore V, Kelly B, Porter R, Harden C. Partners Against Mortality in Epilepsy conference summary. Epilepsy Curr 2013; 13(suppl 2):5–21.

2. Partners Against Mortality in Epilepsy. 2014 conference materials. http://pame.aesnet.org/.

Partners Against Mortality in Epilepsy Conference Summary

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cents, and highest in young and early middle-aged adults. Studies of fatal status epilepticus among persons with epilepsy yield widely varying estimates. Combining data from 3 popu-lation-based studies, we may estimate an annual rate of 0.25 cases of fatal status epilepticus per 1,000 people with epilepsy, substantially lower than the rate of SUDEP. These are averaged estimates; among subgroups of people with epilepsy, risks of SUDEP and fatal status epilepticus may be substantially lower or higher, depending on factors such as type and frequency of seizures.

Causes of Epilepsy as Causes of Death in Epilepsy

Presented by Roland D. Thijs, MD, PhD

Deaths attributable to underlying diseases causing epilepsy include those resulting from brain tumors, cerebrovascular disease, central nervous system infections, as well as some inherited disorders. Among people with epilepsy due to these causes, the risk of premature mortality is much higher, particularly in the first few years following diagnosis. Cohort studies of patients newly diagnosed with epilepsy yield vari-able estimates but consistently show highest risks in the first year following diagnosis and with a median reported SMR of 7 (2). Among all people with epilepsy, the majority of deaths in the first two years after diagnosis appear due to these underly-ing causes. It follows that among people newly diagnosed with idiopathic epilepsy, an early mortality risk elevation is not observed (2). It should also be noted that age is an important determinant of the risk of premature mortality in people with epilepsy. Younger age is associated with higher SMRs in stud-ies both from higher income as well as developing countries (3). Among older adults, SMRs for those with epilepsy show only modest elevation compared to general populations, a finding attributable in large measure to the increased rates of mortality in general populations of seniors. Although there is consistent evidence that premature mortality in epilepsy is driven substantially by the underlying causes of epilepsy, this phenomenon still requires further study.

Occurrence and Risk Factors for Accidents in Epilepsy

Presented by W. Allen Hauser, MD

Accidental injury due to seizures is an important consideration among the causes of increased mortality in people with epi-lepsy (3, 4). Several studies point to an increased occurrence of accidental injuries in this population. Most such injuries are relatively minor, but among more serious injuries are fractures, traumatic brain injury, near-drowning or drowning, and burns. Significant increase in the risk of mortality due to accidents have been found in studies of people with epilepsy in the United States, Sweden, and Iceland, with SMRs ranging from 2.4 to 5.6. Some other studies, however, have yielded smaller, statistically insignificant measures of increased risk. Relatively few studies have adequately evaluated specific causes of accidental death among people with epilepsy. There are insufficient data with respect to traffic injuries, where it is important to distinguish among injured persons who were drivers, passengers, or pedestrians. In contrast, several studies have shown a disproportionately high frequency of drown-

ing deaths among people with epilepsy, as found in Alberta, Canada; Great Britain; and King County, United States. In studies in China, Bangladesh, and Taiwan, SMRs for drowning among people with epilepsy ranged from 9 to 40. Burns are frequent accidents in people with epilepsy, but these seldom lead to death in developed countries. In low-income countries, however, burns account for a substantial proportion of deaths in people with epilepsy, with reports of 5% in Tanzania and 20% in Bangladesh. Finally, people with epilepsy are generally recognized as having an increased risk of traumatic brain in-jury as a result of falls, commonly as a consequence of seizures. There is, however, scant information describing the magnitude of this risk.

SUDEP: New Definition

Presented by Dale C. Hesdorffer, PhD

The measurement of occurrence and risk of premature mortal-ity in epilepsy requires careful definitions, and this is especially true of SUDEP, which was first carefully addressed in two defi-nitions published separately in 1997 by Lina Nashef and Fred Annegers. While broadly similar, the two definitions differed in some aspects of classification. Accordingly, researchers have recently published a unified definition of SUDEP to resolve these differences and clarify ambiguities that have become evident in recent years. This new Unified SUDEP Definition and Classification (5) includes nine recommendations: 1) “unex-pected” should be used instead of “unexplained” when defin-ing SUDEP; 2) SUDEP should be applied when appropriate, whether or not a terminal seizure has occurred; 3) the “Possible SUDEP” category should be used only for cases with compet-ing causes of death; 4) cases that would otherwise fulfill the definition of SUDEP should be designated as “SUDEP Plus,” when evidence indicates that a preexisting condition could have contributed to death otherwise classifiable as SUDEP; 5) to be considered SUDEP, the death should have occurred within 1 hour from the onset of a known terminal event; 6) ter-minal seizure activity lasting 30 minutes or more is classified as status epilepticus, not SUDEP; 7) a specific category of SUDEP due to asphyxia should not be designated; 8) death occurring in water but without circumstantial or autopsy evidence of submersion should be classified as “Possible SUDEP”; 9) a cat-egory of “Near-SUDEP” should be agreed upon to include cases in which cardiorespiratory arrest was reversed by resuscitation efforts with subsequent survival for more than 1 hour.

References1. Thurman DJ, Hesdorffer DC, French JA. Sudden unexpected death

in epilepsy: Assessing the public health burden [published online ahead of print June 5, 2014]. Epilepsia doi:10.1111/epi.12666.

2. Cockerell OC, Johnson AL, Sander JW, Hart YM, Goodridge DM, Shorvon SD. Mortality from epilepsy: Results from a prospective population-based study. Lancet 1994;344:918–921.

3. Ding D, Wang W, Wu J, Yang H, Li S, Dai X, Yang B, Wang T, Yuan C, Ma G, Bell GS, Kwan P, de Boer HM, Hong Z, Sander JW. Premature mortality risk in people with convulsive epilepsy: Long follow-up of a cohort in rural China. Epilepsia 2013;54:512–517.

4. Hauser WA, Annegers JF, Elveback LR. Mortality in patients with epilepsy. Epilepsia 1980;21:399–412.

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5. Nashef L, So EL, Ryvlin P, Tomson T. Unifying the definitions of sudden unexpected death in epilepsy. Epilepsia 2012;53:227–233.

Summary of Session: SUDEP Mechanisms: Respiratory

Moderators: George B. Richerson MD, PhD, Lisa M. Bateman, MD, FRCPC

The goal of this session was to discuss research on how seizures interfere with neural control of breathing in humans and in animals. Parallels between SUDEP and sudden infant death syndrome (SIDS) were described since there appears to be overlap between the mechanisms involved in seizure-induced respiratory arrest and those that cause apnea during sleep in infants. This was followed by data that provide insight into potential cellular, molecular, and genetic defects that may increase the risk of SUDEP, including evidence for links to serotonin, adenosine, and some long QT gene mutations, each of which may increase the chance for unstable respira-tory rhythm generation. These data may lead to a better understanding of why seizures are frequently associated with respiratory dysfunction and to development of novel strate-gies to reduce the risk of SUDEP.

Human Peri-Ictal Physiology: Respiratory

Presented by Lisa M. Bateman, MD, FRCPC

Some form of respiratory distress is frequently reported in witnessed cases of SUDEP and near-SUDEP. While the respiratory rhythm is generated by brainstem neurons, it can be influenced by multiple cortical areas, including those frequently involved in seizures. This talk focused on studies of peri-ictal respiratory function in human seizure recordings obtained in epilepsy monitoring units. Ictal apneas, about 2/3 of which are central, more commonly occur in seizures with electrographic evidence of bi-hemispheric involvement (1). Several studies have demonstrated the frequent occur-rence of ictal hypoxemia, though the clinical characteristics correlated with this finding vary (2–4). Peri-ictal hypoxemia is seen in about 1/3 of focal onset seizures, with a delay of approximately 1 minute after seizure onset, a mean duration of 69 seconds and a probability of recurrence of 0.43 (2). The underlying cause of hypoxemia is undetermined and may be multifactorial. Hypercapnia frequently accompanies hy-poxemia, particularly with more severe desaturations (<85%) and may be prolonged (mean duration 424 seconds), de-spite post-ictal increases in the rate and depth of respiration (5). Hypoxemia and hypercapnia could potentially contrib-ute to SUDEP through known effects of these disturbances on cardiac and cerebral function. Indeed, ictal hypoxemia has been associated with bradycardia, tachycardia, and car-diac repolarization changes (3, 6, 7), in addition to post-ictal generalized EEG suppression (8, 9) and post-ictal immobil-ity (10). Other peri-ictal respiratory complications, such as obstructive apnea due to laryngospasm and neurogenic pulmonary edema, have also been observed in SUDEP and near-SUDEP (11). It remains to be determined how common peri-ictal respiratory accompaniments relate to the relatively rare occurrence of SUDEP, and this will be a focus of future research efforts.

SUDEP, SIDS and Serotonin

Presented by George B. Richerson, MD, PhD

It is not known how seizures cause respiratory arrest. This talk discussed animal experiments aimed at defining the mecha-nisms involved. The serotonin (5-HT) system has emerged as a potential target for more specific treatments because it ap-pears to play a central role in respiratory dysfunction induced by seizures. For example, 5-HT2C receptor knockout mice develop spontaneous seizures followed by respiratory arrest, suggesting that defects in the 5-HT system can induce seizures and also have an independent effect to increase the risk of SUDEP (12). The DBA/1 and DBA/2 strains of mice have audio-genic seizures and a high rate of post-ictal respiratory arrest (13). Treatment with a serotonin reuptake blocker reduces the incidence of respiratory arrest in a dose-dependent manner in DBA/2 mice (14), and in epilepsy patients these drugs are as-sociated with reduced severity of oxygen desaturations during and after seizures (15). We have found that Lmx1b conditional knockout mice, in which >99% of 5-HT neurons have been genetically deleted (15), also have a decreased seizure thresh-old, as well as an increased incidence of respiratory arrest after seizures (16). The association of seizure-induced death in mice with defects in the serotonin system led to the suggestion that SUDEP may share mechanisms with sudden infant death syndrome (SIDS), which has many similarities. For example, both have been proposed to be due to respiratory, arousal or cardiac mechanisms, and both are more likely to occur when individuals are in the prone position (17). An increase in risk of SUDEP and SIDS due to defects in 5-HT neurons would not be unexpected, because 5-HT neurons in mice have been shown to be important for detecting an increase in blood carbon di-oxide levels and causing an increase in breathing and arousal from sleep (18–20). Future experiments will seek biomarkers for defects in 5-HT and ways to reverse 5-HT abnormalities so breathing and arousal would not be inhibited so severely after a seizure.

Respiratory Rhythm Generation and Long QT genes

Presented by Daniel Mulkey, PhD

Mutations of some ion channel genes cause long QT syn-drome (LQTS), an abnormality in the EKG associated with an increased risk of sudden death due to a cardiac arrhythmia. These genes are expressed in the heart, but many are also expressed in the brain. Some have more recently been linked to epilepsy and SUDEP. Many cases of SUDEP in these patients with LQTS mutations are probably due to seizure-induced cardiac arrhythmias, but it has recently been found that some LQTS ion channels are expressed in respiratory nuclei of the brainstem. This talk focused on the role of KCNQ channels in the retrotrapezoid nucleus (RTN), an area important for central chemoreception, and on how serotonin modulates KCNQ channels and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (21). Serotonin alters the activity of RTN neurons via 5-HT2 and 5-HT7 receptors that act on KCNQ and HCN channels, thereby affecting breathing. Mutations in these channels might make a person more susceptible to respiratory arrest if a seizure invades the brainstem. Defining what makes

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the respiratory control network stable or unstable, and how it is affected by 5-HT, may lead to new targets for prevention of SUDEP.

Adenosine in the Brainstem

Presented by Detlev Boison, PhD

Increased availability of the neuromodulator adenosine sup-presses neuronal activity as an innate mechanism to stop seizures, but it also suppresses respiratory functions in the brainstem. This talk focused on the “adenosine hypothesis of SUDEP,” which predicts that a seizure-induced adenosine surge, in combination with impaired metabolic clearance, can trigger lethal apnea. If excessive adenosine triggers SUDEP, then adenosine receptor antagonists, such as caffeine, should prevent SUDEP. When acute seizures are triggered in mice with pharmacological block of metabolic adenosine clearance, all animals develop prolonged apnea and lethal outcome, whereas a single injection of caffeine given immediately after seizure onset significantly prolonged survival time (22). Similarly, in a mouse model of temporal lobe epilepsy in which spontaneous recurrent partial seizures were induced by an intra-hippocampal injection of kainic acid, there was a sig-nificant upregulation of the adenosine metabolizing enzyme adenosine kinase (ADK) in the nucleus tractus solitarius (NTS), likely a compensatory mechanism to protect the brainstem from excessive adenosine. Engineered mice with heterozy-gous deletion of the Adk gene and compromised metabolic clearance of adenosine were characterized by a milder seizure phenotype compared to wild-type littermates; however, 3 out of 8 mutants succumbed to sudden death, whereas none of 11 epileptic wild-type controls died. Histologically, the mutant epileptic animals had lower levels of ADK expression in the NTS compared to epileptic wild-type mice, suggesting that deficient metabolic clearance of adenosine can contribute to SUDEP in chronic epilepsy.

Characterization of Respiratory Arrest-Susceptible DBA/1 TPH2-ChR2 Mice

Presented by Hua-Jun Feng, PhD

DBA/1 mice, a model of sudden unexpected death in epilepsy (SUDEP), exhibit respiratory arrest (RA) leading to death after generalized audiogenic seizures (AGS). Studies suggest that a deficiency of serotonergic (5-HT) transmission may contribute to RA in DBA/1 mice. This talk focused on a new method of studying the pathophysiology of RA in this model. Transgenic DBA/1 mice that specifically express channelrhodopsin (ChR2) in 5-HT neurons (TPH2-ChR2) were created in preparation to dissect the circuitry that contributes to RA using optogenetics. Since this method has not been used in DBA/1 mice previ-ously, it is important to determine if this transgenic approach results in expression of RA phenotype. The DBA/1 TPH2-ChR2 mice were created by backcrossing the available C57 TPH2-ChR2 mice with wild-type DBA/1 mice. Mice exhibiting AGS-induced RA were resuscitated using a rodent respira-tor. Each mouse was subjected to acoustic stimulation three times for priming starting on postnatal day 26–28. Congenic DBA/1 TPH2-ChR2 mice were generated in the offspring of the

fifth generation of backcrossing, and immunohistochemistry confirmed the expression of ChR2 on 5-HT neurons. Of the 52 transgenic DBA/1 mice tested, 9.6% exhibited RA in test 1, 15.4% in test 2 and 86.5% in test 3. The incidence of RA in tests 1 and 2 was significantly lower in transgenic than in wild-type DBA/1 mice, but in test 3 it was not. Our studies indicate that transgenic DBA/1 mice exhibit similar AGS and incidence of RA as wild-type DBA/1 mice. Our results also suggest the back-crossing strategy can be applied to study many other neuro-transmission systems in these mice.

AcknowledgmentsThis work was supported by the NIH (P20NS076916 (GBR, LMB); P01HD36379 (GBR); HL104101 (DM); R03NS078591 (HF)) and the CURE Foundation (HF).

References1. Seyal M, Bateman LM. Ictal apnea linked to contralateral spread of

temporal lobe seizures: Intracranial EEG recordings in refractory temporal lobe epilepsy. Epilepsia 2009;50:2557–2562.

2. Bateman LM, Li CS, Seyal M. Ictal hypoxemia in localization-related epilepsy: Analysis of incidence, severity and risk factors. Brain 2008;131:3239–3245.

3. Moseley BD, Wirrell EC, Nickels K, Johnson JN, Ackerman MJ, Britton J. Electrocardiographic and oximetric changes during partial complex and generalized seizures. Epilepsy Res 2011;95:237–245.

4. 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.

5. Seyal M, Bateman LM, Albertson TE, Lin TC, Li CS. Respiratory changes with seizures in localization-related epilepsy: Analysis of periictal hypercapnia and airflow patterns. Epilepsia 2010;51:1359–1364.

6. Nashef L, Walker F, Allen P, Sander JW, Shorvon SD, Fish DR. Apnoea and bradycardia during epileptic seizures: Relation to sudden death in epilepsy. J Neurol Neurosurg Psychiatry 1996;60:297–300.

7. Seyal M, Pascual F, Lee CY, Li CS, Bateman LM. Seizure-related cardiac repolarization abnormalities are associated with ictal hypoxemia. Epilepsia 2011;52:2105–2111.

8. 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.

9. Seyal M, Hardin KA, Bateman LM. Postictal generalized EEG suppres-sion is linked to seizure-associated respiratory dysfunction but not postictal apnea. Epilepsia 2012;53:825–831.

10. Seyal M, Bateman LM, Li CS. Impact of periictal interventions on respiratory dysfunction, postictal EEG suppression, and postictal im-mobility. Epilepsia 2013;54:377–382.

11. Tomson T, Nashef L, Ryvlin P. Sudden unexpected death in epilepsy: Current knowledge and future directions. Lancet Neurol 2008;7:1021–1031.

12. 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.

13. Purpura, DP. Experimental Models of Epilepsy—A Manual for the Laboratory Worker. New York: Raven Press, 1972.

14. Tupal S, Faingold CL. Evidence supporting a role of serotonin in modulation of sudden death induced by seizures in DBA/2 mice. Epilepsia 2006;47:21–26.

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15. Bateman LM, Li CS, Lin TC, Seyal M. Serotonin reuptake inhibitors are associated with reduced severity of ictal hypoxemia in medically refractory partial epilepsy. Epilepsia 2010;51:2211–2214.

16. Buchanan GF, Murray NM, Hajek MA, Richerson GB. Serotonin neurones have anticonvulsant effects and reduce seizure-induced mortality [published online ahead of print August 8, 2004]. J Physiol PMID:25107926.

17. Massey CA, Sowers LP, Dlouhy BJ, Richerson GB. Mechanisms of sudden unexpected death in epilepsy: The pathway to prevention. Nature Rev Neurol 2014;10:271–282.

18. Richerson GB. Serotonergic neurons as carbon dioxide sensors that maintain pH homeostasis. Nat Rev Neurosci 2004;5:449–461.

19. Buchanan GF, Richerson GB. Central serotonin neurons are required for arousal to CO2. PNAS 2010;107:16354–16359.

20. Teran FA, Massey CA, Richerson GB. Serotonin neurons and central respiratory chemoreception: Where are we now? Prog Brain Res 2014;209:207–233.

21. Hawryluk JM, Moreira TS, Takakura AC, Wenker IC, Tzingounis AV, Mulkey DK. KCNQ channels determine serotonergic modulation of ventral surface chemoreceptors and respiratory drive. J Neurosci 2012;32:16943–16952.

22. Shen HY, Li T, Boison D. A novel mouse model for sudden unexpect-ed death in epilepsy (SUDEP): Role of impaired adenosine clearance. Epilepsia 2010;51:465–468.

Session Summary: Epilepsy Mortality Surveillance and Provider Guidelines

Moderator: Orrin Devinsky, MD

Presented by Lindsey Thomas, MD, Vicky Whittemore, PhD, Cynthia Harden, MD, Cydni Wright

In Sweden in 2008, 1,891 people with epilepsy died. A review of the cause of death (CoD) in this cohort revealed 163 (8.6%) potential epilepsy-related causes. Of these 163 cases, SUDEP was the cause in 65 (39.9%), but epilepsy was coded on the death certificate as the principle CoD in 15 (23%) and men-tioned on the death certificate in 49 (75%). The history of epilepsy was never mentioned on the death certificates of 22 definite or 13 suspected suicides. Among all 1,891, epilepsy was mentioned on 285 (15.2%) death certificates.

Medical examiners and coroners play a central role in the surveillance of mortality in patients with epilepsy (1). Many deaths in people with epilepsy are sudden, unexpected, or unnatural. Natural causes include SUDEP or death during a seizure. Accidental causes include positional asphyxia, drown-ing, motor vehicle accident, and so on. Medical examiners determine CoD and manner of death, including careful exclu-sion of other causes (e.g., drug overdose, heart disease, etc.). The extent of investigation and specific coding vary widely by jurisdiction (2). There are federal efforts to standardize and improve the quality of U.S. medicolegal death investigations.

Efforts are underway in the United States and Canada to improve surveillance of SUDEP and collection of biospecimens. Because SUDEP is rare (3) (~3,200 cases yearly in the United States and Canada), obtaining sufficient data at one center is impossible. Further, epilepsy-center-based ascertainment bi-ases to high-risk patients. The North American SUDEP Registry (NASR) (http://www.sudep-registry.org; 855-432-8555) was created to serve as a repository for clinical, imaging, tissue, and

genetic data that will foster international scientific discov-ery. NASR consists of a broad assemblage of academic and lay groups. The focus is on all subjects with epilepsy-related mortality. Brain can be obtained from patients who have died within 48 hours; in many cases, however, medical examin-ers may still have the brain as part of their investigation. For other cases, inclusion can be based on genetics, imaging, ECG, video-EEG data, or witness report of the SUDEP. All families affected by SUDEP are encouraged to participate. Sudden Death in Young Registry is a collaboration of the NHLBI, NINDS, CDC, and state medical examiners/coroners, and public health officials. The goals are 1) to establish the incidence of sud-den death in the young using a population-based approach through public health offices, and 2) establish etiologies and risk factors for sudden death in the young. Phase I will be for surveillance and collection of blood for genetic studies or oth-er research projects. Phase II will use the clinical information in the registry, genetic data, and biospecimens to understand causes and risk factors for sudden death.

The American Academy of Neurology is currently develop-ing guidelines on SUDEP that will be systematic, transparent, and evidence-based. The strength of the evidence is moderate in many cases since there are well-powered case-control studies. Advocacy for SUDEP has included efforts at the state level to im-prove surveillance. Approaches have included 1) programs to in-crease awareness and educate medical examiners and coroners, 2) state medical examiner reporting/surveillance policy, and 3) state legislative approach (so far, laws have been passed in New Jersey and Illinois). Pros of the education and awareness ap-proach include flexibility and control of content and distribution of SUDEP information, and these does not require legislative action. Cons include time-consuming work, lack of surveillance data, and inconsistent execution. The state medical examiner approach can work well if there is a statewide system, as well as collaboration and funding—a combination that is rare. The state legislative approach can help better guarantee awareness, con-sistency, and surveillance. However, there may be obstacles and lack of buy-in from medical examiners and coroners, as well as the challenges of enforcing an unfunded mandate. The SUDEP Institute (800-332-1000) is working with its partners to improve SUDEP surveillance through awareness efforts and the develop-ment of death investigator training programs.

References1. Zhuo L, Zhang Y, Zielke HR, Levine B, Zhang X, Chang L, Fowler D, Li L.

Sudden unexpected death in epilepsy: Evaluation of forensic autopsy cases. Forensic Sci Int 2012;223:171–175.

2. Devinsky O. Sudden, unexpected death in epilepsy. N Engl J Med 2011;365:1801–1811.

3. Thurman DJ, Hesdorffer DC, French JA. Sudden unexpected death in epilepsy: Assessing the public health burden [published online ahead of print June 5, 2014]. Epilepsia. doi:10.1111/epi.12666.

Session Summary: SUDEP Mechanisms – Sleep & Arousal Systems

Moderators: Gordon F. Buchanan, MD, PhD, Hal Blumenfeld, MD, PhD

Much of the attention in the discussion of etiologies for SUDEP is given to respiratory and cardiac mechanisms. However, it

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is well known that many seizure types—especially general-ized tonic–clonic seizures—are associated with suppression of awareness and decreased arousal. It is becoming recog-nized that these mechanisms may play a role in SUDEP. It is also becoming recognized that there is a time-of-day, if not sleep-state predilection for SUDEP, with a high percentage of SUDEP occurring at night and during sleep. The purpose of this session was to discuss possible roles of sleep and arousal systems in SUDEP. Two speakers addressed mechanisms by which seizures affect arousal and breathing through network interactions, and two speakers addressed neurotransmitter mechanism in mouse models—one discussing serotonin and one addressing adenosine, the two neurotransmitter systems that play a large role in regulation of both arousal and breath-ing. Finally, there was a presentation from the abstract winner investigating a role for sleep position in SUDEP.

Human Peri-Ictal Physiology: Central Shutdown and Arousal Systems

Presented by Hal Blumenfeld, MD, PhD

Through numerous electrophysiological and functional imag-ing studies in patients with epilepsy, Dr. Blumenfeld’s group has shown that seizures have long range effects on cortical and brainstem structures (1). This is presumed to be through interactions with other local networks, a phenomenon dubbed “the network inhibition hypothesis.” Dr. Blumenfeld described a rat model that his group developed which can be used to study these long-range and network effects of seizures (2). New studies were described, demonstrating that in addition to monitoring effects of seizures on cortical systems, this model can also be employed to evaluate effects on brainstem arousal systems and respiratory control networks. In particular, changes in firing characteristics of neurons within serotonergic subnuclei were described. Should preliminary studies hold true, this important work will provide a functional mechanism for the hypothesis that seizure-induced arousal impairment and respiratory dysfunction that contribute to SUDEP involve dysregulation of the serotonin system.

Human & Mouse Mechanisms of Brainstem Invasion

Presented by Brian Dlouhy, MD

An elegant series of studies were described in which elec-trophysiological recordings were made from patients with epilepsy at baseline and then following direct simulation of the amygdala. In one patient, respiratory arrest and oxygen desaturation coincided with spread of the seizure into the amygdala. Respiratory arrest and oxygen desaturation could be reproduced with stimulation of the left or right amygdala. Stimulation outside of the forebrain did not cause respiratory suppression or oxygen desaturation. These studies lend impor-tant insights into the contributions of connections between the amygdala and respiratory control centers in the medulla to the influence of seizures on breathing, suggesting that similar mechanisms exist for the regulation of sleep and wakefulness following a seizure. This lays the groundwork for future studies to better understand mechanisms for respiratory consequenc-es of seizures.

Serotonin and Post-Ictal Breathing and Arousal/Sleep

Presented by Gordon F. Buchanan, MD, PhD

Serotonin is an important regulator of sleep and wakefulness, and breathing. Levels of serotonin are decreased following a seizure, and anti-epileptic drug therapies affect serotonin levels (3). Serotonin can also modulate seizure control (4). Preliminary studies were described using the Lmx1bf/f/p genetic mouse model (5) in which nearly all serotonin neurons in the central nervous system were eliminated developmentally. These mice had previously shown to have impaired ventilatory and arousal responses to carbon dioxide (6, 7). They also have had increased sensitivity to seizure induction in a number of experimental models (8). Preliminary studies were presented, revealing that the degree of the effect of seizures on breathing may depend on the sleep state during which seizures occur. Preliminary studies also reveal that there may be impairment of CO2-iduced arousal and ventilatory responses in the period immediately following the seizure, and that these impairments are serotonin-dependent. Understanding how sleep-state and nighttime interact with seizure occurrence in increasing the likelihood of SUDEP is likely to be important in devising strate-gies to prevent SUDEP.

Adenosine: Sleep and Post-Ictal Respiratory Arrest

Presented by Carl Faingold, PhD

DBA/1 and DBA/2 mice have proved to be important mod-els for understanding seizure-related respiratory arrest and respiratory etiologies of SUDEP. Dr. Faingold’s group has used this model to demonstrate the importance of the serotonin system in seizure-induced respiratory arrest (9–12). Here, he described forays his group is making into understanding the role of another brain chemical—adenosine—in respiratory- and arousal-related etiologies of SUDEP using the DBA animal models. Adenosine, like serotonin, is involved in regulation of breathing and sleep and wakefulness, as well as modu-lating seizure control, making it an important candidate in mechanisms of SUDEP. Preliminary studies were presented that demonstrate that adenosine or blocking the break-down of adenosine increases the proportion of animals that have seizure-related respiratory arrest, whereas blockage of adenosine receptors using drugs such as caffeine reduces the proportion of mice that have respiratory arrest after a seizure. Such studies have intriguing implications for future preventive strategies for SUDEP.

Abstract Presentation Winner

Association of Prone Position With Sudden Unexpected Death in Epilepsy

Presented by James Tao, MD, PhD

Drawing parallels to another sudden death phenomenon, sudden infant death syndrome (SIDS), Dr. Tao presented data from a meta-analysis in which he explored the possibility that at least part of the reason SUDEP tends to occur more often during the night has to do with sleeping position. The prone position increases the likelihood that the nose and mouth

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could be obstructed and lead to blockage of airflow should this happen following a seizure. This is considered a major contributor to death in SIDS and instigated the “Back to Sleep” campaign still advocated today, recommending that all babies be put to sleep on their backs (13), and it seems also pertinent to SUDEP.

References1. Blumenfeld H, Varghese GI, Purcaro MJ, Motelow JE, Enev M, McNally

KA, Levin AR, Hirsch LJ, Tikofsky R, Zubal IG, Paige AL, Spencer SS. Cortical and subcortical networks in human secondarily generalized tonic–clonic seizures. Brain 2009;132:999–1012.

2. Englot DJ, Mishra AM, Mansuripur PK, Herman P, Hyder F, Blumenfeld H. Remote effects of focal hippocampal seizures on the rat neocor-tex. J Neurosci 2008;28:9066–9081.

3. Richerson GB, Buchanan GF. The serotonin axis: Shared mechanisms in seizures, depression, and SUDEP. Epilepsia 2011;52(suppl):28–38.

4. Bagdy G, Kecskemeti V, Riba P, Jakus R. Serotonin and epilepsy. J Neurochem 2007;100:857–873.

5. Zhao ZQ, Scott M, Chiechio S, Wang JS, Renner KJ, Gereau RW, John-son RL, Deneris ES, Chen ZF. Lmx1b is required for maintenance of central serotonergic neurons and mice lacking central serotonergic system exhibit normal locomotor activity. J Neurosci 2006;26:12781–12788.

6. Hodges MR, Richerson GB. Contributions of 5-HT neurons to respira-tory control: Neuromodulatory and trophic effects. Respir Physiol Neurobiol 2008;164:222–232.

7. Buchanan GF, Richerson GB. Central serotonin neurons are required for arousal to CO2. Proc Natl Acad Sci U S A 2010;107:16354–16359.

8. Buchanan GF, Murray NM, Hajek MA, Richerson GB. Serotonin neurons have anticonvulsant effects and reduce seizure-induced mortality [published online ahead of print August 8, 2014]. J Physiol. PMID:25107926.

9. Tupal S, Faingold CL. Evidence supporting a role of serotonin in modulation of sudden death induced by seizures in DBA/2 mice. Epilepsia 2006;47:21–26.

10. Faingold CL, Randall M, Tupal S. DBA/1 mice exhibit chronic suscep-tibility to audiogenic seizures followed by sudden death associated with respiratory arrest. Epilepsy Behav 2010;17:436–440.

11. Faingold CL, Tupal S, Randall M. Prevention of seizure-induced sudden death in a chronic SUDEP model by semichronic admin-istration of a selective serotonin reuptake inhibitor. Epilepsy Behav 2011;22:186–190.

12. Faingold CL, Randall M. Effects of age, sex, and sertraline administra-tion on seizure-induced respiratory arrest in the DBA/1 mouse model of sudden unexpected death in epilepsy (SUDEP). Epilepsy Behav 2013;28:78–82.

13. Task Force on Sudden Infant Death Syndrome. The changing concept of sudden infant death syndrome: Diagnostic coding shifts, contro-versies regarding the sleeping environment, and new variables to consider in reducing risk. Pediatrics 2005;116:1245–1255.

Session Summary: Non-SUDEP Deaths in Epilepsy

Moderator: Dale C. Hesdorffer, PhD

Epilepsy-related causes of death other than SUDEP affect many individuals, may occur unexpectedly and, in most cases, targeted prevention is absent. These deaths, due to status epi-lepticus (SE), acutely provoked seizures, suicide, antiepileptic

drug (AED)-related cardiovascular disease, and adherence to AEDs comprise a second group of deaths, some of which may be preventable.

Status Epilepticus and Acute Symptomatic Seizures

Presented by Dale C. Hesdorffer, Ph.D.

Epidemiological studies have shown that 24% of people with a first episode of SE die (1). These deaths are 6-fold greater in people with acute symptomatic SE compared to those with unprovoked SE, and older people are 1.9-fold more likely to die. The cumulative risk for dying within the first 30 days after SE is greatest for acute symptomatic etiology, and there are no deaths in people with SE of unknown causes (2). Among 30-day survivors of SE, the 10-year mortality is highest in people with degenerative diseases (e.g., Alzheimer disease) compared to all other etiologies of SE (3). SE due to anoxic encephalopa-thy is associated with a 14-fold higher risk of death than other etiologies (4).

Death occurs in 9.5 to 37.3 percent of people with a first acute symptomatic seizure. In the first 30 days after a first acute symptomatic seizure (5), death is higher than in people with a first unprovoked seizure (6). The cumula-tive risk of dying within the first 30 days is 20% for acute symptomatic seizures (6), representing a more than 100-fold increase compared to the general population. The two etiologies with the greatest risk for death in the first 30 days are cerebrovascular disease, followed by encephalopathy (6). Among 30-day survivors of acute symptomatic seizures, the risk of dying over the next 10 years is 80%, a 10-fold increase over the general population (6). The etiologies with the greatest risk for death among 30-day survivors are trau-matic brain injury, and alcohol and drug withdrawal. These etiologies are themselves associated with death without the presence of seizures.

Occurrence and Risk Factors for Completed Suicide in Epilepsy

Presented by Nathalie Jette, MD

Suicide is very rare in the general population. Assessing sui-cide in people with epilepsy, therefore, requires that sizeable populations be followed for 50,000 person-years or longer to obtain statistically significant results (7). Across studies, there is a 3.3-fold increased risk for suicide in people with epilepsy (8).

Risk factors for completed suicide in people with epilepsy include neurodeficits present since birth, psychiatric illness, antipsychotic drugs, onset of epilepsy under 18 years, and alcoholism (9, 10). In a large Danish study, the increased risk for suicide in epilepsy has been observed in those without psychiatric disorders as well as in those with psychiatric disor-ders, where there is a 13.7-fold increased risk (9). Compared to men without epilepsy in this study, men with epilepsy had a 1.8-fold increased risk for suicide in the absence of a psychiat-ric disorder and a 9.9-fold increased risk in the presence of a psychiatric disorder. These estimates were appreciably greater in women with epilepsy (2.5- and 28.6-fold, respectively) (9). Among comorbid psychiatric disorders in people with epilepsy from the Danish study, the increased risk for suicide

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was greatest for mood disorder, followed by chronic alcohol use (9). In contrast, mood disorder and schizophrenia have the greatest increased risk for suicide in people without epilepsy. Among 1,877 Finish people who committed suicide, those with epilepsy were more likely to be female, less likely to have alcohol-related disorders, and more likely to have any psychi-atric disorder (depression in particular) (11). It is important for clinicians taking care of people with epilepsy to identify psychiatric disorders, be familiar with risk factors for suicide in epilepsy, and work with psychiatrists to reduce the risk of suicide in epilepsy.

In 2009, the FDA issued a warning about the risk of suicidal thoughts and behaviors associated with antiepileptic drugs (12). Several observational studies conducted in large data-bases failed to provide further information due to method-ological issues. Recently, a study from the VA system showed that the risk for suicide-related behavior was increased in the 2 months before AEDs were first prescribed and decreased after prescription, suggesting that AEDs were given and acted suc-cessfully as mood-stabilizing drugs (13).

Cardiovascular Disease and Epilepsy/AEDs

Presented by Scott Mintzer, MD

Epidemiological studies of epilepsy have shown statistically significant increased standardized mortality ratios for car-diovascular causes of death, including heart disease, stroke, myocardial infarction, and ischemic heart disease (14–20). AEDs that are strong P450 enzyme inducers (e.g., carbamaze-pine [CBZ]) appear to affect cholesterol synthesis. As such, they may have long-term effects on cardiovascular health, indexed by high levels of cholesterol as well as other markers. This hypothesis has been evaluated in more than 10 cross-sec-tional studies that have found that cholesterol is increased in patients treated with CBZ compared to controls or to patients treated with valproic acid (21). Other studies have shown elevated cholesterol in people on phenobarbital or phenytoin. However, these cross-sectional studies cannot elucidate time order of the association between the P450 enzyme-inducing drugs and elevated cholesterol.

In a study of epilepsy patients who were switched from P450 enzyme-inducing drugs to non-inducers, fasting mea-sures of cardiovascular health were compared on the enzyme-inducing AED versus the non-enzyme inducer AED, six weeks after the last dose of the enzyme inducer AED (22). Statistically significant decreases were seen for total cholesterol, non-HDL cholesterol, HDL cholesterol, triglycerides, C-reactive protein, lipoproteins, and homocysteine. All changes in these values were statistically different from normal controls over the same time period. A Danish study examined the effect of AEDs on cardiovascular morbidity and mortality (20). Compared to CBZ, the risk for these conditions was lower on valproate, consistent with a potentially greater cardiovascular risk form CBA treat-ment. However, some of these other findings were not entirely consistent with this hypothesis.

These studies suggest that enzyme-inducing AEDs have deleterious effects on markers of vascular risk and possibly increase the risk for myocardial infarction and other vascular conditions. Screening for vascular risk in patients on enzyme-

inducing drugs is needed, not only for epilepsy but also for pa-tients given these drugs for mood stabilization. Further studies are needed to determine whether inducing AEDs increase the risk for the endpoint of vascular disease.

Nonadherence to Antiepileptic Drugs and the Risk for Death in Epilepsy

Presented by Daniel Friedman, MD

Medication nonadherence—not taking prescribed antiepilep-tic drugs as directed by the provider—is common in people with epilepsy. Over a 12-month period after starting AEDs, only half the patients maintain a greater than 80% adher-ence as defined by the medication possession ratio, the days of drug supplied by the pharmacy divided by the days in the observation period. Consequences of nonadherence include increased rates of seizure-related hospitalizations and emer-gency department visits, and higher costs associated with nonadherence in the elderly (23). Nonadherence is also associ-ated with an increased rate of injuries and accidents, such as fractures and motor vehicle accidents (24). Most importantly, nonadherence to AEDs as prescribed is associated with a 3-fold increased risk of death (24).

Several SUDEP case series from medical examiner or coroners’ offices show a high frequency of low or absent AED levels, ranging from 46 to 94 percent (25–30). However, results from controlled studies are mixed. In a retrospective study of AED levels in hair samples assessed by high perfor-mance liquid chromatography, SUDEP cases had a greater variation in drug levels compared to controls (31). Postmor-tem toxicology studies have shown varied results; a study in the United States showed significantly more SUDEP dece-dents had low or no AED levels compared to non-SUDEP epilepsy decedent controls (69% vs 34%), whereas a study in Australia showed no difference in the frequency of subthera-peutic/absent AED levels between SUDEP cases and controls (52% in both groups). These studies differ from more meth-odologically sound investigations. In a nested case-control study performed at 3 epilepsy centers comparing 20 SUDEP deaths to 80 living controls with epilepsy, there was no dif-ference in the degree to which the last known AED level was low (32).

Important questions that need to be further addressed are whether AED nonadherence is a modifiable risk factor and whether interventions might lower the risk of SUDEP and other causes of mortality in epilepsy. In considering whether nonadherence is modifiable, it is important to note that memory problems, insurance status, beliefs about medications generally, AED side effects, and psychiatric disorders may all contribute to nonadherence, making common interventions challenging toward improving adherence. Some potential ways to improve AED adherence include: pillboxes and text messages to improve remembering each dose; education and motivational interviewing to better understand the need for medication use; and patient–clinician collaboration to identify the best tolerated yet effective medication regimen. Further studies should examine risk factors for nonadherence toward selecting an intervention that would be most likely to improve AED adherence and reduce mortality in epilepsy.

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References1. Logroscino G, Hesdorffer DC, Cascino G, Annegers JF, Hauser WA.

Time trends in incidence, mortality, and case-fatality after first epi-sode of status epilepticus. Epilepsia 2001;42:1031–1035.

2. Logroscino G, Hesdorffer DC, Cascino G, Annegers JF, Hauser WA. Short-term mortality after a first episode of status epilepticus. Epilep-sia 1997;38:1344–1349.

3. Logroscino G, Hesdorffer DC, Cascino GD, Annegers JF, Bagiella E, Hauser WA. Long-term mortality after a first episode of status epilep-ticus. Neurology 2002;58:537–541.

4. Rossetti AO, Hurwitz S, Logroscino G, Bromfield EB. Prognosis of sta-tus epilepticus: role of aetiology, age, and consciousness impairment at presentation. J Neurol Neurosurg Psychiatry 2006;77:611–615.

5. Logroscino G, Hesdorffer DC, Cascino G, Hauser WA, Coeytaux A, Galobardes B, Morabia A, Jallon P. Mortality after a first episode of status epilepticus in the United States and Europe. Epilepsia 2005;46(suppl):46–48.

6. Hesdorffer DC, D’Amelio M. Mortality in the first 30 days following incident acute symptomatic seizures. Epilepsia 2005;46(suppl):43–45.

7. Bell GS, Sander JW. Suicide risk in epilepsy: Where do we stand? Lancet Neurol 2007;6:666–667.

8. Bell GS, Gaitatzis A, Bell CL, Johnson AL, Sander JW. Suicide in people with epilepsy: How great is the risk? Epilepsia 2009;50:1933–1942.

9. Christensen J, Vestergaard M, Mortensen PB, Sidenius P, Agerbo E. Epilepsy and risk of suicide: A population-based case-control study. Lancet Neurol 2007;6:693–698.

10. Nilsson L, Ahlbom A, Farahmand BY, Asberg M, Tomson T. Risk factors for suicide in epilepsy: A case control study. Epilepsia 2002;43:644–651.

11. Mainio A, Alamaki K, Karvonen K, Hakko H, Särkioja T, Räsänen P. De-pression and suicide in epileptic victims: A population-based study of suicide victims during the years 1988–2002 in northern Finland. Epilepsy & Behav 2007;11:389–393.

12. Katz R. Briefing document for the July 10, 2008, Advisory Committee to discuss antiepileptic drugs (AEDs) and suicidality. http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4372b1-01-FDA-Katz.pdf. Accessed July 2014.

13. Pugh MJ, Hesdorffer D, Wang CP, Amuan ME, Tabares JV, Finley EP, Cramer JA, Kanner AM, Bryan CJ. Temporal trends in new exposure to antiepileptic drug monotherapy and suicide-related behavior. Neurology 2013;81:1900–1906.

14. Annegers JF, Hauser WA, Shirts SB. Heart disease mortality and mor-bidity in patients with epilepsy. Epilepsia 1984;25:699–704.

15. Ding D, Wang W, Wu J, Ma G, Dai X, Yang B, Wang T, Yuan C, Hong Z, de Boer HM, Prilipko L, Sander JW. Premature mortality in people with epilepsy in rural China: A prospective study. Lancet Neurol 2006;5:823–837.

16. Gaitatzis A, Carroll K, Majeed A, Sander JW. The epidemiology of the comorbidity of epilepsy in the general population. Epilepsia 2004;45:1613–1622.

17. Mu J, Liu L, Zhang Q, Si Y, Hu J, Fang J, Gao Y, He J, Li S, Wang W, Wu J, Sander JW, Zhou D. Causes of death among people with convul-sive epilepsy in rural West China: A prospective study. Neurology 2011;77:132–137.

18. Neligan A, Bell GS, Johnson AL, Goodridge DM, Shorvon SD, Sander JW. The long-term risk of premature mortality in people with epi-lepsy. Brain 2011;134(pt 2):388–395.

19. Nilsson L, Tomson T, Farahmand BY, Diwan V, Persson PG. Cause-spe-cific mortality in epilepsy: A cohort study of more than 9,000 patients once hospitalized for epilepsy. Epilepsia 1997;38:1062–1068.

20. Olesen JB, Abildstrom SZ, Erdal J, Gislason GH, Weeke P, Andersson C, Torp-Pedersen C, Hansen PR. Effects of epilepsy and selected anti-epileptic drugs on risk of myocardial infarction, stroke, and death in patients with or without previous stroke: A nationwide cohort study. Pharmacoepidemiol Drug Saf 2011;20:964–971.

21. Lopinto-Khoury C, Mintzer S. Antiepileptic drugs and markers of vascular risk. Curr Treat Options Neurol 2010;12:300–308.

22. Mintzer S, Skidmore CT, Abidin CJ, Morales MC, Chervoneva I, Capuzzi DM, Sperling MR. Effects of antiepileptic drugs on lipids, homocyste-ine, and C-reactive protein. Ann Neurol 2009;65:448–456.

23. Ettinger AB, Manjunath R, Candrilli SD, Davis KL. Prevalence and cost of nonadherence to antiepileptic drugs in elderly patients with epilepsy. Epilepsy Behav 2009;14:324–329.

24. Faught E, Duh MS, Weiner JR, , Guérin A, Cunnington MC. Nonadher-ence to antiepileptic drugs and increased mortality: Findings from the RANSOM Study. Neurology 2008;71:1572–1578.

25. George JR, Davis GG. Comparison of anti-epileptic drug levels in dif-ferent cases of sudden death. J Forensic Sci 1998;43:598–603.

26. Lathers CM, Koehler SA, Wecht CH, Schraeder PL. Forensic anti-epileptic drug levels in autopsy cases of epilepsy. Epilepsy Behav 2011;22:778–785.

27. Lear-Kaul KC, Coughlin L, Dobersen MJ. Sudden unexpected death in epilepsy: A retrospective study. Am J Forensic Med Pathol 2005;26:11–17.

28. Leestma JE. Case analysis of brain-injured admittedly shaken infants: 54 cases, 1969–2001. Am J Forensic Med Pathol 2005;26:199–212.

29. Opeskin K, Harvey AS, Cordner SM, Berkovic SF. Sudden unexpected death in epilepsy in Victoria. J Clin Neurosci 2000;7:34–37.

30. Zhuo L, Zhang Y, Zielke HR, Levine B, Zhang X, Chang L, Fowler D, Li L. Sudden unexpected death in epilepsy: Evaluation of forensic autopsy cases. Forensic Sci Int 2012;223:171–175.

31. 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. J Neurol Neurosurg Psychiatry 2006;77:481–484.

32. Walczak TS, Leppik IE, D’Amelio M, Rarick J, So E, Ahman P, Ruggles K, Cascino GD, Annegers JF, Hauser WA. Incidence and risk factors in sudden unexpected death in epilepsy: A prospective cohort study. Neurology 2001;56:519–525.

Session Summary: SUDEP Mechanisms: Autonomic and Cardiac

Moderators: Jeffrey W. Britton, MD, Jeffrey Noebels, MD, PhD

Acute, transient modulations in cardiac function are common during seizures, and chronic changes in cardiac autonomic tone have been described in patients with intractable epilepsy. Seizure-induced disturbances in the central autonomic modu-lation of heart function can be significant and are a potential SUDEP mechanism. The influence of epilepsy on heart function is an example of a phenomenon referred to as the “heart–brain connection.” The heart–brain connection may have shared physiologic underpinnings as well. For example, genetic ion channel disorders expressed in both the heart and central nervous system may set the stage for a “perfect storm” of neuronal and cardiac excitability resulting in SUDEP. Examples of the latter include seizures and ventricular arrhythmia seen in patients with catecholaminergic polymorphic ventricular tachycardia due to RYR-2 mutations, and the existence of both

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epilepsy and cardiac phenotypes in long QT syndromes due to mutations in KCNQ1 and related genes.

This plenary session focused on the spectrum of central cardiac autonomic control and how it may be affected in epilepsy. Recent discoveries involving human and experimen-tal models were presented, which may help shed light on the underlying physiologic abnormalities that may account for the increased prevalence of SUDEP.

Overview of Central Autonomic Cardiac Anatomy and Physiology

Presented by Jeffrey W. Britton, MD

Dr. Jeffrey W. Britton from Mayo Clinic in Rochester, MN, provided an overview of the central nervous system structures involved in cardiac autonomic modulation (1). A historical review indicated that seizures have been known to produce significant disturbances in central autonomic control of the heart for centuries. In the last 50 years, cortical stimulation studies in humans and animals identified the important roles of the insula, cingulate gyrus, orbital frontal regions, and amygdala in central autonomic modulation of the heart. These limbic regions are often affected by seizures.

Key brainstem structures participating in central cardiac modulation were highlighted, including those involved with sympathetic efferent function (rostral ventrolateral medulla), parasympathetic efferent activity (nucleus ambiguus, and dorsal motor nucleus of the vagus), and integration of afferent input from peripheral baro- and chemoreceptors (nucleus of the tractus solitarius) (2). He also reviewed the literature on the effects of neurologic lesions and seizures on heart rate variability (HRV)—a biomarker of the integrity of the barore-flex—where disturbances have been associated with sudden death. The effects of seizure-induced cardiac sympathetic and parasympathetic modulation were also reviewed. These included cardiac repolarization defects seen in the peri-ictal period, such as QT interval abnormalities, bradycardia, myo-cardial ischemia, and Takotsubo, all of which could serve as potential SUDEP mechanisms.

Patient-Derived Pluripotential Stem Cells and SCN1A Mutation Knock-In Mice Models of Dravet Syndrome

Presented by Lori L. Isom, PhD

Dr. Lori L. Isom, University of Michigan Medical School in Ann Arbor, presented recent discoveries related to cardiac and neuronal pathophysiology in Dravet syndrome. She reviewed recent results of experiments performed on neural progenitor cells derived from induced pluripotential stem cells obtained from Dravet syndrome patients with defined SCN1A sodium channel mutations (3). These neurons showed increased sodium current density, reduced threshold for action poten-tial initiation, and abnormal hyperexcitability firing patterns, including spontaneous burst activity.

She also presented experiments performed in cardiac tissue from knock-in mice heterozygous for an SCN1A mutation associ-ated with Dravet syndrome (4). These demonstrated increased sodium current density in cardiac myocytes, and arrhythmias with repolarization defects including QT prolongation.

Collectively, these findings suggest that both neuronal and cardiac excitability are present in Dravet syndrome and could underlie the increased potential for SUDEP in these patients.

Sodium Channel Deletion, Asystole, and Fatal Seizures in Murine Models of Dravet Syndrome

Presented by Franck Kalume, PhD

Dr. Franck Kalume, from University of Washington in Seattle, presented findings from work involving Nav 1.1 channel knock-out models of Dravet syndrome. These mice are prone to sudden death during thermal-induced seizures. Decreased heart rate variability has been found in this model, which is a biomarker for sudden cardiac death (5). During thermal-in-duced seizures, Dr. Kalume noted that EKG monitoring showed significant bradycardia at seizure onset and offset in fatal sei-zures. Atropine blocked this response, suggesting parasympa-thetic hypertonia in affected cases. Based on these findings, he proposed consideration of inhibiting vagal input by modifying the function of a commercially available vagus nerve stimula-tor as a potential preventative treatment for these patients.

Clinical Cardiologic Consequences of Seizures

Presented by Rainer Surges, MD

Dr. Rainer Surges, from University Hospital in Bonn, Germany, presented a comprehensive overview of the spectrum of car-diac complications encountered in patients with epilepsy (6). Tachycardia occurs in more than 80% of seizures, suggesting that sympathetic excess is common in epilepsy. In contrast, he noted that bradycardia is thought to be present in only 6% of seizures, and 1% of patients. The role of seizure lateralization on the occurrence of ictal bradycardia has been the subject of much research in the past; bradycardia usually occurs at a point when bilateral seizure activity is present. In most cases of ictal asystole, the interruption is transient and resolves spontaneously, casting some doubt upon its role in SUDEP. The role of cardiac pacing to reduce asystole-related SUDEP risk was discussed. He also presented preliminary work that raised questions regarding a role of anticonvulsant treatment in the occurrence of cardiac conduction abnormalities during seizures, which he suggested was worth exploring in future studies as a potential risk factor for SUDEP.

Acquired Cardiac Risk and Potential Cardioprotective Therapy

Presented by Yi-Chen Li, MD

Dr. Yi-Chen Li, from Texas Children’s Hospital at Baylor College of Medicine in Houston, reported the presence of EKG changes that arise early in an experimental pilocarpine-induced rat seizure model. These animals showed abnormal tachycardia induced by ventricular pacing, and beta adrenergic blockade lowered the rate and QTc interval. If recognized early, this strat-egy may be a potential intervention in selected patients.

ConclusionsThe heart is affected by epilepsy, and some seizures may be detrimental to normal cardiac function, potentially contribut-ing to sudden death. Mechanisms underlying the heart–brain

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connection—ranging from acute and chronic seizure-medi-ated derangements of central cardiac autonomic function to shared molecular lesions—are likely to play a pivotal role in the occurrence of SUDEP. Elucidating the precise pathophysiol-ogy will be necessary to identify potential protective therapies.

References1. Britton JW. Syncope and seizures: Differential diagnosis and evalua-

tion. Clin Auton Res 2004;14:148–159. 2. Britton JW, Benarroch E. Seizures and syncope: Anatomic basis and

diagnostic considerations. Clin Auton Res 2006;16:18–28. 3. 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 patient-derived neurons suggest a novel epilepsy mechanism. Ann Neurol 2013;74:128–139.

4. Auerbach DS, Jones J, Clawson BC, Offord J, Lenk GM, Ogiwara I, Yamakawa K, Meisler MH, Parent JM, Isom LL. Altered cardiac elec-trophysiology and SUDEP in a model of Dravet syndrome. PLoS ONE 2013;8:e77843.

5. Kalume F, Westenbroek RE, Cheah CS, Yu FH, Oakley JC, Scheuer T, Catterall WA. Sudden unexpected death in a mouse model of Dravet syndrome. J Clin Invest. 2013;123:1798–1808.

6. Surges R, Sander JW. Sudden unexplained death in epilepsy: Mecha-nisms, prevalence and prevention. Curr Opin Neurol 2012;25:201–207.

Summary of Session: Epilepsy and Grief

Moderator: Jeanne Donalty

The Learning Objectives of this session were: 1) identify the typical stages of grief a bereaved adult will go through; 2) understand the basic differences between complicated and uncomplicated grief, and hallmarks to watch for that could signify complicated grief; 3) understand predisposing factors, both general and SUDEP/epilepsy mortality-related, that can lead to grief complications; 4) identify when or if a referral for grief counseling is needed; 5) have an increased awareness of specific national and community grief support resources, which can be referenced.

Story of Loved One

Presented by Lisa Riley

Lisa Riley’s son, Jorden Buisman, was diagnosed with epilepsy as a child. He was placed on anti-seizure medication and even-tually went into remission. Upon graduating from high school, Jordon joined the Marines. At 22 years of age, Jorden began to have nocturnal seizes and again was placed on medica-tion. Although his seizures were under control, he was forced to retire from active duty after his epilepsy diagnosis. Jorden enrolled in college and was seizure free for almost 16 months, when he had a seizure while talking on the phone with his mother. He immediately contacted the VA for an appointment but was unable to get one for several months. Jordon died of SUDEP on November 26, 2012, weeks before his scheduled appointment. He was 24 years old. Since her son’s death, Lisa has struggled with severe depression and grief. She has sought professional help for both her emotional and physical issues. On the first anniversary of Jordon’s death, Lisa made a PSA to

honor her son’s memory and increase awareness of SUDEP. Lisa now regularly speaks out about SUDEP and epilepsy to help deal with her grief in a positive way.

From Normal to Pathological Grief: Recognition of the Pathogenic Mechanisms

Presented by Andres Kanner, MD

Normal grief, found in the majority of survivors, is unique to each individual but often includes feelings of intense sadness, protest emotions, rumination about the loss, insomnia, poor appetite, and weight loss. As an individual begins to readjust to the loss, the intensity of grief begins to decrease over time, and the individual begins to incorporate it into their life—who they are.

Complicated grief is defined by symptoms, duration, and intensity. The individual becomes incapacitated, exhibiting significant distress and functional impairment, including emo-tional numbness and the inability to feel pleasure. Compli-cated grief is defined as long lasting, six months or more, and is estimated to affect 3–25 percent of loss survivors.

What can physicians do to prepare families for a potential loss and the grief that follows? Let us consider when the first encounter with grief occurs, which happens when a person experiences his or her first seizure. At that point, the individu-al—as well as the whole family—faces a profound loss. It then becomes the physician’s responsibility to understand this loss and help the patient accept the diagnosis of epilepsy by going through the grief process. To ignore this responsibility regard-ing the consequences of the patient and family not accepting the loss and dealing with their grief can create many different and serious complications.

Patients and families need to understand that there are complications that come with a diagnosis of epilepsy, so they can prepare themselves and feel empowered. They should be asked whether or not they have accepted their diagnosis and what are their fears and concerns. The physician’s responsibil-ity is to help get patients and their families to a place where they accept the diagnosis of epilepsy and its consequences.

In this context, physicians should discuss SUDEP. This issue should be brought up by the doctor. When a person experienc-es a tonic–colonic seizure, the first thing that comes to mind is that they are going to die. Doctors routinely talk about this with their patients, and this should be the case with SUDEP.

If patients and their families do not come to terms with their epilepsy, there is an increased risk of complicated grief.

Grief Counseling or Not – Navigating the Grief Journey

Presented by Linda Coughlin Brooks, RN, BSN, CT

Everyone who experiences the death of a loved one will be faced with grief and must learn to cope with it. Grief is normal, but society today does not offer us the time we need to grieve, nor does it understand the grief process. We are expected to “buck up” and move on quickly. There are specific stages of grief: denial, anger, bargaining, depression, and acceptance.

When normal grief becomes complicated grief, it may be time to seek professional help. Signs that it is time for a referral include 1) inadequate coping skills; 2) a sense of hopeless-

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ness; 3) feeling disenfranchised, sudden or traumatic grief; 4) somatic issues or changes in physical health; 5) isolation from friends, family, or prior activities; 6) history of depression, men-tal illness, or suicide ideation; and 7) self-destructive behavior.

Physicians may be helpful in suggesting grief counseling or grief therapy to a patient’s family members when appropriate, when any of the aforementioned symptoms become evident. Grief counseling helps to facilitate the “tasks of mourning” in the recently bereaved so that the individual can better adapt to the loss.

Grief therapy helps to identify and resolve the conflicts of separation that preclude the completion of mourning tasks in individuals whose grief is chronic, delayed, excessive, or masked as physical symptoms.

Neurologists should not hesitate to make these referrals.

Making a Grief Support Referral: Resources and Recommendations

Presented by Paul Scribner, MSW, LCSW-C

As a physician or other health care provider, you are in an ideal position to provide helpful resource referrals to someone who is bereaved by the loss of a loved one to SUDEP or another epilepsy-related cause. To be effective, however, you must:

1. Take time to understand some of the basic values, beliefs, and practices of the family that might impact how they deal with death and loss.

2. Have a researched list of trusted referral resources on hand. It is very important in working with a sudden death to understand and respect the views and wishes of the family. The more deeply you understand their unique needs, values, and rituals (familial, cultural, and religious) in relation to death and grief, the less likely you are to upset an individual or fam-ily, and the more effective you can be in helping them through a very difficult experience (1). The challenge is that it is not possible understand a family’s attitudes and rituals surround-ing death without asking; very few families spontaneously offer the information. Below are few topics you might want to address in your initial assessment that can be woven into the conversation and help you better understand the sociocultural background of your patients and families and their beliefs (2). By asking these questions, you will better understand their readiness for a referral, the best type of referral to make, and whether a referral is wanted or needed at this time. Here are some specific questions you might include:

• Mourning practices immediately following a death: “Are there some family traditions that are important to you in your grieving process?”

• Long-term mourning practices, either cultural or religious: “When you think about the next six months or a year, what kinds of things do you anticipate doing that are part of your family traditions or religious traditions or that will help you in the grieving process?”

• Funeral or memorial preferences: “What traditions will your family use to commemorate your loved one’s life after she dies?”

It is critical that you take time to prepare a list of go-to grief support resources now. It can take as little as an hour or two but will be well worth it the first time you have a bereaved family member walk in the door. The first step is to make sure you really understand your institution’s social work, counseling, and other grief support resources. If you do not have someone specifically trained in SUDEP and complicated grief issues, refer them to the resources on the SUDEP Institute’s website (3), where they can view train-ings on SUDEP and complicated grief, download a bereaved information packet, and find other valuable resources. Second, know the grief and loss resources in your local community. Most major metropolitan areas have at least one grief and loss center. Finally, be sure you have a list of the national organizations that provide list SUDEP-specific or grief-related support. Following is a list of organizations you should include:

SUDEP Specific Organizations and Resources

1. Centers for Disease Control (SUDEP site)2. Chelsea Hutchison Foundation3. Citizens United for Research in Epilepsy (CURE)4. Danny Did Foundation5. North American SUDEP Registry (NASR)6. Partners Against Mortality in Epilepsy7. SUDEP Aware (Canada)8. SUDEP Action (UK)

Bereaved Parent or Grandparent Resources

1. Compassionate Friends2. Mothers In Support and Sympathy (MISS Foundation)3. AGAST: Alliance of Grandparents: A Support In Tragedy4. Sudden Unexplained Death In Children Program (SUDC)5. Griefnet.org

General Counseling and Support Regarding Loss Resources

1. Association of Death Educators and Counselors (ADEC)2. Local grief and loss centers in your community

Medical and Investigative Resources

1. Centers for Disease Control and Prevention: SIDS and SUID2. National Association of Medical Examiners (NAME)3. International Association of Coroners and Medical

Examiners4. National MCH Center for Child Death Review

References1. D. J. Wilkie & TNEEL Investigators. Grief: Sociocultural aspects. http://

www.tneel.uic.edu/tneel-ss/demo/grief/frame1.asp. Accessed XXXXX.2. Grief Speaks. Cultures and grief. http://www.griefspeaks.com/id90.

html. Accessed July 2014.3. Wright C, Shafer P, Sirven J. SUDEP resources. http://www.epilepsy.

com/learn/impact/mortality/sudep/sudep- resource. Accessed July 2014.

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Summary of Session: SUDEP Mechanisms – Genetics

Moderators: Daniel Lowenstein, MD, Alica M. Goldman, MD, PhD

The objective of the session was to provide an update on selected key advances in human and animal translational ge-netic research that inform our quest for precision SUDEP diag-nostics, as well as an improved understanding of the molecular pathophysiology of the premature mortality in epilepsy.

Use of Genomics to Study Human SUDEP

Presented by Alica M. Goldman, MD, PhD

Identification of epidemiological risk factors has been in-strumental in highlighting the societal burden of premature mortality in epilepsy and in identification of patient groups that have increased SUDEP risk (1, 2). However, the scope of in-dividually predictive and actionable epidemiological factors is limited, and the personalized risk assessment will need to take into the account emerging knowledge about the SUDEP mo-lecular mechanisms that appear to drive the complex cardiore-spiratory compromise and are often accompanied by post-ictal generalized EEG suppression (PGES). The currently known candidate SUDEP genes are either associated with the control of respiration and arousal, or they are the molecules dually expressed within the neurocardiac and autonomic pathways (3). Detailed clinical, physiological, and molecular analysis of a child affected by Dravet syndrome who succumbed to SUDEP has uncovered a complex genomic pattern of de novo variants affecting the SCN1A and KCNA1 channels on the background of inherited variants in the cardiac arrhythmia and respiratory pathway genes (4). This case pointed toward the oligogenic molecular SUDEP risk reflective of the inheritance pattern previously observed in large-scale genetic investigations of human epilepsies (5, 6). Precision molecular diagnostic and prediction of individual SUDEP risk will necessitate research in-volving complex collaborative network of families, physicians, forensic pathologists, and basic and translational scientists, piloted by the STOP SUDEP registry and genetic repository and by the SUDEP Research Alliance sponsored by the National Institute of Neurological Disorders and Stroke (NINDS).

Lessons From EPGP and Epi4K

Presented by Daniel Lowenstein, MD, for the EPGP and Epi4K Investigators

As in other areas of neurology and medicine in general, one of the current great challenges in human genetics research is understanding the precise role of genetic factors in com-mon forms of diseases that have a range of clinical presenta-tions. This is certainly the case in the epilepsies, where major advances have been made in the identification of single gene mutations for epilepsy syndromes that have Mendelian pat-terns of inheritance, but the genetic basis of most nonacquired forms of epilepsy remain unknown (7). Twelve years ago, a group of us involved in epilepsy research met. Recognizing the rapid advances being made in genome sequencing technol-ogy, we committed ourselves to an international, collaborative effort to collect a very large cohort of carefully phenotyped individuals with specific forms of epilepsy. This led to the

creation of the NINDS-funded Epilepsy Phenome/Genome Project (EPGP), which has now successfully identified more than 4,100 patients and family members—including almost 2,200 first-degree relatives—having either idiopathic general-ized epilepsy or nonacquired localization-related epilepsy, as well as approximately 630 probands having either infantile spasms (IS), Lennox–Gastaut syndrome (LGS) or specific types of malformations of cortical development, along with both of their unaffected parents (8). Detailed phenotypic information on every participant—including fine details about seizure se-miology, imaging, and electrophysiological studies—reside on a centralized, highly structured and mineable database, and blood samples have all been deposited at the NINDS Human Genetics DNA and Cell Line Repository at Coriell Institute for Medical Research (8).

The second phase of this effort, the genomic analysis of the EPGP cohort, is now underway. The Epi4K –Gene Discovery in Epilepsy Center Without Walls, also funded by NINDS, has a mission to identify the genetic risk factors that contribute to epilepsy and to discover tailored therapies for the treatment and prevention of epilepsy (9). Epi4K has four projects, and the first results from Project 1 (Epileptic Encephalopathies) has relied on the patients with IS or LGS collected in EPGP. Whole exome sequencing of 264 probands and their parents revealed nine genes with de novo mutations in two or more probands, including two (GABRB3 and ALG13) not previously associated with epileptic encephalopathies, with another 100 genes har-boring a de novo mutation in single probands in genes ranked as relatively intolerant to mutations (6). We also found that the mutations were drawn preferentially from specific gene sets, including ion channels, genes known to cause seizures, autism or intellectual disability, and FMRP-regulated genes. Further sequencing of the rest of the EPGP cohort, as well as other epilepsy cohorts from around the world, is currently underway.

Key to the successes of EPGP and Epi4K has been the team’s breadth of scientific expertise, which includes almost 1,000 person-years of postgraduate training in more than 20 scientific disciplines, ranging from statistical genetics to phar-maceutical sciences to neurophysiology. The groups have also made an unambiguous commitment to collaboration, embod-ied by a detailed charter and publication policy that provides clear guidelines and expectations for all investigators. Among other things, the publication policy ensures that appropriate credit is given to the contribution of all members of the team and, in the case of primary papers, no individual is singled out as the first, senior, or corresponding author. For secondary pa-pers, priority is always given to junior investigators for named authorship. Finally, the progress in EPGP and Epi4K has been driven by a clear focus on the patient as the prime beneficiary of these collective efforts, which engenders a commitment to do everything possible to accelerate the speed with which results can be generated and shared.

Isolating and Validating SUDEP Genes in Mouse Models

Presented by Jeffrey L. Noebels, MD, PhD

Patients with variety of epilepsies face unclear SUDEP risk. Identification and mechanistic understanding of genes predisposing to SUDEP is critical for the development of

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personalized biomarkers, risk prediction, effective prevention, and development of novel therapeutic interventions. Discov-ery of SUDEP genes involves an iterative, hypothesis-driven process in which candidate molecules are identified in patients and animal models. They are then evaluated and analyzed in model systems using basic science techniques. The analysis commonly entails addressing several key questions related to the variant deleterious nature, penetrance, mechanism, biological impact, and therapeutic potential.

The first monogenic SUDEP models were mice carrying two independent deleterious human variants in the KCNQ1 gene associated with an inherited cardiac arrhythmia, so-called long QT syndrome (LQTS) (10). The gene was found to be unequivocally expressed in the heart as well as in cortical and subcortical brain structures, including the autonomic nuclei of the brainstem. Both Kcnq1 models displayed a “lock-step” phenomenon where the active interictal epilepti-form activity frequently coincided with brief asystolic pauses seen in the electrocardiogram. The terminal SUDEP event was captured in both models. The animal SUDEP risk was validated by human studies. Johnson et al. showed that 25% of patients affected by LQTS due to KCNQ1 mutations had a history of a seizure phenotype (11). One of the first indica-tions of complexities inherent to functional assessment of genetic variants came from a case report of a 12-year-old male afflicted by LQTS and seizures who died suddenly (12). Genetic screening uncovered a maternally inherited and functionally detrimental KCNQ1 variant that was believed to be benign based on bioinformatics analysis, yet it showed a prolonged QT without epilepsy in one parent. A “Type 2” SUDEP category involves genes dually expressed in the brain and autonomic nervous system but not the heart, such as the Kv1.1 ion channel (13). The channel was found expressed in the paranodal regions of the vagal nerve (14). Administration of the parasympatolytic agent atropine ameliorated the fre-quent interictal atrioventricular blocks observed in the Kv1.1 deficient mouse model (13), thus illustrating that therapeutic interventions in SUDEP are only one step away from under-standing personal molecular make-up. Genetic mouse mod-els also aid in uncovering novel genes with modulating effect on SUDEP risk, such the SENP-2 molecule that is a modifier of potassium channels (Yeh, 2014 submitted) or MAPT encoding the Tau protein (15).

Sodium Channel Mutations and SUDEP

Presented by Miriam Meisler, PhD

The sodium channel gene SCN1A has been extensively studied with relationship to Dravet syndrome, and mouse and human data have shown that de novo loss of function mutations in this gene are linked to SUDEP (4, 16–19). The SCN8A gene is a closely related paralog that is localized at the axon initial segment where it regulates the initiation of the action po-tential (20). SCN8A has documented roles in epilepsy, cogni-tive impairment, and SUDEP, as evidenced by mouse models and human data (21–24). The sodium channel gene family contains 10 evolutionary related genes encoding the large transmembrane pore forming α-subunit of the voltage-gated sodium channels (22). The SCN8A channel was the first SUDEP

gene discovered by next-generation whole genome sequenc-ing of the nuclear family of a proband affected by infantile epileptic encephalopathy and SUDEP (23). The de novo variant c.5302A>G (p.Asn1768Asp) altered an evolutionarily conserved residue in the Nav1.6 channel, and subsequent analysis of the biophysical properties of the channel demonstrated a large increase in persistent sodium current. Current-clamp analy-sis in hippocampal neurons transfected with p.Asn1768Asp mutant channels revealed increased spontaneous firing and paroxysmal depolarizing shift-like complexes, consistent with a dominant gain-of-function phenotype in the heterozygous proband. There has been rapid progress in techniques for gen-eration of animal models, and TALEN and CRSPR/Cas are cur-rently the leading technologies. We used TALENs to generate a mouse model carrying the missense mutation p.Asn1768Asp in murine Scn8a (25). The knock-in mouse model recapitulates the phenotype of severe, early onset seizures, and SUDEP. Video/EEG analysis detected ictal discharges that coincide with tonic seizures, generalized tonic–clonic seizures, and myoclonic jerks. Prior to seizure onset, heterozygous mutants were not defective in motor learning or fear conditioning but did exhibit mild impairment of motor coordination and social discrimination. This new mouse model provides a unique op-portunity to evaluate the pathophysiological role of SCN8A in the mechanism of SUDEP.

Abstract Winner Presentation: Modeling SUDEP and Stress in Genetically Epilepsy Prone Rats (GEPR-9s)

Presented by Srinivasa Kommajosyula

GEPR-9 rarely die as a result of their seizures and are thus an optimal model system to study environmental influences on seizure-related death. Postictal surge in adenosine has been implicated in the electro-clinically evident postictal general-ized EEG suppression (PGES) (3, 26). Pretreatment of GEPR-9 with adenosine receptor blockers lead to prolonged postictal depression and hypoxemia and a seizure-induced death rate, thus providing supporting evidence for adenosine contribu-tion to the epileptic seizure-related lethal cascade. One of the many effects of alcohol is alteration of the brain’s adenosine level (27). Alcohol withdrawal was used to model an environ-mental stressor triggering increase in the brain adenosine levels, and rats exposed to alcohol withdrawal exhibited an increase in seizure-related death rate. These experimental findings offer preliminary explanation for the observed increased SUDEP risk in epilepsy patients with a history of alcohol use (1).

Summary Novel genes and biological pathways are being identified and next-generation platform will speed up the rate of their discovery. A focused, collaborative network involving patients, families, interdisciplinary experts, and basic and translational researchers is essential for progress in understanding SUDEP mechanisms and in the development of appropriate diag-nostic and preventative strategies. Detailed ascertainment of patients will be critical for meaningful association of the genotype with the appropriate phenotype. Careful validation of uncovered genetic variation, together with forward and

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reverse analysis of the gene function in model systems, will be critical for meaningful translation into clinical practice.

References1. Hesdorffer DC, Tomson T, Benn E, Sander JW, Nilsson L, Langan Y, Wal-

czak TS, Beghi E, Brodie MJ, Hauser A; ILAE Commission on Epidemiol-ogy; Subcommission on Mortality. Combined analysis of risk factors for SUDEP. Epilepsia 2011;52:1150–1159.

2. Thurman DJ, Hesdorffer DC, French JA. Sudden unexpected death in epilepsy: Assessing the public health burden [published online ahead of print June 5, 2004]. Epilepsia. doi:10.1111/epi.12666.

3. Massey CA, Sowers LP, Dlouhy BJ, Richerson GB: Mechanisms of sud-den unexpected death in epilepsy: The pathway to prevention. Nat Rev Neurol 2014;10:271–282.

4. 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.

5. Klassen T, Davis C, Goldman A, Burgess D, Chen T, Wheeler D, McPherson J, Bourquin T, Lewis L, Villasana D, Morgan M, Muzny D, Gibbs R, Noebels J. Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Cell 2011;145:1036–1048.

6. Epi KC, Epilepsy Phenome/Genome P, Allen AS, Berkovic SF, Cossette P, Delanty N, Dlugos D, Eichler EE, Epstein MP, Glauser T, Goldstein DB, Han Y, Heinzen EL, Hitomi Y, Howell KB, Johnson MR, Kuzniecky R, Lowenstein DH, Lu YF, Madou MR, Marson AG, Mefford HC, Esmaeeli Nieh S, O’Brien TJ, Ottman R, Petrovski S, Poduri A, Ruzzo EK, Scheffer IE, Sherr EH, Yuskaitis CJ, Abou-Khalil B, Alldredge BK, Bautista JF, Berkovic SF, Boro A, Cascino GD, Consalvo D, Crumrine P, Devinsky O, Dlugos D, Epstein MP, Fiol M, Fountain NB, French J, Friedman D, Geller EB, Glauser T, Glynn S, Haut SR, Hayward J, Helmers SL, Joshi S, Kanner A, Kirsch HE, Knowlton RC, Kossoff EH, Kuperman R, Kuzniecky R, Lowenstein DH, McGuire SM, Motika PV, Novotny EJ, Ottman R, Paolicchi JM, Parent JM, Park K, Poduri A, Scheffer IE, Shellhaas RA, Sherr EH, Shih JJ, Singh R, Sirven J, Smith MC, Sullivan J, Lin Thio L, Venkat A, Vining EP, Von Allmen GK, Weisenberg JL, Widdess-Walsh P, Winawer MR. De novo mutations in epileptic encephalopathies. Nature 2013;501:217–221.

7. Helbig I, Lowenstein DH. Genetics of the epilepsies: Where are we and where are we going? Curr Opin Neuro 2013;26:179–185.

8. EPGP Collaborative, Abou-Khalil B, Alldredge B, Bautista J, Berkovic S, Bluvstein J, Boro A, Cascino G, Consalvo D, Cristofaro S, Crumrine P, Devinsky O, Dlugos D, Epstein M, Fahlstrom R, Fiol M, Fountain N, Fox K, French J, Freyer Karn C, Friedman D, Geller E, Glauser T, Glynn S, Haas K, Haut S, Hayward J, Helmers S, Joshi S, Kanner A, Kirsch H, Knowlton R, Kossoff E, Kuperman R, Kuzniecky R, Lowenstein D, Mc-Guire S, Motika P, Nesbitt G, Novotny E, Ottman R, Paolicchi J, Parent J, Park K, Poduri A, Risch N, Sadleir L, Scheffer I, Shellhaas R, Sherr E, Shih JJ, Shinnar S, Singh R, Sirven J, Smith M, Sullivan J, Thio LL, Venkat A, Vining E, von Allmen G, Weisenberg J, Widdess-Walsh P, Winawer M. The epilepsy phenome/genome project. Clin Trials 2013;10:568–586.

9. Epi K Consortium. Epi4K: Gene discovery in 4,000 genomes. Epilepsia 2012;53:1457–1467.

10. 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.

11. Towart R, Linders JT, Hermans AN, Rohrbacher J, van der Linde HJ, Ercken M, Cik M, Roevens P, Teisman A, Gallacher DJ. Blockade

of the I(Ks) potassium channel: An overlooked cardiovascular liability in drug safety screening? J Pharmacol Toxicol Methods 2009;60:1–10.

12. Skinner JR, Chong B, Fawkner M, Webster DR, Hegde M. Use of the newborn screening card to define cause of death in a 12-year-old diagnosed with epilepsy. J Paediatr Child Health 2004;40:651–653.

13. Glasscock E, Yoo JW, Chen TT, Klassen TL, Noebels JL. Kv1.1 potas-sium channel deficiency reveals brain-driven cardiac dysfunction as a candidate mechanism for sudden unexplained death in epilepsy. J Neurosci 2010;30:5167–5175.

14. Glasscock E, Qian J, Kole MJ, Noebels JL. Transcompartmental reversal of single fibre hyperexcitability in juxtaparanodal Kv1.1-deficient vagus nerve axons by activation of nodal KCNQ channels. J Physiol 2012;590:3913–3926.

15. Holth JK, Bomben VC, Reed JG, Inoue T, Younkin L, Younkin SG, Paut-ler RG, Botas J, Noebels JL. Tau loss attenuates neuronal network hy-perexcitability in mouse and Drosophila genetic models of epilepsy. J Neurosci 2013;33:1651–1659.

16. Hindocha N, Nashef L, Elmslie F, Birch R, Zuberi S, Al-Chalabi A, Crotti L, Schwartz PJ, Makoff A. Two cases of sudden unexpected death in epilepsy in a GEFS+ family with an SCN1A mutation. Epilepsia 2008;49:360–365.

17. Le Gal F, Korff CM, Monso-Hinard C, Mund MT, Morris M, Malafosse A, Schmitt-Mechelke T. A case of SUDEP in a patient with Dravet syndrome with SCN1A mutation. Epilepsia 2010;51:1915–1918.

18. Kalume F, Westenbroek RE, Cheah CS, Yu FH, Oakley JC, Scheuer T, Catterall WA. Sudden unexpected death in a mouse model of Dravet syndrome. J Clin Invest 2013;123:1798–1808.

19. Cheah CS, Yu FH, Westenbroek RE, Kalume FK, Oakley JC, Potter GB, Rubenstein JL, Catterall WA. Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome. Proc Natl Acad Sci U S A 2012;109:14646–14651.

20. Van Wart A, Trimmer JS, Matthews G. Polarized distribution of ion channels within microdomains of the axon initial segment. J Comp Neurol 2007:500:339–352.

21. Trudeau MM, Dalton JC, Day JW, Ranum LP, Meisler MH. Heterozygos-ity for a protein truncation mutation of sodium channel SCN8A in a patient with cerebellar atrophy, ataxia, and mental retardation. J Med Genet 2006;43:527–530.

22. Meisler MH, O’Brien JE, Sharkey LM. Sodium channel gene family: Epilepsy mutations, gene interactions and modifier effects. J Physiol 2010;588:1841–1848.

23. Veeramah KR, O’Brien JE, Meisler MH, Cheng X, Dib-Hajj SD, Waxman SG, Talwar D, Girirajan S, Eichler EE, Restifo LL, Erickson RP, Hammer MF. De novo pathogenic SCN8A mutation identified by whole-ge-nome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Am J Hum Genet 2012;90:502–510.

24. O’Brien JE, Meisler MH. Sodium channel SCN8A (Nav1.6): Properties and de novo mutations in epileptic encephalopathy and intellectual disability. Front Genet 2013;4:213.

25. Jones JM, Meisler MH. Modeling human epilepsy by TALEN targeting of mouse sodium channel Scn8a. Genesis 2014;52:141–148.

26. Shen HY, Li T, Boison D. A novel mouse model for sudden unexpect-ed death in epilepsy (SUDEP): Role of impaired adenosine clearance. Epilepsia 2010;51:465–468.

27. Butler TR, Prendergast MA. Neuroadaptations in adenosine receptor signaling following long-term ethanol exposure and withdrawal. Alcohol Clin Ex Res 2012:36:4–13.

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Session Summary: What Organizations Are Doing to Promote Understanding of SUDEP

Moderators: Jeffrey Buchhalter MD, PhD, Cyndi Wright, BS

The major advances in medicine that have occurred within the last few decades have been the result of careful clinical investiga-tion and basic science discoveries from the laboratory. We need to acknowledge, however, that much of the motivation and funding for these discoveries comes from the communities of people who suffer the specific illnesses. In the case of epilepsy, this com-munity is comprised of those who are bereaved from loss of a loved one (i.e., SUDEP) and those affected by seizures as part of their daily lives. A variety of organizations representing different constituencies have been established that advocate for those living with epilepsy in general and those who are bereaved. The reality that SUDEP is a common cause of mortality associated with epilepsy—especially when seizures are refractory to available therapies—has spawned the existence of several organizations to educate patients and professionals, support those who have lost a loved one, raise awareness in society, and lead the efforts to prevent this tragedy. In this session, we recounted the origins and activities of those organizations.

In 1995, five women in England joined together to create Epilepsy Bereaved. During the first 10 years, they motivated an international workshop on SUDEP (1996), the first national register of epilepsy-related deaths (2002), as well as national pathology (2003) and clinical (2004) guidelines regarding the reporting and discussion of deaths related to epilepsy. In recognition of the advances made thus far, the name of the organization was recently (2013) changed to SUDEP Action (1), the activities of which include: providing information, offering support, involving stakeholders, sponsoring research, and capturing data via the Epilepsy Deaths Register.

The late 1990s also saw the beginning of SUDEP-related activities in Australia. These efforts involved increasing aware-ness via the media, providing information to epilepsy-related websites, presentations to professionals (nurses and physi-cians) and members of Parliament. In 2005, the first edition of “SUDEP: A Global Conversation” (2) was published by Epilepsy Australia and Epilepsy Bereaved. This unique collection of essays provides a description of the experience of SUDEP and issues around mortality and epilepsy in a manner that is acces-sible to all individuals—patients, families, health care profes-sionals, as well as advocacy organizations and governmental agencies. The second edition in 2011 added SUDEP Aware and the International Bureau of Epilepsy as partners.

The effort spread to North America in 2008 with founding of SUDEP Aware (3) in Canada. This small nonprofit organiza-tion created the first SUDEP specific online information reposi-tory, provided support services options for those affected by SUDEP, and introduced families to the possibility of participat-ing in research. As part of a collaborative awareness campaign (4), user-friendly brochures were created for patients and fam-ily members of different ages that were made available, free online and in print.

The SUDEP Institute (5) was created within the Epilepsy Foundation in 2013. The activities of this relatively new orga-nization have been extensive and include: 1) SUDEP education and awareness programs for lay and professional audiences, 2)

drives and support for research efforts, 3) a support network providing counseling and community resources, and 4) coordi-nation with other epilepsy organizations to enhance knowl-edge of SUDEP. The SUDEP Institute has sponsored webinars as well as an Infographic that has more than 100,000 views on social media. Most recently, the Institute has organized the incorporation of the medical examiner and coroner communi-ties in the effort to better ascertain the occurrence of SUDEP.

The power of individuals to enhance awareness and action is illustrated by the Danny Did Foundation (6). This founda-tion, created after the loss of a little boy to SUDEP, sponsors local educational and awareness efforts. In addition, it has sponsored, via fund-raising, several important research efforts involving seizure detection devices.

Finally, the Chicago-based Citizens United for Research in Epilepsy (CURE) has added SUDEP to its portfolio of important research initiatives (7). CURE has funded several key discover-ies regarding the pathogenesis and epidemiology of SUDEP, including: 1) the potential primary respiratory basis of SUDEP and intervention via serotonin uptake inhibitors, 2) potential cardiac etiology of SUDEP via physiology similar to the long QT syndrome, 3) creation of several mouse models of SUDEP, and 4) establishing tonic–clonic seizures as a clear risk factor for SUDEP. In addition, CURE has been an active collaborator in national and international SUDEP education and research activities with the National Institutes of Health and Centers for Disease Control and Prevention.

In summary, the last two decades have witnessed a tre-mendous international effort to increase awareness, educa-tion, and research into the most devastating consequence of seizures, SUDEP. Marked gains have been made by organiza-tions founded by individuals who have rallied human and financial resources to prevent this tragedy to the greatest degree possible in future years.

References1. Epilepsy Bereaved: SUDEP action. http://www.sudep.org. Accessed

July 2014.2. SUDEP Global Conversation. http://www.sudepglobalconversation.

com/. Accessed July 2014.3. SUDEP Aware. http://www.sudepaware.org. Accessed July 2014.4. SUDEP Aware. Making sense of SUDEP. http://www.makingsenseofsudep.

org. Accessed July 2014.5. Epilepsy Foundation, Epilepsy Therapy Project. About the SUDEP

Institute. http://www.epilepsy.com/get-help/about-sudep-institute. Accessed July 2014.

6. Danny Did Foundation. Advancing Awareness of epilepsy & sudden unexpected death in epilepsy. http://www.dannydid.org/. Accessed July 2014.

7. CURE – Citizens United for Research in Epilepsy. http://www.cureepilepsy.org/. Accessed July 2014.

Summary of Session: SUDEP – Devices, Treatment & Prevention

Moderator: Elizabeth J. Donner, MD, FRCPC

OverviewThe last decade has seen a significant increase in research aimed to unravel the mystery of SUDEP. As teams work toward

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an understanding of why and how SUDEP occurs, prevention remains the most critical goal of all SUDEP research. At pres-ent, risk reduction is the best approach to prevention. Given that the occurrence of frequent generalized tonic–clonic sei-zures is the best-described risk factor for SUDEP, any therapy that reduces the frequency of seizures may reduce SUDEP risk. Further, by modifying other risk factors—such as longer dura-tion of epilepsy, poor adherence to treatment, and reducing the comorbidities of epilepsy—these therapies may reduce both overall mortality in epilepsy and SUDEP. Studies of surgi-cal populations have demonstrated lower all-cause mortality in patients who are seizure-free following epilepsy surgery (1), and comparisons of SUDEP rates among people with epilepsy who received epilepsy surgery and those who did not have demonstrated higher SUDEP rates among those who have received surgery (2, 3). However, these studies cannot account for the inherent differences between people who are consid-ered candidates for epilepsy surgery and those who are not.

In this session, we explored beyond the role of traditional epilepsy therapies, considering seizure detection devices, bed-side interventions, supervision, and behavioral modification for the prevention of SUDEP.

The Accuracy and Clinical Utility of Devices

Presented by Daniel Friedman, MD

An effective device for seizure detection offers the possibility for caregivers to be alerted soon after seizure onset to deliver interventions that may shorten the seizure or minimize harm. Dr. Daniel Friedman, Assistant Professor of Neurology at the New York University – Langone School of Medicine, explained that such devices use one or a combination of detection meth-ods to identify a seizure. Many seizures, especially tonic–clonic seizures, are associated with characteristic motor activity. Non-invasive sensors, such as accelerometers or surface electromy-ography electrodes, can be incorporated into devices worn by the person with epilepsy to detect seizure-related motion. Mattress motion or video motion detection devices can be used to identify nocturnal seizures. Monitoring for motion is relatively non-invasive and less costly than other methods; however, this approach is mostly limited to convulsive seizure and may be further limited by where the sensors are placed (mattress sensors in the bed, or video sensors in certain rooms). Devices may also use physiological parameters such as heart rate, pulse oximetry, and electrodermal activity to detect changes characteristic of seizures. Physiological monitor-ing may be more invasive than motor-only monitoring but provides the opportunity to focus detection on seizures with a higher risk of danger, such as those with persistent hypoxia.

Among the challenges in the development of seizure detection devices is the need to establish a balance of optimal specificity and sensitivity. While it is important that a device not miss a critical seizure (particularly if caregivers are relying on these devices as their only method of being alerted to a sei-zure), it is equally important to minimize false positive alarms that can have a significant negative effect on the quality of life of both the caregiver and person with epilepsy. Both motor activity and physiologic characteristics may lack specificity for seizures, resulting in high false positive alarm rates.

Monitoring Devices: What to Know and What to Ask

Presented by Tom Stanton

At present, several devices are commercially available in North America for detection of seizure-related motion, and other de-vices are under development. Tom Stanton, Executive Director of the Danny Did Foundation, outlined an approach for fami-lies when considering a device for seizure detection at home. He suggested that families speak with the treating physician to determine whether a device would be useful and appropri-ate; specifically, which type of seizures are most important to monitor, whether there are concerns about specific physiologi-cal parameters, and whether data from a device would be of use to the physician in making treatment recommendations. Other considerations for families and people with epilepsy include the cost of devices and the comfort and feasibility of device use. The role of devices for individuals with epilepsy who live alone remains a challenge for device developers.

Dr. Friedman and Mr. Stanton agreed that no seizure detec-tion device has been proven to prevent seizures or SUDEP. There is some evidence from a study of deaths occurring in Epilepsy Monitoring Units that earlier resuscitation by a health care worker following seizure-related asystole increases the chances of successful resuscitation (4); how this translates to the community setting and the use of seizure detection devices is not known. Whether the fatal cascade that follows some seizures can be terminated is not clear. Further, it will be difficult to obtain definitive data to support any device as a SUDEP prevention tool, given the rarity of SUDEP and the large number of subjects required for such a trial. As such, the role of devices in SUDEP prevention remains difficult to establish.

Nocturnal Supervision and Peri-Ictal Stimulation

Presented by Lisa Bateman, MD

The relationship between sleep and SUDEP is intriguing. The observation that SUDEP occurs most frequently at night or in bed is longstanding, and people with nocturnal seizures have been shown to be at higher risk of SUDEP (5). Dr. Lisa Bate-man, Associate Professor of Neurology at Columbia University, identified how sleep may contribute to SUDEP risk. Most often, SUDEP follows a convulsive seizure and, in many epilepsies, seizures are more likely to occur from sleep; such seizures are more likely to secondarily generalize (6). Sleep may also affect autonomic function, resulting in altered cerebral autoregula-tion in response to seizure-related hypoxemia, hypercapnia, and reduced heart rate variability (7).

Environmental factors may also contribute to an increased SUDEP risk at night, when people with epilepsy are more likely to be alone and unsupervised. The role of nocturnal supervi-sion has been explored in limited literature. A study of SUDEP deaths among a cohort of young people with epilepsy and learning difficulties at a United Kingdom residential school found that all deaths occurred while students were away from the school, suggesting a protective effect of the more supervised school environment (8). A case-control study of 154 SUDEP deaths found nocturnal supervision (defined as room-sharing or the use of an auditory monitor) to be protec-tive for SUDEP (9).

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The benefits of supervision are likely tied to an interven-tion, yet the optimal intervention for SUDEP prevention has not been established. Dr. Bateman, in collaboration with Dr. Masud Seyal, reviewed the effects of nursing interventions, ad-ministration of supplemental oxygen, oropharyngeal suction-ing, and patient repositioning on potential SUDEP biomarkers. Earlier peri-ictal interventions were associated with reduced respiratory dysfunction, postictal EEG suppression, and shorter seizure duration (10). Further studies using established SUDEP biomarkers are required to identify the role for interventions in both hospital and home settings. Studies of interventions to prevent SUDEP will face the same challenges as those for evaluating the effect of devices due to the infrequency of deaths and the large number of study subjects required.

Behavioral Modification

Presented by Martha Sajatovic, MD

Epilepsy self-management encompasses the skills a person with epilepsy uses to optimize their treatment adherence, con-trol seizures and their consequences, and manage the effects of epilepsy on daily life. Dr. Martha Sajatovic, Professor of Psy-chiatry and Neurology and Willard Brown Chair in Neurologi-cal Outcomes at Case Western Reserve University, described the significant impact of formal epilepsy self-management programs on the mental health comorbidities of epilepsy. The Managing Epilepsy Well Network has demonstrated the effect of e-Health in the support of epilepsy self-management and maintains a complement of MEW e-Tools to complement self-management practices (11).

SUDEP Prevention from a Public Health Perspective: Changing Behavior

Presented by Tanya Spruill, PhD

Given the established link between poorly controlled seizures and SUDEP, optimization of epilepsy self-management may be a powerful risk-reduction technique. Dr. Tanya Spruill, As-sistant Professor of Population Health and Medicine at New York University – Langone School of Medicine, described the behavioral risk factors that may affect seizure control and contribute to SUDEP, such as sleep deprivation, alcohol use, and AED nonadherence. Among these, AED nonadherence has been strongly linked to an increase in all-cause mortality in epilepsy (12). Nonadherence may take many forms: failing to fill prescriptions, omitting medication doses or taking extra doses, and taking medications at the wrong time or with pro-hibited foods or medications.

Well-designed strategies to improve AED adherence target modifiable patient-level adherence barriers, such as memory difficulties, depression and anxiety, pre-existing negative feelings about medications, lack of social support, and low self-efficacy. Dr. Spruill explained that patient education alone is not sufficient to improve nonadherence and change behavior. Tailored patient education tools should be used in combination with memory aids and reminders, social sup-ports, and approaches such as motivational interviewing to obtain maximum effect.

ConclusionAs we consider preventative strategies for SUDEP, it is impor-tant to remember that the best way to reduce SUDEP risk is to reduce seizure frequency. While we await the development of devices and interventions targeted to reduce mortality, it re-mains imperative that all people with epilepsy work with their health care providers to reduce the burden of seizures. Epilep-sy self-management tools should be combined with AEDs, and when seizures continue despite medical management, people with epilepsy should be referred for surgical evaluation. Finally, talking about SUDEP to people with epilepsy (including as-sessing risk and how to reduce that risk) is an important tool in the fight to save lives. Only when people with epilepsy are fully informed of the risks of their disorder can they actively pursue strategies to reduce their risk and prevent SUDEP.

References1. Sperling MR, Harris A, Nei M, Liporace JD, O’Connor MJ. Mortality after

epilepsy surgery. Epilepsia 2005;46(suppl):49–53.2. Almeida AG, Nunes ML, Palmini AL, Costa JC. Incidence of SUDEP in

a cohort of patients with refractory epilepsy: The role of surgery and lesion localization. Arq Neuropsiquiatr 2010;68:898–902.

3. Bell GS, Sinha S, Tisi J, Stephani C, Scott CA, Harkness WF, McEvoy AW, Peacock JL, Walker MC, Smith SJ, Duncan JS, Sander JW. Premature mortality in refractory partial epilepsy: Does surgical treatment make a difference? J Neurol Neurosurg Psychiatry 2010;81:716–718.

4. 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 JMK, 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.

5. Lamberts RJ, Thijs RD, Laffan A, Langan Y, Sander JW. Sudden unex-pected death in epilepsy: People with nocturnal seizures may be at highest risk. Epilepsia 2012;53:253–257.

6. Ramgopal S, Vendrame M, Shah A, Gregas M, Zarowski M, Rotenberg A, Alexopoulos AV, Wyllie E, Kothare SV, Loddenkemper T. Circadian patterns of generalized tonic–clonic evolutions in pediatric epilepsy patients. Seizure 2012;21:535–539.

7. Nobili L, Proserpio P, Rubboli G, Montano N, Didato G, Tassinari CA. Sudden unexpected death in epilepsy (SUDEP) and sleep. Sleep Med Rev 2010;15:237–246.

8. 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.

9. Langan Y, Nashef L, Sander JW. Case-control study of SUDEP. Neurol-ogy 2005;64:1131–1133.

10. Seyal M, Bateman LM, Li CS. Impact of periictal interventions on respiratory dysfunction, postictal EEG suppression, and postictal im-mobility. Epilepsia 2013;54:377–382.

11. Shegog R, Bamps YA, Patel A, Kakacek J, Escoffery C, Johnson EK, Ilozumba UO. Managing Epilepsy Well: Emerging e-tools for epilepsy self-management. Epilepsy & Behavior 2013;29:133–140. http://web1.sph.emory.edu/ManagingEpilepsyWell/.

12. Faught E, Duh MS, Weiner JR, Guerin A, Cunnington MC. Nonad-herence to antiepileptic drugs and increased mortality. Neurology 2008;71:1572–1578.

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