Definite Sudden Unexpected Death In Epilepsy Research Articles

The incidence of sudden unexpected death in epilepsy (SUDEP) in the Republic of Ireland

BackgroundThe incidence of sudden unexpected death in epilepsy (SUDEP) in Ireland has previously been studied in only a small geographical area. Our aim was to calculate an incidence rate for the whole of the Republic of Ireland in 2019. MethodsAll deaths referred to the coroner in 2019 were examined. Those with a history of possible epilepsy were noted and subjected to a more detailed assessment. Cases fulfilling the definition of definite SUDEP were identified. The incidence of SUDEP was calculated using the population of the Republic of Ireland in 2019 and the known prevalence of epilepsy in Ireland. ResultsThirty-three cases of definite SUDEP were identified in the Republic of Ireland in 2019. The estimated incidence of SUDEP in the epilepsy population as a whole was 0.7/1000(0.46 – 0.94) person years. This may be a conservative estimate. More men than women were identified, and most individuals were found dead at home. SUDEP was mentioned on the death certificate in only 52 % of cases. ConclusionThis is the first nationwide study of SUDEP incidence in Ireland and provides an incidence rate in keeping with other populations. This work demonstrates that the interrogation of coronial records is a useful way to monitor epilepsy mortality albeit with certain limitations.

Sudden unexpected death in epilepsy during cenobamate clinical development.

We assessed mortality, sudden unexpected death in epilepsy (SUDEP), and standardized mortality ratio (SMR) among adults treated with cenobamate during the cenobamate clinical development program. We retrospectively analyzed deaths among all adults with uncontrolled focal (focal to bilateral tonic-clonic [FBTC], focal impaired awareness, focal aware) or primary generalized tonic-clonic (PGTC) seizures who received ≥1 dose of adjunctive cenobamate in completed and ongoing phase 2 and 3 clinical studies. In patients with focal seizures from completed studies, median baseline seizure frequencies ranged from 2.8 to 11 seizures per 28 days and median epilepsy duration ranged from 20 to 24 years. Total person-years included all days a patient received cenobamate during completed studies or up to June 1, 2022 for ongoing studies. All deaths were evaluated by two epileptologists. All-cause mortality and SUDEP rates were expressed per 1000 person-years. A total of 2132 patients (n=2018 focal epilepsy; n=114 idiopathic generalized epilepsy) were exposed to cenobamate for 5693 person-years. Approximately 60% of patients with focal seizures and all patients in the PGTC study had tonic-clonic seizures. A total of 23 deaths occurred (all in patients with focal epilepsy), for an all-cause mortality rate of 4.0 per 1000 person-years. Five cases of definite or probable SUDEP were identified, for a rate of 0.88 per 1000 person-years. Of the 23 overall deaths, 22 patients (96%) had FBTC seizures, and all 5 of the SUDEP patients had a history of FBTC seizures. The duration of exposure to cenobamate for patients with SUDEP ranged from 130-620 days. The SMR among cenobamate-treated patients in completed studies (5515 person-years of follow-up) was 1.32 (95% CI 0.84-2.0), which was not significantly different from the general population. These data suggest that effective long-term medical treatment with cenobamate may reduce excess mortality associated with epilepsy.

Stratifying sudden death risk in adults with drug-resistant focal epilepsy: The SUDEP-CARE score.

A clinical risk score for sudden unexpected death in epilepsy (SUDEP) in patients with drug-resistant focal epilepsy could help improve prevention. A case-control study was conducted including (i) definite or probable SUDEP cases collected by the French National Sentinel Mortality Epilepsy Network and (ii) control patients from the French national research database of epilepsy monitoring units. Patients with drug-resistant focal epilepsy were eligible. Multiple logistic regressions were performed. After sensitivity analysis and internal validation, a simplified risk score was developed from the selected variables. Sixty-two SUDEP cases and 620 controls were included. Of 21 potential predictors explored, seven were ultimately selected, including generalized seizure frequency (>1/month vs. <1/year: adjusted odds ratio [AOR] 2.6, 95% confidence interval [CI] 1.25-5.41), nocturnal or sleep-related seizures (AOR 4.49, 95% CI 2.68-7.53), current or past depression (AOR 2.0, 95% CI 1.19-3.34) or the ability to alert someone of an oncoming seizure (AOR 0.57, 95% CI 0.33-0.98). After internal validation, a clinically usable score ranging from -1 to 8 was developed, with high discrimination capabilities (area under the receiver operating curve 0.85, 95% CI 0.80-0.90). The threshold of 3 has good sensitivity (82.3%, 95% CI 72.7-91.8), whilst keeping a good specificity (82.7%, 95% CI 79.8-85.7). These results outline the importance of generalized and nocturnal seizures on the occurrence of SUDEP, and show a protective role in the ability to alert someone of an oncoming seizure. The SUDEP-CARE score is promising and will need external validation. Further work, including paraclinical explorations, could improve this risk score.

Impact of fenfluramine on the expected SUDEP mortality rates in patients with Dravet syndrome

PurposeTo assess the impact of fenfluramine (FFA) on the expected mortality incidence, including sudden unexpected death in epilepsy (SUDEP), in persons with Dravet syndrome (DS). MethodsIn this pooled analysis, total time of exposure for persons with DS who were treated with FFA in phase 3 clinical trials, in United States and European Early Access Programs, and in two long-term open-label observational studies in Belgium was calculated. Literature was searched for reports of SUDEP mortality in DS, which were utilized as a comparison. Mortality rates were expressed per 1000 person-years. ResultsA total of 732 persons with DS were treated with FFA, representing a total of 1185.3 person-years of exposure. Three deaths occurred, all in the phase 3 program: one during placebo treatment (probable SUDEP) and two during treatment with FFA (one probable SUDEP and one definite SUDEP). The all-cause and SUDEP mortality rates during treatment with FFA was 1.7 per 1000 person-years (95% CI, 0.4 to 6.7), a value lower than the all-cause estimate of 15.8 per 1000 person-years (95% CI, 9.9 to 25.4) and SUDEP estimate of 9.3 (95% CI, 5.0 to 17.3) reported by Cooper et al. (Epilepsy Res 2016;128:43−7) for persons with DS receiving standard-of-care. ConclusionAll-cause and SUDEP mortality rates in DS patients treated with FFA were substantially lower than in literature reports. Further studies are warranted to confirm that FFA reduces SUDEP risk in DS patients and to better understand the potential mechanism(s) by which FFA lowers SUDEP risk.Clinical Trial Registration: NCT02926898, NCT02682927, NCT02826863, NCT02823145, NCT03780127.

Paediatric sudden unexpected death in epilepsy: A parental report cohort.

Sudden unexpected death in epilepsy (SUDEP) accounts for a large percentage of deaths in children with epilepsy. Contributing factors to paediatric SUDEP are incompletely understood. The Epilepsy Deaths Register (EDR) is an anonymized register that compiles information on deaths related to epilepsy, across all ages and epilepsy classifications. Using the EDR, we sought to identify key risk factors for SUDEP in children to assist the development of preventive measures. All registrations between the ages of 1 and 16years were reviewed to identify definite or probable SUDEP. These cases were analysed to identify common demographics, comorbidities, monitoring, treatments and circumstances near to the deaths. We identified forty-six cases (27 males) of definite or probable SUDEP. Paediatric SUDEP is more common in a 12- to 16-year age group and in those with neuro-disability. Most paediatric SUDEP occurs during apparent sleep. There were four cases with a vagus nerve stimulator. SUDEP can occur early after the onset of seizures. This is the largest single cohort of SUDEP reported in children. Reports from caregivers can augment population data. Surveillance in sleep is a priority area of development.

SUDEP classification: Discordances between forensic investigators and epileptologists.

We compared sudden unexpected death in epilepsy (SUDEP) diagnosis rates between North American SUDEP Registry (NASR) epileptologists and original death investigators, to determine degree and causes of discordance. In 220 SUDEP cases with post-mortem examination, we recorded the epileptologist adjudications and medical examiner- and coroner- (ME/C) listed causes of death (CODs). COD diagnosis concordance decreased with NASR's uncertainty in the SUDEP diagnosis: highest for Definite SUDEP (84%, n=158), lower in Definite Plus (50%, n=36), and lowest in Possible (0%, n=18). Rates of psychiatric comorbidity, substance abuse, and toxicology findings for drugs of abuse were all higher in discordant cases than concordant cases. Possible SUDEP cases, an understudied group, were significantly older, and had higher rates of cardiac, drug, or toxicology findings than more certain SUDEP cases. With a potentially contributing or competing COD, ME/Cs favored non-epilepsy-related diagnoses, suggesting a bias toward listing CODs with structural or toxicological findings; SUDEP has no pathognomonic features. A history of epilepsy should always be listed on death certificates and autopsy reports. Even without an alternate COD, ME/Cs infrequently classified COD as "SUDEP." Improved collaboration and communication between epilepsy and ME/C communities improve diagnostic accuracy, as well as bereavement and research opportunities.

Temporal trends and autopsy findings of SUDEP based on medico-legal investigations in the United States.

To determine time trends and distinguishing autopsy findings of sudden unexpected death in epilepsy (SUDEP) in the United States. We identified decedents where epilepsy/seizure was listed as cause/contributor to death or comorbid condition on the death certificate among all decedents who underwent medico-legal investigation at 3 medical examiner (ME) offices across the country: New York City (2009-2016), San Diego County (2008-2016), and Maryland (2000-2016). After reviewing all available reports, deaths classified as definite/probable/near SUDEP or SUDEP plus were included for analysis. Mann-Kendall trend test was used to analyze temporal trends in SUDEP rate for 2009-2016. Definite SUDEPs were compared to sex- and age ±2 years-matched non-SUDEP deaths with a history of epilepsy regarding autopsy findings, circumstances, and comorbidities. A total of 1,086 SUDEP cases were identified. There was a decreasing trend in ME-investigated SUDEP incidence between 2009 and 2016 (z = -2.2, S = -42, p = 0.028) among 3 regions. There was a 28% reduction in ME-investigated SUDEP incidence from 2009 to 2012 to 2013-2016 (confidence interval, 17%-38%, p < 0.0001). We found no correlation between SUDEP rates and the month of year or day of week. There was no difference between SUDEP and non-SUDEP deaths regarding neurodevelopmental abnormalities, pulmonary congestion/edema, and myocardial fibrosis. There was a decreasing monotonic trend in ME-investigated SUDEP incidence over 8 years, with a 28% reduction in incidence from 2009-2012 to 2013-2016. Unlike SIDS and sudden cardiac death, we found no correlation between SUDEP and the season of year or day of week. No autopsy findings distinguished SUDEP from non-SUDEP deaths.

Knowledge and experience with Sudden Unexpected Death in Epilepsy (SUDEP) among neurologists in the Eastern Mediterranean Region (EMR)

Abstract Objective SUDEP is one of the causes of mortality in patients with epilepsy. We investigated SUDEP discussion practices among neurologists in the EMR to identify gaps in knowledge and to increase awareness. Methods An online survey was sent out to neurologists practicing in the EMR through registered emails and to attendees of local neurology conferences. Results: 132 practitioners completed the survey. 19.7% respondents were from Egypt, 15.2% from Sudan, 8.3% from KSA, and 4.5% from Syria. Only 1.5% of the respondents discussed SUDEP with their patients nearly all of the time, while 46.2% rarely discuss SUDEP. 18% of the respondents had experienced definite or probable SUDEP in the past 24 months of their clinical practice. Top three reactions to SUDEP discussion were distress (74%), anxiety (70.5%), and depression (65.9%). 77.3% of the respondents believe that patients are at minimal risk of SUDEP, 37.9% fear it would affect patients’ mood or quality of life, and 27.3% believe SUDEP is so rare and the risks of discussion outweigh potential benefits. We found no significant association between years of independent practice, number of patients seen annually, number of SUDEP in the past 24 months and how often respondents discussed SUDEP. Conclusion Neurologists in the EMR rarely discuss SUDEP with their patients / caregivers. Negative reactions and underestimating the risk of SUDEP may be the reason, suggesting lack of awareness among practitioners, patients, and caregivers. Framing the discussion positively and using different resources to support patients / caregivers around SUDEP may minimize negative reactions.

Sudden unexpected death in epilepsy. A nationwide population‐based study

The incidence of sudden unexpected death in epilepsy (SUDEP) varies between studies. We determined the incidence of SUDEP in the entire Icelandic population during a 20-year period. All individuals in Iceland with epilepsy who died unexpectedly from January 1, 1991 through December 31, 2010 were included. Case ascertainment was based on autopsies, reimbursement for antiepileptic drugs, death certificates, information from neurologists, and medical records. The incidence of SUDEP was calculated according to the total number of residents in Iceland during the study period and an estimated epilepsy population of Iceland. We identified 37 individuals (26 men, 11 women) with definite SUDEP (n=29), definite SUDEP plus (n=4), and probable SUDEP (n=4). Incidence of SUDEP was 0.6 per 100000 person-years for the general population, and higher among men. The estimated incidence of SUDEP in the epilepsy population was 1.3 per 1000 person-years. SUDEP accounted for 0.1% of all deaths in Iceland during the study period. SUDEP is an important cause of death in working-age people. This study provides the incidence of SUDEP in an unselected population of an entire country. The SUDEP incidence in the epilepsy population is comparable to that of previous studies.

Incidence of sudden unexpected death in epilepsy in children is similar to adults.

To determine the incidence of sudden unexpected death in epilepsy (SUDEP) in children in Ontario, Canada. Cases of suspected pediatric SUDEP occurring between January 1, 2014, and December 31, 2015, in Ontario, Canada, were eligible for inclusion. Potential cases were identified through 3 sources: a national pediatrician surveillance program, child neurologist report, and screening of provincial forensic autopsies. Cases were classified as definite, definite plus, probable, possible, and near/near plus according to criteria described by Nashef et al. (Epilepsia 2012). Overall crude pediatric SUDEP incidence and the incidence of definite or probable pediatric SUDEP were calculated using estimates of the prevalence of pediatric epilepsy in Canada drawn from government survey data and the number of children living in Ontario. Capture-recapture analysis was used to estimate the number of missing cases and determine an adjusted definite/probable SUDEP incidence. Seventeen cases of pediatric SUDEP resulted in an overall incidence of 1.17 (95% confidence interval 0.68-1.88) per 1,000 pediatric epilepsy person-years. The definite/probable incidence, including definite (n = 11), definite plus (n = 2), or probable (n = 3) SUDEP cases, was 1.11 (0.63-1.79). Capture-recapture analysis indicated an estimated 21 (16-39) definite/probable SUDEP cases occurred during the study period, giving an adjusted incidence of definite/probable SUDEP of 1.45 (0.90-2.22) per 1,000 pediatric epilepsy person-years. SUDEP may be more common in children than widely reported, with the incidence rate of definite/probable SUDEP in children being similar to rates reported in adults.

Resolving ambiguities in SUDEP classification.

To examine the consistency of applying the Nashef et al (2012) criteria to classify sudden unexpected death in epilepsy (SUDEP). We reviewed cases from the North American SUDEP Registry (n = 250) and Medical Examiner Offices (n = 1301: 698 Maryland, 457 New York City, 146 San Diego). Two epileptologists with expertise in SUDEP and epilepsy-related mortality independently reviewed medical records, scene investigation, autopsy, and toxicology and assigned a SUDEP class. Major areas of disagreement arose between adjudicators concerned differentiating (1) Definite SUDEP Plus Comorbidity from Possible SUDEP and (2) Resuscitated (Near) SUDEP from SUDEP. In many cases, distinguishing between contributing and competing causes of death when trying to classify Definite SUDEP Plus Comorbidity versus Possible SUDEP is ambiguous and relies on judgement. Similarly, determining if an intervention was lifesaving or not (Resuscitated SUDEP or Not SUDEP), or if resuscitation merely delayed SUDEP (Resuscitated SUDEP or SUDEP) is often a judgement call and can differ between experienced adjudicators. Given these persisting ambiguities, we propose more explicit criteria for distinguishing these categories. Accurate and consistent classification of cause of death among individuals with epilepsy remains a dire public health concern. SUDEP is likely underestimated in national health statistics. Greater standardization of criteria among epilepsy researchers, medical examiners, and epidemiologists to determine cause and classify death will lead to more accurate tracking of SUDEP and other epilepsy-related mortalities.

Circumstances of SUDEP: A nationwide population-based case series.

Given the increasing attention being paid to potential strategies for sudden unexpected death in epilepsy (SUDEP) prevention, we analyzed the circumstances of SUDEP and its incidence in relation to time of year, week, and day. Prospective case-series based on persons with an International Classification of Diseases (ICD-10) code for epilepsy in the Swedish Patient Registry 1998-2005, who were alive on June 30, 2006 (n = 60 952). Linkage to the National Cause-of-Death Registry identified all deaths from July 2006 through December 2011, with epilepsy mentioned on death certificate, together with all deaths during 2008 (n = 3166). Death certificates, medical charts, autopsy, and police reports were reviewed to identify SUDEP cases and related circumstances. Autopsied non-SUDEP deaths (n = 60) from the study population served as a reference. There were 329 SUDEPs (63% men) of which 167 were definite, 89 probable, and 73 possible. SUDEP cases were younger at death (50.8 years) than non-SUDEP deaths (73.3 years) (P < .001) and more likely to be male (63% vs 55%, P = .0079). Most SUDEP cases died at night (58%), at home (91%), and 65% were found dead in bed. When documented, 70% were found in prone position. In 17%, death was witnessed and in 88% of these, a seizure was observed. Of the 329 SUDEP cases, 71% were living alone and 14% shared a bedroom. Compared to an autopsied non-SUDEP reference group, definite SUDEPs were more likely to die at home, during the night, unwitnessed, in the prone position, to live alone, and more often with a preceding seizure. SUDEP cases live alone, die unwitnessed at home at night, with indication of a preceding seizure, supporting the critical role of lack of supervision. These facts need to be considered in the development of preventive strategies.

Sudden unexpected death in epilepsy in patients treated with brain-responsive neurostimulation.

To study the incidence and clinical features of sudden unexpected death in epilepsy (SUDEP) in patients treated with direct brain-responsive stimulation with the RNS System. All deaths in patients treated in clinical trials (N = 256) or following U.S. Food and Drug Administration (FDA) approval (N = 451) through May 5, 2016, were adjudicated for SUDEP. There were 14 deaths among 707 patients (2208 postimplantation years), including 2 possible, 1 probable, and 4 definite SUDEP events. The rate of probable or definite SUDEP was 2.0/1000 (95% confidence interval [CI] 0.7-5.2) over 2036 patient stimulation years and 2.3/1000 (95% CI 0.9-5.4) over 2208 patient implant years. Stored electrocorticograms around the time of death were available for 4 patients with probable/definite SUDEP and revealed the following: frequent epileptiform activity ending abruptly (n = 2), no epileptiform activity or seizures (n = 1), and an electrographic and witnessed seizure with cessation of postictal electrocorticography (ECoG) activity associated with apnea and pulselessness (n = 1). The SUDEP rate of 2.0/1000 patient stimulation years among patients treated with the RNS System is favorable relative to treatment-resistant epilepsy patients randomized to the placebo arm of add-on drug studies or with seizures after resective surgery. Our findings support that treatments that reduce seizures reduce SUDEP risk and that not all SUDEPs follow seizures.

Obstructive apnea due to laryngospasm links ictal to postictal events in SUDEP cases and offers practical biomarkers for review of past cases and prevention of new ones.

Seizure spread into autonomic and respiratory brainstem regions is thought to play an important role in sudden unexpected death in epilepsy (SUDEP). As the clinical dataset of cases of definite SUDEP available for study grows, evidence points to a sequence of events that includes postictal apnea, bradycardia, and asystole as critical events that can lead to death. One possible link between the precipitating seizure and the critical postictal sequence is seizure-driven laryngospasm sufficient to completely obstruct the airway for an extended period, but ictal laryngospasm is difficult to fully assess. Herein, we demonstrate in a rat model how the electrical artifacts of attempts to inspire during airway obstruction and features of the cardiac rhythm establish this link between ictal and postictal activity and can be used as practical biomarkers of obstructive apnea due to laryngospasm or other causes of airway obstruction.

Sudden Unexpected Death in Epilepsy Among Patients With Benign Childhood Epilepsy With Centrotemporal Spikes

ImportanceChildren with benign epilepsy with centrotemporal spikes (BECTS) have traditionally been considered to have a uniformly good prognosis. However, benign may be a misnomer because BECTS is linked to cognitive deficits, a more severe phenotype with intractable seizures, and the potential for sudden unexpected death in epilepsy (SUDEP).ObjectiveTo determine if cases of BECTS are present in the North American SUDEP Registry (NASR).Design, Setting, and ParticipantsThe NASR is a clinical and biospecimen repository established in 2011 to promote SUDEP research. The NASR database, which includes medical records, results of electroencephalographic tests, and interviews with family members of patients with epilepsy who died suddenly without other identifiable causes of death, was queried from June 3, 2011, to June 3, 2016, for cases of BECTS. The patients with epilepsy had died suddenly without other identifiable causes of death (eg, drowning, trauma, exposure to toxic substances, or suicide); SUDEP classification was determined by the consensus of 2 epileptologists.Main Outcomes and MeasuresCases of SUDEP among children who received a diagnosis of BECTS among patients reported in the NASR.ResultsThree boys (median age at death, 12 years; range, 9-13 years) who received a diagnosis of BECTS by their pediatric epileptologist or neurologists were identified among 189 cases reported in the NASR. The median age of epilepsy onset was 5 years (range, 3-11 years), and the median duration of epilepsy was 4 years (range, 1-10 years). Two deaths were definite SUDEP, and 1 was probable SUDEP. Independent review of clinical and electroencephalographic data supported the diagnosis of BECTS in all 3 patients. None of the patients was prescribed antiseizure drugs, either owing to physician recommendation or mutual decision by the physician and parents. All 3 patients were found dead in circumstances typical of SUDEP. The 3 patients spanned the spectrum of BECTS severity: 1 had only a few seizures, 1 had more than 30 focal motor seizures, and 1 had 4 witnessed generalized tonic-clonic seizures and approximately 30 suspected generalized tonic-clonic seizures.Conclusions and RelevanceSudden unexpected death in epilepsy is a very rare outcome in BECTS that clinicians should consider discussing in appropriate circumstances and possibly factoring into treatment decisions.

B.06: Two definite sudden unexpected deaths in epilepsy in a family with a DEPDC5 mutation

Background:DEPDC5 gene, mapped to 22q12.2-q12.3, has been associated with a variety of familial epilepsies, including FFEVF, autosomal dominant nocturnal frontal lobe epilepsy, and familial TLE. Notably, DEPDC5 has never been linked to increased risk of sudden unexpected death in epilepsy (SUDEP). Methods: Cases review. Results: We studied a three-generation, non-consanguineous, French-Canadian family with nine clinically affected individuals. The index case is a 39-year-old man who started having seizures (as 2rily GTCS) at the age of 13 years. EEGs showed interictal discharges over the right anterior-temporal region. Brain MRI was unremarkable. Two individuals in this family suffered definite autopsy-confirmed SUDEP, at the ages of 58 and 50 years, respectively. Overall, seizure-history in this family can be summarized by an onset before reaching adulthood followed by subsequent progressive decrease in seizure frequency. Seizures were predominantly nocturnal 2rily GTC. Genetic analysis revealed a pathogenic heterozygous variant in the DEDPC5 gene (p.Gln216, c.646C&gt;T), which results in a premature stop codon, in all affected family members plus on heatlhy relative. Importantly, all the subjects were cognitively intact, and there was no history of cardiac symptomatology/cardiovascular risk factor. Conclusions: The finding in this family suggests that DEPDC5 mutations may be a risk factor for SUDEP.

Nonseizure SUDEP: Sudden unexpected death in epilepsy without preceding epileptic seizures.

To describe the phenomenology of monitored sudden unexpected death in epilepsy (SUDEP) occurring in the interictal period where death occurs without a seizure preceding it. We report a case series of monitored definite and probable SUDEP where no electroclinical evidence of underlying seizures was found preceding death. Three patients (two definite and one probable) had SUDEP. They had a typical high SUDEP risk profile with longstanding intractable epilepsy and frequent generalized tonic-clonic seizures (GTCS). All patients had varying patterns of respiratory and bradyarrhythmic cardiac dysfunction with profound electroencephalography (EEG) suppression. In two patients, patterns of cardiorespiratory failure were similar to those seen in some patients in the Mortality in Epilepsy Monitoring Units Study (MORTEMUS). SUDEP almost always occur postictally, after GTCS and less commonly after a partial seizure. Monitored SUDEP or near-SUDEP cases without a seizure have not yet been reported in literature. When nonmonitored SUDEP occurs in an ambulatory setting without an overt seizure, the absence of EEG information prevents the exclusion of a subtle seizure. These cases confirm the existence of nonseizure SUDEP; such deaths may not be prevented by seizure detection-based devices. SUDEP risk in patients with epilepsy may constitute a spectrum of susceptibility wherein some are relatively immune, death occurs in others with frequent GTCS with one episode of seizure ultimately proving fatal, while in others still, death may occur even in the absence of a seizure. We emphasize the heterogeneity of SUDEP phenomena.

Mortality in isodicentric chromosome 15 syndrome: The role of SUDEP.

To ascertain the cause of mortality and incidence of sudden unexpected death in epilepsy (SUDEP) in patients with supernumerary isodicentric chromosome 15 (idic15). Cases were obtained from those reported to the Dup15q Alliance (www.dup15q.org) between April 2006 and June 2012; ~709 families were registered in their database. We performed a case-control study comparing reported SUDEP cases to living patients with epilepsy from the Dup15q Alliance registry who volunteered to be interviewed to examine clinical risk factors. There were nineteen deaths with idic15; 17 had epilepsy, and nine deaths were due to probable or definite SUDEP (4 females, median age of death was 13.5years, range: 3-26years). Possible SUDEP occurred in 2 others. The remainder died from status epilepticus (3), pneumonia (3), aspiration (1), and drowning (1). Nonambulatory status and lack of seizure control were more common among SUDEP cases than living dup15q patients. Our findings suggest that SUDEP is a common cause of death among children and young adults with isodicentric chromosome 15q11.2q13 duplications and patients with the most severe neurologic dysfunction may be at highest risk. Further studies are needed to examine if this specific genetic defect plays a role in the mechanism of SUDEP in these patients.

Implications of Death Certification on Sudden Unexpected Death in Epilepsy (SUDEP) Research.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in individuals with chronic, uncontrolled epilepsy. Epidemiologists use information on death certificates to study SUDEP. Certification of seizure-related deaths varies. Multiple classification schemes have been proposed to categorize SUDEP type deaths. Nashef et al. recently proposed categorizing death into Definite SUDEP, Definite SUDEP Plus, Probable SUDEP, Possible SUDEP, Near-SUDEP, and Not SUDEP. This study analyzes certification of seizure-related deaths by our office and considers how it relates to Nashef's classifications. Investigative reports from 2011-2015 from the archives of the Jefferson County Coroner/Medical Examiner's Office were searched for the terms "seizure(s)" and "epilepsy." Cases (N=61) were categorized as Definite SUDEP (n=13), Definite SUDEP Plus (n=12), Probable SUDEP (n=1), Possible SUDEP (n=2), and Not SUDEP (n=33). The term SUDEP was only used in one case of Definite SUDEP. The other 12 cases were certified with variations of terms "seizure" and "epilepsy." Cases categorized as Definite SUDEP Plus were overwhelmingly certified as deaths due to heart disease. Categories Probable SUDEP or Possible SUDEP comprised three cases, and in one of those a seizure-related term was used on the death certificate. Thirty-three cases were classified as Not SUDEP. The finding that the majority of cases of Definite SUDEP were certified as some variation of "seizure" or "epilepsy" but not "SUDEP" has important implications for SUDEP research. Our study also suggests that cases of Definite SUDEP Plus would be difficult for epidemiologists to identify because cardiovascular diseases are more frequently implicated.

Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy.

The leading cause of epilepsy-related premature mortality is sudden unexpected death in epilepsy (SUDEP). The cause of SUDEP remains unknown. To search for genetic risk factors in SUDEP cases, we performed an exome-based analysis of rare variants. Demographic and clinical information of 61 SUDEP cases were collected. Exome sequencing and rare variant collapsing analysis with 2,936 control exomes were performed to test for genes enriched with damaging variants. Additionally, cardiac arrhythmia, respiratory control, and epilepsy genes were screened for variants with frequency of <0.1% and predicted to be pathogenic with multiple in silico tools. The 61 SUDEP cases were categorized as definite SUDEP (n = 54), probable SUDEP (n = 5), and definite SUDEP plus (n = 2). We identified de novo mutations, previously reported pathogenic mutations, or candidate pathogenic variants in 28 of 61 (46%) cases. Four SUDEP cases (7%) had mutations in common genes responsible for the cardiac arrhythmia disease, long QT syndrome (LQTS). Nine cases (15%) had candidate pathogenic variants in dominant cardiac arrhythmia genes. Fifteen cases (25%) had mutations or candidate pathogenic variants in dominant epilepsy genes. No gene reached genome-wide significance with rare variant collapsing analysis; however, DEPDC5 (p = 0.00015) and KCNH2 (p = 0.0037) were among the top 30 genes, genome-wide. A sizeable proportion of SUDEP cases have clinically relevant mutations in cardiac arrhythmia and epilepsy genes. In cases with an LQTS gene mutation, SUDEP may occur as a result of a predictable and preventable cause. Understanding the genetic basis of SUDEP may inform cascade testing of at-risk family members.