Investigation Of Sudden Unexpected Death Research Articles

Complications and Mortality Rate of Vagus Nerve Stimulation for Drug-Resistant Epilepsy.

The goal of this study is to evaluate the complications and mortality associated with vagus nerve stimulation (VNS). We retrospectively reviewed medical records of patients who underwent VNS implantation for the treatment of drug-resistant epilepsy (DRE) between 2000 and 2023. The mean follow-up time was 10.6 years, ranging from three months to 22 years. In total, 55 adult and pediatric patients received VNS therapy with 117 procedures performed over 23 years. The most common early complications were hoarseness and cough which were reported in eight adult patients (6.8%). Four children with intellectual disability (ID) had infection (3.4%), eight patients had lead breakage (6.8%), and two had device migration (1.7%). Fourof all patients (7.3%) demonstrated late complications due to chronic nerve stimulation including vocal cord dysfunction, late-onset severe AV block, and obstructive sleep apnea (OSA). Three patients (5.5%) had VNS deactivated permanently due to complications and/or lack of efficacy. Two patients died from probable sudden unexpected death in epilepsy (SUDEP) with an incidence of 3.4/1000 person-years. VNS therapy is safe over long-term follow-up but not without risks. Most post-operative complications are minor and transient for adults. Children with ID tend to have infection and device migration. Late-onset cardiac complications and OSA can develop in some patients during VNS therapy and should not be overlooked. The SUDEP rate may decrease with VNS therapy over time.

Long-term survival and factors associated with mortality among children with infantile epileptic spasms syndrome - A retrospective cohort study.

The existing literature indicates a higher risk of mortality among children with Infantile epileptic spasms syndrome (IESS). Our aim was to find the mortality pattern and factors that affect survival among children with IESS. Children with IESS who had age of onset between one month and 24 months were included. The primary outcome was survival. We used Kaplan-Meier estimates for survival analysis and Cox regression analyses to evaluate possible factors associated with mortality. During the follow-up period (120 months), 19/160 children (11.9%) expired. Three children expired in the first week after initiation of ACTH. There were six deaths (3.8%; 31.6% of deaths), within two years. Clinical findings and laboratory investigations revealed the cause of death to be severe pneumonia in ten children. Three died of severe sepsis. Four died due to metabolic crisis and two children died due to probable Sudden unexpected death in epilepsy (SUDEP). On multivariable analysis, mortality was predicted by 'presence of seizures other than spasms' and an inborn error of metabolism (IEM) as the underlying cause. None of the children in the idiopathic group died. Survival in our single center cohort with IESS was good in comparison to previous studies. Considering that pneumonia and sepsis were the most common cause of mortality that we detected, steps for prevention of sepsis might be worth considering in these children. Presence of seizures other than epileptic spasms, and an IEM should prompt the physician to let the family know that risk of mortality is high.

Serious gaps in the investigation of sudden unexpected deaths in infancy in Australia

Medical Journal of AustraliaEarly View Editorial Serious gaps in the investigation of sudden unexpected deaths in infancy in Australia Paul N Goldwater, Corresponding Author Paul N Goldwater [email protected] orcid.org/0000-0003-4822-8488 Adelaide Medical School, University of Adelaide, Adelaide, SA[email protected]Search for more papers by this author Paul N Goldwater, Corresponding Author Paul N Goldwater [email protected] orcid.org/0000-0003-4822-8488 Adelaide Medical School, University of Adelaide, Adelaide, SA[email protected]Search for more papers by this author First published: 15 March 2023 https://doi.org/10.5694/mja2.51884Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Early ViewOnline Version of Record before inclusion in an issue RelatedInformation

Hiding in plain sight? A review of post-convulsive leukocyte elevations.

During physiological stress responses such as vigorous exercise, emotional states of fear and rage, and asphyxia, the nervous system induces a massive release of systemic catecholamines that prepares the body for survival by increasing cardiac output and redirecting blood flow from non-essential organs into the cardiopulmonary circulation. A curious byproduct of this vital response is a sudden, transient, and redistributive leukocytosis provoked mostly by the resultant shear forces exerted by rapid blood flow on marginated leukocytes. Generalized convulsive seizures, too, result in catecholamine surges accompanied by similar leukocytoses, the magnitude of which appears to be rooted in semiological factors such as convulsive duration and intensity. This manuscript reviews the history, kinetics, physiology, and clinical significance of post-convulsive leukocyte elevations and discusses their clinical utility, including a proposed role in the scientific investigation of sudden unexpected death in epilepsy (SUDEP).

Adrenocorticotropic Hormone-Induced Dyskinesia and Probable Sudden Unexpected Death in an Infant with Early Infantile Developmental and Epileptic Encephalopathy—Infantile Epileptic Spasm Syndrome Overlap

AbstractA 2.5-month-old infant with global developmental delay, initially had generalized tonic spasms followed by appearance of infantile spasms from 4.5 months of age. Thus, he had evolution from early infantile developmental and epileptic encephalopathy (EIDEE) to infantile epileptic spasm syndrome (IESS). Neuroimaging and screening of inborn errors of metabolism were normal, but sleep electroencephalogram showed suppression-burst pattern. Treatment with intramuscular injections of adrenocorticotropic hormone (ACTH) was associated with significant control of infantile spasms, but was followed by development of right hemichoreiform movements 2 days later. Upon continuing ACTH treatment, the dyskinesia generalized, prompting us to stop it and shift to vigabatrin which resulted in partial control of his spasms. Whole-exome sequencing revealed an autosomal dominant heterozygous variation of uncertain significance in the NPRL3 gene. At 6 months of age, he suffered of a probable sudden unexpected death, without any notable illness. The case is unique because both the phenomena—ACTH-induced dyskinesia and probable sudden unexpected death in infancy—are rarely described in the EIDEE-IESS continuum.

A bibliometric analysis of the cause of sudden unexplained death in forensic medicine: Research trends, hot spots and prospects

To better understand the cause of sudden unexplained death, our group evaluated the scientific results of related studies in a global context. A systematic search of the Web of Science, PubMed and MEDLINE databases identified 2001 studies related to this field published from 1997 to 2020. The studies were analyzed using bibliometric methods, and statistical maps were drawn to explore research trends and research frontiers. Sudden cardiac death and sudden unexpected epilepsy death were the two major causes of sudden unexplained deaths. With the rapid development of high-throughput sequencing technology and bioinformatics in the past 10 years, molecular autopsy has become an effective research method as well as a research hotspot for exploring the cause of sudden unexplained deaths. However, molecular autopsy is underutilized in the investigation of sudden unexpected death in epilepsy. Developing standardized guidelines for diagnostic strategies for the deceased and their families, expanding the screening of mutation spectrum of related diseases, studying the association between variants and diseases in complex genetic diseases, and improving variants interpretation guidelines and disease sequencing databases are future research directions.

Mortality and causes of death among people with convulsive epilepsy in northwestern China

ObjectiveWe analyzed mortality and causes of death among people with convulsive epilepsy in rural areas of northwestern China. MethodsWe established a population-based prospective cohort of people with convulsive epilepsy in an epilepsy prevention and management program in rural northwestern China from January 2012 to December 2013. A uniform cause of death questionnaire was used to obtain detailed information on participants who died during the follow-up until December 2016. We calculated the standardized mortality ratios (SMRs) and proportional mortality rate for major causes of death. Cox proportional hazards regression analysis was used to investigate the risk factors associated with mortality. ResultsAmong 4296 people with convulsive epilepsy, 216 died during a median follow-up of 59 months. The overall mortality rate was 10.9 per 1000 person-years, and the overall SMR was 2.0. Accidents (25.5%) ranked first in the cause of death, followed by status epilepticus (SE) (22.9%), probable sudden unexpected death in epilepsy (SUDEP) (22.7%), cerebrovascular disease (13.0%), and cardiovascular disease (6.5%). Drowning (10.6%), motor vehicle accidents (13.6%), and falls (4.6%) were the major causes of death by accidents. Female participants had a reduced risk of death from accidents with the hazard ratio (HR) of 0.3 (95% confidence interval (CI): 0.1–0.6). A high risk of death from cerebrovascular disease (HR: 7.2; 95% CI: 2.1–23.6) was found in participants with an onset age of epilepsy older than 16 years. SignificanceThe risk of death from convulsive epilepsy in rural northwestern China is twice that of the general population. Accidents, SE, and SUDEP are the leading putative causes of death. Educating people with epilepsy in different regions may help reduce death-related events.

Understanding the role of uncertainty and anxiety in police decision‐making during the investigation of sudden unexpected deaths in children

AbstractExisting policing policy offers a rational approach to decision‐making with minimal reference to human judgement within child death investigations. This study adopted a mixed methodology to capture decisional processes of 26 serving detective inspectors and detective sergeants whilst responding to an immersive scenario which simulated the first hours of a Sudden and Unexpected Death in Children (SUDC) investigation. Participants were presented with four decision points, during which they were asked to choose from decision options while reflecting upon personal and situational factors influencing that decision. Thematic analysis of responses found that investigators disclosed ‘anxiety’ and ‘uncertainty’ throughout their decision‐making during the scenario. In addition, there was no evidence of investigators utilising the models formally advocated within policing literature to make their decisions and assessments. As a result, it is suggested that further improvements are made regarding investigative decision‐making models within operational policing where ‘anxiety’ and ‘uncertainty’ is heightened.

Local recommendations for death scene investigation of sudden unexpected death in infants (SUDI) based on prospective observations.

The analyses of death scenes of sudden unexpected death in infants (SUDI) form an integral part of postmortem investigations. However, previous research has suggested that death scene investigation in SUDI cases is inconsistent and limited in South Africa. To suggest realistic and feasible improvements for SUDI scene investigation by means of prospective observation. Ten SUDI cases were followed up from death scene until autopsy and detailed observations were made using a semi-structured checklist. Data were analysed in conjunction with published data from the same mortuary to suggest realistic improvements. In all observed cases, the infant was moved prior to the arrival of forensic pathology officers; yet, reconstruction of the events leading to death were never demonstrated with a doll. The use of photography varied, with a median of 15 (standard deviation 6.5) photographs taken at each scene. However, critical photographs, such as those of medication, were often omitted. Furthermore, medicine was not collected from any scene. The use of documentation was inconsistent, where the intended longitudinal use was achieved in only 2 of 10 cases. Forms were inadequately filled in, due to the sensitivity or lack of understanding of various questions, rendering the forms incomplete. Training of specialised staff should therefore focus on five areas: doll re-enactment, photography, handling of medicine, accurate use of relevant documentation and use of a glossary. The implementation of these recommendations is deemed to be feasible in a resource-scarce mortuary setting and could assist other mortuaries in the development of locally relevant strategies.

Probable Sudden Unexpected Death in Dogs With Epilepsy (pSUDED).

Sudden unexpected death in human epileptic patients (SUDEP) is defined as death related to recurrent unprovoked seizures, death occurring unexpectedly, and suddenly in a patient with reasonable state of health, without an obvious medical cause of death, trauma, asphyxia, or intractable status epilepticus, and in post mortem examination no obvious reason for death can be found. “Probable SUDEP” (pSUDEP) is defined as SUDEP not confirmed pathologically. The adapted abbreviation for dogs is used in the following: “pSUDED” (probable sudden unexpected death in dogs with epilepsy). The aim of the present monocentric retrospective study using an online questionnaire was to evaluate the occurrence of pSUDED. Data of canine patients presented with seizures between 01/1998 and 05/2018 were retrospectively analyzed and classified according to their etiology (n = 1,503). Owners were contacted by telephone to participate in answering a validated questionnaire. A total of 509 owners were reached, and 373 owners completed the questionnaire. In addition to signalement (e.g., breed), special attention was paid to the frequency and presentation of seizures and seizures in the context of death. Fifty-one percent (191/373) of the dogs were dead at the endpoint of the study. A large proportion of the dogs was euthanized (149/191) because of seizure severity or health problems unrelated to seizures. Idiopathic epilepsy (IE) was diagnosed in 19/34 dogs which died unexpectedly. Of these seven animals had to be excluded for further investigation of pSUDED because of status epilepticus or aspiration pneumonia as a result of the seizures. In 12 dogs with IE the last seizure event occurred between 6 h and ~3 months before death. pSUDED was suspected in these dogs and an occurrence rate of 4.5–10% was calculated. pSUDED appears in a similar occurrence rate as human SUDEP and should be considered as a possible complication in epileptic dogs. The results of this study suggest that dogs with IE but especially those with brachycephalic syndrome and cluster seizures have an increased risk to die of pSUDED. Owners of dogs with seizures should be educated about the risk of sudden death in dogs with epilepsy.

Deciphering the premature mortality in PIGA-CDG – An untold story

ObjectiveCongenital disorder of glycosylation (CDG) due to a defective phosphatidylinositol glycan anchor biosynthesis class A protein (PIGA) is a severe X-linked developmental and epileptic encephalopathy. Seizures are often treatment refractory, and patients have intellectual disability and global developmental delay. Previous reports have suggested that patients with PIGA-CDG have a high risk of premature mortality. This study aimed to evaluate the observed high mortality and the causes of death in PIGA-CDG patients. MethodsWe reviewed the literature and collected additional unpublished patients through an international network. ResultsIn total, we reviewed the data of 88 patients of whom 30 patients born alive were deceased, and the overall mortality before the age of 20 years was 30 % (26/88). Age at death ranged from 15 days to 48 years of life. The median age at death was two years and more than half of the patients deceased in early childhood. The PIGA-specific mortality rate/1000 person-years was 44.9/1000 person-years (95 %, CI 31.4–64.3). There were no cases of definite or probable sudden unexpected death in epilepsy (SUDEP) and half of the patients died due to respiratory failure (15/30, 50 %) or possible SUDEP (3/30, 10 %). Three patients (10 %) died from severe cardiomyopathy, liver failure and gastrointestinal bleeding, respectively. The cause of death was unclassified in nine patients (30 %). Autopsies were rarely performed and the true cause of death remains unknown for the majority of patients. SignificanceOur data indicate an increased risk of premature death in patients with PIGA-CDG when compared to most monogenic developmental and epileptic encephalopathies.

Genetic generalized and focal epilepsy prevalence in the North American SUDEP Registry.

ObjectiveTo assess relative rates and clinical features of patients with genetic generalized epilepsy (GGE), focal epilepsy (FE), and developmental encephalopathic epilepsy (DEE) in the North American SUDEP Registry (NASR).MethodsWe identified all adjudicated definite, definite plus, and probable sudden unexpected death in epilepsy (SUDEP) cases (n = 262) and determined epilepsy type (GGE, FE, or DEE) from medical record review including history, imaging and EEG results, genetics, and next-of-kin interviews.ResultsOf the 262 SUDEP cases, 41 occurred in GGE, 95 in FE, 24 in DEE, and 102 were unclassifiable. GGE cases comprised 26% of NASR cases with an epilepsy syndrome diagnosis. The relative frequency of FE:GGE was slightly lower (2.3:1) than in population cohorts (2.1–6:1). Compared to patients with FE, patients with GGE had similar (1) ages at death and epilepsy onset and rates of (2) terminal and historical antiseizure medication adherence; (3) abnormal cardiac pathology; (4) illicit drug/alcohol use histories; and (5) sleep state when SUDEP occurred.ConclusionsGGE cases were relatively overrepresented in NASR. Because GGEs are less often treatment-resistant than FE or DEE, seizure type rather than frequency may be critical. Many people with GGE predominantly have generalized tonic-clonic seizures (GTCS) when they have uncontrolled or breakthrough seizures, whereas patients with FE more commonly experience milder seizures. Future mechanistic SUDEP studies should assess primary and focal-to-bilateral GTCS to identify potential differences in postictal autonomic and arousal disorders and to determine the differential role that lifestyle factors have on breakthrough seizures and seizure types in GGE vs FE to effectively target SUDEP mechanisms and prevention.

Working Together to Understand Why Infants Die: A Qualitative Study of Professionals' Experiences of Joint Agency Investigation of Sudden Unexpected Death in Infancy

A comprehensive Child Death Review programme commenced in England in 2008; police, healthcare and social care professionals now work together, using a joint agency approach (JAA) to investigate unexpected child deaths. The aim of this paper is to explore professionals' experiences of the JAA investigation of sudden unexpected death in infancy (SUDI). This was part of a mixed‐methods study evaluating the JAA investigation of SUDI. Professionals participated in qualitative interviews and case notes were scrutinised. Data were analysed using a framework approach. A total of 23 of a possible 113 eligible SUDI cases were recruited. Twenty‐six professionals involved in investigating 12 of the 23 SUDI cases were interviewed giving theoretical saturation of data. The overarching theme was the conflict between the need to investigate deaths while remaining sensitive to families. Other themes were working together, supporting parents, and the benefits and difficulties of joint working practices. All professionals were positive about the JAA, especially joint police and paediatric interviews and home visits. The difficulties included non‐engagement by social care and poor liaison with coroners. The JAA seems to be a thorough investigative process but could be improved by closer joint agency working and information sharing, and more support and training for professionals. © 2018 John Wiley & Sons, Ltd.Key Practitioner Messages Joint agency investigation of unexpected infant deaths enables a detailed understanding of the causes of death and the provision of support to families. Joint home visits by police and paediatricians following unexpected infant deaths provide more detailed information and can be more sensitive to families than police death scene examination alone. Prompt information sharing across all agencies is a key part of effective investigation of unexpected infant deaths. ‘Explore[s] professionals' experiences of the joint agency approach investigation of sudden unexpected death in infancy’

Late-onset Lennox-Gastaut syndrome: Diagnostic evaluation and outcome.

We describe the clinical features and outcome in patients with late-onset Lennox-Gastaut syndrome (LGS). Adult patients evaluated between January 1, 2000, and March 1, 2017, who presented with onset of LGS ≥10 years were identified. Data abstracted included age at seizure onset, seizure types, etiology, treatments, EEG and neuroimaging results, cerebrospinal fluid (CSF) findings, and autoimmune evaluation. Ten patients (8 females) were identified. The mean age at onset of seizures consistent with LGS was 16.5 years (range, 10-32 years). Seizure types included tonic, atonic, and tonic-clonic seizures (all), myoclonic seizures (n = 3), and atypical absence seizures (n = 7). Five patients had normal intellectual function at onset. Prolonged video-EEG monitoring recorded seizures and generalized interictal epileptiform discharges in all. All patients had drug-resistant epilepsy (range of antiseizure drugs tried, 7-16). Two patients had a history of intrathecal methotrexate to treat acute lymphoblastic leukemia. Two patients had malformations of cortical development. CSF analysis (n = 5) showed a mild elevation in the protein level without other abnormalities. Autoantibody determinations in the serum (n = 4) or the CSF (n = 5) and genetic testing (n = 5) were negative. At final follow-up, all but 1 patient was disabled and required a caregiver, and none were driving. One patient died of probable sudden unexpected death in epilepsy (SUDEP). Late-onset LGS represents a rare, treatment-resistant generalized epilepsy that is disabling and may be associated with progressive cognitive impairment. The elevated CSF protein level in our cohort could have been due to high seizure burden but increases the possibility of an inflammatory component to the pathophysiology of this disorder.

Predictors of Seizure-Related Injuries in an Epilepsy Cohort from North India.

Background and PurposeTo identify predictors of seizure-related injury (SRI) and death in people with epilepsy (PWE) in a North Indian cohort.MethodsThis ambispective cohort study included PWE registered in an epilepsy clinic in Delhi between May 2010 and December 2011. Five hundred twenty-six patients were enrolled and followed for 25 months. Patients were categorized into two groups based on SRI/no SRI during the study period. We analyzed various factors to identify predictors of SRI and death.ResultsOf 526 patients, 355 (67.5%) reported having no SRIs and 171 (32.5%) had sustained an SRI. Among patients with SRI, 72.5% were male; 62% of those with no SRI were male. The injury type included soft tissue (60%), head trauma (20%), dental trauma (10%), orthopedic (10%), and burns (5%). On univariate analysis, factors predicting SRI occurrence were male gender, abnormal birth history (p < 0.01), abnormal mental status (p < 0.01), seizure duration (p < 0.04), daytime seizures (p < 0.05), dependence on a caregiver (p < 0.008), and uncontrolled seizures (p < 0.001), history of cluster seizures or status epilepticus (p < 0.001), occurrence of generalized tonic-clonic seizures (GTCS), and use of >3 antiepileptic drugs (p < 0.008). On multiple logistic regression analysis, male gender, uncontrolled seizures, history of cluster seizures or status epilepticus, and GTCS were significant risk factors. Sixteen deaths occurred in our cohort, and 13 fit the definition of probable sudden unexpected death in epilepsy (SUDEP). Most patients with SUDEP had an unwitnessed event (69.2%). The only significant factor in predicting death was uncontrolled seizures.ConclusionsMale gender, occurrence of GTCS, uncontrolled seizures, and history of cluster seizures or status epilepticus predicted SRI occurrence in PWE. Precautions should be taken by caregivers of patients with these risk factors, to prevent injury.

Editors' note: Wrist sensor reveals sympathetic hyperactivity and hypoventilation before probable SUDEP

In “Wrist sensor reveals sympathetic hyperactivity and hypoventilation before probable SUDEP,” authors Picard et al. reported probable sudden unexpected death in epilepsy (SUDEP) in a 20-year-old man wearing a smartwatch that recorded wrist motion via 3-axis accelerometer and electrodermal activity. They suggest, based on the extremely elevated peri-ictal electrodermal response (EDR) recorded by the smartwatch at the time of death, that the reported case supports autonomic dysfunction and severe postictal cerebral dysfunction as SUDEP mechanisms. Commenting on the article, Dr. Stewart argues that the EDR is exactly as one expects in the case of sudden onset airway obstruction and is not indicative of cerebral dysfunction. In response, Picard et al. explain that the movement data measured by the smartwatch did not show a change of position, the normal response to obstructive apnea. They add that prior studies have demonstrated large EDRs during or following tonic-clonic seizures without observed obstructive apnea. In “Wrist sensor reveals sympathetic hyperactivity and hypoventilation before probable SUDEP,” authors Picard et al. reported probable sudden unexpected death in epilepsy (SUDEP) in a 20-year-old man wearing a smartwatch that recorded wrist motion via 3-axis accelerometer and electrodermal activity. They suggest, based on the extremely elevated peri-ictal electrodermal response (EDR) recorded by the smartwatch at the time of death, that the reported case supports autonomic dysfunction and severe postictal cerebral dysfunction as SUDEP mechanisms.

A New Approach to the Investigation of Sudden Unexpected Death.

* Abbreviations: OCME — : Office of the Chief Medical Examiner SIDS — : sudden infant death syndrome SUDP — : sudden unexplained death in pediatrics Sudden unexplained death in pediatrics (SUDP) is an inclusive term for sudden deaths in children that remain unexplained by standard autopsy and death scene investigation, including sudden infant death syndrome (SIDS), sudden unexpected infant death, sudden unexplained death in childhood, and undetermined deaths. Mortality from SUDP is significant and exceeds that from either cardiac disease or cancer in children <19 years of age.1 Its diagnostic considerations overlap with sudden unexpected death in epilepsy and unexplained sudden cardiac death in youth, also occurring predominantly during sleep, although salient findings in such cases include a history of epilepsy or notable cardiac results. Among children ultimately diagnosed with SUDP, those dying unexpectedly who are <3 years of age are the least likely to have explanations found with the current standard approach to investigation.2 Pediatricians have focused largely on preventive measures in the child’s sleep environment and the detection of child abuse in SUDP. Achievements in research and new approaches in medical care have created possibilities for understanding unapparent biological vulnerabilities in a small child that may become lethal. Research continues to find evidence for a biological basis in SUDP,3 including abnormalities in the hippocampus seen both across the age ranges of SUDP4 and epilepsy. The epidemiology of SIDS is predicted by general trends in infant mortality that are themselves attributed to biological risk reduction and medical care.5 Undiagnosed diseases programs, where living patients undergo extensive clinical evaluation to … Address correspondence to Richard D. Goldstein, MD, Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, 450 Brookline Ave, D2008, Boston, MA 02115. E-mail: richard.goldstein{at}childrens.harvard.edu

Genetic investigation of sudden unexpected death in epilepsy cohort by panel target resequencing

Objective: Sudden unexpected death in epilepsy (SUDEP) is the abrupt, no traumatic, witnessed or unwitnessed death, occurring in benign circumstances, in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus (seizure duration ≥ 30 min or seizures without recovery), and in which postmortem examination does not reveal a cause of death. Although the physiopathological mechanisms that underlie SUDEP remain to be clarified, the genetic background has been described to play a role in this disorder. Pathogenic variants in genes associated with epilepsy and encoding cardiac ion channels could explain the SUDEP phenotype. To test this we use the next-generation sequencing technology to sequence a cohort of SUDEP cases. Methods: A panel target resequencing was used to study 14 SUDEP cases from both postmortem (2 cases) and from living patients (12 cases). Genes already associated with SUDEP and also candidate genes had been investigated. Results: Overall, 24 rare genetic variants were identified in 13 SUDEP cases. Four cases showed rare variants with complete segregation in the SCN1A, FBN1, HCN1, SCN4A, and EFHC1 genes, and one case with a rare variant in KCNQ1 gene showed incomplete pattern of inheritance. In four cases, rare variants were detected in CACNA1A, SCN11A and SCN10A, and KCNQ1 genes, but familial segregation was not possible due to lack of DNA from relatives. Finally, in the four remaining cases, the rare variants did not segregate in the family. Conclusion: This study confirms the link between epilepsy, sudden death, and cardiac disease. In addition, we identified new potential candidate genes for SUDEP: FBN1, HCN1, SCN4A, EFHC1, CACNA1A, SCN11A, and SCN10A. Further confirmation in larger cohorts will be necessary especially if genetic screening for SUDEP is applied to clinics. Nevertheless, this study supports the emerging concept of a genetically determined cardiocerebral channelopathy.

Risks of probable SUDEP among people with convulsive epilepsy in rural West China

PurposeThis study aimed to examine the risk factors of probable sudden unexpected death in epilepsy (SUDEP) among patients with convulsive epilepsy in rural communities. MethodA total of 35 cases with identified probable SUDEP were recruited in the study and compared with three survival controls that were sex and age matched from the same cohort for each case. Three healthy controls per case were chosen as a control group. Risk factors were analyzed using the logistic regression model. The odds ratio (OR) was calculated to determine the risk or protective effect. ResultsThe following three factors significantly increased the risk of probable SUDEP: early-onset age of seizures (≤10 years vs. >10 years) with an OR of 6.8 (95% CI: 1.5–32.6), high seizure frequency at baseline (>10 years vs. ≤10 years) before regular phenobarbital treatment with an OR of 5.9 (95% CI: 2.2–16.6), and experiencing one or more seizures (vs. seizure-free) in the month prior to probable SUDEP with an OR of 9.5 (95% CI: 3.0–30.1). ConclusionLack of seizure freedom before and during regular antiepileptic drug treatment increase the risk of probable SUDEP. Special attention should be given to patients with early convulsive epilepsy-onset, and the proper control of convulsive seizures is critical for the prevention of probable SUDEP.

Genetic investigation of sudden unexpected death in epilepsy cohort by panel target resequencing.

Sudden unexpected death in epilepsy (SUDEP) is defined as the abrupt, no traumatic, witnessed or unwitnessed death, occurring in benign circumstances, in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus (seizure duration ≥ 30 min or seizures without recovery), and in which postmortem examination does not reveal a cause of death. Although the physiopathological mechanisms that underlie SUDEP remain to be clarified, the genetic background has been described to play a role in this disorder. Pathogenic variants in genes associated with epilepsy and encoding cardiac ion channels could explain the SUDEP phenotype. To test this we use the next-generation sequencing technology to sequence a cohort of SUDEP cases and its translation into clinical and forensic fields. A panel target resequencing was used to study 14 SUDEP cases from both postmortem (2 cases) and from living patients (12 cases). Genes already associated with SUDEP and also candidate genes had been investigated. Overall, 24 rare genetic variants were identified in 13 SUDEP cases. Four cases showed rare variants with complete segregation in the SCN1A, FBN1, HCN1, SCN4A, and EFHC1 genes, and one case with a rare variant in KCNQ1 gene showed incomplete pattern of inheritance. In four cases, rare variants were detected in CACNA1A, SCN11A and SCN10A, and KCNQ1 genes, but familial segregation was not possible due to lack of DNA from relatives. Finally, in the four remaining cases, the rare variants did not segregate in the family. This study confirms the link between epilepsy, sudden death, and cardiac disease. In addition, we identified new potential candidate genes for SUDEP: FBN1, HCN1, SCN4A, EFHC1, CACNA1A, SCN11A, and SCN10A. Further confirmation in larger cohorts will be necessary especially if genetic screening for SUDEP is applied to forensic and clinical medicine. Nevertheless, this study supports the emerging concept of a genetically determined cardiocerebral channelopathy.