Sudden unexpected death in epilepsy: addressing the challenges.

Sudden unexpected death in epilepsy

Sudden unexpected death in people with down syndrome and epilepsy: another piece in this complicated puzzle

Sudden Unexpected Death in Epilepsy (SUDEP): How Do We Prevent This Childhood Tragedy?

The purpose. To analyze the current state of scientific data related to sudden unexpected death in epilepsy (SUDEP) based on the study of recent investigations presented in the sources of scientific information about definition and classification of SUDEP, its risk factors, epidemiological data, pathophysiology, validity of proposed biomarkers, results of post-mortem examinations, measures of SUDEP prevention and also to present own observations of deaths with their classification. Numerous studies of the recent years have demonstrated the high medical and social significance of the problem of sudden unexpected death in epilepsy, the prevalence of which in patients with epilepsy is 20 times higher than in the general population. The proven association of such a death with a generalized tonic-clonic seizure (GTCS) indicates a real potential threat to life of patients with an unfavorable pharmacoresistant course of the disease. Possible, but not definitively evident, risk factors for SUDEP could be nighttime seizures during sleep, absence of witnesses who could help, prone position during sleep, male gender, age of epilepsy onset before 16 years and its duration more than 15 years, psychiatric comorbidity, simultaneous use of several anti-epileptic drugs (AEDs) or absence of any treatment, symptomatic etiology of epilepsy, use of lamotrigine in idiopathic epilepsy. The exact pathophysiology of SUDEP is unknown. The proposed clinical, genetic, electrophysiological, radiological SUDEP biomarkers for the purpose of identifying individuals with an increased risk of sudden death also do not have sufficient evidence base. Possible preventive SUDEP measures include monitoring of patients’ night sleep with the use of acoustic and biosensor devices, special smart-watches, usage of oxygen mask during or immediately after GTCS. There is a need to inform patients, especially those with unsatisfactory adherence to treatment, about the possibility of sudden death in order to improve their compliance. The main measure of prevention is the search for effective treatment with the best seizure control and minimal AEDs side effects. At present, only this way has an evidence base for reducing the risk of SUDEP. Own observations that meet the criteria for different types of SUDEP are presented.

We found very low-quality evidence of a preventative effect for nocturnal supervision against SUDEP. Further research is required to identify the effectiveness of other current interventions, for example seizure detection devices, safety pillows, SSRIs, early surgical evaluation, educational programmes, and opiate and adenosine antagonists in preventing SUDEP in people with epilepsy.

(a) To compare postmortem antiepileptic drug (AED) levels in patients with sudden unexpected death in epilepsy (SUDEP) with those in a control group of subjects with epilepsy. If SUDEP patients more frequently had undetectable or subtherapeutic AED levels, this would suggest that compliance with AED treatment is poorer in this group and that poor compliance is a risk factor for SUDEP. (b) To determine whether a particular AED was detected more commonly in the SUDEP group, suggesting that this AED is associated with a higher risk of SUDEP. A retrospective study of coronial cases was performed. Postmortem AED levels in 44 SUDEP cases and 44 control cases were compared. The control group consisted of epileptics who died of causes other than epilepsy, including natural disease (e.g., ischemic heart disease, accidents, and suicide). The AEDs measured included carbamazepine (CBZ), phenytoin, (PHT), valproate (VPA), phenobarbitone (PB), lamotrigine (LTG), clonazepam (CZP), and clobazam (CLB). The number of SUDEP and control cases in which CBZ only was detected were compared, as were the number in which PHT only was detected. Compared with the controls, the SUDEP group showed no difference in the number with no detectable AEDs (13 vs. 11), the number with subtherapeutic AEDs (10 vs. 13), and the number with therapeutic levels (21 in both groups). CBZ only was detected in 11 SUDEPs and 11 controls, and PHT only in five SUDEPs and 10 controls. Our study suggests the SUDEP group were no less compliant with AED treatment than the control group. This study does not support the hypothesis that poor compliance with AED treatment is a risk factor for SUDEP. There was no evidence that PHT or CBZ is associated with a higher risk of SUDEP.

Sudden unexpected death in epilepsy (SUDEP) is a category of death in people with epilepsy occurring in the absence of a known structural cause of death and is most likely heterogeneous with regard to mechanisms and circumstances. SUDEP is particularly difficult to investigate in research studies for several reasons, including its relatively low incidence, its unpredictable occurrence often in unwitnessed settings, and its low rate of complete autopsy examinations. Over the past two decades, two complementary definitions have been used in most SUDEP studies, but often with variations. We propose here a unified SUDEP definition and classification to resolve current ambiguities and to retrieve cases that would not have been further studied if the previous definitions were used. The proposed Unified SUDEP Definition and Classification contains, in addition to concepts inherent in the previous definitions, nine main recommendations. (1) The word "unexpected," and not the word "unexplained," should be uniformly used in the term SUDEP. (2) The SUDEP category should be applied when appropriate, whether or not a terminal seizure is known to have occurred. (3) The "Possible SUDEP" category should be used only for cases with competing causes of death, with cases left unclassified when data are insufficient to reasonably permit their classification. (4) Cases that would otherwise fulfill the definition of SUDEP should be designated as "SUDEP Plus" when evidence indicates that a preexisting condition, known before or after autopsy, could have contributed to the death, which otherwise is classified as SUDEP (e.g., coronary insufficiency with no evidence of myocardial infarction or long-QT syndrome with no documented primary ventricular arrhythmia leading to death). (5) To be considered SUDEP, the death should have occurred within 1 h from the onset of a known terminal event. (6) For status epilepticus as an exclusion criterion for SUDEP, the duration of seizure activity should be 30 min or more. (7) A specific category of SUDEP due to asphyxia should not be designated, the distinction being largely impractical on circumstantial or autopsy evidence, with more than one mechanism likely to be contributory in many cases. (8) Death occurring in water but without circumstantial or autopsy evidence of submersion should be classified as "Possible SUDEP." If any evidence of submersion is present, the death should not be classified as SUDEP. (9) A category of "Near-SUDEP" should be agreed to include cases in which cardiorespiratory arrest was reversed by resuscitation efforts with subsequent survival for more than 1 h. Scenarios that demonstrate the basis for each SUDEP category are described. If disagreement exists about which category fits a particular case, we suggest the use of consensus decision by a panel of informed reviewers to adjudicate the classification of the case.

Profile of neurologists in Brazil: a glimpse into the future of epilepsy and sudden unexpected death in epilepsy

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with intractable epilepsy. The substantial lifetime risk of SUDEP and the lack of a clear...

ObjectiveMost cases of sudden unexpected death in epilepsy (SUDEP) follow a seizure, and most deaths occur while people are in bed, presumably sleeping. Nocturnal seizures are reported to be a risk factor for SUDEP. People with nocturnal frontal lobe epilepsy (NFLE) have seizures predominantly or exclusively during sleep, often many times per night. The present study aimed to assess whether NFLE represents a high-risk condition for SUDEP. MethodsThe present study retrospectively assessed the incidence of SUDEP in a cohort reconstructed from a dedicated database of consecutive patients referred to the Epilepsy and Sleep Centres of the Institute of Neurological Sciences of Bologna from 1980 to 2012 with: (1) a diagnosis of NFLE, (2) at least 90% of seizures during sleep, and (3) at least one-year of follow-up. ResultsOne hundred and three people were included. The median time from seizure onset to last observation was 26 years, equal to a follow-up of 2789 person-years. One person died of SUDEP during the follow-up period. The incidence rate of SUDEP was 0.36 per 1000 person-years (95% CI 0.01 to 2.0). ConclusionsThe incidence of SUDEP in the participant population was not higher than the rates previously reported in prevalent epilepsy populations (0.4 to 2.3 per 1000 person-years). The low prevalence of SUDEP might reflect the low occurrence of generalised tonic-clonic seizures in people with NFLE.

Sudden unexpected death in epilepsy: From the lab to the clinic setting

Editors' Note: “Association of prone position with sudden unexpected death in epilepsy” raised several inquiries from our readers. Sethi suggests that since the pathogenesis of sudden unexpected death in epilepsy (SUDEP) is not yet elucidated, advising patients to sleep in the supine position, which risks aspiration, warrants careful consideration. Furthermore, based on their prior study, Lhatoo et al. believe that forced ictal version, rather than prone position, may be a SUDEP risk factor. Authors Tao et al. argue that supine sleeping can help prevent SUDEP and, although it could be associated with aspiration, babies seizing face-down risk suffocation. —Chafic Karam, MD, and Robert C. Griggs, MD Liebenthal et al.1 studied the association of prone position with sudden unexpected death in epilepsy (SUDEP). The central dogma underlying SUDEP is unclear. Does postictal cerebral shutdown represented by postictal generalized EEG suppression (PGES) cause hypoxemia, hypercapnia, pulmonary edema, and autonomic instability, resulting in death? It is also possible that the primary peri-ictal involvement of brainstem neurons (pre-Botzinger complex) sets off the cascade that manifests as PGES at the end of a terminal seizure. …

Sudden unexpected death in epilepsy: is carbamazepine implicated?

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.

Sudden unexpected death in epilepsy (SUDEP) is possibly the most common cause of death as a result of complications from epilepsy, accounting for between 7.5% to 17% of all epilepsy-related deaths1 and 50% of all deaths in refractory epilepsy.2 The UK has 600 000 people with epilepsy (PWE), 30% being treatment resistant. Sudden death is 20-fold higher in PWE than the general population. Epilepsy is the fifth highest cause of life-years lost in men and eighth in women in the UK. The public health burden of SUDEP alone is estimated as second only to stroke among neurological conditions.3 Forty-two per cent of all deaths are considered avoidable.4 Consequently, the National Institute for Health and Care Excellence (NICE) epilepsy guidelines in 2004 and 20125 recommend discussion of SUDEP with newly-diagnosed PWE. This is rarely delivered and until recently only 4% of PWE had a recorded SUDEP discussion.6 In their current publication of the NHS Outcomes Framework, the government prioritises the prevention of amenable mortality, making it a core focus for NHS services. Epilepsy mortality features in new NICE Standards as well as NICE Clinical Guidelines.5 However, the dilemma remains of when, where, how, and what to discuss about epilepsy risk, especially SUDEP. Further to the discussion there is a lack of a structured monitoring of risk especially in primary care. Meaningful management of SUDEP risk in particular, and epilepsy risk in general, is arbitrary, non-person centred and with no evidenced mechanism. In clinical practice, especially in primary care, the lack of any tools to support risk management is of concern. Risk management has been highlighted as vitally important to reducing avoidable epilepsy-related deaths, both in research and reporting but also via Prevention of Future Death reports …