Risk Factors For Sudden Unexpected Death In Epilepsy Research Articles

Association of hyperventilation-induced heart rate variability and sudden unexpected death in epilepsy in drug-resistant epilepsy.

Within the general epilepsy population, the incidence of Sudden Unexpected Death in Epilepsy (SUDEP) ranges from approximately 0.35 to 2.3 per 1,000 individuals per year. We aimed to evaluate the relationship between SUDEP risk factors and heart rate variability (HRV) parameters as a potential biomarker of SUDEP in patients with drug-resistant epilepsy (DRE). There were 52 patients diagnosed with DRE and under follow-up, and controls including 45 healthy subjects, included in the study. Hyperventilation-induced HRV (HRVHV) parameters, including the standard deviation of all RR intervals (SDRR), mean heart rate (HR), root mean squares of successive differences (RMSSD), SD of mean NN intervals recordings (SDANN), and HRV triangular index, were assessed during resting. To predict the risk of SUDEP, the relationship between HRV parameters and SUDEP risks was evaluated using the Risk Assessment for Sudden Death in Epilepsy (SUDEP-7) Risk Inventory. No statistically significant difference was found in sympathetic skin response (SSR) latency and amplitudes between the patient and control groups. In comparing healthy control subjects with patients experiencing DRE, we observed significant decreases in SDRRHV and hyperventilation-induced RMSSD (RMSSDHV) values, specifically within HRVHV. Notably, a significant correlation emerged concerning the RMSSDHV values (p < 0.01), when examining the correlation between the SUDEP-7 inventory and HRVHV parameters. This correlation between RMSSDHV and the SUDEP-7 Risk Inventory in patients with DRE represents a novel and consequential finding, suggesting its potential as an indicator of SUDEP risk.

Quantitative cellular pathology of the amygdala in temporal lobe epilepsy and correlation with magnetic resonance imaging volumetry, tissue microstructure, and sudden unexpected death in epilepsy risk factors.

Amygdala enlargement can occur in temporal lobe epilepsy, and increased amygdala volume is also reported in sudden unexpected death in epilepsy (SUDEP). Apnea can be induced by amygdala stimulation, and postconvulsive central apnea (PCCA) and generalized seizures are both known SUDEP risk factors. Neurite orientation dispersion and density imaging (NODDI) has recently provided additional information on altered amygdala microstructure in SUDEP. In a series of 24 surgical temporal lobe epilepsy cases, our aim was to quantify amygdala cellular pathology parameters that could predict enlargement, NODDI changes, and ictal respiratory dysfunction. Using whole slide scanning automated quantitative image analysis methods, parallel evaluation of myelin, axons, dendrites, oligodendroglia, microglia, astroglia, neurons, serotonergic networks, mTOR-pathway activation (pS6) and phosphorylated tau (pTau; AT8, AT100, PHF) in amygdala, periamygdala cortex, and white matter regions of interest were compared with preoperative magnetic resonance imaging data on amygdala size, and in 13 cases with NODDI and evidence of ictal-associated apnea. We observed significantly higher glial labeling (Iba1, glial fibrillary acidic protein, Olig2) in amygdala regions compared to cortex and a strong positive correlation between Olig2 and Iba1 in the amygdala. Larger amygdala volumes correlated with lower microtubule-associated protein (MAP2), whereas higher NODDI orientation dispersion index correlated with lower Olig2 cell densities. In the three cases with recorded PCCA, higher MAP2 and pS6-235 expression was noted than in those without. pTau did not correlate with SUDEP risk factors, including seizure frequency. Histological quantitation of amygdala microstructure can shed light on enlargement and diffusion imaging alterations in epilepsy to explore possible mechanisms of amygdala dysfunction, including mTOR pathway activation, that in turn may increase the risk for SUDEP.

Type, Etiology, and Duration of Epilepsy as Risk Factors for SUDEP: Further Analyses of a Population-Based Case-Control Study.

We conducted a nationwide case-control study in Sweden to investigate the risk of sudden unexpected death in epilepsy (SUDEP) in relation to epilepsy duration, epilepsy type, and etiology in combination with occurrence and frequency of tonic-clonic seizures (TCS) and nocturnal TCS. The study comprised 255 SUDEP cases and 1,148 epilepsy controls. Clinical information was obtained from medical records. The association between SUDEP and risk factors was estimated by odds ratios (ORs) with 95% CIs calculated by conditional logistic regression to account for matching by sex and calendar time. The risk of SUDEP was elevated in people with focal (OR 1.48, 95% CI 1.00-2.20), generalized and focal (OR 3.51, 95% CI 1.55-7.96), or unknown (OR 2.43, 95% CI 1.29-4.57) vs generalized epilepsy type. Increased risk of SUDEP was also observed in relation to epilepsy with traumatic causes (OR 2.27, 95% CI 1.33-3.89 vs genetic etiology) or short duration (OR 1.71, 95% CI 1.01-2.87 for 0-5 vs 6-15 years duration). Among those with 1-3 TCS during the preceding year, structural epilepsy etiology was associated with a more than 10-fold increase 10.84 (4.85-24.27) in SUDEP risk compared with people with genetic epilepsy without TCS. The risk with ≥4 TCS the preceding year was similar among those with generalized and focal epilepsies. Those with ≥4 TCS had an OR of 210.73 (95% CI 28.40-∞) during years 0-5 compared with those free from TCS and an epilepsy duration of 6-15 years. The combination of short epilepsy duration (0-5 years) and nocturnal TCS conferred an OR of 45.99 (95% CI 12.19-173.61) compared with having longer duration (6-15 years) and being free from nocturnal TCS. Although certain etiologies, such as post-traumatic epilepsy, seem to entail a higher SUDEP risk, our data indicate that frequent and nocturnal TCS carry a similar level of risk whether focal or generalized from onset. The tonic-clonic part of the seizure seems to be decisive for the fatal outcome. SUDEP risk associated with TCS is highest during the first years after the epilepsy diagnosis which calls for effective TCS treatment and vigilance from the onset of diagnosis.

Medicate or operate: epilepsy surgery could save lives.

Drug-resistant epilepsy is a complex neurological disorder with a significant impact on the lives of affected children and their families. A child is diagnosed with drug-resistant epilepsy if seizure control is not achieved despite receiving the maximally optimised doses of two appropriately chosen antiepileptic medications. 1 Kwan P Arzimanoglou A Berg AT et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010; 51: 1069-1077 Crossref PubMed Scopus (2851) Google Scholar Mortality risk is seven times higher in children with epilepsy than in the general population. 2 Callenbach PM Westendorp RG Geerts AT et al. Mortality risk in children with epilepsy: the Dutch study of epilepsy in childhood. Pediatrics. 2001; 107: 1259-1263 Crossref PubMed Scopus (98) Google Scholar One contributor to the mortality associated with drug-resistant epilepsy is sudden unexpected death in epilepsy (SUDEP); ie, unexpected death with no obvious cause. 3 Nashef L So EL Ryvlin P Tomson T Unifying the definitions of sudden unexpected death in epilepsy. Epilepsia. 2012; 53: 227-233 Crossref PubMed Scopus (397) Google Scholar One in 833 children with drug-resistant epilepsy is estimated to die from SUDEP every year. 4 Ryvlin P Rheims S Lhatoo SD Risks and predictive biomarkers of SUDEP. Curr Opin Neurol. 2019; 32: 205-212 Crossref PubMed Scopus (0) Google Scholar The most common risk factors for SUDEP are high seizure frequency, early age of seizure onset, and multiple antiseizure drugs. 5 Abdel-Mannan O Taylor H Donner EJ Sutcliffe AG A systematic review of sudden unexpected death in epilepsy (SUDEP) in childhood. Epilepsy Behav. 2019; 90: 99-106 Summary Full Text Full Text PDF PubMed Scopus (46) Google Scholar Other causes of death include status epilepticus, injury related to seizures, and suicide. Comparison of long-term survival with continued medical therapy, vagus nerve stimulation, and cranial epilepsy surgery in paediatric patients with drug-resistant epilepsy in the USA: an observational cohort studyPaediatric patients with drug-resistant epilepsy who underwent cranial epilepsy surgery or VNS had a higher survival rate than those who received only medical treatment. These findings highlight the importance of a multidisciplinary comprehensive team approach to the treatment of epilepsy, which includes tailored evaluation and deployment of medical and surgical treatment options for patients with this challenging disease. Full-Text PDF

Single-nuclear RNA sequencing reveals sex-specific differences in cell composition and recruitment of neuroinflammatory pathways after repeated seizures within the NA/pre-Bötzinger Complex region

Epilepsy affects millions worldwide, but a significant portion suffers from uncontrollable epilepsy. Repeated seizures have many consequences, including a high risk of post-ictal cardiorespiratory failure and Sudden Unexpected Death in Epilepsy (SUDEP). Major risk factors for SUDEP include biological sex and the occurrence of generalized tonic-clonic seizures (GTCSs). How repeated seizures lead to cardiorespiratory dysfunction remains unknown. It was reported that a key factor in many neurological diseases is neuroinflammation, which is mediated mostly by microglia and astrocytes that become dysfunctional. Mechanistically, questions remain how they affect neuronal function in epilepsy and contribute to cardiorespiratory dysfunction and increased SUDEP risk. Here we tested the hypothesis that repeated seizures lead to differential neuroinflammatory activation after repeated seizures in CNS regions of ventilatory control in a sex-specific manner. Preliminary data in our novel rat model with genetic mutations in Kcnj16, a gene encoding an inwardly-rectifying potassium channel Kir5.1 in Dahl salt-sensitive rat (SS kcnj16-/- ) show that repeated sound-induced seizures lead to progressively more severe post-ictal suppression of breathing frequency and heart rate and increased mortality in males. Single-nuclear RNA sequencing of Nucleus Ambiguous/pre-Bötzinger Complex (NA/preBötC) cells (roughly 80,000 and 40,000) was performed in tissues from male and female SS kcnj16-/- rats (n=3/group) exposed to 0, 3, 7, or 10 seizures to measure cell type-specific gene expression changes induced by seizures. Bioinformatic analyses of transcriptomic changes across sex revealed the identification of 19 unique cell types in males and 21 unique cell types in females in this brainstem region. Differentially expressed genes (DEGs; Seurat) in both males and females showed significant ( p&lt;0.05) recruitment of various inflammatory and stress-related pathways (e.g. CXCR4 signaling, Immunogenic Cell Death Signaling). Data integration across sex enabled sex-specific comparisons across days of the seizure (around 120,000 cells). Importantly, males show significant upregulation in DEGs with seizures in mTOR signaling and Extracellular Neutrophil Trap Signaling when compared to females. Importantly, this dataset helps characterize at a genetic and cell-type specific manner, sex differences in a crucial region not characterized before in the literature. Also, these data show clear sex differences in the cellular milieu and transcriptomic profiles in the NA/preBötC region before and after repeated seizures, suggesting different neuroinflammatory pathways may play a larger role in males than females. Understanding sex differences and how they may be playing a role in neuroinflammaton after repeated seizures may provide novel insights into identifying new therapeutic drugs aimed at reducing the risk of SUDEP in males and, more broadly, those suffering from uncontrolled epilepsy. Supported by HL122358, HL160122 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sudden unexpected death in epilepsy in children.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality in children and adults living with epilepsy. The incidence of SUDEP is comparable in both children and adults; it is approximately 1.2 per 1000 person years. The pathophysiology of SUDEP is not well understood but may involve mechanisms such as cerebral shutdown, autonomic dysfunction, altered brainstem function, and cardiorespiratory demise. Risk factors for SUDEP include the presence of generalized tonic-clonic seizures, nocturnal seizures, possible genetic predisposition, and non-adherence to antiseizure medications. Pediatric-specific risk factors are not fully elucidated. Despite recommendations from consensus guidelines, many clinicians still do not follow the practice of counseling their patients about SUDEP. SUDEP prevention has been an area of important research focus and includes several strategies, such as obtaining seizure control, optimizing treatment regimens, nocturnal supervision, and seizure detection devices. This review discusses what is currently known about SUDEP risk factors and reviews current and future preventive strategies for SUDEP.

Risk of sudden unexpected death in epilepsy (SUDEP) with lamotrigine and other sodium channel-modulating antiseizure medications.

In vitro data prompted U.S Food and Drug Administration warnings that lamotrigine, a common sodium channel modulating anti-seizure medication (NaM-ASM), could increase the risk of sudden death in patients with structural or ischaemic cardiac disease, however, its implications for Sudden Unexpected Death in Epilepsy (SUDEP) are unclear. This retrospective, nested case-control study identified 101 sudden unexpected death in epilepsy (SUDEP) cases and 199 living epilepsy controls from Epilepsy Monitoring Units (EMUs) in Australia and the USA. Differences in proportions of lamotrigine and NaM-ASM use were compared between cases and controls at the time of admission, and survival analyses from the time of admission up to 16 years were conducted. Multivariable logistic regression and survival analyses compared each ASM subgroup adjusting for SUDEP risk factors. Proportions of cases and controls prescribed lamotrigine (P=0.166), one NaM-ASM (P=0.80), or ≥2NaM-ASMs (P=0.447) at EMU admission were not significantly different. Patients taking lamotrigine (adjusted hazard ratio [aHR]=0.56; P=0.054), one NaM-ASM (aHR=0.8; P=0.588) or ≥2 NaM-ASMs (aHR=0.49; P=0.139) at EMU admission were not at increased SUDEP risk up to 16 years following admission. Active tonic-clonic seizures at EMU admission associated with >2-fold SUDEP risk, irrespective of lamotrigine (aHR=2.24; P=0.031) or NaM-ASM use (aHR=2.25; P=0.029). Sensitivity analyses accounting for incomplete ASM data at follow-up suggest undetected changes to ASM use are unlikely to alter our results. This study provides additional evidence that lamotrigine and other NaM-ASMs are unlikely to be associated with an increased long-term risk of SUDEP, up to 16 years post-EMU admission.

Perspectives on the basis of seizure-induced respiratory dysfunction.

Epilepsy is an umbrella term used to define a wide variety of seizure disorders and sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in epilepsy. Although some SUDEP risk factors have been identified, it remains largely unpredictable, and underlying mechanisms remain poorly understood. Most seizures start in the cortex, but the high mortality rate associated with certain types of epilepsy indicates brainstem involvement. Therefore, to help understand SUDEP we discuss mechanisms by which seizure activity propagates to the brainstem. Specifically, we highlight clinical and pre-clinical evidence suggesting how seizure activation of: (i) descending inhibitory drive or (ii) spreading depolarization might contribute to brainstem dysfunction. Furthermore, since epilepsy is a highly heterogenous disorder, we also considered factors expected to favor or oppose mechanisms of seizure propagation. We also consider whether epilepsy-associated genetic variants directly impact brainstem function. Because respiratory failure is a leading cause of SUDEP, our discussion of brainstem dysfunction focuses on respiratory control.

Advances in sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is the major cause of premature death in epilepsy patients, particularly those with refractory epilepsy. Sudden unexpected death in epilepsy is thought to be related to peri-ictal cardiac dysfunction, respiratory depression, and autonomic dysfunction, albeit the exact etiology is unknown. Sudden unexpected death in epilepsy prevention remains a huge challenge. The sole presence and frequency of generalized tonic-clonic seizures (GTCS) are the most important risk factors for SUDEP, and nocturnal monitoring may lower the risk with the use of remote listening devices. In addition, studies in animal models of SUDEP have discovered that multiple neurotransmitters, including serotonin (5-HT) and adenosine, may be involved in the pathophysiological mechanisms of SUDEP and that these neurotransmitters could be the targets of future pharmacological intervention for SUDEP. The latest research findings on the epidemiology, clinical risk factors, and probable causes of SUDEP are presented in this review.

Forensic Analysis of 9 Cases of Sudden Unexpected Death in Epilepsy.

To analyze the case, scene and forensic pathological characteristics of sudden unexpected death in epilepsy (SUDEP), to provide a practical basis for forensic identification. A total of 9 autopsy cases of SUDEP were collected. The basic information of the cases, the scene characteristics, the forensic pathological changes, the common drugs and antiepileptic drug test results, and pericardial fluid biochemical test results were analyzed. All of the 9 cases were male epilepsy patients died during sleep at night, the age of death was (37.1±8.6) years, and the course of epilepsy was (21.3±5.6) years. Six corpses were in prone position and three in left lateral position. The hemorrhage of the sternocleidomastoid muscle, sternal thyroid muscle and sternohyoid muscle were found with 8 cases, 5 cases and 4 cases, respectively, all of them were unilateral. Six cases had bilateral hemorrhage of pectoralis minor muscle. Brain edema, phagocytosis of frontotemporal neurons and gliosis, cardiac fibers bend in wavy patterns and eosinophilic staining enhancement, pulmonary edema, pulmonary congestion, alveolar hemorrhage, pulmonary small bronchiole wall shrinking, tubular proteinuria and pancreatic parenchymal hemorrhage were the common histopathological changes. The biochemical test results of pericardial fluid indicated that there were myocardial ischemic damage. Young male, early onset, long course of disease, sleep in the prone position, poor drug compliance or combination, epileptic seizure may be the risk factors of SUDEP. Cardiac dysfunction and respiratory depression might be the main death mechanism of SUDEP.

Perinatal risk factors for SUDEP: A population-based case-control study.

Sudden unexpected death in epilepsy (SUDEP) is a leading epilepsy-related cause of death. Researchers have highlighted the similarities between SUDEP and sudden infant death syndrome (SIDS), but perinatal risk factors such as those identified for SIDS have not been assessed previously for SUDEP. We conducted a population-based case-control study of 58 SUDEP individuals and 384 living epilepsy controls born after 1982, utilizing the Swedish Medical Birth Register together with other national health registers and individual medical records to examine if prenatal and perinatal factors are associated with SUDEP risk. We observed a 3-fold SUDEP risk increase for infants who were small for gestational age (SGA) (odds ratio [OR] 3.13; 95%confidence interval [CI] 1.05-9.30) and for those with an Apgar score of 0-6 compared to 9-10 at 10 min (OR 3.22; 95%CI 1.05-9.87). After adjusting for a number of known SUDEP risk factors, we observed that the Apgar score between 0 and 6 after 10 min had a 10-fold increased risk for SUDEP OR 10.37 (95%CI 1.49-72.01) and over a 2-fold risk for those born after the 40th gestational week (OR 2.42; 95%CI 1.03-5.65). The potential mechanisms linking low Apgar score, gestational age, and SGA to SUDEP risk remain to be explored.

Sudden Unexpected Death in Epilepsy.

Epilepsy is a complex neurological condition with numerous etiologies and treatment options. In a subset of these patients, sudden unexpected death can occur, and to date, there are numerous explanations as to the pathophysiological mechanisms and how to mitigate these catastrophic outcomes. Approximately 2.3 million Americans have epilepsy, and nearly 150,000 people develop the condition each year. Sudden unexpected death in epilepsy (SUDEP) accounts for 2–18% of all epilepsy-related deaths and this is equivalent to one death in 1000 person-years of diagnosed epilepsy. It is more common in young adults aged 20–45. Seizures in the past year; the absence of terminal remission in the last five years; increased seizure frequency, particularly GTCS; and nocturnal seizures are the most potent modifiable risk factors for SUDEP. Patients not receiving any antiepileptic drug therapy are at higher risk of SUDEP. Patient education on medication compliance; care plans for seizure clusters (rescue medicines); epilepsy self-management programs; and lifestyle changes to avoid seizure-triggering factors, including avoiding excessive alcohol use and sleep deprivation, should be provided by health care providers. Continued research into SUDEP will hopefully lead to effective interventions to minimize occurrences. At present, aggressive control of epilepsy and enhanced education for individuals and the public are the most effective weapons for combating SUDEP. This narrative review focuses on updated information related to SUDEP epidemiology; pathophysiology; risk factor treatment options; and finally, a discussion of important clinical studies. We seek to encourage clinicians who care for patients with epilepsy to be aggressive in controlling seizure activity and diligent in their review of risk factors and education of patients and their families about SUDEP.

Leveraging electronic patient diaries in SUDEP risk evaluation

ObjectiveOur aim was to describe the risk factors known to be related to sudden unexpected death in epilepsy (SUDEP) that can be extracted from patients that utilizes an online seizure diary tool (SeizureTracker™). MethodWe conducted a descriptive analysis of SeizureTracker™ users across factors relevant to SUDEP risk. We also compared our app-using cohort to published SUDEP case-control studies. ResultsWe report across seven risk factors from 30,813 users of SeizureTracker™ who had a median length of time using the app of 5.69 years (range from 1 month to 15 years). We found that they are at greater risk for SUDEP than groups from published studies (p < .00001) based on the risk factor of generalized tonic-clonic seizures. SignificanceWe demonstrated that the population using the SeizureTracker™ tool can be a valuable population for expanding investigation of SUDEP risk factors and is a first step towards establishing a large sample with a method to ascertain data prospectively that might be critical to developing a SUDEP risk algorithm.

Alterations in aortic vasorelaxation in rats with epilepsy induced by the electrical amygdala kindling model

Cardiovascular alterations are frequently related to epilepsy in both clinical and experimental models, and have been hypothesized as a potential contributor to sudden unexpected death in epilepsy (SUDEP). Further, the frequency of generalized tonic-clonic seizures (GTCS) is a primary risk factor for SUDEP. Therefore, we aimed to evaluate the vascular response of rats subjected to the electrical amygdala kindling model of epilepsy. Male Wistar rats were randomly distributed into the following groups: without seizures (sham, n = 8), 5 GTCS (5 S, n = 5), and 10 GTCS (10 S, n = 6). One day after the last seizure, the rats were euthanized, and the thoracic aorta rings with (E+) and without (E-) endothelium were used to evaluate vascular reactivity ex vivo using the organ bath system. The maximum response to acetylcholine-induced vasorelaxation in the E+ aortic ring was lower in the 5 S group than in the sham and 10 S groups. A reduced concentration of sodium nitroprusside was required to induce vasorelaxation in the E- aortic rings. These results suggest an impairment in endothelial function and alterations in the nitric oxide (NO) pathway. In conclusion, epilepsy altered the vasorelaxation of the aortic rings and the number of seizures influenced these alterations; therefore, an analysis of endothelial function in patients with a high risk of SUDEP may be beneficial.

Omega-3 Fatty Acids May Prevent Sudden Unexpected Death in Epilepsy in Children.

Sudden unexpected death in epilepsy (SUDEP) accounts for a large number of deaths in children with epilepsy, causing considerable concerns in patients and their families.1–3 Although specific causes of SUDEP in children remain unknown, children with uncontrolled epilepsy or frequent generalized tonic-clonic seizures are at a high risk for SUDEP.3 Furthermore, the most common mechanisms of SUDEP in children are related to cardiac and respiratory abnormalities during and between seizures.2,3 Even considering that the best way to prevent SUDEP in childhood is still elusive, some procedures have been proposed, including education, pharmacologic therapy, surgical treatment, and dietary modifications, to minimize the occurrence of tragic SUDEP events.1–5 With these considerations in mind, we enjoyed reading the excellent review article by Wicker and Cole,6 published in your esteemed journal. Elegantly, the authors discussed the current knowledge and understanding of SUDEP in children and adolescents. Although we agree with the authors' positioning to further understand the etiology and risk factors of SUDEP,6 we want to highlight that other actions than medical and surgical therapies may be useful to minimize SUDEP occurrence.4,5,7 In this way, omega-3 fatty acid (omega-3 FA) supplementation and regular fish consumption have increasingly attracted the attention of neuroscientists.4,5,7,8Historically, one of the first reports of fish consumption as a medical therapy is described in the Old Testament book of Tobias, “Then the angel said to him: Take out the entrails of the fish, and lay up his heart, and his gall, and his liver for thee; for these are necessary for useful medicines.”7,9,10 Actually, it has been clearly shown that omega-3 FAs promote beneficial effects to the health system and several human diseases7,11,12 Concerning epilepsy per se, there are robust translational studies highlighting the importance of the recommended levels of fish consumption or omega-3 FA supplementation in order to minimize the frequency of seizures in adult and children with epilepsy and, especially, to reduce the occurrence of SUDEP.4,8,13 In brief, neuroprotective, antioxidant, and anti-inflammatory properties of omega-3 FAs are recognized as contributing to reduce the epilepsy risk and severity.4,8,13–15 Additionally, emerging research indicates that omega-3 FAs may improve children's health and brain development.16–18 Importantly, because there is no established adequate dose of omega-3 FAs in children, scientists from multiple countries have made statements concerning the recommended intake of omega-3 FAs for young children.11,16–18 For example, the United States Environmental Protection Agency recommends a weekly intake of less than 60 g of fish, always taking into account the effects of water pollutants and other chemicals on fish.16,18 In parallel, the World Health Organization recommends that infants start receiving 450 mg/day per 10 kg of body weight of omega-3 FAs, whereas the International Society for the Study of Fatty Acids and Lipids opts for 350 to 750 mg/day per 10 kg of body weight.16,18Overall, which lessons did we learn? Firstly, epilepsy in children is a multicausal and systemic condition. Secondly, the risk of a child dying from SUDEP is now widely recognized. Third, omega-3 FAs are crucial for children's health. Finally, the excellent article discussed here6 should stimulate translational research to explore the potential benefits of omega-3 FAs for children with epilepsy.

Sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is a major contributor to premature mortality in people with epilepsy. This review provides an update on recent findings on the epidemiology of SUDEP, clinical risk factors and potential mechanisms. The overall risk rate of SUDEP is approximately 1 per 1000 patients per year in the general epilepsy population and that children and older adults have a similar incidence. Generalized convulsive seizures (GCS), perhaps through their effects on brainstem cardiopulmonary networks, can cause significant postictal respiratory and autonomic dysfunction though other mechanisms likely exist as well. Work in animal models of SUDEP has identified multiple neurotransmitter systems, which may be future targets for pharmacological intervention. There are also chronic functional and structural changes in autonomic function in patients who subsequently die from SUDEP suggesting that some SUDEP risk is dynamic. Modifiable risks for SUDEP include GCS seizure frequency, medication adherence and nighttime supervision. Current knowledge of SUDEP risk factors has identified multiple targets for SUDEP prevention today as we await more specific therapeutic targets that are emerging from translational research studies.

Evaluation of QT dispersion in epileptic patients and its association with SUDEP risk

BackgroundMortality in epileptic patients was attributed to sudden unexpected death in epilepsy (SUDEP). The precise pathophysiology of SUDEP is not fully understood, yet prolongation of ventricular repolarization particularly QTc interval suggested to be one of the contributing risk factor for SUDEP. ObjectivesWe aimed at evaluation of QTc and QT dispersion (QTD) in patients with epilepsy (both refractory and well-controlled epilepsy) and their association with the epileptic severity and sudden unexplained death (SUDEP) risk. Patients and methodsThe study included eighty epileptic patients (40 controlled epileptic patients and 40 refractory epileptic patients) compared to thirty non-epileptic volunteers as the control group (patients with history of cardiovascular comorbidities or exposure to antiarrhythmic drugs were excluded from the study). All participants were subjected to clinical evaluation including detailed epileptic history with assessment of SUDEP 7 risk, severity scale, 12 leads surface ECG to measure QTc & QTD, 24 h Holter monitoring to assess heart rate variability (HRV) parameters. ResultsControlled and refractory epileptic patients demonstrated increased average QTc and QTD values compared to control group (450.1 ± 18.9 vs. 412.3 ± 12.3 ms, p < 0.0001, 452.1 ± 19.0 vs. 412.3 ± 12.3 ms, p < 0.0001 respectively) (45.6 ± 14.9 vs. 15.4 ± 6.8 ms, p < 0.001, 70.6 ± 18.1 vs. 15.4 ± 6.8 ms, p < 0.0001 respectively). Refractory epileptic patients had a significantly higher incidence of abnormal QTD > 50 ms compared to controlled epileptic patients (32.5% vs. 90%, p < 0.005). Refractory epileptic patients with generalized form had significantly higher severity scale in addition to significantly impaired rMSSD and pNN50 compared to those with focal form (1072.7 ± 722.7 vs. 429.1 ± 180.4, p < 0.03, 17.11 ± 4.6 vs. 26.4 ± 7.9 ms, p < 0.004 and 2.9 ± 1.8 vs. 7.8 ± 4.1%, p < 0.003 respectively). Among refractory epileptic patients, the duration of epilepsy, rMSSD and QTD significantly correlated with SUDEP-7 risk (r2 =0.199, p < 0.005, r2 =0.623, p < 0.0001 and r2=0.44, p < 0.0001 respectively). ConclusionsThe current study stands out the importance of evaluating QTc and QTD in 12-lead ECG recordings in epileptic patients and signifying their association with SUDEP-7 risk among refractory epileptic patients.

SUDEP in adults and children

Sudden unexpected death in epilepsy (SUDEP) represents an important cause of death in patients with epilepsy and it exceeds the expected rate of sudden death in the general population by nearly 24 times. We searched the electronic databases (Cochrane, EMBASE, Scopus, Medline, Pubmed) for studies related to etiology and risk stratification of SUDEP including data on Takotsubo cardiomyopathy (TKC) following seizures resulting in death or near death.: SUDEP is more common among males in the fourth decade of life. Risk for SUDEP is increased by early onset of seizures, low IQ, generalised tonic clonic seizures, nocturnal seizures and seizure frequency. Nonadherance to antiepileptic medications, absence of therapeutic drug level monitoring, presence of neuropathological lesions on imaging and certain subgroups like Dravet syndrome increase its risk. The risk for premature death in patients undergoing temporal lobe resection for drug resistant epilepsy decreased over time but remained above the standard population. Prolonged postictal electroencephalographic suppression was a risk factor for SUDEP in patients with generalised seizures which may indicate a cerebral electrical shutdown. Documented ictal/postictal hypoventilation, laryngeal spasm and cardiac rhythm abnormalities prior to SUDEP may suggest central apnea, neurogenic pulmonary edema, cardiac arrhythmia, or a combination of the above as a cause. Seizure triggered TKC does not seem to play a major role in the pathogenesis of SUDEP.

Sudden unexpected death in epilepsy in persons younger than 50years: A retrospective nationwide cohort study in Denmark.

Persons with epilepsy have an increased mortality including a high risk of sudden unexplained death (SUD), also referred to as sudden unexpected death in epilepsy (SUDEP). We aimed to evaluate the risk of SUDEP in comparison to other causes of death and the risk of SUD in persons with and without epilepsy. We undertook a retrospective population-based cohort study of all Danish citizens with and without epilepsy aged 1-49years during 2007-2009. All deaths in the population were evaluated, and all cases of SUD identified. Primary causes of death in persons with epilepsy were evaluated independently by three neurologists and one neuropediatrician, using the unified SUDEP criteria. The three most frequent causes of death in persons with epilepsy were cancer (2.38 per 1000 person-years), SUDEP (1.65 per 1000 person-years), and pneumonia (1.09 per 1000 person-years) compared with cancer (.17 per 1000 person-years), accident-related deaths (.14 per 1000 person-years), and cardiovascular disease (.09 per 1000 person-years) in persons without epilepsy. Considering definite, definite plus, and probable cases, the SUDEP incidence was .27 per 1000 person-years (95% confidence interval [CI] = .11-.64) in children aged 1-17years and 1.21 per 1000 person-years (95% CI = .96-1.51) in adults aged 18-49years. Adjusted for age and sex, persons with epilepsy younger than 50years had a 10.8-fold (95% CI = 9.97-11.64, p<.0001) increased all-cause mortality and a 34.4-fold (95% CI = 23.57-50.28, p<.0001) increased risk of SUD compared with persons without epilepsy. SUDEP accounted for 23.3% of all SUD. This nationwide study of all deaths in persons with epilepsy younger than 50years found a lower SUDEP risk in children compared with adults, and that epilepsy was a major risk factor for SUD in the background population. This underlines the importance of addressing risk factors for SUDEP to prevent premature death.

Sudden Unexpected Death in Epilepsy (SUDEP): A Review of Risk Factors and Possible Interventions in Children.

Sudden unexpected death in epilepsy (SUDEP) is a serious and devastating, yet poorly understood outcome in epilepsy. This review discusses the current knowledge and understanding of SUDEP in children and adolescents. Established risk factors for SUDEP include history of generalized tonic-clonic seizures and nocturnal seizures. Other proposed risk factors include the use of multiple antiseizure medications and poor medication adherence. Possible prevention strategies for SUDEP include improved medication adherence, surgical interventions, nighttime safety, seizure detection devices, and diet. Pediatric providers have a great opportunity to educate families about SUDEP, assess medication adherence, and provide families with tools to improve medication adherence and learn about SUDEP in children and adolescents with epilepsy. Future research in SUDEP aims to further understand the etiology and risk factors of SUDEP, while developing more intervention strategies to prevent SUDEP.