Epilepsy-related Deaths Research Articles

Long-term outcome of vagus nerve stimulation for drug-resistant epilepsy using continuous assessment, with a note on mortality

PurposeTo examine the outcome of vagus nerve stimulation (VNS) for drug-resistant epilepsy using data from a National Health Service VNS clinic. MethodsClinical records of patients implanted with VNS for epilepsy between1995 and 2010 were examined. Patients were selected for study who had at least one year of therapeutic stimulation (minimum 1 mA stimulator current) and follow-up by our service with analysable electronic records, providing continuous assessment of seizure control during available follow-up. Seizure status at each attendance was assessed and graded 1–4 (1=seizure free or <5 seizures/year; 2 =≥50%reduction in seizure frequency; 3=<50% reduction; 4=no improvement compared to baseline). Responders were those whose grades improved consistently (Grades 1,2 and 3). ResultsOf 464 patients, 171 fulfilled the inclusion criteria and were divided into three groups: a) Responders (n = 81); b) non-responders (n = 80) and c) others (n = 10), the latter showing a late step-wise change (six improved; four deteriorated). After initial ramping up of current, groups were very stable over subsequent periods varying from one to 12 years (median 3.8 years). Sixteen patients died, 10 of non-epilepsy causes with 6 epilepsy-related deaths. There was a significant relation between epilepsy-related deaths and response (p < 0.00001). Patients with longer time as non-responders had more likelihood of suffering an epilepsy death than responders, though numbers were small. ConclusionThis study shows that meaningful data can be obtained retrospectively from routine clinic records. In this cohort about half of patients treated with VNS responded and the response generally remaining stable over time.

Epilepsy-Related Mortality in Children and Young Adults in Denmark

Background and Objectives Mortality is increased in epilepsy, but the important issue is that a proportion of epilepsy-related death is potentially preventable by optimized therapy and therefore needs to be identified. A new systematic classification of epilepsy-related mortality has been suggested to identify these preventable deaths. We applied this classification to an analysis of premature mortality in persons with epilepsy who were &lt;50 years of age. Methods The study was a population-based retrospective cohort of all Danish citizens with and without epilepsy 1 to 49 years of age during 2007 to 2009. Information on all deaths was retrieved from the Danish Cause of Death Registry, autopsy reports, death certificates, and the Danish National Patient Registry. The primary cause of death in persons with epilepsy was evaluated independently by 3 neurologist, 1 neuro-pediatrician, and 2 cardiologists. In case of uncertainty, a pathologist was consulted. All deaths were classified as either epilepsy related or not epilepsy related, and the underlying causes or modes of death were compared between persons with and without epilepsy. Results During the study period, 700 deaths were identified in persons with epilepsy, and 440 (62.9%) of these were epilepsy related, 169 (38%) directly related to seizures and 181 (41%) due to an underlying neurologic disease. Sudden unexpected death in epilepsy accounted for 80% of deaths directly related to epilepsy. Aspiration pneumonia was the cause of death in 80% of cases indirectly related to epilepsy. Compared with the background population, persons with epilepsy had a nearly 4-fold increased all-cause mortality (adjusted mortality hazard ratio 3.95 [95% confidence interval [CI] 3.64–4.27], p &lt; 0.0001) and a higher risk of dying of various underlying causes, including alcohol-related conditions (hazard ratio 2.91 [95% CI 2.23–3.80], p &lt; 0.0001) and suicide (hazard ratio 2.10 [95% CI 1.18–3.73], p = 0.01). Discussion The newly proposed classification for mortality in persons with epilepsy was useful in an unselected nationwide cohort. It helped in classifying unnatural causes of death as epilepsy related or not and in identifying potentially preventable deaths. The leading causes of premature mortality in persons &lt;50 years of age were related to epilepsy and were thus potentially preventable by good seizure control.

Epilepsy and mortality: a retrospective cohort analysis with a nested case–control study identifying causes and risk factors from primary care and linkage-derived data

ObjectivesPeople with epilepsy (PWE) have a higher mortality rate than the general population. Epilepsy-related deaths have increased despite all-cause mortality decreasing in the general population pre-COVID-19. We hypothesised that clinical...

A national study of epilepsy-related deaths in Scotland: Trends, mechanisms, and avoidable deaths.

This study was undertaken to investigate the trends and mechanisms of epilepsy-related deaths in Scotland, highlighting the proportion that were potentially avoidable. This was a retrospective observational data-linkage study of administrative data from 2009-2016. We linked nationwide data encompassing mortality records, hospital admissions, outpatient attendance, antiepileptic drug (AED) prescriptions, and regional primary care attendances. Adults (aged ≥16years) suffering epilepsy-related death were identified for study using International Classification of Diseases, 10th Revision coding combined with AED prescriptions. We reported epilepsy-related mortality rate (MR), age-specific mortality ratios, multiple cause-of-death frequencies, and the proportion of potentially avoidable deaths (identified as those with an underlying cause listed as avoidable by the Office for National Statistics). A total of 1921 epilepsy-related deaths were identified across Scotland; 1185 (62%) decedents were hospitalized for seizures in the years leading up to death, yet only 518 (27%) were seen in a neurology clinic during the same period. MR remained unchanged over time, ranging from 5.9 to 8.7 per 100000 Scottish population (95% confidence interval [CI] = -.05 to .66 per 100000 for annual change in MR). Mortality ratios were significantly increased in young adults aged 16-54years (2.3, 95% CI = 1.8-2.8), peaking at age 16-24years (5.3, 95% CI = 1.8-8.8). Sudden unexpected death in epilepsy (SUDEP) constituted 30% of the 553 young adult epilepsy-related deaths, with several other non-SUDEP fatal mechanisms identified including aspiration pneumonia, cardiac arrest, AED or narcotic poisoning, drowning, and alcohol dependence. Seventy-six percent of young adult epilepsy-related deaths were potentially avoidable. Epilepsy-related deaths are a major public health problem in Scotland, given that they are not reducing, people are dying young, and many deaths are potentially avoidable. SUDEP is only one of several important mechanisms by which epilepsy-related deaths are occurring in young adults. Services may need to be re-evaluated to improve specialist referral following seizure-related hospital admissions.

Changes in epilepsy causes of death: A US population study.

Since 2000, medical treatment for epilepsy and cardiovascular risk-reduction strategies have advanced significantly in the United States (US). However, seizure-free rates remain unchanged, and people with epilepsy are at higher risk than the general population for heart disease and stroke. The purpose of this study is to determine how cardiovascular, epilepsy-related, and other causes of death are changing in epilepsy in comparison with the US population. Changes in the 15 underlying causes of death in epilepsy (ICD-10 G40-G40.9) and the US population were analyzed and compared from 2000 to 2018. The CDC multiple cause-of-death database was utilized as the primary data source. Changes in the relative proportions for each cause-of-death over were evaluated using logistic regression. The proportions of deaths in epilepsy due to heart disease declined 34.4% (p<.001), a rate similar to the general population (39.9%). Epilepsy-related deaths declined 25% as a percentage of all epilepsy deaths (p<.001). The proportions of deaths due to stroke and neoplasms increased significantly in epilepsy versus the US population (p<.001 linear trend). The reduction in ischemic heart disease in epilepsy is a novel and highly significant finding, which reflects widespread implementation of cardiovascular risk-factor reduction and treatment in the United States. Reductions in epilepsy-related deaths are an exciting development which requires further investigation into causality. The increase in deaths due to neoplasms and stroke relative to the US population is concerning, warranting vigilance and increased efforts at recognition, prevention, and treatment.

Neuropathology in the North American sudden unexpected death in epilepsy registry.

Sudden unexpected death in epilepsy is the leading category of epilepsy-related death and the underlying mechanisms are incompletely understood. Risk factors can include a recent history and high frequency of generalized tonic-clonic seizures, which can depress brain activity postictally, impairing respiration, arousal and protective reflexes. Neuropathological findings in sudden unexpected death in epilepsy cases parallel those in other epilepsy patients, with no implication of novel structures or mechanisms in seizure-related deaths. Few large studies have comprehensively reviewed whole brain examination of such patients. We evaluated 92 North American Sudden unexpected death in epilepsy Registry cases with whole brain neuropathological examination by board-certified neuropathologists blinded to the adjudicated cause of death, with an average of 16 brain regions examined per case. The 92 cases included 61 sudden unexpected death in epilepsy (40 definite, 9 definite plus, 6 probable, 6 possible) and 31 people with epilepsy controls who died from other causes. The mean age at death was 34.4 years and 65.2% (60/92) were male. The average age of death was younger for sudden unexpected death in epilepsy cases than for epilepsy controls (30.0 versus 39.6 years; P = 0.006), and there was no difference in sex distribution respectively (67.3% male versus 64.5%, P = 0.8). Among sudden unexpected death in epilepsy cases, earlier age of epilepsy onset positively correlated with a younger age at death (P = 0.0005) and negatively correlated with epilepsy duration (P = 0.001). Neuropathological findings were identified in 83.7% of the cases in our cohort. The most common findings were dentate gyrus dysgenesis (sudden unexpected death in epilepsy 50.9%, epilepsy controls 54.8%) and focal cortical dysplasia (FCD) (sudden unexpected death in epilepsy 41.8%, epilepsy controls 29.0%). The neuropathological findings in sudden unexpected death in epilepsy paralleled those in epilepsy controls, including the frequency of total neuropathological findings as well as the specific findings in the dentate gyrus, findings pertaining to neurodevelopment (e.g. FCD, heterotopias) and findings in the brainstem (e.g. medullary arcuate or olivary dysgenesis). Thus, like prior studies, we found no neuropathological findings that were more common in sudden unexpected death in epilepsy cases. Future neuropathological studies evaluating larger sudden unexpected death in epilepsy and control cohorts would benefit from inclusion of different epilepsy syndromes with detailed phenotypic information, consensus among pathologists particularly for more subjective findings where observations can be inconsistent, and molecular approaches to identify markers of sudden unexpected death in epilepsy risk or pathogenesis.

Vagus nerve stimulation does not alter brainstem nuclei morphology in patients with refractory epilepsy

ObjectiveTo describe morphological characteristics of the brainstem nuclei in response to chronic vagus nerve stimulation (VNS) in patients with refractory epilepsy. BackgroundVNS is a treatment option for individuals with medically refractory epilepsy. While treatment with VNS may achieve up to 50% seizure reduction and is protective against sudden unexpected death in epilepsy (SUDEP), its mechanism of action is not fully understood. Long-term structural and cellular changes in response to VNS have rarely been addressed in humans. MethodsFour autopsy cases with history of chronic epilepsy treated with VNS (VNS+) and 4 age- and sex-matched chronic epilepsy-related death cases without VNS (VNS-) were included. Detailed clinical and postmortem data were obtained. Serial horizontal sections of the brainstem were prepared and stained with hematoxylin, eosin, and luxol fast blue (HE/LFB). Three regions of interest (ROIs) were delineated, including nucleus tractus solitarius (NTS), locus coeruleus (LC), and the rostral pontine group of raphe nuclei (rRN). Immunohistochemistry studies were performed using antibodies to GFAP, NeuN, HLA-DR, and IBA-1. Immunolabeling index was analyzed. ResultsThree of the 4 VNS+ patients and all 4 control (VNS-) patients died of SUDEP. There was no laterality difference in the NeuN, GFAP, HLA-DR and IBA-1 expression in LC and NTS of VNS+ patients. Similarly, there was no difference in the rRN, LC, and NTS between the VNS+ and VNS- groups. ConclusionThis study represents the first histopathological study of the long-term effects of VNS therapy in the human brain. There was no difference observed in the neuronal cell number, degree of astrocytosis, and neuroinflammation in the main brainstem vagal afferent nuclei after prolonged VNS treatment in patients with refractory epilepsy.

The effect of time-of-day and circadian phase on vulnerability to seizure-induced death in two mouse models.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of premature death in patients with refractory epilepsy. SUDEP typically occurs during the night, although the reason for this is unclear. We found that, in normally entrained mice, time-of-day alters vulnerability to seizure-induced death. We found that, in free-running mice, circadian phase alters the vulnerability to seizure-induced death. These findings suggest that circadian rhythmicity may be responsible for the increased night-time prevalence of SUDEP ABSTRACT: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death. SUDEP typically occurs during the night following a seizure. Many aspects of mammalian physiology are regulated by circadian rhythms in ways that might make seizures occuring during the night more dangerous. Using two mouse models of seizure-induced death, we demonstrate that time-of-day and circadian rhythms alter vulnerability to seizure-induced death. We exposed normally entrained DBA/1 mice to a potentially seizure-inducing acoustic stimulus at different times of day and compared the characteristics and outcomes of the seizures. Time-of-day did not alter the probability of a seizure but it did alter the probability of seizure-induced death. To determine whether circadian rhythms alter vulnerability to seizure-induced death, we induced maximal electroshock seizures in free-running C57BL/6J mice at different circadian time points at the same time as measuring breathing via whole body plethysmography. Circadian phase did not affect seizure severity but it did alter postictal respiratory outcomes and the probability of seizure-induced death. By contrast to our expectations, in entrained and free-running mice, vulnerability to seizure-induced death was greatest during the night and subjective night, respectively. These findings suggest that circadian rhythmicity may be responsible for the increased night-time prevalence of SUDEP and that the underlying mechanism is phase conserved between nocturnal and diurnal mammals. All of the seizures in the present study were induced during wakefulness, indicating that the effect of time point on vulnerability to seizure-induced death was not the result of sleep. Understanding why SUDEP occurs more frequently during the night may inform future preventative countermeasures.

Physico-Chemical and Microbiological Study for the Stability of Phenytoin Sodium Extemporaneously Compounded Suspension in Saudi Arabia Hospitals

Epilepsy is a chronic and the fourth most common neurological disorder which affects people of all age groups. Recently research and awareness on epilepsy-related deaths have rapidly grown over the past two decades. Many previous studies are attributed to the guidelines that apprise health care professionals in handling these deaths, but there is a relative scarcity of information accessible for clinicians and pharmacists who are responsible for manufacturing or preparing the extemporaneous anti-epileptic suspensions in the hospitals. Mostly in partial seizures, phenytoin is one of the first-choice drugs. In Saudi Arabian hospitals, the extemporaneous preparation of phenytoin suspension is common, but the hot climatic weather in Saudi Arabia possesses stability problems that should be tackled as the prepared suspension should pass all the stability tests to ensure uniform dosage of the extemporaneous formulation. In the current study, the commercial capsules were used to prepare the oral phenytoin sodium extemporaneous suspension. The physical, chemical and microbiological stability of phenytoin sodium suspension is analyzed at various temperatures.

Mortality in infantile spasms: A hospital-based study.

To determine risk factors and causes for mortality during childhood in patients with infantile spasms (IS). We describe the overall goals of care for those who died. This is a retrospective chart review of IS patients born between 2000 and 2011. We examined potential risk factors for mortality, including etiology, neurologic impairment, medication use, persistence of epileptic spasms, and comorbid systemic involvement (requirement for G-tube feedings, respiratory interventions). For patients who died, we describe cause of death and resuscitation status or end-of-life care measures. We identified 150 IS patients with median follow-up of 12years. During the study period, 25 (17%) patients died, 13 before 5years of age. Univariate analysis demonstrated that developmental delay, identifiable etiology, hormonal use for IS, persistence of epileptic spasms, polypharmacy with antiseizure medications, refractory epilepsy, respiratory system comorbidity, and the need for a G-tube were significant risk factors for mortality. In a multivariate analysis, mortality was predicted by persistence of epileptic spasms (odds ratio [OR] = 4.30, 95% confidence interval [CI] = 1.11-16.67, P=.035) and significant respiratory system comorbidity (OR = 12.75, 95% CI = 2.88-56.32, P=.001). Mortality was epilepsy-related in one-third of patients who died with sudden unexpected death in epilepsy (SUDEP), accounting for 88% of epilepsy-related deaths. Most deaths before age 5years were related to respiratory failure, and SUDEP was less common (17%) whereas SUDEP was more common (45%) with deaths after 5 years. For the majority (67%) of patients with early mortality, an end-of-life care plan was in place (based on documentation of resuscitation status, comfort measures, or decision not to escalate medical care). Mortality at our single-center IS cohort was 17%, and persistence of epileptic spasms and comorbid respiratory system disorders were the most important determinants of mortality. Early deaths were related to neurological impairments/comorbidities. SUDEP was more common in children who died after 5years of age than in those who died younger than 5 years.

Mortality of all causes and sudden unexplained death in epilepsy (SUDEP) in a cohort of 235 persons living with epilepsy in Rwanda using WHO Verbal Autopsy Questionnaire.

IntroductionMortality in persons living with epilepsy (PwE) is 1.6–9.3-fold higher than in the general population. Mortality from definite/probable Sudden Unexpected Death in EPilepsy (SUDEP) is estimated at 1.2 per 1000 person-years. We report mortality and SUDEP rate in a cohort of Rwandan PwE.MethodsPwE presenting for a first visit at the Ndera epilepsy center between January and June 2016 were followed-up prospectively. For PwE who did not attend their follow-up visit, home visits were organized. Deaths were assessed using World Health Organization Verbal Autopsy Standards age-specific questionnaires.ResultsOf 235 PwE enrolled, home visits were organized for 81 (34.4%) PwE who did not return for their follow-up consultation. Seven fatalities (mortality 16.7/1000 patient-years [CI 6.7–34.3]) were recorded (aged 2–80 years). Four had an identified cause. Three were classified as probable SUDEP, resulting in a probable SUDEP rate of 7.1/1000 patient-years (CI 1.47–20.86). Probable SUDEP occurred in PwE (age: 2, 21, 34 years) showing no symptoms of illness while receiving antiepileptic treatment; in two cases, death occurred during sleep.ConclusionAlthough autopsies were absent, the high mortality and probable SUDEP rates warrant future studies to establish causes of epilepsy-related deaths in Rwanda and sub-Saharan Africa.

Epilepsy deaths: Learning from health service delivery and trying to reduce risk

Two recent UK reports have highlighted data of concern in relation to potentially preventable epilepsy deaths. Public Health England, an executive agency of the Government Department of Health, using National Health Service data from 2001 to 2014 reported a rise in direct age-standardised mortality for epilepsy-associated deaths, in contrast to a reduction in all-cause deaths over the same period. Premature death was seen in people aged below 50 years, especially in men, and where epilepsy was a contributory cause rather than an association. The Scottish Epilepsy Deaths Study, analysing deaths between 2009 and 2016, similarly found death in those with epilepsy was significantly higher than the matched population below the age of 54, especially between the ages of 16 and 24 (6 times higher). Sudden unexpected death in epilepsy accounted for 38% of epilepsy-related deaths under the age of 45. Both studies found a strong relationship between risk of death and deprivation; we discuss the implications of these and other data for planning service delivery and improving epilepsy care.This paper is for the Special Issue: Prevent 21: SUDEP Summit - Time to Listen

Epilepsy Related Death: the London Health Sciences Center Experience

Premature mortality among epilepsy patients is well recognized. Except a few identifiable causes of unnatural death, more than half of the epilepsy related death remains unexplained after extensive workup. These cases are classified as sudden unexpected death in epilepsy (SUDEP). SUDEP incidence varies significantly depending on the population, the methods documenting cause of death and the availability of Neuropathological examination. An accurate diagnosis of the cause of death is needed for epilepsy related death. The goal of this study is to present the relevant clinical data, the general autopsy and Neuropathology findings of epilepsy related death investigated in London Health Sciences Center during the period of 2000 to 2011. We identified 71 cases with known history of chronic epilepsy. In the 29 cases of epilepsy associated death, the causes of death have been classified as cardiac, pulmonary, accidental (e.g. drowning), toxic (e.g. drug overdose) and non-related causes. Forty two cases are considered to be SUDEP, and were categorized according to the recently proposed SUDEP Definition and Classification. Half of the SUDEP cases have no specific Neuropathological findings. The most common identifiable lesions in SUDEP cases are perinatal/neonatal destructive lesions (29%), hippocampal sclerosis (24%), and focal cortical dysplasia (20%). These are followed by neuronal heterotopia (9%), previous head trauma (9%), and cavernoma (5%).LEARNING OBJECTIVESThis presentation will enable the learner to:1.Review cause of death in epilepsy related deaths2.Discuss the practice guideline in neuropathology autopsy of epilepsy related deaths

P15-T Increased HCN4 expression in hippocampus of SUDEP patients

Background Sudden Unexpected Death in Epilepsy (SUDEP) accounts for approximately 17% of epilepsy related deaths though the pathophysiological mechanisms remain poorly understood. Seizure related cardiac and respiratory dysfunction if often seen as the terminal event with sodium and potassium cardiac channelopathies causing a long QT syndrome. More recently the hyperpolarization-activated cyclic nucleotide–gated (HCN) channels have been shown to be involved in animal models of epilepsy and abnormal genotypes seen in some patients. Here we report the first studies of HCN expression in tissue form human SUDEP patients. Methods Anonymous donor human brain tissue from patients aged 19–31 years and normal controls was obtained from Oxford Brain Bank, UK. Standardised Immunohistochemistry was performed using primary antibodies against HCN1-4 subunits. Cells expressing the HCN were counted using Volocity Software (Perkin Elmer). All results were expressed as a mean (±SEM). Results Immunoreactivity for HCN channels was detected principally in pyramidal neurons of the CA1 area and in the dentate gyrus (DG) of the hippocampus. The only observed difference was a significant increase in HCN4 expression in the DG of SUDEP tissue. (231 ± 41 vs. 111 ± 10, p = 0.044). Discussion HCN4 has been implicated in patients with cardiac dysfunction and one HCN4 gene abnormality linked directly to SUDEP. We are unable to tell whether this upregulation represents a primary cause of the epilepsy of a secondary bystander phenomenon that has led to sudden death but feel that the role of HCN channel regulation in epilepsy and SUDEP has yet to be fully understood.

Parental perspectives on provider adherence to AAN epilepsy quality measures in rural and urban tertiary care centers

Several American Academy of Neurology (AAN) epilepsy practice guidelines recommend conversations that neurologists should have with patients and their parents. We sought to determine whether parents of pediatric patients with epilepsy had knowledge of epilepsy quality measures (EQMs) and whether they recalled having discussions with their child's neurologist about each of the EQM. Surveys were distributed to parents at five clinic sites associated with epilepsy centers in Washington, DC and Charlottesville, Virginia. Key questions on the parent survey included whether neurologists had discussed, or parents had knowledge of, EQM topics which included medication side effects, safety, reproductive health, transition to adult care, learning and attention problems, bone health, sudden unexpected death in epilepsy (SUDEP), and risk of epilepsy-related death. No data were collected from the neurologist or the medical record about EQM discussions. Among 233 completed surveys, parental knowledge and neurologist discussion of EQM were highly correlated (p < .00001). Epilepsy quality measures most discussed with high parental knowledge were medication side effects, safety, learning and attention problems, and bone health. Sudden unexpected death in epilepsy was least discussed and known. We found consistent care practices in adherence to EQM across settings from urban to rural communities, with patients of all ages and epilepsy severities and staffed by neurologists with various levels of epilepsy expertise. Despite reported high rates of adherence on several measures, we identified opportunities for improvement. Querying and counseling about EQM should be an ongoing conversation which evolves with the child's age and epilepsy-associated risks.

Risk Factors for Sudden Unexpected Death in Epilepsy (SUDEP) and Their Mitigation.

People with epilepsy have an increased risk of mortality when compared to the general population. Sudden unexpected death in epilepsy (SUDEP) is the most common cause of epilepsy-related death in children and adults. The purpose of this review is to discuss SUDEP, with an emphasis on SUDEP risk factors, their mitigation and prevention. SUDEP affects approximately 1 in 1000 people with epilepsy each year. Recent studies suggest that the incidence in children is similar to that of adults. The most important risk factor for SUDEP is the presence and frequency of generalized tonic-clonic seizures. The presence of nocturnal supervision may decrease risk along with the use of nocturnal listening devices. Underlying genetic influences, both cardiac and epilepsy-related may further alter risk. Risk mitigation strategies include reducing seizure frequency, optimizing therapy, and the use of nocturnal supervision/seizure detection devices. Risk factors for SUDEP are well established; however, pediatric specific risk factors have not been identified. Current prevention strategies are focused on reduction of risk factors and the possible role of seizure detection devices. More research is needed to better understand the varied underlying pathological mechanisms and develop targeted prevention strategies. Further understanding the genetic factors that influence SUDEP risk may potentially aid in understanding the underlying pathophysiology of SUDEP.

Dead in the Night: Sleep-Wake and Time-Of-Day Influences on Sudden Unexpected Death in Epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death in patients with refractory epilepsy. Convergent lines of evidence suggest that SUDEP occurs due to seizure induced perturbation of respiratory, cardiac, and electrocerebral function as well as potential predisposing factors. It is consistently observed that SUDEP happens more during the night and the early hours of the morning. The aim of this review is to discuss evidence from patient cases, clinical studies, and animal research which is pertinent to the nocturnality of SUDEP. There are a number of factors which might contribute to the nighttime predilection of SUDEP. These factors fall into four categories: influences of (1) being unwitnessed, (2) lying prone in bed, (3) sleep-wake state, and (4) circadian rhythms. During the night, seizures are more likely to be unwitnessed; therefore, it is less likely that another person would be able to administer a lifesaving intervention. Patients are more likely to be prone on a bed following a nocturnal seizure. Being prone in the accouterments of a bed during the postictal period might impair breathing and increase SUDEP risk. Sleep typically happens at night and seizures which emerge from sleep might be more dangerous. Lastly, there are circadian changes to physiology during the night which might facilitate SUDEP. These possible explanations for the nocturnality of SUDEP are not mutually exclusive. The increased rate of SUDEP during the night is likely multifactorial involving both situational factors, such as being without a witness and prone, and physiological changes due to the influence of sleep and circadian rhythms. Understanding the causal elements in the nocturnality of SUDEP may be critical to the development of effective preventive countermeasures.

Reducing the Risk of Sudden Unexpected Death in Epilepsy (SUDEP).

Recent reports have highlighted an increase in the number of epilepsy-related deaths. Sudden unexpected death in epilepsy (SUDEP) is thought to be the number one cause of death in chronic epilepsy. This review provides a summary of the current evidence of how to communicate, stratify, and mitigate known risk factors for SUDEP. There is now a clearer understanding of the possible pathological mechanisms that contribute to SUDEP. SUDEP is the culmination of multifactorial predisposing and precipitating factors and has been linked to particular candidate genes. A number of static and modifiable risk factors for SUDEP have been consistently identified. Recent guidance has emphasised the importance of communicating SUDEP risk to individuals at the earliest appropriate time. SUDEP risk assessment should be integral to the care of individuals with epilepsy. The use of evidence-based risk assessment tools may provide an opportunity to communicate identified risks in a person-centred holistic way. There is increasing evidence to support the use of wearable seizure monitoring devices to help reduce the frequency and impact of convulsive seizures, perhaps the number one risk factor for SUDEP.

Astroglial role in the pathophysiology of status epilepticus: an overview.

Status epilepticus is a medical emergency with elevated morbidity and mortality rates, and represents a leading cause of epilepsy-related deaths. Though status epilepticus can occur at any age, it manifests more likely in children and elderly people. Despite the common prevalence of epileptic disorders, a complete explanation for the mechanisms leading to development of self-limited or long lasting seizures (as in status epilepticus) are still lacking. Apart from neurons, research evidence suggests the involvement of immune and glial cells in epileptogenesis. Among glial cells, astrocytes represent an ideal target for the study of the pathophysiology of status epilepticus, due to their key role in homeostatic balance of the central nervous system. During status epilepticus, astroglial cells are activated by the presence of cytokines, damage associated molecular patterns and reactive oxygen species. The persistent activation of astrocytes leads to a decrease in glutamate clearance with a corresponding accumulation in the synaptic extracellular space, increasing the chance of neuronal excitotoxicity. Moreover, major alterations in astrocytic gap junction coupling, inflammation and receptor expression, facilitate the generation of seizures. Astrocytes are also involved in dysregulation of inhibitory transmission in the central nervous system and directly participate in ionic homeostatic alterations during status epilepticus. In the present review, we focus on the functional and structural changes in astrocytic activity that participate in the development and maintenance of status epilepticus, with special attention on concurrent inflammatory alterations. We also include potential astrocytic treatment targets for status epilepticus.

Reader response: Underestimation of sudden deaths among patients with seizures and epilepsy.

The article by Devinsky et al.1 focuses on the determination of the definite and potential frequency of seizures and epilepsy as a cause of death (COD) and how often this goes unrecognized. As the authors state, “Epilepsy is underdiagnosed among decedents. Among patients with seizures and epilepsy who die suddenly, seizures and SUDEP (sudden unexpected death in epilepsy) often go unrecognized as a potential or definite COD.”1 Although it is evident that findings from the pathology of the deceased open a discussion about a more organized postmortem collaboration among medical experts, something that is needed in order to improve the recognition and coding of epilepsy-related deaths, a plethora of characteristics of these patients (i.e., age, sex, other comorbidities, health care provision characteristics, seizure history, treatment, medical and psychological history, cognitive status, habits, events at the time of death) should be taken into consideration as grouping variables,2 and more complex analyses of data in larger samples of such patients should support conclusions. In addition, care should be taken for living patients, who must be better educated about prevention and encouraged to be compliant with medications, especially in times of unusual life stress that can be linked to mortality.3 As generalized tonic-clonic seizures precede most cases of SUDEP,4 this could serve as a starting point of research and discussion.