Seizure-related deaths in children: The expanding spectrum.

Although seizures are common in children, they are often overlooked as a potential cause of death. Febrile and nonfebrile seizures can be fatal in children with or without an epilepsy diagnosis and may go unrecognized by parents or physicians. Sudden unexpected infant deaths, sudden unexplained death in childhood, and sudden unexpected death in epilepsy share clinical, neuropathological, and genetic features, including male predominance, unwitnessed deaths, death during sleep, discovery in the prone position, hippocampal abnormalities, and variants in genes regulating cardiac and neuronal excitability. Additionally, epidemiological studies reveal that miscarriages are more common among individuals with a personal or family history of epilepsy, suggesting that some fetal losses may result from epileptic factors. The spectrum of seizure-related deaths in pediatrics is wide and underappreciated; accurately estimating this mortality and understanding its mechanism in children is critical to developing effective education and interventions to prevent these tragedies.

Febrile seizures prior to sudden cardiac death: a Danish nationwide study.

Aims: Febrile seizure (FS) is a common disorder affecting 2-5% of children up to 5 years of age. The aim of this study was to determine whether FS in early childhood are over-represented in young adults dying from sudden cardiac death (SCD). Methods and results: We included all deaths (n = 4595) nationwide and through review of all death certificates, we identified 245 SCD in Danes aged 1-30 years in 2000-09. Through the usage of nationwide registries, we identified all persons admitted with first FS among SCD cases (14/245; 5.7%) and in the corresponding living Danish population (71 027/2 369 785; 3.0%) and also in victims of transport accidents (26/917; 2.8%). The frequency of FS among SCD cases was significantly increased by an odds ratio of 1.96 [95% confidence interval (CI) 1.14-3.36; P = 0.021] compared with the living Danish population and with an odds ratio of 2.08 (95% CI 1.07-4.04; P = 0.046) compared with transport accident victims. SCD cases did not differ statistically in birth year (P = 0.272), age at SCD (P = 0.667) or prior medical conditions, except for epilepsy (P < 0.001), when comparing SCD with and without prior FS. The most common cause of death in autopsied SCD cases with FS was sudden arrhythmic death syndrome (5/8; 62.5%). Conclusion: In conclusion, this study demonstrates a significantly two-fold increase in the frequency of FS prior to death in young SCD cases compared with the two control groups, suggesting that FS could potentially contribute in a risk stratification model for SCD and warrant further studies.

Sudden unexpected death in early childhood: general observations in a series of 151 cases: Part 1 of the investigations of the San Diego SUDC Research Project.

PURPOSE: The purpose of this study was to determine the major subcategories and clinicopathologic features of sudden unexpected death in young children in a large retrospective cohort, and to confirm the association of sudden unexplained death in children (abbreviated by us for unexplained deaths as SUDC) with hippocampal pathology and/or febrile seizures. METHODS: We undertook analysis of a retrospective cohort of 151 cases, of which 80% (121/151) were subclassified as SUDC, 11% (16/151) as explained, 7% (10/151) as undetermined, and 3% (4/151) as seizure-related. RESULTS: There were no significant differences between SUDC and explained cases in postnatal, gestational, or postconceptional age, frequency of preterm birth, gender, race, or organ weights. In contrast, 96.7% (117/121) of the SUDC group were discovered during a sleep period compared to 53.3% (8/15) of the explained group (p < 0.001), and 48.8% (59/121) of the SUDC cases had a personal and/or family history of febrile seizures compared to 6.7% (1/15) of the explained group (p < 0.001). Of the explained deaths, 56% (9/16) were subclassified as infection, 31% (5/16) cardiac, 6% (1/16) accidental, and 6% (1/16) metabolic. Two of the three cases specifically tested for cardiac channelopathies at autopsy based upon clinical indications had genetic variants in cardiac genes, one of uncertain significance. Bacterial cultures at autopsy typically revealed organisms interpreted as contaminants. Two of the four seizure-related deaths were witnessed, with two of the brains from these cases showing generalized malformations. Hippocampal anomalies, including a specific combination we termed hippocampal maldevelopment associated with sudden death, were found in almost 50% (40/83) of the SUDC and undetermined cases in which hippocampal sections were available. CONCLUSIONS: This study highlights the key role for the hippocampus, febrile seizures, and sleep in SUDC pathophysiology. It also demonstrates the role of known predisposing conditions such as cardiac channelopathies and infections in causing sudden unexpected death in childhood, and the need for improved ancillary testing and protective strategies in these cases, even when the cause of death is established at autopsy.

Death within 8 years after childhood convulsive status epilepticus: a population-based study.

The risk of long-term mortality and its predictors following convulsive status epilepticus in childhood are uncertain. We report mortality within 8 years after an episode of convulsive status epilepticus, and investigate its predictors from a paediatric, prospective, population-based study from north London, UK. In the current study, we followed-up a cohort previously ascertained during a surveillance study of convulsive status epilepticus in childhood. After determining the survival status of the cohort members, we defined cause of death as that listed on their death certificates. We estimated a standardized mortality ratio to compare mortality in our cohort with that expected in the reference population. Multivariable Cox regression analysis was used to investigate any association between the clinical and demographic factors at the time of status epilepticus and subsequent risk of death. The overall case fatality was 11% (95% confidence interval 7.5-16.2%); seven children died within 30 days of their episode of convulsive status epilepticus and 16 during follow-up. The overall mortality in our cohort was 46 times greater than expected in the reference population, and was predominantly due to higher mortality in children who had pre-existing clinically significant neurological impairments when they had their acute episode of convulsive status epilepticus. Children without prior neurological impairment who survived their acute episode of convulsive status epilepticus were not at a significantly increased risk of death during follow-up. There were no deaths in children following prolonged febrile convulsions and idiopathic convulsive status epilepticus. A quarter of deaths during follow-up were associated with intractable seizures/convulsive status epilepticus, and the rest died as a complication of their underlying medical condition. On regression analysis, presence of clinically significant neurological impairments prior to convulsive status epilepticus was the only independent risk factor for mortality. In conclusion, there is a high risk of death within 8 years following childhood convulsive status epilepticus but most deaths are not seizure related. Presence of pre-existing clinically significant neurological impairments at the time of convulsive status epilepticus is the main risk factor for mortality within 8 years after the acute episode. The attributable role of convulsive status epilepticus on mortality remains uncertain, but appears less than is generally perceived.

The long-term risk of premature mortality in people with epilepsy.

People with epilepsy have an increased risk of premature death. The risk is highest soon after onset of seizures. We report the findings of a long-term follow-up population-based study of people with epilepsy with regards to premature mortality. The National General Practice Study of Epilepsy is a prospective study flagged at the National Health Service Information Centre in the UK. Over 1000 people with new onset seizures were followed from the mid 1980s until April 2009. Of these, 564 people were classified at 6 months as having definite epileptic seizures, 228 as having possible epileptic seizures and 220 as having febrile seizures. The remainder were excluded (n=104 because of an unknown prior diagnosis of epilepsy or neonatal seizures) or classified as not having epilepsy (n=79). At median follow-up of 22.8 years there had been 301 deaths in the cohort; 300 of these were in people with definite or possible seizures. Death certificates were obtained for all but three of those who died. The overall standardized mortality ratio for those with definite or possible epilepsy was 2.2 (95% confidence interval 1.97-2.47), and was higher in those with definite seizures (2.6). In those who were alive at 20 years follow-up, the standardized mortality ratio in the subsequent years remained significantly elevated (2.2, 95% confidence interval 1.6-3.2). Pneumonia (standardized mortality ratio 6.6, 95% confidence incidence 5.1, 8.4) was a common cause of death with a consistently elevated standardized mortality ratio throughout follow-up. The standardized mortality ratio for ischaemic heart disease was significantly elevated for the first time in the last 5 years of follow-up (3.3, 95% confidence interval 1.6-7.0). Few people died from epilepsy-related causes. The risk of premature death remains significantly elevated at 20-25 years after the index seizure despite most of the cohort being in terminal remission (defined as 5 years or more seizure-free, on or off anti-epileptic medication) at the last follow-up. Further studies are needed to explore the reasons for this long-term increase in premature mortality.

Death in children with febrile seizures: a population-based cohort study.

BACKGROUND: No studies have had sufficient size to estimate mortality in children with febrile seizures. We studied mortality after febrile seizures in a large population-based cohort of children in Denmark with up to 28 years of follow-up. METHODS: We identified 1 675 643 children born in Denmark between Jan 1, 1977, and Dec 31, 2004, by linking information from nationwide registers for civil service, health, and cause of death. Children were followed up from 3 months of age, until death, emigration, or Aug 31, 2005. We estimated overall and cause-specific mortality after first febrile seizures with survival analyses. Furthermore, we undertook a case-control study nested within the cohort and retrieved information from medical records about febrile seizure and neurological abnormalities for children who died (N=8172) and individually-matched controls (N=40 860). FINDINGS: We identified 8172 children who died, including 232 deaths in 55 215 children with a history of febrile seizures. The mortality rate ratio was 80% higher during the first year (adjusted mortality rate ratio 1.80 [95% CI 1.31-2.40]) and 90% higher during the second year (1.89 [1.27-2.70]) after the first febrile seizure; thereafter it was close to that noted for the general population. 132 of 100 000 children (95% CI 102-163) died within 2 years of a febrile seizure compared with 67 (57-76) deaths per 100 000 children without a history of this disorder. In the nested case-control study, children with simple (15 min or recurrence within 24 h) febrile seizures (1.99 [1.24-3.21]). This finding was partly explained by pre-existing neurological abnormalities and subsequent epilepsy. INTERPRETATION: Long-term mortality is not increased in children with febrile seizures, but there seems to be a small excess mortality during the 2 years after complex febrile seizures. Parents should be reassured that death after febrile seizures is very rare, even in high-risk children.

The mortality and morbidity of febrile seizures.

Approaches to the treatment and investigation of febrile seizures have changed since the main reference studies on outcomes were conducted in the 1960s and 1970s. We have, therefore, conducted a systematic review of literature from the past 15 years to see whether outcomes have also changed. We found that simple febrile seizures do not carry a risk of death, but there is a very small risk of death after complex febrile seizures (CFSs), particularly febrile status epilepticus. There is no evidence that SUDEP (sudden unexpected death in epilepsy) occurs in association with febrile seizures. The risk of later epilepsy after a febrile seizure lies between 2.0% and 7.5%, and the risk of developing epilepsy after CFSs is estimated at around 10-20%. There is no evidence of any risk of hippocampal or mesial temporal sclerosis (HS/MTS) in association with simple febrile seizures. Serial imaging has shown that HS/MTS develops in 0-25% of patients over time after prolonged febrile seizures; the range in prevalence reflects selection bias in different studies. The overall risk of HS/MTS associated with CFSs is around 3%. Approximately 40% of patients with medically refractory temporal lobe epilepsy and HS/MTS on neuroimaging have a history of febrile seizures.

Early risk factors for mortality in children with seizure and/or impaired consciousness accompanied by fever without known etiology.

BACKGROUND: Children who present with seizure and/or impaired consciousness accompanied by fever without known etiology (SICF) may be diagnosed with either acute encephalopathy (AE) or febrile seizure (FS). Although approximately 5% of AE cases are fatal, it is difficult to identify fatal cases among children with SICF, which are often critical by the time of diagnosis. Thus, early prediction of outcomes for children with SICF, prior to diagnosis, may help to reduce mortality associated with AE. The aim of the present study was to identify clinical and laboratory risk factors for mortality acquired within 6 h of onset among children with SICF. METHODS: We retrospectively reviewed the medical records of children who had been admitted to Kobe Children's Hospital (Kobe, Japan) with SICF between October 2002 and September 2015. We compared clinical and laboratory characteristics acquired within 6 h of onset and outcomes between survivors and non-survivors using univariate and multivariate analyses. RESULTS: The survivor and non-survivor groups included 659 and nine patients, respectively. All patients in the non-survivor group received a final diagnosis of AE. Univariate analysis revealed significant differences between the groups with regard to seizure duration and the following laboratory parameters: aspartate transaminase (AST), alanine aminotransferase, lactate dehydrogenase, sodium, and lactate. The multivariate analysis identified AST as a significant independent factor associated with mortality. CONCLUSIONS: Elevation of AST within 6 h of onset is independently correlated with mortality in children with SICF. Our result may elucidate earlier intervention for patients with high risk of mortality.

Therapeutic burst-suppression coma in pediatric febrile refractory status epilepticus.

BACKGROUND: Evidence for the beneficial effect of therapeutic burst-suppression coma in pediatric patients with febrile refractory status epilepticus is limited, and the clinical outcomes of this treatment strategy are largely unknown. Therefore, the aim of this study was to explore the outcomes of therapeutic burst-suppression coma in a series of children with febrile refractory status epilepticus. METHODS: We retrospectively reviewed consecutive pediatric patients with febrile refractory status epilepticus admitted to our pediatric intensive care unit between January 2000 and December 2013. The clinical characteristics were analyzed. RESULTS: Thirty-five patients (23 boys; age range: 1-18years) were enrolled, of whom 28 (80%) developed super-refractory status epilepticus. All of the patients received the continuous administration of intravenous antiepileptic drugs for febrile refractory status epilepticus, and 26 (74.3%) achieved therapeutic burst-suppression coma. All of the patients received mechanical ventilatory support, and 26 (74.3%) received inotropic agents. Eight (22.9%) patients died within 1month. The neurologically functional outcomes at 6months were good in six (27.3%) of the 22 survivors, of whom two returned to clinical baseline. The patients with therapeutic burst-suppression coma were significantly associated with hemodynamic support than the patients with electrographic seizures control (p=0.03), and had a trend of higher 1-month mortality rate, worse 6months outcomes, and a longer duration of hospitalization. CONCLUSIONS: Our results suggest that therapeutic burst-suppression coma to treat febrile refractory status epilepticus may lead to an increased risk of hemodynamic instability and a trend of worse outcomes.

Outcomes in pediatric epilepsy: seeing through the fog.

To identify clinical and predictive features of outcome in cryptogenic epilepsy in pediatric neurology practice, the medical records of all patients with cryptogenic epilepsy (as defined by the International League Against Epilepsy) in a single pediatric neurology practice over a 12-year interval with at least 2 years of follow-up were systematically and retrospectively reviewed. Review revealed 60 children with cryptogenic epilepsy: 32 (53.3%) males, 11 (18.3%) prior febrile seizure, 9 (15.0%) developmental delay at onset, and 38 (63.3%) placement in regular classes. Twenty-two (35.7%) had generalized seizures. Mean follow-up after initiating antiepileptic medication was 53 months (range 24-128 months). Four (6.7%) were intractable; 4 (6.7%) had very poor outcomes; 8 (13.3%) had poor outcomes; 44 (73.3%) were well controlled. Sixteen (26.7%) and 31 (51.7%) had seizure recurrence within the last 12 and 24 months, respectively. Twenty-nine (48.3%) were seizure-free for at least 24 months. Factors associated with a poor outcome include seizure recurrence in the 6- to 12-month interval after therapy initiation (P = 0.006) and developmental delay at onset (P = 0.023). This case series suggests that children with cryptogenic epilepsy tend to have a favorable outcome. Seizure recurrence in the first months after therapy initiation and developmental delay apparent at onset are predictive of poor outcome.

The use of simplified verbal autopsy in identifying causes of adult death in a predominantly rural population in Ethiopia.

BACKGROUND: Information on adult mortality is essentially non-existent in Ethiopia particularly from rural areas where access to health services is limited and most deaths occur at home. This study was conducted with the aim of identifying causes of adult death in a rural population of Ethiopia using a simplified verbal autopsy instrument. METHODS: All deaths in the age-group 15-49 years during the period of 1995-99 were taken from computerized demographic surveillance database maintained by the Butajira Rural Health Program. Data on the causes of death were collected from close relatives of the deceased persons by lay interviewers. Causes of death were diagnosed using "expert algorithm" programmed onto a computer. RESULTS: The major causes of death were acute febrile illnesses (25.2%), liver diseases (11.3%), diarrheal diseases (11.1%), tuberculosis (9.7%) and HIV/AIDS (7.4%). Overall communicable diseases accounted for 60.8% of the deaths. The high levels of mortality from communicable diseases reflect the poor socioeconomic development of the country, and the general poor coverage of health and education services in rural Ethiopia. The tools used in this study can easily be added-on to the numerous health surveys conducted in the country. CONCLUSION: The simplified approach to verbal autopsy diagnosis can produce useful data that can effectively guide priority health interventions in rural areas where routine information system is either very weak or non-existent.

Loss of synaptic Zn2+ transporter function increases risk of febrile seizures.

Febrile seizures (FS) are the most common seizure syndrome and are potentially a prelude to more severe epilepsy. Although zinc (Zn(2+)) metabolism has previously been implicated in FS, whether or not variation in proteins essential for Zn(2+) homeostasis contributes to susceptibility is unknown. Synaptic Zn(2+) is co-released with glutamate and modulates neuronal excitability. SLC30A3 encodes the zinc transporter 3 (ZNT3), which is primarily responsible for moving Zn(2+) into synaptic vesicles. Here we sequenced SLC30A3 and discovered a rare variant (c.892C > T; p.R298C) enriched in FS populations but absent in population-matched controls. Functional analysis revealed a significant loss-of-function of the mutated protein resulting from a trafficking deficit. Furthermore, mice null for ZnT3 were more sensitive than wild-type to hyperthermia-induced seizures that model FS. Together our data suggest that reduced synaptic Zn(2+) increases the risk of FS and more broadly support the idea that impaired synaptic Zn(2+) homeostasis can contribute to neuronal hyperexcitability.

A case-control study evaluating the relationship between thimerosal-containing haemophilus influenzae type b vaccine administration and the risk for a pervasive developmental disorder diagnosis in the United States.

Thimerosal is an organic mercury (Hg)-containing compound (49.55 % Hg by weight) historically added to many multi-dose vials of vaccine as a preservative. A hypothesis testing case-control study evaluated automated medical records in the Vaccine Safety Datalink (VSD) for organic Hg exposure from Thimerosal in Haemophilus influenzae type b (Hib)-containing vaccines administered at specific times within the first 15 months of life among subjects diagnosed with pervasive developmental disorder (PDD) (n = 534) in comparison to controls. The generally accepted biologically non-plausible linkage between Thimerosal exposure and subsequent diagnosis of febrile seizure (n = 5886) was examined as a control outcome. Cases diagnosed with PDD received significantly more organic Hg within the first 6 months of life (odds ratio (OR) = 1.97, p < 0.001) and first 15 months of life (OR = 3.94, p < 0.0001) than controls, whereas cases diagnosed with febrile seizure were no more likely than controls to have received increased organic Hg. On a per microgram of organic Hg basis, cases diagnosed with a PDD in comparison to controls were at significantly greater odds (OR = 1.0197, p < 0.0001) of receiving increasing organic Hg exposure within the first 15 months of life, whereas cases diagnosed febrile seizure were no more likely than controls (OR = 0.999, p > 0.20) to have received increasing organic Hg exposure within the first 15 months of life. Routine childhood vaccination is an important public health tool to reduce the morbidity and mortality associated with infectious diseases, but the present study provides new epidemiological evidence of a significant relationship between increasing organic Hg exposure from Thimerosal-containing vaccines and the subsequent risk of PDD diagnosis in males and females.

Analysis of convulsive status epilepticus in children of Taiwan.

Convulsive status epilepticus is a medical emergency with significantly associated mortality and morbidity. The demographic data and outcomes of convulsive status epilepticus in children were collected for descriptive analysis. We retrospectively reviewed cases of convulsive status epilepticus in the Pediatric Intensive Care Unit of Chang Gung Children's Hospital between 1999 and 2006. We enrolled 141 patients with 198 episodes of convulsive status epilepticus, aged 2 months to 18 years: 24.8% of first episodes developed convulsive status epilepticus, with a duration of over 60 minutes. First episodes of convulsive status epilepticus were most often evidenced in febrile status during acute central nerve system infections (48.2%), and in nonfebrile status during acute noncentral nerve system illness in previously epileptic children (28.4%). Before their first episode, 63.8% of children were neurologically healthy, and 12.2% exhibited a prolonged febrile seizure. The most common etiology of mortality was acute central nervous system infection. The immediate mortality rate was 7.1%. Convulsive status epilepticus in childhood is more common, with a different range of causes and a lower risk of death, than convulsive status epilepticus in adults. Acute central nervous system infections appear to be markers for morbidity and mortality.

Febrile convulsions and cot death.

Examination of the records of hospital admissions and all deaths among the 40,544 Sheffield children who were aged less than two years in the period 1975-79 revealed 475 children admitted with their first febrile convulsion and 50 children who presented as cot deaths. Rectal temperatures taken before refrigeration were traced for 24 of the latter. 10 of these 24 children had temperatures in excess of 38 degrees C and 5 were greater than 40 degrees C. There was a transition in age at presentation between the two groups, with most cot deaths occurring before six months of age and febrile convulsions after that age. No time-based clustering between the date of presentation with cot death or febrile convulsion was found to suggest a single aetiological agent. It is suggested that febrile convulsions and some inexplicable sudden infant deaths may be equivalent responses to a febrile stimulus, but with a different outcome because of the difference in age of occurrence. A common mechanism could be thermolabile syncope which, in the susceptible younger infant, leads to irreversible cerebral ischaemia. The rectal temperature should be taken as soon as possible in all cot deaths. An aberration of a vagally mediated reflex may be responsible for some cot deaths.

Recurrence after a first unprovoked cryptogenic/idiopathic seizure in children: a prospective study from São Paulo, Brazil.

PURPOSE: To evaluate the recurrence risk after a first unprovoked seizure in a large population of children and adolescents of a developing country. METHODS: This prospective study was conducted at two tertiary hospitals, between September 1989 and August 1998. Children were enrolled if they had a first unprovoked cryptogenic/idiopathic seizure and maximal interval to the enrollment < or =90 days. EEG and computed tomography (CT) were performed in most patients. Potential predictors of recurrence were compared by using the Cox proportional hazards model in univariate and multivariate analyses. Survival analysis was performed by using the Kaplan-Meier curves. RESULTS: Two hundred thirteen children were included. Recurrence occurred in 34% of the patients, and mean time for recurrence was 12 months. Statistical analysis showed significance for seizure recurrence only for patients with abnormal EEGs. CT was performed in 182 patients, and abnormalities were found in 9.5%. Small calcifications were the most frequent finding, and this was not a predictor for recurrence. CONCLUSIONS: The risk of recurrence after a first unprovoked seizure in children from a developing country is similar to that found in developed countries. An abnormal EEG is a risk factor for seizure recurrence in children with a cryptogenic/idiopathic seizure. Calcifications on CT do not increase the risk of recurrence.

Sample selection and the natural history of disease. Studies of febrile seizures.

We have compared published reports on the frequency of unfavorable sequelae in a common disorder of childhood, febrile seizures, as ascertained from hospital clinics or referral units, with the frequency as reported from population-based studies. Studies on defined populations, in which the attempt was made to recognize and follow up all affected persons regardless of medical care sought for the condition, are in close agreement and indicate relatively low rates of unfavorable sequelae. Clinic-based studies of febrile seizures have reported disparate results, including high frequencies of adverse outcomes. A possible explanation is that patients in clinic-based studies may not be representative of persons with the disorder in the general population.

Convulsive status epilepticus in children.

Status epilepticus (SE) occurs most commonly in infancy and childhood. Children with prior neurological abnormalities are most susceptible. More than 90% of cases are convulsive and the majority are generalized. SE may occur in the setting of an acute illness, in patients with established epilepsy or as a first unprovoked seizure. The etiology can be classified as idiopathic, remote symptomatic, febrile, acute symptomatic, or associated with a progressive encephalopathy. The morbidity and mortality of status have dramatically declined in recent years. Overall mortality in recent pediatric series was 3-10%, with almost all fatalities associated with acute central nervous system insults or progressive neurologic disorders. Neurological sequelae in children with idiopathic or febrile status are rare. Neurologically normal children with SE as their first unprovoked seizure have the same risk of experiencing subsequent seizures of any type as children who present with a brief first seizure. The risk of recurrent episodes of convulsive SE approaches 50% in neurologically abnormal children but is very low in neurologically normal children. The favorable outcome of SE in children may be related to advances in therapy and to the resistance of the immature brain to damage from seizures.