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Department of Pediatrics, Weill Cornell Medicine, New York, NY, United StatesNew-York Presbyterian Hospital, New York, NY, United StatesDepartment of Healthcare Policy & Research, Weill Cornell Medicine, New York, NY, United States
The incidence of pediatric SE is 20 per 100,000 children per year.
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The overall mortality of 3%.
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Symptomatic etiology (acute more so than remote) is the most important risk factor for morbidity, and mortality.
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SE is expensive, regularly costing more than $10,000 per episode and often more than $100,000 for refractory cases.
Abstract
Purpose
To summarize the epidemiology, morbidity, mortality, and costs of status epilepticus (SE) in the pediatric population.
Method
Review of the medical literature.
Results
The overall incidence of pediatric SE is roughly 20 per 100,000 children per year, with overall mortality of 3%. Underlying etiology is the biggest risk factor for SE, with symptomatic (acute > remote) etiologies associated with worse outcomes. The most common cause of SE in children is febrile SE, though this entity occurs primarily in early childhood. After a first episode, the risk of recurrence is similar to the risk after a first unprovoked seizure (25–40%). SE is expensive, regularly costing more than $10,000 per episode and often more than $100,000 for refractory cases.
Conclusion
SE is not an uncommon neurologic emergency and depending on the associated etiology can carry significant morbidity, mortality, and cost especially if treatment is not performed in a timely manner.
Status epilepticus (SE) is among the most common neurologic emergencies in pediatrics. An understanding of the epidemiology of SE can guide management and help clinicians counsel children and families. In this section, we aim to describe the epidemiology of pediatric SE and its subtypes while also examining the associated mortality and morbidity.
2. Incidence
The overall incidence of pediatric SE ranges between 3–42 episodes per 100,000 population per year worldwide [
] tend to report lower rates. A consistent finding across multiple studies is that the highest incidence of SE and refractory SE (RSE) is among children under 2 years of age. [
] This may be due to a higher rate of symptomatic causes of SE, the natural course of genetic/metabolic diseases, or an increased susceptibility to seizures in the developing brain [
] a neurological emergency that requires rapid treatment to minimize morbidity and mortality. Roughly half begin as focal seizures that subsequently generalize; the other half are generalized from onset [
Of importance, there are settings and populations in which nonconvulsive seizures other than absence status are common. For example, a large multicenter study of 550 children in the pediatric intensive care unit who had received EEG monitoring found one in ten had NCSE (30% of the cohort had at least one nonconvulsive electrographic seizure, and 33% of those with nonconvulsive seizures also had NCSE). [
] Independent risk factors for electrographic seizures included younger age, clinical seizures prior to EEG monitoring, an abnormal initial EEG background, interictal epileptiform discharges, and a prior diagnosis of epilepsy [
]. Among children with CSE, NCSE is often a sequelae. One third of children initially presenting with CSE subsequently have electrographic seizures without a clinical correlate [
]. Risk factors associated with the development of electrographic seizures after CSE included a prior diagnosis of epilepsy and the presence of interictal epileptiform discharges [
Although epileptic encephalopathies are not typically conceptualized as NCSE, they are important disorders in which frequent or continuous epileptic activity impairs cognition and development. There are population based epidemiological estimates for some epileptic encephalopathies. Infantile spasms occur in 1 in 3300 live births. [
For others, the epidemiology can be coarsely estimated from hospital-based studies. For example, neonatal epileptic encephalopathy occurred in 35 of a cohort of 611 newborns with seizures [
], suggesting neonatal epileptic encephalopathy has an incidence of 1 in 18,000 live births.
Continuous spike-and-wave during sleep (CSWS) and the Landau Kleffner Syndrome (LKS) have been described through several hundred published cases, though most were hospital based. [
] A back-of-the-envelope calculation can be made using a study of 440 children with epilepsy followed in an outpatient clinic, which found only a single case with CSWS / LKS [
], suggesting the prevalence of CSWS / LKS is 1–2 per 100,000 children. This may be a lower limit – tertiary care centers regularly care for children with these disorders. Reports suggest the EEG signature of CSWS/LKS occur in 1%–7% of children admitted for epilepsy monitoring and evaluation [
When children with SE continue to have seizures despite two appropriate antiepileptic drugs, it is called refractory SE (RSE), which is covered in depth elsewhere in this volume [
]. In children, an analysis of a database including roughly 20% of pediatric admissions in the US found that over five years, there were 678 children admitted to an ICU for SE who received pentobarbital, presumably for iatrogenic coma [
]. These data roughly suggest that RSE occurs in 2.5–8 per 100,000 children per year, and super RSE occurs roughly once per 100,000 children per year. In a retrospective study that examined all cases of SE between 1994 and 2004 and compared aborted SE versus RSE, epilepsy related risk factors for RSE include a first degree relative with seizures, use of 5 antiepileptic medications, and multiple seizures per week despite adequate treatment [
As per recommendations by the International League Against Epilepsy, the etiology of SE can be divided into three categories, (1) known/symptomatic, (2) SE in defined electroclinical syndromes, and (3) unknown/cryptogenic. Symptomatic causes are then subdivided into acute, remote, and progressive (Fig. 1). [
FSE occurs in young children (6 months–five years) with fever and seizures (continuous or intermittent without return to baseline) that last 30 min or longer, with no evidence of a central nervous system infection, explanatory metabolic abnormality, nor history of seizures without fever. FSE has been well characterized via an ongoing multicenter prospective cohort (The Consequences of Prolonged Febrile Seizures in Childhood; FEBSTAT study). The majority (75%) had FSE as the initial febrile seizure. Several viruses are associated with febrile seizures in children, though HHV-6 and/or HHV-7 (38% of FSE in the FEBSTAT study [
]. Seizures are typically convulsive, though two thirds begin with focal features that generalize. Interestingly, 25% of the patients had a first degree relative with a history of febrile seizures, suggesting a genetic predisposition [
], and thus a full evaluation including lumbar puncture is often indicated.
Other common causes of SE in children appear in Table 2. In a retrospective study of patients who had epilepsy due to a symptomatic cause there was an increased risk of SE if there were focal background EEG abnormalities, partial seizures with secondary generalization, or generalized abnormalities on neuroimaging [
]. Among people with epilepsy, several factors have been associated with an increased risk for SE. These include age of onset <1 year old, symptomatic etiology, and history of prior SE [
Seizures, syndromes, and etiologies in childhood epilepsy: The International League Against Epilepsy 1981, 1989, and 2017 classifications used in a population-based cohort.
Seizures, syndromes, and etiologies in childhood epilepsy: The International League Against Epilepsy 1981, 1989, and 2017 classifications used in a population-based cohort.
Seizures, syndromes, and etiologies in childhood epilepsy: The International League Against Epilepsy 1981, 1989, and 2017 classifications used in a population-based cohort.
Only a minority with classic neonatal epilepsy syndromes. Of 35 with neonatal encephalopathy, four had Ohtahara syndrome and one early myoclonic encephalopathy [
Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES.
Recent consensus definition: new onset refractory SE in a child without prior neurologic condition with no clear acute cause. Fever must have been present for 24 h–2 weeks prior to seizures, making FIRES distinct from febrile SE. [
Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions.
]). A particularly difficult to treat form of SE with unknown etiology is febrile infection-related epilepsy syndrome (FIRES) which has an estimated incidence 1/1,000,000 [
Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES.
]. This severe subtype of RSE has a high mortality rate (∼10%) and frequent neurological sequelae including refractory epilepsy, cognitive impairment, brain atrophy, and vegetative state [
Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES.
An appreciation of the monetary costs associated with caring children with epilepsy highlights the economic burden of the disease. A 15-year U.S study of the cost for any epilepsy admission between 1993 and 2008 saw the cost per day of admission rise from $1703 to $6131 with the average hospital stay cost rising from $10,050 to $23,909 [
A United States study from 1993 to 1994 and a German study from 2008 examined the cost of SE. The estimated mean inpatient costs were $18,834 in the USA and to €8347 (US $10,071) in Germany per admission [
A recent multicenter study in the US involving pediatric patients with SE included information about hospital costs. In children with RSE who received pentobarbital for iatrogenic coma, the average length of stay was 30 days, with a daily hospital cost of about $5000 per day and an average hospital stay cost of $148,000. In a smaller group who received pentobarbital and ketamine (i.e., suggesting a more refractory phenotype) the average hospital stay was 51 days, average daily cost of $6,000, and average cost of stay was $298,000 [
The immediate consequences of SE can be severe, and may include tachycardia, hypertension, respiratory failure, metabolic and/or respiratory acidosis, increased intracranial pressure, cerebral edema, electrolyte abnormalities, rhabdomyolysis, and renal failure [
Survivors of SE are at risk of remote neurologic disability including focal neurologic deficits (ie diplegia, extrapyramidal syndromes, cerebellar syndrome), cognitive impairment, seizure recurrence/epilepsy, and behavioral problems. Neurologic morbidities may occur in less than 15%, [
The risk of subsequent unprovoked seizures two years after a first-ever unprovoked episode of SE is 25–40%, which is similar to the risk of recurrence after first self-limited unprovoked seizure [
]. However, children with acute symptomatic causes, previous neurological abnormalities, or unclassified causes are at particularly high risk: half these children may develop epilepsy after a first episode of convulsive SE [
The estimated overall recurrence of convulsive SE is 20% after 4 years. When SE recurs, most (69%) recurrences occur within 1 year of the first episode of SE. Etiology is again the most important risk factor: the recurrence risk for SE is roughly 3% for febrile SE, 4% for SE of unknown etiology, 11% for acute symptomatic etiologies, 44% for remote symptomatic etiologies, and 67% for progressive symptomatic etiologies [
Children with nonfebrile CSE often have developmental scores 1–2 standard deviations lower than a reference group of normal children in multiple domains (motor, language, and cognition) [
]. A retrospective analysis of 460 patients with new onset SE found that children with symptomatic etiology had greater odds of cognitive and behavioral problems compared with children with unknown etiology [
]. Of importance, however, it is unclear if these developmental differences are due to the underlying etiology of the SE, or a sequelae of the SE itself. The population-based North London Convulsive Status Epilepticus in Childhood Surveillance Study examined the long-term developmental and psychiatric outcomes of 134 of 203 children with CSE in their cohort. After a mean of 8 years, 37% had behavioral problems and 28% had a psychiatric disorder that met criteria in the Diagnostic and Statistical Manual mental disorder IV (DSM-IV), including autism, attention deficit disorder, pervasive developmental disorder not otherwise specified, and developmental coordination disorder. Seizures before CSE (AOR 2.9) and recurrent CSE (AOR 1.9) increased the risk. These data indicate that patients with CSE often have behavioral and psychiatric manifestations several years after an event and require screening [
A multicenter Canadian study followed children with new onset epilepsy and found that convulsive SE was independently associated with a significantly worse quality of life as evidenced by scores on the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE) [
]. The QOLCE Questionnaire offers assessment of health related quality of life in a broad age group of children and several functional domains including physical function, social function, emotional well-being, behavior, and cognition [
The long-term effects of electrographic SE are still being determined. Among children with acute neurologic disorders who were reported to be neurodevelopmentally normal before PICU admission, electrographic SE (but not electrographic seizures) was associated with an increased risk of unfavorable global outcome, lower health-related quality of life scores, and an increased risk of subsequently diagnosed epilepsy [
]. A study of the effect of electrographic seizure burden on outcome found that the odds of neurological decline increased by 1.13 for every 1% increase in the maximum hourly seizure burden [
Mortality after SE in children is 3–11%. Deaths occur either due to the underlying cause or due to the complications of SE itself. Etiology is the most important predictor of outcome; symptomatic etiologies have the highest risk [
Short term mortality of SE, defined as up to 30 days post discharge, ranges from 3 to 9%, with symptomatic causes associated with a higher risk of mortality [
]. A multicenter review of 12,365 pediatric inpatients (age 0–20 years) with convulsive SE examined causes for mortality in the hospital. Several patient comorbidities corresponded to a greater mortality risk: near drowning, hemorrhagic shock, sepsis, massive aspiration, mechanical ventilation >96 h, transfusion, structural brain lesion, and hypoglycemia [
]. A retrospective observational study of 625 patients found that in critically ill neonates and children, the time from ICU admission to continuous EEG initiation and the presence of electrographic SE were independently associated with increased in-hospital mortality [
Electrographic SE is associated with a high risk of in-hospital mortality. In a multicenter retrospective study of 550 pediatric patients, electrographic SE was associated with odds ratio of 2.42 for mortality. In that study, 25% of the children with electrographic SE died. Electrographic seizures themselves were not an independent risk factor for mortality [
]. In the Rochester cohort, patients who survived 30 days after the episode of SE were followed until death or the completion of the study. Mortality for patients <1 year old at time of presentation was 16% compared to 3% for those age 1–19 years old. All those who died had a symptomatic etiology [
]. The mortality rate of all patients without a known cause was no different than that of the general population. Analysis of a Finnish cohort of individuals with childhood epilepsy followed prospectively for 30 years found that SE did not affect mortality, after controlling for etiology [
]. These population-based studies suggest that SE itself does not confer an increased risk of mortality, rather, similar to the short term mortality, it is the underlying etiology that is most predictive.
Some studies suggest that younger age is associated with increased mortality. In the Richmond cohort, the majority of all pediatric SE deaths occurred in the first year of life, 62% (23 of 37). SE mortality was low after the first year of life at 3% [
Refractory SE, expectedly, confers a higher risk of mortality with a wide range from 16 to 32%. The presence of generalized or multifocal epileptiform discharges, acute symptomatic etiology, and age <5 years old were risk factors for death [
Mortality in children is much lower as compared to adults, as demonstrated in several studies of SE that included both children and adults. In a California based cohort of convulsive SE case fatality was 1.4% for ages <5 years old and 2.4% for ages 5–19 years old, compared to 7.6% for 20–54, 16.1% for 55–74, and 19% for >75 [
]. In the Richmond cohort, the mortality for pediatric patients was 3%, while the mortality of adults was 26%. In the Rochester cohort, short term (within 30 days of SE) the overall mortality was 19%, 84% of which was comprised of adults (age >19 years old) [
]. The long-term mortality was 82% for patients above 65 years old and 32% between 20–64 years old. On the other hand, mortality was 16% for <1 year old and 3% in the 1–19 years old group [
A longer time to treatment has been associated with increased morbidity and mortality. In a prospective, observational cohort study of 218 pediatric SE patients, patients were divided into two cohorts: those who received a benzodiazepine within 10 min of seizure onset versus those who reeved a benzodiazepine after 10 min. Patients who received a benzodiazepine after 10 min had longer convulsive seizure duration (adjusted odds ratio (AOR), 2.6), were more likely to require a continuous infusion for treatment (AOR, 1.8), had more frequent hypotension (AOR 2.3), and were more likely to die (AOR 11) [
SE is among the most common neurologic emergencies in children. FSE is the most common cause of SE. The most important risk and prognostic factor is etiology, with symptomatic causes having worse outcomes. Children who have an acute symptomatic cause have a higher risk of recurrent SE and of developing epilepsy. SE carries significant cost, mortality, and morbidity making prompt diagnosis and treatment critical.
Conflict of interest
There are no conflict of interests to disclose for this paper. The authors alone are responsible for the content and writing of this article.
References
DeLorenzo R.J.
Hauser W.A.
Towne A.R.
Boggs J.G.
Pellock J.M.
Penberthy L.
et al.
A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia.
Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES.
Seizures, syndromes, and etiologies in childhood epilepsy: The International League Against Epilepsy 1981, 1989, and 2017 classifications used in a population-based cohort.
Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions.
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