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New-onset seizure presenting as status epilepticus: Etiology and clinical characteristics in a cohort of 236 children

Open ArchivePublished:May 21, 2018DOI:https://doi.org/10.1016/j.seizure.2018.05.011

      Highlights

      • Nearly 60% of all status epilepticus (SE) in children is the first epileptic event.
      • Febrile and acute symptomatic SE represents the largest etiology subgroup.
      • The etiology and SE duration are the main determinants of the first SE outcome.

      Abstract

      Purpose

      Evaluation of the etiology, clinical characteristics and outcome of the first status epilepticus (fSE) event in children.

      Method

      The patients with fSE hospitalized in our Institute from 1995 to 2011 were included. The etiology was characterized as either known (symptomatic) or unknown (cryptogenic). Outcome was assessed at the end of hospitalization. Logistic regression analyses were used to assess predictors of the outcome, with odds ratio adjusted by age as a measure effect.

      Results

      The study included 236 patients with a median age of 2.0 years (IQR 4.0). Etiology was identified as secondary to: defined electroclinical syndromes 108 (45.8), acute symptomatic conditions 63 (26.7%), unknown 24 (10.1%), progressive encephalopathy 23 (9.7%), or remote symptomatic 18 (7.6%). Recurrence rate was 16.9%, neurological consequences were in 24.6% and case-fatality ratio was 4.7%. The main predictors were for: a) death – progressive encephalopathy (OR = 14.68, 95% CI 4.06–23.11. p = 0.001); b) neurological sequelae – acute symtomatic (OR 3.44, 95% CI 4.82–6.47) p = 0.001, remote symptomatic (OR = 13.84, 95% CI 4.34–44.12. p = 0.001), progressive encephalopathy (OR = 3.94, 95% CI 1.64–9.56. p = 0.002), seizure duration >60 min (OR = 0.44, 95% CI 0.24–0.81. p = 0.001); c) seziure recurrence – acute symptomatic etiology (OR = 3.59, 95% CI 41.76–7.21. p = 0.001), seizure duration >60 min (OR = 0.30, 95% CI 0.15–0.61. p = 0.001).

      Conclusions

      In children with fSE, exploring acute disorders and immediate etiological treatment is essential. The outcome of fSE is favorable concerning the recurrence rate, while neurological sequelae are seen in one quarter of the patients. The etiology and fSE duration are the main determinants of outcome.

      Keywords

      1. Introduction

      Status epilepticus (SE) is a common, life-threatening medical condition which requires immediate diagnosis and treatment. In children, it may be a part of clinical presentation of heterogeneous disorders, as well as the first epileptic event. The new definition proposed by ILAE [
      • Trinka E.
      • Cock H.
      • Hesdorffer D.
      • Rossetti A.O.
      • Scheffer I.E.
      • Shinnar S.
      A definition and classification of status epilepticus – report of ILAE Task Force of classification of status epilepticus.
      ] defines SE as a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to abnormally prolonged seizures (after time point 1). It is a condition that can have long-term consequences (after time point 2), including neuronal death, neuronal injury, and the alteration of neuronal networks, depending on the type and duration of seizures [
      • Trinka E.
      • Cock H.
      • Hesdorffer D.
      • Rossetti A.O.
      • Scheffer I.E.
      • Shinnar S.
      A definition and classification of status epilepticus – report of ILAE Task Force of classification of status epilepticus.
      ]. For convulsive SE, the time point 1 is 5 min and the time point 2 is 30 min.
      The new classification of SE proposed by ILAE [
      • Trinka E.
      • Cock H.
      • Hesdorffer D.
      • Rossetti A.O.
      • Scheffer I.E.
      • Shinnar S.
      A definition and classification of status epilepticus – report of ILAE Task Force of classification of status epilepticus.
      ] has four axes: semiology, etiology, electroencephalographic correlates and age. The semiology classification depends on the presence or absence of prominent motor symptoms, and the degree of impaired consciousness. According to those criteria, all SE are summarized as convulsive SE or nonconvulsive SE. The etiologies of SE can be known (symptomatic) and unknown (cryptogenic). Symptomatic etiologies include acute, remote and progressive disorders and as well as SE in defined electroclinical syndromes [
      • Trinka E.
      • Cock H.
      • Hesdorffer D.
      • Rossetti A.O.
      • Scheffer I.E.
      • Shinnar S.
      A definition and classification of status epilepticus – report of ILAE Task Force of classification of status epilepticus.
      ]. The particular features of SE as the initial seizure are the subject of only a small number of publications. The frequency of those presenting with SE is variable in different studies. The Status Epilepticus Study Group of Japan found that SE was the first seizure in 121 of 201 children with SE and suggested good outcome (in 89% patients) in that group of patients [
      • Maegaki Y.
      • Kurozawa Y.
      • Tamasaki A.
      • Togawa M.
      • Tamura A.
      • Hirao M.
      • et al.
      Early predictors of status epilepticus-associated mortality and morbidity in children.
      ].The North London Status Epilepticus in Childhood Surveillance Study (NLSTEPSS): a prospective, population-based study of convulsive status epilepticus in childhood enrolled 226 children, 176 of whom had a first ever episode of convulsive status epilepticus. Ninety eight (56%) children had been neurologically healthy before their first ever episode and 56 (57%) of those children had a prolonged febrile seizure. Acute bacterial meningitis was diagnosed in 11 (12%) of the children with first ever febrile convulsive status epilepticus. The case-fatality ratio was 3% for the first episode of convulsive status [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Bedford H.
      • Wade A.
      • Scott R.C.
      • et al.
      Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study.
      ]. Mortality caused by SE was not associated with recurrence rate in pediatric patients [
      • De Lorenzo R.J.
      Incidence and causes of status epilepticus.
      ].The initial seizures in the form of SE were provoked by drugs in less than 5% of SE [
      • Cock H.
      Drug-induced status epilepticus.
      ]. The recent study by Singh et al. analysed 144 children with new-onset seizures presenting as status epilepticus in a tertiary care children’s hospital. The most common etiology was febrile SE, followed by unknown etiology. The most common acute symptomatic cause was CNS infection and the most common remote symptomatic cause was cerebral dysgenesis [
      • Singh R.K.
      • Stephens S.
      • Berl M.M.
      • et al.
      Prospective study of new-onset seizures presenting as status epilepticus in childhood.
      ].
      Our study aim was to describe the etiology of new-onset SE and to identify the predictors of early recurrence and outcome and, to analyse separately, those parameters in children with new-onset SE with duration of more than 60 min.

      2. Methods

      The retrospective study included children aged two months to eighteen years with a new-onset seizure presenting as convulsive SE. All patients were treated in the Intensive Care Unit (ICU) and/or the Department of Neurology in the Institute for Mother and Child Healthcare of Serbia during the period of January 1995 to January 2011. The criteria for ICU admission were: seizing on admission with no response to initial treatment in emergency room, severity of underlying disorder, disturbances of consciousness or vital functions. Status epilepticus is defined as a continuous seizure or intermittent seizures without full recovery of consciousness between seizures for more than 30 min. In the term of SE duration, all patients were divided in two groups: SE duration under 60 min, or SE lasting more than 60 min. Super refractory status epilepticus (SRSE) was identified if the SE continued, or recurred, 24 h or more after the onset of anesthetic drugs given in continuous infusion. This designation included those cases that recurred after reduction or withdrawal of anaesthesia [
      • Wasterlain C.G.
      • Chen J.W.
      Definition and classification of status epilepticus.
      ,
      • Shorvon S.
      • Ferlisi M.
      The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol.
      ]. Diagnosis of convulsive SE was made by pediatrician, according to medical history data and clinical assessment, with early consultation with epileptologist. Duration of SE was assessed clinically including the data given from observers about the seizure duration before and after admission. Patients with history of previous seizure, neonatal or febrile seizures, or the patients without previous seizures but with continuous epileptic discharges during sleep, or burst suppression recorded on EEG in any time before SE, were excluded. According to the recent classification the etiology was summarized in two categories: known (symptomatic) or unknown (cryptogenic). Symptomatic etiologies included acute, remote and progressive disorders and SE in defined electroclinical syndromes. Remote symptomatic etiologies included: previous hypoxic ischemic encephalopathy, intracranial hemorrhage, cerebral palsy, CNS malformations, vascular and other abnormalities, previous head injury or CNS surgery. Acute symptomatic etiologies included: acute brain disease or injuries, such as CNS infections, cerebrovascular insults, acute systemic disease, hypertension, drugs or acute metabolic disorders. Progressive encephalopathies included different disorders with a progressive course: neurodegenerative, metabolic, neurogenetic, malignant or neurocutaneous disorders. Febrile SE werefebrile seizures which lasted for more than 30 min and weredefined as electroclinical syndromes [
      • Trinka E.
      • Cock H.
      • Hesdorffer D.
      • Rossetti A.O.
      • Scheffer I.E.
      • Shinnar S.
      A definition and classification of status epilepticus – report of ILAE Task Force of classification of status epilepticus.
      ]. Encephalitis is characterized by brain inflammation, as a consequence of, direct infection of the brain parenchyma, a post-infectious process or a noninfectious condition. The diagnosis of encephalitis was established according to diagnostic criteria: mental status in all patients was altered and lasted ≥24 h (decreased or altered level of consciousness, lethargy or personality change) with no alternative cause identified, associated with fever, seizure and at least one additional characteristic: new onset of focal neurologic findings, cerebrospinal fluid (CSF) WBC count ≥5/cubic mm, abnormality of brain parenchyma on neuroimaging suggestive of encephalitis or abnormality of electroencephalography (EEG) consistent with encephalitis and not attributable to another cause [
      • Venkatesan A.
      • Tunkel A.R.
      • Bloch K.C.
      • et al.
      Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium.
      ,
      • Bloch K.C.
      • Glaser C.
      Diagnostic approaches for patients with suspected encephalitis.
      ,
      • Dalmau J.
      • Lancaster E.
      • Martinez-Hernandez E.
      • et al.
      Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis.
      ,
      • Gable M.S.
      • Sheriff H.
      • Dalmau J.
      • et al.
      The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project.
      ].
      In all cases of clinically suspected CNS inflammation, biochemical, serological, microbacteriological, immunological analyses of CSF and blood and neuroradiological evaluations were performed. Polymerase chain reaction (PCR) and/or serological analyses of CSF and blood were performed. Retrospectively, the criteria for febrile infection–related epilepsy syndrome (FIRES) [
      • Krame U.
      • Chi Ch.
      • Li K.
      • et al.
      Febrile infection–related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children.
      ] were analysed.
      According to the recent semiologic classification, only patients with prominent motor symptoms were evaluated. An EEG was done in all cases within 48 h from the onset of SE. Depending on the clinical course, some patients had serial EEGs done, although the EEG was not used for assessment of SE duration.
      Genetic analyses for epileptic encephalopathies and epilepsies were not available during the time of investigation.
      A standardized hospital protocol was used for termination of seizures in all cases: midazolam iv/im and diazepam rectally were given as the first line drugs, phenobarbital as the second line drug, and midazolam and thiopenthal, in continuous intravenous infusion, as third line drugs. The termination of SE was assessed clinically. Simultaneous with SE treatment and intensive care, if needed, therapy for the underlying etiology was given if possible. Treatment prior to hospitalization included administration of first and second line drugs for SE.The outcome of fSE was assessed at the end of hospitalization, within 30 days, in relation to SE recurrence, neurological consequences and death. Recurrence of SE was defined as recurrence of SE episode lasting at least 6 h after the previous episode had stopped. Neurological sequelae included new neurological abnormalities or worsening of preexisting neurological abnormalities.
      Logistic regression analyses were used to assess predictors for the outcome. Odds ratio (OR) with 95% CI (confidence interval), adjusted by age, was calculated. The following potential predictors were evaluated: the age of patients, fSE etiology, type and seizure duration, prehospital treatment and necessity for intensive therapy.
      The study was approved by our Institutional Ethics Board.

      3. Results

      The retrospective study evaluated 236 children with status epilepticus as the first epileptic event treated in the Neurology Department and/or ICU in the Institute for Mother and Child Healthcare in Belgrade, during a 16-year period. This cohort of 236 patients was 59.7% of 395 patients with any status epilepticus treated in the same period in our hospital. The age of the patients varied from two months to 18 years, with median age 2.0 years (IQR-Interquartile range 4.0). The gender distribution was similar, 129 male and 107 female. According to the semiologic classification, all patients had prominent motor manifestations. 130 patients (55.1%) had generalized fSE and 106 patients (44.9%) had focal fSE. In 156 patients (66.1%) the seizures lasted between 30 and 60 min, and in 80 children (33.9%) more than 60 min, including four patients with SRSE. Demographic features and clinical characteristics of fSE are presented in Table 1.
      Table 1Demographic and clinical features of investigated patients.
      VariablesValues
      Gender
      - Male

      - Female
      129 (54.7%)

      107 (45.3%)
      Age (years)2.0 (4.0)
      Median (IQR-Interquartile range).
      Status epilepticus duration
      - Less than 60 min

      - More than 60 min
      156 (66.1%)

      80 (33.9%)
      Status epilepticus semiology
      - Generalized

      - Focal
      136 (55.1%)

      106 (44.9%)
      Prehospital treatment159 (67.4%)
      Effective drugs
      - Midazolam intravenous/infusion

      - Diazepam

      - Phenobarbital
      98/108 (91.7%)

      87/144 (60.4%)

      50/74 (67.6%)
      Intensive care therapy
      - Prolonged oxygen therapy

      - Artificial ventilation

      - Artificial ventilation + circulatory support
      50 (21.2%)

      2

      33

      15
      Side effects20 (8.5%)
      Outcomes
      - Recurrence

      - Neurological squelae

      - Lethal outcome
      40 (16.9%)

      58 (24.6%)

      11 (24.6%)
      a Median (IQR-Interquartile range).
      The etiology of SE as the first epileptic event in children is presented in Table 2. Two groups are delineated, those with SE lasting less and those lasting more than 60 min. The most frequent SE etiology, in our cohort, was that seen in defined electroclinical syndromes and diagnosed in 108 (45.8%) with febrile SE. Febrile SE was experienced by 93 patients (39.4% of all patients with fSE) and in 74 (79.6%) with a SE duration under 60 min. Other etiologies included: acute symptomatic in 63 (26.7%), unknown in 24 (10.1%), progressive encephalopathy in 23 (9.7%) and remote symptomatic in 18 (7.6%). CNS Inflammation was associated with status epilepticus as the first epileptic event in 49 children (20.8%). Etiology identified was: acute (28 cases), immune-mediated encephalitis (6 cases), meningitis (11 cases), tuberculoses (2 cases), ventriculitis (single case), and abscess (single case). Polymerase chain reaction (PCR) and/or serological analyses of cerebrospinal fluid (CSF) and blood showed that pathogens in the group of acute encephalitis (28 patients) were Herpes simplex virus (5), and Mycoplasma pneumonia (2 cases). In other patients with acute encephalitis, the pathogen was not identified. The blood and CSF cultures showed meningitis was caused by Streptococcus pneumonia (3 cases), Neisseria meningitides (single case), and Escherichia coli (single case). About half of the patients with CNS inflammation had SE with duration of more than 60 min (49%) including three patients with SRSE. Despite the appropriate treatment and intensive care, children with CNS inflammation had neurological consequences in 45%. Three children died: two with fulminate acute encephalitis and one with tuberculoses. FIRES was not diagnosed at presentation orretrospectivly.
      Table 2The etiology of status epilepticus as the first epileptic event in children.
      Etiology groupAll patient with fSE

      Number (%)
      SE duration <60 min

      Number (%)
      SE duration >60 min

      Number (%)
      p-value
      SE in defined electroclinical syndromes

      - Febrile SE

      - Other electroclinical syndromes
      108 (45.8)

      93

      15
      82 (52.6)

      74

      8
      26 (32.5)

      19

      7
      0.027
      Acute symptomatic

      - CNS inflammation

      - Acute systemic, GI, RS

      - Acute metabolic disorder

      -PRES

      -CVI

      -Drugs
      63 (26.7)

      49

      4

      6

      2

      1

      1
      31 (19.9)

      25

      1

      4

      2

      1

      0
      32 (40)

      24

      5

      2

      0

      0

      1
      0.196
      Unknown24 (10.1)6 (3.8)8 (10)
      Progressive encephalopathy

      - Neurodegenerative

      - Malignant neoplasm

      - NC, mitochondrial disease
      23 (9.7)

      11

      8

      4
      18 (11.5)

      7

      6

      4
      5 (6.3)

      4

      2

      0
      0.364
      Remote symptomatic

      - HIE

      - ICH

      - Cerebral palsy

      - Vascular CNS abnormalities
      18 (7.6%)

      6

      3

      7

      2
      9 (5.8)

      2

      2

      4

      1
      9 (11.3)

      4

      1

      3

      1
      0.767
      Total number236 (100)156 (100)80 (100)
      CNS – central nervous system, CVI – cerebrovascular insult, GI – gastrointestinal, RS – respiratory system, PRES – posterior reversible encephalopathy syndrome, NC – neurocutaneous, HIC – hypoxic ischemic encephalopathy, ICH – intracranial hemorrhage.
      Prior to admission to our hospital, SE treatment was started in 159 (67.4%) patients. In 126 (79.2%) of these 159 patients, rectal diazepam was administered. Phenobarbital was given to 38 patients (23.9%) and midazolam to 10 patients (6.3%) before hospitalization. Prehospital treatment was started in 52 (65%) patients with SE lasting more than 60 min. We have no data about the period from the onset of seizure to the start of medication administration. Midazolam was the most effective drug for termination of SE when given intravenously or in continuous infusion in 98 of 108 patients, (91.7%). Phenobarbital terminated SE in 50 of 74 patients (67.6%) while the most frequently used drug, diazepam, was effective in 87 of 144 children (60.4%). Continuous intravenous infusion of thiopental was given in four cases. Midazolam and/or thiopental infusion was given in total of 57 patients with duration range of infusion 2–720 h (mean 92.5). Intensive care was necessary in 50 patients (21.2%): artificial ventilation in 33 (66%), circulatory support in association with artificial ventilation in 15 (30%), and prolonged oxygen therapy in 2 patients. Prolonged depression of consciousness and/or respiratory impairment occurred in 20 of the treated patients (8.5%). Treatment given to patients with status epilepticus, as the first epileptic event, is presented in Table 1.

      3.1 Outcomes

      SE recurrence rate was 16.9% (40 patients), neurological sequelae were observed in 58 children (24.6%) and the case-fatality ratio was 4.7% (11 patients). Outcomes are presented in Table 1.

      3.2 Predictors for recurrence

      Patients with acute symptomatic etiology (OR = 3.59, 95% CI 41.76–7.21. p = 0.001), or with fSE duration more than 60 min (OR = 0.30, 95% CI 0.15–0.61. p = 0.001), had significantly higher risk for SE recurrence (Table 3). SE of unknown etiology (OR = 0.11, 95% CI 0.01–0.80. p = 0.030) and SE in defined electroclinical syndromes (OR = 0.27, 95% CI 0.11–0.64. p = 0.003) were associated with very low risk for SE recurrence. Focal SE was associated with a higher recurrence rate (OR = 0.48, 95% CI 0.24–0.96. p = 0.038).
      Table 3Predictors for status epilepticus recurrence.
      Variablep-ValueOdds ratio95% CI
      Age0.5751.030.94–1.12
      fSE type0.0380.480.24–0.96
      SE duration > 60 min0.0010.300.15–0.61
      Prehospital treatment0.2770.680.34–1.37
      ICU treatment0.0882.750.86–8.78
      Remote symptomatic etiology0.2102.010.67–6.00
      SE in defined electroclinical syndromes0.0030.270.11–0.64
      Acute symptomatic etiology0.0013.561.76–7.21
      Progressive encephalopathy0.0772.290.91–6.25
      Unknown etiology0.0300.110.01–0.80

      3.3 Predictors for neurological sequelae

      The risk factors for neurological sequelae (Table 4) included SE duration of more than 60 min (OR = 0.44, 95% CI 0.24–0.81. p = 0.001), acute symtomatic etiology(OR = 3.44, 95% CI 4.82–6.47. p = 0.001), remote symptomatic etiology (OR = 13.84, 95% CI 4.34–44.12. p = 0.001) and progressive encephalopathy (OR = 3.94, 95% CI 1.64–9.56. p = 0.002). Status epilepticus in defined electroclinical syndromes (OR = 0.04, 95% CI 0.01–0.14. p = 0.001), or of unknown etiology (OR = 0.22, 95% CI 0.06–0.73. p = 0.013), was associated with low risk for neurological sequelae.
      Table 4Predictors for neurologic sequelae after first SE.
      Variablep-ValueOdds ratio95% CI
      Age0.4681.030.95–1.11
      fSE type0.3710.760.42–1.38
      SE duration >60 min0.0090.440.24–0.81
      Prehospital treatment0.5040.810.43–1.51
      ICU treatment0.1412.480.74–8.33
      Remote symptomatic etiology0.00113.844.34–44.12
      SE in defined electroclinical syndromes0.0010.030.01–0.14
      Acute symptomatic etiology0.0013.431.82–6.47
      Progressive encephalopathy0.0023.961.64–9.56
      Unknown etiology0.0130.220.06–0.73

      3.4 Predictors for lethal outcome

      The main predictor for death in fSE (Table 5) is a diagnosis of progressive encephalopathy (OR = 14.68, 95% CI 4.06-23.11. p = 0.001). SE in defined electroclinical syndromes (OR = 0.12, 95% CI 0.01–0.89. p = 0.033) was associated with low risk for lethal outcome.
      Table 5Predictors for lethal outcome after first status epilepticus.
      Variablep-ValueOdds ratio95% CI
      Age0.7211.030.87–1.22
      fSE type0.0883.870.80–18.30
      SE duration >60 min0.6361.390.36–5.38
      Prehospital treatment0.7870.840.24–2.96
      ICU treatment0.2472.280.56–9.18
      Remote symptomatic etiology0.8521.220.15–10.13
      SE in defined electroclinical syndromes0.0330.120.01–0.89
      Acute symptomatic etiology0.9651.030.26–4.02
      Progressive encephalopathy0.00114.684.06–23.11
      Unknown etiology0.5050.490.06–3.96
      Patients treated in the ICU, who required artificial ventilation and circulatory support, were at high risk for SE recurrence, neurological sequelae and/or death, but not with statistical significance. SE in defined electroclinical syndromes, including febrile SE as the largest subgroup, showed a favorable etiology with low risk of SE recurrence, neurological sequelae and death.

      3.5 Status epilepticus with duration of more than 60 min

      The mean age of the patients with SE, with a duration of more than 60 min, was 4.2 years. Etiologies are presented in Table 2. Acute symptomatic etiology was the predominant group, and CNS inflammation was identified in 78.1% of all acute etiologies. Prehospital Treatment prior to hospitalization was started in 65% of the patients. In patients with SE of more than 60 min duration, SE recurrence rate was 28.7%, neurological sequelae were seen in 35%, and the case-fatality ratio was 3.75%. As presented in the Results section, SE duration of more than 60 min has significant impact on the recurrence rate (QR = 0.30; 95% CI 0.15-0.61. p = 0.001) and neurological sequelae (QR = 0.44; 95% CI 0.24-0.81.p = .009). In the group of SRSE, two of four cases had limbic encephalitis; one had CNS tuberculosis, and one child had a cerebral neoplasm.

      4. Discussion

      Different clinical aspects of status epilepticus are of great interest for both scientists and clinicians. Despite the progress in basic science, translation into the clinical field remains difficult [
      • Trinka E.
      • Brigo F.
      • Shorvon S.
      Recent advances in status epilepticus.
      ]. SE as the first epileptic event is an important percentage of all SE episodes in children [
      • Maegaki Y.
      • Kurozawa Y.
      • Tamasaki A.
      • Togawa M.
      • Tamura A.
      • Hirao M.
      • et al.
      Early predictors of status epilepticus-associated mortality and morbidity in children.
      ,
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Bedford H.
      • Wade A.
      • Scott R.C.
      • et al.
      Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study.
      ]. In comparing to similar investigations in pediatric populations [
      • Kravljanac R.
      • Djuric M.
      • Jankovic B.
      • et al.
      Etiology, clinical course and response to the treatment of status epilepticus in children: a 16-year single-center experience based on 602 episodes of status epilepticus.
      ,
      • Kravljanac R.
      • Jovic N.
      • Djuric M.
      • et al.
      Outcome of status epilepticus in children treated in the intensive care unit: a study of 302 cases.
      ], we found that fSE has specific features in regards to etiology, duration, response to the treatment and outcome. There was no difference in the mean age orgender distribution between this current study and published data, [
      • Kravljanac R.
      • Djuric M.
      • Jankovic B.
      • et al.
      Etiology, clinical course and response to the treatment of status epilepticus in children: a 16-year single-center experience based on 602 episodes of status epilepticus.
      ,
      • Kravljanac R.
      • Jovic N.
      • Djuric M.
      • et al.
      Outcome of status epilepticus in children treated in the intensive care unit: a study of 302 cases.
      ].
      In the prospective study of Maytal et al. [
      • Maytal J.
      • Shinnar S.
      • Moshé S.L.
      • et al.
      Low morbidity and mortality of status epilepticus in children.
      ] which included pediatric patients with SE, similar etiologies were identified in our study (idiopathic, acute, remote symptomatic and febrile SE). Only the presence of a progressive encephalopathy was seen less frequently. In our study, the frequency of febrile SE was twice as high as in the Maytal et al. study. Acute systemic or brain insult was more frequent in our investigation, while remote symptomatic and progressive disease in etiology in our study are found in similar percentage as in the literature [
      • Maytal J.
      • Shinnar S.
      • Moshé S.L.
      • et al.
      Low morbidity and mortality of status epilepticus in children.
      ]. Similarly to the recently published study by Singh et al. [
      • Singh R.K.
      • Stephens S.
      • Berl M.M.
      • et al.
      Prospective study of new-onset seizures presenting as status epilepticus in childhood.
      ], we found that CNS inflammation was the most frequent cause in the group of acute symptomatic etiologies, especially among the patients with fSE and with SE duration ofmore than 60 min. A prospective, population-based study of convulsive SE in childhood showed that prolonged febrile seizures were the predominant etiology of SE. The authors pointed out that among febrile children with SE, 12% had acute bacterial meningitis [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Bedford H.
      • Wade A.
      • Scott R.C.
      • et al.
      Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study.
      ]. Similar to the literature data [
      • Cock H.
      Drug-induced status epilepticus.
      ], medications rarely provoked fSE in our patients. According to the literature, about 150 genetic mutations associated with SE have been identified [
      • Bhatnagar M.
      • Shorvon S.
      Genetic mutations associated with status epilepticus.
      ]. Although we did not have genetic testing data, it is supposed that some of our patients with an unknown etiology might have a genetic cause.
      fSE less frequently lasted for more than 60 min (33.9%), in comparison to other studies in which about one half of SE lasted more than 60 min [
      • Kravljanac R.
      • Djuric M.
      • Jankovic B.
      • et al.
      Etiology, clinical course and response to the treatment of status epilepticus in children: a 16-year single-center experience based on 602 episodes of status epilepticus.
      ,
      • Kravljanac R.
      • Jovic N.
      • Djuric M.
      • et al.
      Outcome of status epilepticus in children treated in the intensive care unit: a study of 302 cases.
      ]. Eighty percent of patients with febrile SE had seizure duration less than 60 min. In fSEwith prolonged duration, it is very important to explore the underlying etiology, especially CNS inflammation, as well as to start appropriate etiological treatment early. Immune-mediated encephalitis is not frequent among children, but early recognition and treatment using immunosuppressive therapy, including ketogenic diet, is essential [
      • Haberlandt E.
      • Bast T.
      • Ebner A.
      • et al.
      Limbic encephalitis in children and adolescents.
      ,
      • Nabbout R.
      • Mazzuca M.
      • Hubert P.
      • et al.
      Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES).
      ,
      • Appavu B.
      • Vanatta L.
      • Condie J.
      • et al.
      Ketogenic diet treatment for pediatric super-refractory status epilepticus.
      ,
      • Fong J.S.
      • Hantus S.
      • Altay E.
      • et al.
      De novo sustained refractory status epilepticus and encephalopathy: a retrospective case series.
      ]. In patients with a fulminate course, and despite specific and early treatment, poor outcome may occur [
      • Kravljanac R.
      • Jovic N.
      • Djuric M.
      • et al.
      Epilepsia partialis continua in children with fulminant subacute sclerosing panencephalitis.
      ], as in our patients with SRSE and lethal outcome.
      We found that patients with fSE had better response to the treatment with less need for ICU treatment. They also had fewer anticonvulsive drug side effects compared to published papers which included patients with all SE [
      • Kravljanac R.
      • Djuric M.
      • Jankovic B.
      • et al.
      Etiology, clinical course and response to the treatment of status epilepticus in children: a 16-year single-center experience based on 602 episodes of status epilepticus.
      ,
      • Kravljanac R.
      • Jovic N.
      • Djuric M.
      • et al.
      Outcome of status epilepticus in children treated in the intensive care unit: a study of 302 cases.
      ]. The literaturesuggests that early and prehospital treatment has beneficial effect on seizure duration [
      • Alldredge B.K.
      • Wall D.B.
      • Ferriero D.M.
      Effect of prehospital treatment on the outcome of status epilepticus in children.
      ,
      • Eriksson K.
      • Metsaranta P.
      • Huhtala H.
      • et al.
      Treatment delay and the risk of prolonged status epilepticus.
      ]. Our results, however, showed that prehospital treatment did not have significant impact on fSE duration. The literature indicates that children with refractory SE do not receive more timely treatment if they have a prior diagnosis of epilepsy. However, a history of SE is overall associated with a more timely administration of abortive medication [
      • Sánchez Fernández I.
      • Jackson M.C.
      • Abend N.S.
      • et al.
      Pediatric Status Epilepticus Research Group (pSERG): Refractory status epilepticus in children with and without prior epilepsy or status epilepticus.
      ].
      The outcome of fSE is favorable in regards tothe recurrence rate,although neurologic consequences are frequent due to acute underlying disorders. The case fatality ratio in our patients was 4.7%. This is slightly higher compared to the literature: 3% [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Bedford H.
      • Wade A.
      • Scott R.C.
      • et al.
      Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study.
      ] and 3.6% [
      • Kravljanac R.
      • Djuric M.
      • Jankovic B.
      • et al.
      Etiology, clinical course and response to the treatment of status epilepticus in children: a 16-year single-center experience based on 602 episodes of status epilepticus.
      ], but significantly lower than the mortality (9.3%) in children with SE treated in an ICU [
      • Kravljanac R.
      • Jovic N.
      • Djuric M.
      • et al.
      Outcome of status epilepticus in children treated in the intensive care unit: a study of 302 cases.
      ]. A systematic review of the outcome of pediatric convulsive SE, which included 63 studies, showed short-term mortality between 2.7% and 5.2% and morbidity, other than epilepsy, of less than 15% [
      • Raspall-Chaure M.
      • Chin R.F.
      • Neville B.G.
      • et al.
      Outcome of paediatric convulsive status epilepticus: a systematic review.
      ].
      In our study, the recurrence rate (16.9%) was lower in comparison to the recurrence rate (21%) reported in the literature [
      • Kravljanac R.
      • Jovic N.
      • Djuric M.
      • et al.
      Outcome of status epilepticus in children treated in the intensive care unit: a study of 302 cases.
      ]. We found that neurological sequelae (24.6%) were more frequent in our study compared to children with SE treated in ICU (12.9%) [
      • Kravljanac R.
      • Jovic N.
      • Djuric M.
      • et al.
      Outcome of status epilepticus in children treated in the intensive care unit: a study of 302 cases.
      ]. The reason for this high rate of neurological sequelae might be the high percentage of acute CNS disease in our cohort, which per se can be associated with a high rate of neurological impairment. In the group of 49 patients with acute CNS inflammation, neurological consequences were seen in 45%. In the study of Michaeli et al., of 47 children enrolled with acute encephalitis, one died and 29 had neurologic sequelae [
      • Michaeli O.
      • Kassis I.
      • Shachor-Meyouhas Y.
      • et al.
      Long-term motor and cognitive outcome of acute encephalitis.
      ]. In the group of adult patients with in-hospital SE, prognosis is poor. A mortality rate of 61% appears more related to underlying conditions rather than to the SEduration [
      • Delanty N.
      • French J.A.
      • Labar D.R.
      • et al.
      Status epilepticus arising de novo in hospitalized patients: an analysis of 41 patients.
      ]. In a retrospective study, the 30-day mortality rate of all subjects with SE was 18.4% [
      • Lui H.
      • Hui K.
      • Fong W.
      • et al.
      De novo status epilepticus is associated with adverse outcome: an 11-year retrospective study in Hong Kong.
      ]. fSE was associated with longer status duration, longer ICU stay and poorer outcome [
      • Lui H.
      • Hui K.
      • Fong W.
      • et al.
      De novo status epilepticus is associated with adverse outcome: an 11-year retrospective study in Hong Kong.
      ].
      Our study indicates thatetiology and fSE duration are the main determinants of fSE outcome. The literature also suggests that etiology is the most important predictor of prognosis [
      • Kravljanac R.
      • Jovic N.
      • Djuric M.
      • et al.
      Outcome of status epilepticus in children treated in the intensive care unit: a study of 302 cases.
      ,
      • Raspall-Chaure M.
      • Chin R.F.
      • Neville B.G.
      • et al.
      Outcome of paediatric convulsive status epilepticus: a systematic review.
      ]. Patients age, fSE type and prehospital treatment, have no significant impact on outcome. Our data suggests that patients treated in an ICU, and who required artificial ventilation and circulatory support, are at high risk of SE recurrence, neurological sequelae or death, but without statistical significance. Similar to reports in the literature [
      • Maytal J.
      • Shinnar S.
      • Moshé S.L.
      • et al.
      Low morbidity and mortality of status epilepticus in children.
      ,
      • Raspall-Chaure M.
      • Chin R.F.
      • Neville B.G.
      • et al.
      Outcome of paediatric convulsive status epilepticus: a systematic review.
      ], febrile SE is a favorable etiology with low risk of SE recurrence, neurological consequences or death.
      There are some limitations of this study. The retrospective design precludesdata on treatment delay and EEG monitoring. Genetic analyses for epileptic encephalopathies was not available in the investigation period. It is possible that some of the patients with unknown etiology may have a genetic etiology. A subset of this cohort has been reported in previous studies [
      • Kravljanac R.
      • Djuric M.
      • Jankovic B.
      • et al.
      Etiology, clinical course and response to the treatment of status epilepticus in children: a 16-year single-center experience based on 602 episodes of status epilepticus.
      ,
      • Kravljanac R.
      • Jovic N.
      • Djuric M.
      • et al.
      Outcome of status epilepticus in children treated in the intensive care unit: a study of 302 cases.
      ].
      In conclusion, our study has shown that fSE is common among all the children with SE. Febrile SE represents the largest etiology subgroup, followed by acute symptomatic SE, attributed primarily to CNS infections. A large proportion had SE with a duration of more than 60 min, and these included primarily those in the acute symptomatic category. Etiology and fSE duration are the main determinants of fSE outcome. In the clinical approach topatients with fSE, it is important to explore the underlying, mostly acute disorders, since concomitant therapy is important and may have significant impact on the clinical outcome.

      Conflict of interest

      None of the authors has any conflict of interest to disclose.

      Acknowledgment

      Tatjana Pekmezovic was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (grant no. 175087 ).

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