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Pediatric refractory and super-refractory status epilepticus

Open ArchivePublished:May 19, 2018DOI:https://doi.org/10.1016/j.seizure.2018.05.012

      Highlights

      • Pediatric RSE and SRSE are neurological emergencies with high morbidity and mortality.
      • NORSE and FIRES are relatively rare epilepsy syndromes, but common in SRSE population.
      • Treatment approaches are variable and with limited evidence after anesthetic agents.
      • Prolonged seizures and hospital stay lead to neurologic and systemic complications.

      Abstract

      Purpose

      To summarize the available evidence related to pediatric refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE), with emphasis on epidemiology, etiologies, therapeutic approaches, and clinical outcomes.

      Methods

      Narrative review of the medical literature using MEDLINE database.

      Results

      RSE is defined as status epilepticus (SE) that fails to respond to adequately used first- and second-line antiepileptic drugs. SRSE occurs when SE persist for 24 h or more after administration of anesthesia, or recurs after its withdrawal. RSE and SRSE represent complex neurological emergencies associated with long-term neurological dysfunction and high mortality. Challenges in management arise as the underlying etiology is not always promptly recognized and therapeutic options become limited with prolonged seizures. Treatment decisions mainly rely on case series or experts’ opinions. The comparative effectiveness of different treatment strategies has not been evaluated in large prospective series or randomized clinical trials. Continuous infusion of anesthetic agents is the most common treatment for RSE and SRSE, although many questions on optimal dosing and rate of administration remain unanswered. The use of non-pharmacological therapies is documented in case series or reports with low level of evidence. In addition to neurological complications resulting from prolonged seizures, children with RSE/SRSE often develop systemic complications associated with polypharmacy and prolonged hospital stay.

      Conclusion

      RSE and SRSE are neurological emergencies with limited therapeutic options. Multi-national collaborative efforts are desirable to evaluate the safety and efficacy of current RSE/SRSE therapies, and potentially impact patients’ outcomes.

      Abbreviations:

      ASD (Anti-seizure drug), BZD (Benzodiazepine), CEEG (Continuous Encephalography), CI (Continuous infusions), CNS (Central Nervous System), FIRES (Febrile illness-related epilepsy syndrome), GCSE (Generalized convulsive status epilepticus), ICU (Intensive Care Unit), KD (Ketogenic diet), NCS (Neurocritical Care Society), NCSE (Non convulsive status epilepticus), NORSE (New onset refractory status epilepticus), RSE (Refractory status epilepticus), RCSE (Refractory convulsive status epilepticus), SRSE (Super-refractory status epilepticus), TBI (Traumatic brain injury)

      Keywords

      1. Introduction

      Refractory status epilepticus (RSE) is a life-threatening neurological emergency associated with significant morbidity and mortality. RSE is defined as seizure activity that persists after administration of a first-line benzodiazepine (BZD) and a second-line antiseizure drug (ASD) [
      • Falco-Walter J.J.
      • Bleck T.
      Treatment of established status epilepticus.
      ]. Primarily encountered and treated in the intensive care unit (ICU), RSE patients usually receive additional boluses of second-line ASDs (e.g. fosphenytoin, levetiracetam, and valproate) or are placed in a medically induced coma with intravenous (IV) continuous infusions (CI) of an anesthetic (e.g. midazolam, propofol, barbiturates) for seizure control. Nevertheless, continuous or intermittent seizures may persist for 24 h or more following the administration of general anesthesia or recur after its withdrawal. The resulting condition is known as super-refractory status epilepticus (SRSE) [
      • Shorvon S.
      Super-refractory status epilepticus: an approach to therapy in this difficult clinical situation.
      ]. Identifying the underlying etiology of RSE and SRSE can be challenging. Treatment decisions mainly rely on case series or experts’ opinions. The comparative effectiveness of heterogeneous treatment strategies has not been systematically evaluated in large prospective series or randomized clinical trials.
      The annual incidence of status epilepticus (SE) is estimated to be 17–23 episodes per 100,000 children [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Bedford H.
      • Wade A.
      • Scott R.C.
      Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study.
      ,
      • Raspall-Chaure M.
      • Chin R.F.
      • Neville B.G.
      • Bedford H.
      • Scott R.C.
      The epidemiology of convulsive status epilepticus in children: a critical review.
      ]. Of these SE patients, between 10% and 40% develop RSE [
      • Lewena S.
      • Young S.
      When benzodiazepines fail: how effective is second line therapy for status epilepticus in children.
      ,
      • Eriksson K.
      • Metsaranta P.
      • Huhtala H.
      • Auvinen A.
      • Kuusela A.L.
      • Koivikko M.
      Treatment delay and the risk of prolonged status epilepticus.
      ,
      • Barzegar M.
      • Mahdavi M.
      • Galegolab Behbehani A.
      • Tabrizi A.
      Refractory convulsive status epilepticus in children: etiology, associated risk factors and outcome.
      ] with a mortality rate of 16–43.5% [
      • Sahin M.
      • Menache C.C.
      • Holmes G.L.
      • Riviello J.J.
      Outcome of severe refractory status epilepticus in children.
      ,
      • Gilbert D.L.
      • Gartside P.S.
      • Glauser T.A.
      Efficacy and mortality in treatment of refractory generalized convulsive status epilepticus in children: a meta-analysis.
      ,
      • Kim S.J.
      • Lee D.Y.
      • Kim J.S.
      Neurologic outcomes of pediatric epileptic patients with pentobarbital coma.
      ]. The few epidemiological studies on SRSE are based mainly in adult population [
      • Chateauneuf A.L.
      • Moyer J.D.
      • Jacq G.
      • Cavelot S.
      • Bedos J.P.
      • Legriel S.
      Super-refractory status epilepticus: epidemiology, early predictors, and outcomes.
      ] indicating that 10–15% of RSE cases progress to SRSE [
      • Novy J.
      • Logroscino G.
      • Rossetti A.O.
      Refractory status epilepticus: a prospective observational study.
      ,
      • Ferlisi M.
      • Shorvon S.
      The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy.
      ], and approximately one-third of RSE and SRSE patients die [
      • Novy J.
      • Logroscino G.
      • Rossetti A.O.
      Refractory status epilepticus: a prospective observational study.
      ,
      • Ferlisi M.
      • Shorvon S.
      The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy.
      ,
      • Hocker S.E.
      • Britton J.W.
      • Mandrekar J.N.
      • Wijdicks E.F.M.
      • Rabinstein A.A.
      Predictors of outcome in refractory status epilepticus.
      ]. In children, a retrospective study showed that of 602 convulsive SE episodes, SRSE occurred in 7.14% [
      • Kravljanac R.
      • Djuric M.
      • Jankovic B.
      • Pekmezovic T.
      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.
      ]. In the United States, most data come from case series or case reports. Without large series, estimating the exact incidence and mortality of SRSE is challenging. In this review we present existing evidence on pediatric RSE/SRSE including clinical presentations and etiologies. We address current diagnostic and treatment approaches, as well as clinical outcomes of RSE/SRSE in children.

      1.1 Clinical presentation

      Patients who develop RSE/SRSE present clinically in different ways. The most common presentation is generalized convulsive SE (GCSE), the major seizure type for pediatric SE [
      • Gross-Tsur V.
      • Shinnar S.
      Convulsive status epilepticus in children.
      ,
      • Treiman D.M.
      Generalized convulsive status epilepticus.
      ,
      • Shorvon S.
      Tonic clonic status epilepticus.
      ], or focal SE with impaired consciousness after failure to initial treatment. Other common clinical presentations are subtler and thus, are suggestive of non-convulsive SE (NCSE). In the latter clinical scenario, patients usually present with stupor/coma after a GCSE or after an acute brain insult [
      • Hocker S.
      • Tatum W.O.
      • LaRoche S.
      • Freeman W.D.
      Refractory and super-refractory status epilepticus–an update.
      ,
      • Holtkamp M.
      • Meierkord H.
      Nonconvulsive status epilepticus: a diagnostic and therapeutic challenge in the intensive care setting.
      ]. Although convulsive SE often evolves to NCSE, the distinction between these two phenotypes is crucial as the therapeutic approaches and outcomes are different, being NCSE more often associated with medical refractoriness due to delayed recognition [
      • Holtkamp M.
      • Meierkord H.
      Nonconvulsive status epilepticus: a diagnostic and therapeutic challenge in the intensive care setting.
      ].

      1.2 Etiology

      The etiologies for pediatric RSE and SRSE reported in the literature vary. The most commonly reported etiologies include: acute symptomatic causes (e.g. presumed infectious or immune mediated encephalitis, central nervous system (CNS) infections, traumatic brain injury (TBI), brain ischemia), remote symptomatic with acute precipitant causes (e.g. CNS lymphoproliferative disease, human immunodeficiency virus (HIV) infection, hypoxic-ischemic encephalopathy, developmental delay, epilepsy), remote symptomatic and progressive encephalopathies (e.g. Alpers disease, metabolic diseases such as medium chain acyl-CoA dehydrogenase deficiency, epileptic encephalopathies), febrile SE (excluding CNS infections), and unknown etiologies (e.g. cryptogenic) [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Bedford H.
      • Wade A.
      • Scott R.C.
      Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study.
      ,
      • Sahin M.
      • Menache C.C.
      • Holmes G.L.
      • Riviello J.J.
      Outcome of severe refractory status epilepticus in children.
      ,
      • Hussain N.
      • Appleton R.
      • Thorburn K.
      Aetiology, course and outcome of children admitted to paediatric intensive care with convulsive status epilepticus: a retrospective 5-year review.
      ,
      • Freilich E.R.
      • Schreiber J.M.
      • Zelleke T.
      • Gaillard W.D.
      Pediatric status epilepticus: identification and evaluation.
      ]. Nonetheless, previous studies show that etiology varies according to age groups and geographic location. In a study of 151 refractory convulsive SE (RCSE) episodes, the most common etiology was acute symptomatic (28.5%) in neonates and infants; prolonged febrile convulsions (33.8%) in children 1–5 years; and remote symptomatic etiologies in 40% of patients between 5 and 10 years old, and in 36.8% patients between 10 and 16 years old [
      • Tully I.
      • Draper E.S.
      • Lamming C.R.
      • Mattison D.
      • Thomas C.
      • Martland T.
      • et al.
      Admissions to paediatric intensive care units (PICU) with refractory convulsive status epilepticus (RCSE): a two-year multi-centre study.
      ]. In contrast, the etiologies contributing to RSE and SRSE development in the adult population include acute brain injury (e.g. cerebrovascular disease, CNS infections, brain tumor, traumatic brain injury), intoxication/withdrawal syndromes, low levels of antiepileptic drugs, metabolic distrubances, and systemic infections [
      • Hocker S.
      • Tatum W.O.
      • LaRoche S.
      • Freeman W.D.
      Refractory and super-refractory status epilepticus–an update.
      ]. In developing countries, acute symptomatic etiology remains the most frequent etiology in children, followed by remote symptomatic and unknown etiologies. Within the acute symptomatic etiology, CNS infections (e.g. herpes simplex virus (HSV), HIV, neurocysticercosis, malaria, tuberculosis), viral/autoimmune encephalitis and meningitis are common causes [
      • Barzegar M.
      • Mahdavi M.
      • Galegolab Behbehani A.
      • Tabrizi A.
      Refractory convulsive status epilepticus in children: etiology, associated risk factors and outcome.
      ,
      • Lingappa L.
      • Konanki R.
      • Patel R.
      • Vooturi S.
      • Jayalakshmi S.
      Clinical profile and outcome of refractory convulsive status epilepticus in older children from a developing country.
      ,
      • Li Y.
      • Tian L.
      • Zeng T.
      • Chen J.
      • Chen L.
      • Zhou D.
      Clinical features and outcome of super-refractory status epilepticus: a retrospective analysis in West China.
      ,
      • Saz E.U.
      • Karapinar B.
      • Ozcetin M.
      • Polat M.
      • Tosun A.
      • Serdaroglu G.
      • et al.
      Convulsive status epilepticus in children: etiology, treatment protocol and outcome.
      ,
      • Gupta N.
      • Jain P.
      • Singh K.
      • Bhattacharya S.
      Super-refractory status epilepticus with hemophagocytic syndrome in a child with HIV infection.
      ,
      • Ozdemir D.
      • Gulez P.
      • Uran N.
      • Yendur G.
      • Kavakli T.
      • Aydin A.
      Efficacy of continuous midazolam infusion and mortality in childhood refractory generalized convulsive status epilepticus.
      ,
      • Aroor S.
      • Shravan K.
      • Mundkur S.C.
      • Jayakrishnan C.
      • Rao S.S.
      Super-refractory status epilepticus: a therapeutic challenge in paediatrics.
      ,
      • Reddy Y.
      • Balakrishna Y.
      • Mubaiwa L.
      Convulsive status epilepticus in a quaternary hospital paediatric intensive care unit (PICU) in South Africa: an 8 year review.
      ].
      New Onset RSE (NORSE), on the other hand, is a clinical presentation described in patients without epilepsy or a relevant preexisting neurological disorder, who present with RSE without an identifiable acute cause or active structural, toxic or metabolic cause [
      • Hirsch L.J.
      • Gaspard N.
      • van Baalen A.
      • Nabbout R.
      • Demeret S.
      • Loddenkemper T.
      • et al.
      Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions.
      ]. A subcategory of NORSE known as febrile infection-related epilepsy syndrome (FIRES) commonly presents in previously healthy school-aged children [
      • Fox K.
      • Wells M.E.
      • Tennison M.
      • Vaughn B.
      Febrile infection-related epilepsy syndrome (FIRES): a literature review and case study.
      ,
      • van Baalen A.
      • Hausler M.
      • Boor R.
      • Rohr A.
      • Sperner J.
      • Kurlemann G.
      • et al.
      Febrile infection-related epilepsy syndrome (FIRES): a nonencephalitic encephalopathy in childhood.
      ]. These patients usually have a preceding febrile illness, with fever starting between 2 weeks and 24 h prior to the onset of SE, and can present with or without fever at the onset of SE [
      • Hirsch L.J.
      • Gaspard N.
      • van Baalen A.
      • Nabbout R.
      • Demeret S.
      • Loddenkemper T.
      • et al.
      Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions.
      ]. The etiology of this syndrome remains unknown, and the seizures in this patient population are notoriously difficult to control in both the acute and chronic settings. While NORSE and FIRES are relatively rare epilepsy syndromes, they are frequent in the SRSE population. In a small study of ketogenic diet (KD) usage for SRSE, the most common etiologies included encephalitis/FIRES (55.55%), followed by FIRES (22.22%), epileptic encephalopathy (11.11%), and central nervous system-hemophagocytic lymphohistiocytosis (11.11%) [
      • Farias-Moeller R.
      • Bartolini L.
      • Pasupuleti A.
      Brittany cines RD, kao A, carpenter JL: a practical approach to ketogenic diet in the pediatric intensive care unit for super-refractory status epilepticus.
      ]. Another study showed that 40% patients with SRSE had a diagnosis of immune-mediated encephalitis (Rasmussen’s syndrome, post-infectious mycoplasma encephalitis and Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis), followed by FIRES (20%), genetic epilepsies (PCDH19 and GABRG2 mutations) (20%), epilepsy of a known metabolic etiology (10%) and NORSE (10%) [
      • Appavu B.
      • Vanatta L.
      • Condie J.
      • Kerrigan J.F.
      • Jarrar R.
      Ketogenic diet treatment for pediatric super-refractory status epilepticus.
      ]. Therefore, when initial diagnostic workup reveals negative results, these epilepsy syndromes should be considered in the differential diagnosis.

      1.3 Pathophysiology

      In RSE and particularly SRSE, mechanisms responsible for seizure termination fail and additional pathophysiologic processes develop leading to persistence of SE. At a cellular level, SE intensifies the internalization of synaptic γ-amino butyric acid type A (GABA-A) receptors whereas the function of extra synaptic receptors is preserved. This synaptic “receptor trafficking” leads to an overall reduction of the inhibitory activity of GABA, playing a key role in the development of pharmacoresistance [
      • Macdonald R.L.
      • Kapur J.
      Acute cellular alterations in the hippocampus after status epilepticus.
      ]. Additionally, increased number of glutaminergic receptors at the neuronal surface may contribute to seizure perpetuation due to changes in concentrations of ions, like chloride, in the cellular environment. Furthermore, the persistence of seizures and development of SRSE may be explained by sensitivity to NMDA-mediated neuronal stimulation [
      • Borris D.J.
      • Bertram E.H.
      • Kapur J.
      Ketamine controls prolonged status epilepticus.
      ], mitochondrial failure [
      • Cock H.
      The role of mitochondria in status epilepticus.
      ], blood-brain barrier damage, and neuro inflammation (i.e. pro-inflammatory cytokines, autoantibodies to neural elements) [
      • Shorvon S.
      Super-refractory status epilepticus: an approach to therapy in this difficult clinical situation.
      ]. All of these factors result in excitotoxicity [
      • Fujikawa D.G.
      Prolonged seizures and cellular injury: understanding the connection.
      ], which is directly responsible for neuronal injury and cell loss, and ultimately poor clinical outcomes. Finally, previous studies demonstrate the important role of time from seizure onset to treatment administration on seizure duration [
      • Waterhouse E.J.
      • Garnett L.K.
      • Towne A.R.
      • Morton L.D.
      • Barnes T.
      • Ko D.
      • et al.
      Prospective population-based study of intermittent and continuous convulsive status epilepticus in Richmond, Virginia.
      ,
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ]. If treatment is delayed or inadequate, seizures can rapidly become self-sustained and fail to respond to the intrinsic mechanisms normally involved in seizure termination [
      • Lado F.A.
      • Moshe S.L.
      How do seizures stop.
      ].

      2. Diagnosis & treatment

      2.1 Diagnostic approach

      Approximately 15% of patients with a prolonged convulsive seizure episode (>5 min) may achieve seizure cessation without medical intervention [
      • Eriksson K.
      • Metsaranta P.
      • Huhtala H.
      • Auvinen A.
      • Kuusela A.L.
      • Koivikko M.
      Treatment delay and the risk of prolonged status epilepticus.
      ]; however, the majority of patients experience a seizure lasting more than 30 min. Therefore, RSE recognition is crucial and requires prompt diagnostic evaluation and treatment in order to prevent long-term sequelae. At this point in time, SE patients may have already completed a battery of testing [
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      Guidelines for the evaluation and management of status epilepticus.
      ,
      • Glauser T.
      • Shinnar S.
      • Gloss D.
      • Alldredge B.
      • Arya R.
      • Bainbridge J.
      • et al.
      Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the american epilepsy society.
      ,
      • Van Mater H.
      Pediatric inflammatory brain diseases: a diagnostic approach.
      ], yet efforts should remain focused on identifying the etiology of RSE/SRSE (Table 1) [
      • Freilich E.R.
      • Schreiber J.M.
      • Zelleke T.
      • Gaillard W.D.
      Pediatric status epilepticus: identification and evaluation.
      ,
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      Guidelines for the evaluation and management of status epilepticus.
      ,
      • Glauser T.
      • Shinnar S.
      • Gloss D.
      • Alldredge B.
      • Arya R.
      • Bainbridge J.
      • et al.
      Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the american epilepsy society.
      ,
      • Van Mater H.
      Pediatric inflammatory brain diseases: a diagnostic approach.
      ]. Laboratory investigations for inflammatory and immune-related etiologies (e.g. serum and CSF-autoantibodies, IgG index) should be tiered according to the disease phenotype [
      • Van Mater H.
      Pediatric inflammatory brain diseases: a diagnostic approach.
      ,
      • Graus F.
      • Titulaer M.J.
      • Balu R.
      • Benseler S.
      • Bien C.G.
      • Cellucci T.
      • et al.
      A clinical approach to diagnosis of autoimmune encephalitis.
      ]. With more readily available genetic testing, evaluations for genetic epilepsy syndromes should be considered in patients in whom an etiology is not established with the initial testing. These should be suspected particularly in patients that present at young ages, or with a history of dysmorphic features, developmental delay or a family history of epilepsy.
      Table 1Recommended diagnostic workup for pediatric RSE/SRSE.
      Always recommended
       Finger stick blood glucose

       Monitor vital signs

       CT/MRI (almost always appropriate except in epileptic patients with a prior normal neuroimaging or with a generalized seizure syndrome and generalized seizures)

       Serum electrolytes including calcium and magnesium

       cEEG monitoring
      Specific circumstances
      Known epilepsy patient

      ASD levels

      Consider CT/MRI

      Consider Electrolytes

      *Decision making largely dependent on the patient’s seizure history and associated comorbidities.
      Febrile patient
      SE with fever (presumed Febrile SE) in a patient ≤5 years, improved clinical state and SE resolving (no concerns for CNS infection)

      Identification of primary source of fever
      SE with fever in a patient>5 years, improved clinical state and SE resolving

      Identification of primary source of fever

      CT/MRI consider giving IV contrast if possible
      SE with fever of unknown etiology and no improvement of clinical state

      CBC

      Lumbar puncture with CSF investigation of infectious etiologies

      CT/MRI consider giving IV contrast if possible
      Suspected non-infectious encephalitis (immune/inflammatory)

      CRP

      ESR

      Auto-antibodies including ANA, anti-dsDNA, ANCA, APS & ENA panel

      Serum anti-neuronal antibodies including anti-NMDAR, –AMPA & –VGKC, –GABA

      Lumbar puncture with oligoclonal bands, and CSF anti-neuronal antibodies (as above)

      Paraneoplastic evaluation if appropriate
      Suspected genetic syndrome

      Genetic consultation

      Tiered genetic testing per age, clinical exam and seizure phenotype
      Additional considerations

      Toxicology screen

      Consider medication side effect (chemotherapeutics, immune-modulators, etc.)

      In rheumatologic disease consider: CRP, ESR, CMP, ANA, ANCA, APS panel, ENA panel
      Abbreviations: CT: computed tomography, MRI: magnetic resonance imaging, cEEG: continuous electroencephalogram, ASD: anti-seizure drug, SE: status epilepticus, CNS: central nervous system, IV: intravenous, CBC: complete blood count, CSF: cerebrospinal fluid, CRP: C-reactive protein, ESR: erythrocyte sedimentation rate, ANA: anti-nuclear antibody, ANCA: anti-neutrophil cytoplasmic antibody, APS: anti-phospholipid syndrome (lupus anticoagulant, anti-β2-glycoprotein,-cardiolipin), ENA: extractable nuclear antigen (anti-Smith, –RNP,-Ro,-La), NMDAR (N-methyl-d-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), VGKC (voltage gated potassium channel), GABA (γ-Amino butyric acid)
      Lastly, continuous electroencephalography (cEEG) monitoring is essential for the diagnosis and management of RSE/SRSE [
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      Guidelines for the evaluation and management of status epilepticus.
      ,
      • Herman S.T.
      • Abend N.S.
      • Bleck T.P.
      • Chapman K.E.
      • Drislane F.W.
      • Emerson R.G.
      • et al.
      Consensus statement on continuous EEG in critically ill adults and children, part I: indications.
      ,
      • Herman S.T.
      • Abend N.S.
      • Bleck T.P.
      • Chapman K.E.
      • Drislane F.W.
      • Emerson R.G.
      • et al.
      Consensus statement on continuous EEG in critically ill adults and children, part II: personnel, technical specifications, and clinical practice.
      ]. Monitoring with cEEG allows clinicians to target electrographic seizure cessation or achievement of burst-suppression as the case requires [
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      Guidelines for the evaluation and management of status epilepticus.
      ,
      • Herman S.T.
      • Abend N.S.
      • Bleck T.P.
      • Chapman K.E.
      • Drislane F.W.
      • Emerson R.G.
      • et al.
      Consensus statement on continuous EEG in critically ill adults and children, part I: indications.
      ,
      • Herman S.T.
      • Abend N.S.
      • Bleck T.P.
      • Chapman K.E.
      • Drislane F.W.
      • Emerson R.G.
      • et al.
      Consensus statement on continuous EEG in critically ill adults and children, part II: personnel, technical specifications, and clinical practice.
      ]. It is helpful to guide the induction of pharmacological coma as well as the identification of subsequent electrographic seizures, often recurring during titration or weaning of anesthetic agents [
      • Abend N.S.
      • Topjian A.A.
      • Gutierrez-Colina A.M.
      • Donnelly M.
      • Clancy R.R.
      • Dlugos D.J.
      Impact of continuous EEG monitoring on clinical management in critically ill children.
      ]. Furthermore, there is evidence that approximately 1/3 of the children with convulsive SE may develop electrographic seizures and of these, almost half evolve to electrographic SE [
      • Sanchez Fernandez I.
      • Abend N.S.
      • Arndt D.H.
      • Carpenter J.L.
      • Chapman K.E.
      • Cornett K.M.
      • et al.
      Electrographic seizures after convulsive status epilepticus in children and young adults: a retrospective multicenter study.
      ]. There is certainly an increased awareness of the valuable aid of cEEG in the initial treatment and diagnosis of RSE/SRSE [
      • Cardoso I.
      • Acevedo K.
      • Hernandez M.
      • Santin J.
      • Moya P.
      • Godoy J.
      • et al.
      [Refractory status epilepticus in children: characterisation of epilepsies, continuous electroencephalographic monitoring and response to treatment].
      ,
      • Sanchez S.M.
      • Arndt D.H.
      • Carpenter J.L.
      • Chapman K.E.
      • Cornett K.M.
      • Dlugos D.J.
      • et al.
      Electroencephalography monitoring in critically ill children: current practice and implications for future study design.
      ]; however, not all of the available pediatric studies include it in their RSE/SRSE management. This highly limits the generalizability of results and comparison of clinical outcomes across studies, particularly in NCSE.

      2.2 Treatment

      The therapeutic approach in RSE/SRSE aims to achieve seizure control with prevention of excitotoxicity, neuroprotection and avoidance of systemic complications [
      • Shorvon S.
      • Ferlisi M.
      The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol.
      ]. Coma induction with anesthetic agents is the most common treatment after failure of first- and second-line ASDs. The choice of anesthetic agent is often individualized. Unfortunately, due to the lack of randomized clinical trials to guide clinical practice, the goal of pharmacological induced coma (termination of seizures, burst-suppression or complete suppression of EEG activity [
      • Abend N.S.
      • Bearden D.
      • Helbig I.
      • McGuire J.
      • Narula S.
      • Panzer J.A.
      • et al.
      Status epilepticus and refractory status epilepticus management.
      ]), duration, and weaning parameters remain unclear. In general, CIs should be titrated to achieve electrographic seizure cessation or burst-suppression; which should be maintained for at least 24–48h before withdrawal of CI agents [
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      Guidelines for the evaluation and management of status epilepticus.
      ]. If seizures recur after the weaning period, CIs are usually up-titrated until cessation is re-attained and for additional 24–48h. In addition to coma induction with anesthetic agents, the use of adjunctive therapies such as immunomodulation, ketogenic diet, hypothermia, electroconvulsive therapy and vagus nerve stimulation might be considered despite their low level of evidence. The treatment approaches for RSE/SRSE are heterogeneous and usually employed in a trial and error fashion until a response is achieved. Table 2 summarizes the most common pharmacological and non-pharmacological therapies for the treatment of RSE/SRSE [
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      Guidelines for the evaluation and management of status epilepticus.
      ,
      • Bayrlee A.
      • Ganeshalingam N.
      • Kurczewski L.
      • Brophy G.M.
      Treatment of super-refractory status epilepticus.
      ,
      • Loddenkemper T.
      • Goodkin H.P.
      Treatment of pediatric status epilepticus.
      ] and their corresponding level of evidence.
      Table 2Pharmacological and non-pharmacological therapies for the treatment of RSE/SRSE.
      Mechanism of actionDoseAdverse EventsClinical ConsiderationsLevel of evidenceReferences
      Pharmacological therapies
      Benzodiazepines
      MidazolamPositive allosteric modulation of GABA-A receptors, Increases frequency of CI channel openingLoading dose: 0.2 mg/kg; administer at an infusion rate of 2 mg/min

      Infusion rate: 0.05–2 mg/kg/h

      Breakthrough SE: 0.1–0.2 mg/kg bolus, increase rate by 0.05–0.1 mg/kg/h. every 3–4 h
      Hypotension, respiratory depressionProlonged use may cause tachyphylaxis and drug accumulationClass IIA, Level B
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      Guidelines for the evaluation and management of status epilepticus.
      Class IV
      • Gilbert D.L.
      • Gartside P.S.
      • Glauser T.A.
      Efficacy and mortality in treatment of refractory generalized convulsive status epilepticus in children: a meta-analysis.
      ,
      • Hayashi K.
      • Osawa M.
      • Aihara M.
      • Izumi T.
      • Ohtsuka Y.
      • Haginoya K.
      • et al.
      Efficacy of intravenous midazolam for status epilepticus in childhood.
      IV anesthetic agents
      Barbiturates

       Pentobarbital
      Activation of GABA receptors- increase mean CI channel opening duration, inhibition of NMDA receptors, alteration in conductance of Cl, K+, Ca2+ ion channels.

      Same as Pentobarbital
      Loading dose: 5–15 mg/kg; infusion rate ≤ 50 mg/min

      Infusion rate: 0.5–5 mg/kg/h

      Breakthrough SE: 5 mg/kg bolus, increase rate by 0.5–1 mg/kg/h. every 12 h
      Hypotension, cardiac and respiratory depression, paralytic ileus, infectionLong half-life (15–50 h)

      Requires mechanical ventilation. Can exacerbate porphyria

      Hepatic enzyme inducer

      Drug accumulation with prolonged use
      Class IIB, Level B
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      Guidelines for the evaluation and management of status epilepticus.
      Class IV
      • Kim S.J.
      • Lee D.Y.
      • Kim J.S.
      Neurologic outcomes of pediatric epileptic patients with pentobarbital coma.
      ,
      • Barberio M.
      • Reiter P.D.
      • Kaufman J.
      • Knupp K.
      • Dobyns E.L.
      Continuous infusion pentobarbital for refractory status epilepticus in children.
      .
       ThiopentalSame as the mechanism described above2–7 mg/kg, infusion rate ≤ 50 mg/min

      Infusion/maintenance rate: 0.5–5 mg/kg/h

      Breakthrough SE:1–2 mg/kg bolus, titrate by 0.5–1 mg/kg/h. every 12 h.
      Hypotension, cardiac and respiratory depressionRequires mechanical ventilation, titrate infusion rates to EEG burst-suppressionClass IV
      • van Gestel J.P.
      • Blusse van Oud-Alblas H.J.
      • Malingre M.
      • Ververs F.F.
      • Braun K.P.
      • van Nieuwenhuizen O.
      Propofol and thiopental for refractory status epilepticus in children.
      PropofolChloride channel conductance, enhances GABA-A receptorInitial loading dose: 1–2 mg/kg

      Initial infusion rate

      20 mcg/kg/min titrated by 5–10 mcg/kg/min

      Use with caution with doses > 65 mcg/kg/min

      Breakthrough SE: Increase infusion rate by 5–10 mcg/kg/min every 5 min
      PRIS,

      hypotension,

      cardiac and respiratory depression
      Requires mechanical ventilation

      Prolonged infusion of propofol is a relative contraindication in children (due to risk of PRIS) and in patients with metabolic acidosis, mitochondrial disorders or hypertriglyceridemia

      Reduces ICP

      Caution with concomitant use of steroid or catecholamine therapy
      Class IIB, Level B
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      Guidelines for the evaluation and management of status epilepticus.
      Class IV
      • van Gestel J.P.
      • Blusse van Oud-Alblas H.J.
      • Malingre M.
      • Ververs F.F.
      • Braun K.P.
      • van Nieuwenhuizen O.
      Propofol and thiopental for refractory status epilepticus in children.
      KetamineNoncompetitive NMDA glutamate receptor antagonist-reduces neuronal excitability0.5–3 mg/kg

      Infusion rate:

      1–10 mg/kg/h
      Tachycardia, hypertension, ICP elevationRelative contraindication in patients with ICP. Ketamine is an enzyme inducer and inhibitor (CYP2C9)Class IV
      • Gaspard N.
      • Foreman B.
      • Judd L.M.
      • Brenton J.N.
      • Nathan B.R.
      • McCoy B.M.
      • et al.
      From the Critical Care EEGMRC. Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multi-center study.
      ,
      • Rosati A.
      • L’Erario M.
      • Ilvento L.
      • Cecchi C.
      • Pisano T.
      • Mirabile L.
      • et al.
      Efficacy and safety of ketamine in refractory status epilepticus in children.
      Inhalational anesthesia
      IsofluraneEnhancement of GABA-A receptors, noncompetitive antagonist of NMDA receptorConcentration 1–5%

      Titrate to achieve burst-suppression on EEG
      Hypotension requiring use of vasopressors, atelectasis, paralytic ileus, infection, deep vein thrombosisHigh seizure recurrence rateClass IV
      • Kofke W.A.
      • Young R.S.
      • Davis P.
      • Woelfel S.K.
      • Gray L.
      • Johnson D.
      • et al.
      Isoflurane for refractory status epilepticus: a clinical series.
      ,
      • Alexopoulos A.
      • Lachhwani D.K.
      • Gupta A.
      • Kotagal P.
      • Harrison A.M.
      • Bingaman W.
      • et al.
      Resective surgery to treat refractory status epilepticus in children with focal epileptogenesis.
      ,
      • Mirsattari S.M.
      • Sharpe M.D.
      • Young G.B.
      Treatment of refractory status epilepticus with inhalational anesthetic agents isoflurane and desflurane.
      Immunomodulatory therapy
      IVIGAlteration of IgG-specific receptors (FcγR) expression and function (decreases cytokine production), attenuation of complement mediated cell damage1–2 g/kg divided over 3–5 daysHypersensitivity reactions, transfusion related acute lung injury, thromboembolic events, renal dysfunction with concentrated solutions, aseptic meningitisImmunomodulatory therapies may be considered in patients with cryptogenic, autoimmune etiologies of RSE/SRSE.Class IV
      • van Baalen A.
      • Hausler M.
      • Boor R.
      • Rohr A.
      • Sperner J.
      • Kurlemann G.
      • et al.
      Febrile infection-related epilepsy syndrome (FIRES): a nonencephalitic encephalopathy in childhood.
      ,
      • Moreno-Medinilla E.E.
      • Negrillo-Ruano R.
      • Calvo-Medina R.
      • Mora-Ramirez M.D.
      • Martinez-Anton J.L.
      Status epilepticus in paediatrics: a retrospective study and review of the literature.
      ,
      • Kramer U.
      • Chi C.S.
      • Lin K.L.
      • Specchio N.
      • Sahin M.
      • Olson H.
      • et al.
      Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children.
      ,
      • Gaspard N.
      • Foreman B.P.
      • Alvarez V.
      • Cabrera Kang C.
      • Probasco J.C.
      • Jongeling A.C.
      • et al.
      New-onset refractory status epilepticus: etiology, clinical features, and outcome.
      Corticosteroids:

       Methyl prednisolone
      Inhibition of inflammation-associated proteins (e.g. cytokines, chemokines) and immunosuppressive action1 g/day for 3–5 daysGlucose intolerance, psychiatric disturbances, altered immune function, adrenal suppressionClass IV
      • Almaabdi K.H.
      • Alshehri R.O.
      • Althubiti A.A.
      • Alsharef Z.H.
      • Mulla S.N.
      • Alshaer D.S.
      • et al.
      Intravenous methylprednisolone for intractable childhood epilepsy.
      ,
      • Erol I.
      • Alehan F.
      • Yalcin K.
      Refractory status epilepticus owing to human parvovirus B19 encephalitis in a child.
      ,
      • Moreno-Medinilla E.E.
      • Negrillo-Ruano R.
      • Calvo-Medina R.
      • Mora-Ramirez M.D.
      • Martinez-Anton J.L.
      Status epilepticus in paediatrics: a retrospective study and review of the literature.
      ,
      • Kramer U.
      • Chi C.S.
      • Lin K.L.
      • Specchio N.
      • Sahin M.
      • Olson H.
      • et al.
      Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children.
      ,
      • Illingworth M.A.
      • Hanrahan D.
      • Anderson C.E.
      • O'Kane K.
      • Anderson J.
      • Casey M.
      • et al.
      Elevated VGKC-complex antibodies in a boy with fever-induced refractory epileptic encephalopathy in school-age children (FIRES).
      ,
      • Caputo D.
      • Iorio R.
      • Vigevano F.
      • Fusco L.
      Febrile infection-related epilepsy syndrome (FIRES) with super-refractory status epilepticus revealing autoimmune encephalitis due to GABAAR antibodies.
       PrednisoneSame as the mechanism described above60 mg daily
      PlasmapheresisRemoval of circulating autoantibodies, immune factors or high weight proteins that may participate in inflammatory process5 exchanges over 5 daysClass IV
      • van Baalen A.
      • Hausler M.
      • Boor R.
      • Rohr A.
      • Sperner J.
      • Kurlemann G.
      • et al.
      Febrile infection-related epilepsy syndrome (FIRES): a nonencephalitic encephalopathy in childhood.
      ,
      • Kramer U.
      • Chi C.S.
      • Lin K.L.
      • Specchio N.
      • Sahin M.
      • Olson H.
      • et al.
      Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children.
      ,
      • Chevret L.
      • Husson B.
      • Nguefack S.
      • Nehlig A.
      • Bouilleret V.
      Prolonged refractory status epilepticus with early and persistent restricted hippocampal signal MRI abnormality.
      ,
      • Howell K.B.
      • Katanyuwong K.
      • Mackay M.T.
      • Bailey C.A.
      • Scheffer I.E.
      • Freeman J.L.
      • et al.
      Long-term follow-up of febrile infection-related epilepsy syndrome.
      ,
      • Caraballo R.H.
      • Reyes G.
      • Avaria M.F.
      • Buompadre M.C.
      • Gonzalez M.
      • Fortini S.
      • et al.
      Febrile infection-related epilepsy syndrome: a study of 12 patients.
      ,
      • Finne X.
      • Sindic C.
      • van Pesch V.
      • El Sankari S.
      • de Tourtchaninoff M.
      • Denays R.
      • et al.
      Anti-N-methyl-D-aspartate receptor encephalitis with favorable outcome despite prolonged status epilepticus.
      ,
      • Lousa M.
      • Sanchez-Alonso S.
      • Rodriguez-Diaz R.
      • Dalmau J.
      Status epilepticus with neuron-reactive serum antibodies: response to plasma exchange.
      Non-pharmacological alternatives
      Ketogenic dietKetosis mediated decreased glycolysis, increase in free and polyunsaturated fatty acids, anti-inflammatory action, stabilization of neuronal membrane4:1 (ratio fat to carbohydrates and proteins)Hypoglycemia, hyperlipidemia, weight loss, acute pancreatitis, metabolic acidosisContraindicated in pyruvate carboxylase deficiency, disorders of fatty acid oxidation and metabolism, or porphyriaClass IV
      • Farias-Moeller R.
      • Bartolini L.
      • Pasupuleti A.
      Brittany cines RD, kao A, carpenter JL: a practical approach to ketogenic diet in the pediatric intensive care unit for super-refractory status epilepticus.
      ,
      • Appavu B.
      • Vanatta L.
      • Condie J.
      • Kerrigan J.F.
      • Jarrar R.
      Ketogenic diet treatment for pediatric super-refractory status epilepticus.
      ,
      • Caraballo R.H.
      • Flesler S.
      • Armeno M.
      • Fortini S.
      • Agustinho A.
      • Mestre G.
      • et al.
      Ketogenic diet in pediatric patients with refractory focal status epilepticus.
      ,
      • Fung E.L.
      • Chang S.K.
      • Yam K.K.
      • Yau P.Y.
      Ketogenic diet as a therapeutic option in super-refractory status epilepticus.
      ,
      • Nabbout R.
      • Mazzuca M.
      • Hubert P.
      • Peudennier S.
      • Allaire C.
      • Flurin V.
      • et al.
      Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES).
      ,
      • Caraballo R.H.
      • Valenzuela G.R.
      • Armeno M.
      • Fortini S.
      • Mestre G.
      • Cresta A.
      The ketogenic diet in two paediatric patients with refractory myoclonic status epilepticus.
      ,
      • Amer S.
      • Shah P.
      • Kommineni V.
      Refractory status epilepticus from NMDA receptor encephalitis successfully treated with an adjunctive ketogenic diet.
      ,
      • Lin J.J.
      • Lin K.L.
      • Chan O.W.
      • Hsia S.H.
      • Wang H.S.
      Intravenous ketogenic diet therapy for treatment of the acute stage of super-refractory status epilepticus in a pediatric patient.
      ,
      • Singh R.K.
      • Joshi S.M.
      • Potter D.M.
      • Leber S.M.
      • Carlson M.D.
      • Shellhaas R.A.
      Cognitive outcomes in febrile infection-related epilepsy syndrome treated with the ketogenic diet.
      ,
      • Cobo N.H.
      • Sankar R.
      • Murata K.K.
      • Sewak S.L.
      • Kezele M.A.
      • Matsumoto J.H.
      The ketogenic diet as broad-spectrum treatment for super-refractory pediatric status epilepticus: challenges in implementation in the pediatric and neonatal intensive care units.
      ,
      • O'Connor S.E.
      • Ream M.A.
      • Richardson C.
      • Mikati M.A.
      • Trescher W.H.
      • Byler D.L.
      • et al.
      The ketogenic diet for the treatment of pediatric status epilepticus.
      ,
      • Sort R.
      • Born A.P.
      • Pedersen K.N.
      • Fonsmark L.
      • Uldall P.
      Ketogenic diet in 3 cases of childhood refractory status epilepticus.
      HypothermiaReduction of Na+ exchange, decreased K+ conductance, regulation of glutamatergic synaptic transmission, disruption of synchronized discharges32–35°C x 24h Rewarming ≤ 0.5 °C/hDeep venous thrombosis, infections, cardiac arrhythmias, electrolyte disturbances, acute intestinal ischemia, coagulation disordersRequires EEG monitoringClass IV
      • Lin J.J.
      • Lin K.L.
      • Hsia S.H.
      • Wang H.S.
      Therapeutic hypothermia for febrile infection-related epilepsy syndrome in two patients.
      ,
      • Shein S.L.
      • Reynolds T.Q.
      • Gedela S.
      • Kochanek P.M.
      • Bell M.J.
      Therapeutic hypothermia for refractory status epilepticus in a child with malignant migrating partial seizures of infancy and SCN1A mutation: a case report.
      ,
      • Orlowski J.P.
      • Erenberg G.
      • Lueders H.
      • Cruse R.P.
      Hypothermia and barbiturate coma for refractory status epilepticus.
      ,
      • Guilliams K.
      • Rosen M.
      • Buttram S.
      • Zempel J.
      • Pineda J.
      • Miller B.
      • et al.
      Hypothermia for pediatric refractory status epilepticus.
      ,
      • Vastola E.F.
      • Homan R.
      • Rosen A.
      Inhibition of focal seizures by moderate hypothermia: a clinical and experimental study.
      ,
      • Cereda C.
      • Berger M.M.
      • Rossetti A.O.
      Bowel ischemia: a rare complication of thiopental treatment for status epilepticus.
      ,
      • Miras Veiga A.
      • Moreno D.C.
      • Menendez A.I.
      • Siscart I.M.
      • Fernandez M.D.
      • Sanchez E.G.
      • et al.
      Effectiveness of electroconvulsive therapy for refractory status epilepticus in febrile infection-related epilepsy syndrome.
      Electroconvulsive therapyEnhancement of GABA neurotransmission, increase of seizure threshold and reduction of neural metabolic activityVariable protocolsMay induce seizures and non-convulsive SE after treatment, amnesia, headache, cognitive impairmentRelative contraindication in patients with cardiovascular conditions

      Requires EEG monitoring
      Class IV
      • Morales O.G.
      • Henry M.E.
      • Nobler M.S.
      • Wassermann E.M.
      • Lisanby S.H.
      Electroconvulsive therapy and repetitive transcranial magnetic stimulation in children and adolescents: a review and report of two cases of epilepsia partialis continua.
      ,
      • Griesemer D.A.
      • Kellner C.H.
      • Beale M.D.
      • Smith G.M.
      Electroconvulsive therapy for treatment of intractable seizures: initial findings in two children.
      ,
      • Shin H.W.
      • O’Donovan C.A.
      • Boggs J.G.
      • Grefe A.
      • Harper A.
      • Bell W.L.
      • et al.
      Successful ECT treatment for medically refractory nonconvulsive status epilepticus in pediatric patient.
      ,
      • Viparelli U.
      • Viparelli G.
      ECT and grand mal epilepsy.
      Vagus nerve stimulationModulation of the locus coeruleus, thalamus and limbic circuit through noradrenergic and serotoninergic projections, elevation of GABA levels in brainstemSurgical implantationHoarseness, surgical infection, rarely asystole or bradycardiaClass IV
      • Yamazoe T.
      • Okanishi T.
      • Yamamoto A.
      • Yamada T.
      • Nishimura M.
      • Fujimoto A.
      • et al.
      New-onset refractory status epilepticus treated with vagus nerve stimulation: a case report.
      ,
      • De Herdt V.
      • Waterschoot L.
      • Vonck K.
      • Dermaut B.
      • Verhelst H.
      • Van Coster R.
      • et al.
      Vagus nerve stimulation for refractory status epilepticus.
      ,
      • De Benedictis A.
      • Freri E.
      • Rizzi M.
      • Franzini A.
      • Ragona F.
      • Specchio N.
      • et al.
      Vagus nerve stimulation for drug-resistant Epilepsia Partialis Continua: report of four cases.
      ,
      • Howell K.B.
      • Katanyuwong K.
      • Mackay M.T.
      • Bailey C.A.
      • Scheffer I.E.
      • Freeman J.L.
      • et al.
      Long-term follow-up of febrile infection-related epilepsy syndrome.
      ,
      • Winston K.R.
      • Levisohn P.
      • Miller B.R.
      • Freeman J.
      Vagal nerve stimulation for status epilepticus.
      ,
      • Zamponi N.
      • Rychlicki F.
      • Corpaci L.
      • Cesaroni E.
      • Trignani R.
      Vagus nerve stimulation (VNS) is effective in treating catastrophic 1 epilepsy in very young children.
      Abbreviations: RSE: Refractory status epilepticus; SRSE, Super-refractory status epilepticus GABA-A, ϒ-amino-butyric acid type A; mg, milligrams; MCG, micrograms; kg, kilograms; PRIS: Propofol related infusion syndrome; NMDA, N-methyl-d-aspartate; EEG: Electroencephalogram.

      2.2.1 Anesthetics and continuous infusions

      The most commonly used agents for coma induction are midazolam [
      • Kravljanac R.
      • Djuric M.
      • Jankovic B.
      • Pekmezovic T.
      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.
      ,
      • Saz E.U.
      • Karapinar B.
      • Ozcetin M.
      • Polat M.
      • Tosun A.
      • Serdaroglu G.
      • et al.
      Convulsive status epilepticus in children: etiology, treatment protocol and outcome.
      ,
      • Tasker R.C.
      • Goodkin H.P.
      • Sanchez Fernandez I.
      • Chapman K.E.
      • Abend N.S.
      • Arya R.
      • et al.
      Pediatric status epilepticus research G. refractory status epilepticus in children: intention to treat with continuous infusions of midazolam and pentobarbital.
      ,
      • Patten W.
      • Naqvi S.Z.
      • Raszynski A.
      • Totapally B.R.
      Complications during the management of pediatric refractory status epilepticus with benzodiazepine and pentobarbital infusions.
      ,
      • Hayashi K.
      • Osawa M.
      • Aihara M.
      • Izumi T.
      • Ohtsuka Y.
      • Haginoya K.
      • et al.
      Research Committee on Clinical Evidence of Medical Treatment for Status Epilepticus in C. Efficacy of intravenous midazolam for status epilepticus in childhood.
      ], barbiturates and propofol [
      • Shorvon S.
      • Ferlisi M.
      The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol.
      ,
      • Tasker R.C.
      • Goodkin H.P.
      • Sanchez Fernandez I.
      • Chapman K.E.
      • Abend N.S.
      • Arya R.
      • et al.
      Refractory status epilepticus in children: intention to treat with continuous infusions of midazolam and pentobarbital.
      ]. Midazolam is a fast-acting BZD that enhances the action of GABA on the GABA-A receptors in the CNS [
      • Kaye A.D.
      • Fox C.J.
      • Padnos I.W.
      • Ehrhardt Jr., K.P.
      • Diaz J.H.
      • Cornett E.M.
      • et al.
      Pharmacologic considerations of anesthetic agents in pediatric patients: a comprehensive review.
      ,
      • Macdonald R.L.
      • McLean M.J.
      Mechanisms of anticonvulsant drug action.
      ]. It has a short duration of action and is generally administered as an initial loading dose of 0.2 mg/kg followed by an infusion rate of 0.05–2 mg/kg/h. It is used to achieve electrographic/clinical seizure cessation or burst-suppression [
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      Guidelines for the evaluation and management of status epilepticus.
      ,
      • Bayrlee A.
      • Ganeshalingam N.
      • Kurczewski L.
      • Brophy G.M.
      Treatment of super-refractory status epilepticus.
      ]. A randomized, open label study showed that the efficacy of continuous midazolam in controlling RSE was similar to infusion of diazepam (86% vs 89% with diazepam). Midazolam however, was associated with a higher recurrence rate (57% vs. 16% with diazepam) [
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      Guidelines for the evaluation and management of status epilepticus.
      ,
      • Singhi S.
      • Murthy A.
      • Singhi P.
      • Jayashree M.
      Continuous midazolam versus diazepam infusion for refractory convulsive status epilepticus.
      ]. Similarly, a study of 27 children with refractory generalized convulsive SE, demonstrated that midazolam infusion (0.2 mg/kg as bolus followed by 5 mcg/kg/min as CI) was effective in the control of RSE in 26 (96%) children within 65 min, with no adverse events [
      • Ozdemir D.
      • Gulez P.
      • Uran N.
      • Yendur G.
      • Kavakli T.
      • Aydin A.
      Efficacy of continuous midazolam infusion and mortality in childhood refractory generalized convulsive status epilepticus.
      ]. Even though the use of CI midazolam may cause cardiorespiratory depression and hypotension; the risk is still low compared to other anesthetics [
      • Wilkes R.
      • Tasker R.C.
      Intensive care treatment of uncontrolled status epilepticus in children: systematic literature search of midazolam and anesthetic therapies*.
      ]. Another important aspect to consider is the risk of tachyphylaxis, which may occur after prolonged midazolam use. Thus, requiring constant monitoring and adjustment of the dosing [
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      Guidelines for the evaluation and management of status epilepticus.
      ].
      If midazolam fails to control SE, clinicians typically resort to using barbiturates as a second agent. Pentobarbital and thiopental are both barbiturates that act similar to midazolam, through the enhancement of GABA activity. Additionally, they inhibit glutamate NMDA receptors and alter the ion conductance in the axonal membrane. Pentobarbital is administered with an initial bolus of 5–15 mg/kg (may give additional 5–10 mg/kg) followed by an infusion rate of 0.5–5 mg/kg/h. to achieve electrographic/clinical seizure cessation or burst-suppression. A case series of 26 children treated with pentobarbital showed that 75% of patients achieved burst-suppression pattern on EEG, with a relapse rate of 22% upon its weaning [
      • Kim S.J.
      • Lee D.Y.
      • Kim J.S.
      Neurologic outcomes of pediatric epileptic patients with pentobarbital coma.
      ]. Another study of 30 patients presenting RSE showed that 33% achieved burst-suppression with pentobarbital without relapse; while 66.7% required titration of pentobarbital to reachieve burst-suppression. The authors also found that patients older than five years and those who achieved burst-suppression within one day of pentobarbital initiation were more likely to have positive outcomes [
      • Barberio M.
      • Reiter P.D.
      • Kaufman J.
      • Knupp K.
      • Dobyns E.L.
      Continuous infusion pentobarbital for refractory status epilepticus in children.
      ]. Thiopental is less commonly used, but can be administered with an initial bolus of 2–7 mg/kg followed by an infusion rate of 0.5–5 mg/kg/h. [
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      Guidelines for the evaluation and management of status epilepticus.
      ]. Its efficacy in terminating seizures showed to be lower (55%; 11/20 patients) than propofol (64%; 14/22 patients) in a retrospective study [
      • van Gestel J.P.
      • Blusse van Oud-Alblas H.J.
      • Malingre M.
      • Ververs F.F.
      • Braun K.P.
      • van Nieuwenhuizen O.
      Propofol and thiopental for refractory status epilepticus in children.
      ]. A major drawback of barbiturates is the long half-life, which leads to a delayed recovery time. In addition, barbiturates are associated with a high rate of side effects including hypotension, respiratory depression, infections, anemia and prolonged length of ICU stay [
      • Wilkes R.
      • Tasker R.C.
      Intensive care treatment of uncontrolled status epilepticus in children: systematic literature search of midazolam and anesthetic therapies*.
      ,
      • Bellante F.
      • Legros B.
      • Depondt C.
      • Creteur J.
      • Taccone F.S.
      • Gaspard N.
      Midazolam and thiopental for the treatment of refractory status epilepticus: a retrospective comparison of efficacy and safety.
      ]. Reported effectiveness in SE termination with barbiturates varies between 64% and 69% with an estimated seizure recurrence rate of 22% [
      • Kim S.J.
      • Lee D.Y.
      • Kim J.S.
      Neurologic outcomes of pediatric epileptic patients with pentobarbital coma.
      ,
      • Wilkes R.
      • Tasker R.C.
      Intensive care treatment of uncontrolled status epilepticus in children: systematic literature search of midazolam and anesthetic therapies*.
      ,
      • Barberio M.
      • Reiter P.D.
      • Kaufman J.
      • Knupp K.
      • Dobyns E.L.
      Continuous infusion pentobarbital for refractory status epilepticus in children.
      ,
      • Bellante F.
      • Legros B.
      • Depondt C.
      • Creteur J.
      • Taccone F.S.
      • Gaspard N.
      Midazolam and thiopental for the treatment of refractory status epilepticus: a retrospective comparison of efficacy and safety.
      ]. Because the majority of patients initiated on pentobarbital infusions have failed to stop ongoing seizure activity with midazolam, showing the potential for a more severe form of SRSE, the higher seizure recurrence rate associated with pentobarbital infusions should be interpreted cautiously.
      The use of propofol is reported in the treatment of adult RSE [
      • Ferlisi M.
      • Shorvon S.
      The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy.
      ]. Although the mechanism of action is similar to midazolam and barbiturates (GABA-A receptor agonist), its use in children is limited. A previous report showed that children have increased risk of propofol infusion syndrome (PRIS), a life-threatening condition characterized by metabolic acidosis, rhabdomyolysis, arrhythmias, myocardial and renal failure, that results from administering a dose higher than 4 mg/kg/h. during 48 or more hours [
      • Fodale V.
      • La Monaca E.
      Propofol infusion syndrome: an overview of a perplexing disease.
      ]. Thus, propofol should be used with caution in pediatric patients, particularly with doses greater than 65 mcg/kg/min.
      Ketamine is an alternative therapy for control of RSE [
      • Keros S.
      • Buraniqi E.
      • Alex B.
      • Antonetty A.
      • Fialho H.
      • Hafeez B.
      • et al.
      Increasing ketamine use for refractory status epilepticus in US pediatric hospitals.
      ]. It acts as a noncompetitive antagonist of NMDA receptor and has been postulated to reduce epileptiform burst discharges and prevent glutamate-mediated neuro-toxicity [
      • Wasterlain C.G.
      • Mechanistic Chen J.W.
      pharmacologic aspects of status epilepticus and its treatment with new antiepileptic drugs.
      ,
      • Aram J.A.
      • Martin D.
      • Tomczyk M.
      • Zeman S.
      • Millar J.
      • Pohler G.
      • et al.
      Neocortical epileptogenesis in vitro: studies with N-methyl-D-aspartate, phencyclidine, sigma and dextromethorphan receptor ligands.
      ]. Since, in late stages of SE, there is a decrease in the number of active GABA-A receptors and up-regulated glutamate NMDA receptors, ketamine emerged as a promising treatment. A retrospective multicenter study including 46 adults and 12 children reported that permanent SE control was likely attributed to ketamine in 32% (19/60) of patients, and transient control in 13% (8/60) when used early. When ketamine was administered as third- or fourth-line treatment, SE control was achieved in 60% (6/10) of patients [
      • Gaspard N.
      • Foreman B.
      • Judd L.M.
      • Brenton J.N.
      • Nathan B.R.
      • McCoy B.M.
      • et al.
      From the Critical Care EEGMRC. Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multi-center study.
      ]. Similarly, a systematic review of 162 adults and 52 children, showed that ketamine was effective in 56.5% and 36.5%, of the adults and children, respectively. From the pediatric studies included in the review, those who reported ketamine dosing indicated either an initial bolus followed by CI, isolated CI or oral administration. The initial bolus dosing ranged between 2 and 3 mg/kg, followed by an infusion rate of 7.5 mcg/kg/h. to 10 mg/kg/h. When ketamine was administered as isolated CI, the dose ranged between 7 and 60 mcg/kg/min [
      • Zeiler F.A.
      • Teitelbaum J.
      • Gillman L.M.
      • West M.
      NMDA antagonists for refractory seizures.
      ]. Despite the sympathomimetic properties, ketamine has a relative safe profile [
      • Zeiler F.A.
      • Teitelbaum J.
      • Gillman L.M.
      • West M.
      NMDA antagonists for refractory seizures.
      ]. Compared to other anesthetics, it has the advantage of avoiding endotracheal intubation due to lack of respiratory compromise [
      • Ilvento L.
      • Rosati A.
      • Marini C.
      • L'Erario M.
      • Mirabile L.
      • Guerrini R.
      Ketamine in refractory convulsive status epilepticus in children avoids endotracheal intubation.
      ]. There is a current ongoing multicenter, randomized, controlled trial [
      • Rosati A.
      • Ilvento L.
      • L'Erario M.
      • De Masi S.
      • Biggeri A.
      • Fabbro G.
      • et al.
      Efficacy of ketamine in refractory convulsive status epilepticus in children: a protocol for a sequential design, multicentre, randomised, controlled, open-label, non-profit trial (KETASER01).
      ] evaluating the efficacy of ketamine in pediatric RSE. We anticipate that the results will be essential to stratify anesthetic utilization for the treatment of RSE/SRSE. They could help to overcome current limitations of retrospective data particularly, heterogeneity of medications prior to ketamine use, dosing and timing of administration.
      One of the last resorts of the SE/RSE treatment protocols is inhalational anesthesia. The antiepileptic effects of inhaled anesthetics likely involve potentiation of GABA-A receptors and inhibition of glutamate NMDA receptors [
      • Kudo M.
      • Aono M.
      • Lee Y.
      • Massey G.
      • Pearlstein R.D.
      • Warner D.S.
      Effects of volatile anesthetics on N-methyl-D-aspartate excitotoxicity in primary rat neuronal-glial cultures.
      ,
      • Solt K.
      • Eger E.I.
      2nd, Raines DE. Differential modulation of human N-methyl-D-aspartate receptors by structurally diverse general anesthetics.
      ]. Isoflurane and desflurane are commonly used for the treatment of RSE and have shown to be effective in inducing burst-suppression that is easily titratable [
      • Savard M.
      • Dupré N.
      • Turgeon A.
      • Desbiens R.
      • Langevin S.
      • Brunet D.
      POLG mitochondrial disorder heralded by propofol infusion syndrome: A case report.
      ,
      • Tasker R.C.
      • Vitali S.H.
      Continuous infusion, general anesthesia and other intensive care treatment for uncontrolled status epilepticus.
      ]. In the children, the most common inhalational anesthetic used is isoflurane [
      • Tobias J.D.
      Therapeutic applications and uses of inhalational anesthesia in the pediatric intensive care unit.
      ,
      • Wheless J.W.
      Treatment of refractory convulsive status epilepticus in children: other therapies.
      ,
      • Kofke W.A.
      • Young R.S.
      • Davis P.
      • Woelfel S.K.
      • Gray L.
      • Johnson D.
      • et al.
      Isoflurane for refractory status epilepticus: a clinical series.
      ,
      • Alexopoulos A.
      • Lachhwani D.K.
      • Gupta A.
      • Kotagal P.
      • Harrison A.M.
      • Bingaman W.
      • et al.
      Resective surgery to treat refractory status epilepticus in children with focal epileptogenesis.
      ,
      • Fugate J.E.
      • Burns J.D.
      • Wijdicks E.F.
      • Warner D.O.
      • Jankowski C.J.
      • Rabinstein A.A.
      Prolonged high-dose isoflurane for refractory status epilepticus: is it safe.
      ,
      • Lippert M.M.
      Isoflurane anaesthesia for status epilepticus.
      ]. It is administered with end-tidal concentrations of 0.5–2.3% [
      • Wheless J.W.
      Treatment of refractory convulsive status epilepticus in children: other therapies.
      ,
      • Kofke W.A.
      • Young R.S.
      • Davis P.
      • Woelfel S.K.
      • Gray L.
      • Johnson D.
      • et al.
      Isoflurane for refractory status epilepticus: a clinical series.
      ] through an anesthetic machine. This poses a potential logistical limitation in the ICU [
      • Tobias J.D.
      Therapeutic applications and uses of inhalational anesthesia in the pediatric intensive care unit.
      ,
      • Wheless J.W.
      Treatment of refractory convulsive status epilepticus in children: other therapies.
      ]. A clinical series of 11 RSE episodes in 9 patients (4 adults, 5 children) demonstrated achievement of seizure cessation (EEG burst-suppression pattern) with isoflurane in all patients. Nonetheless, 8/11 (72.7%) episodes relapsed upon discontinuation of isoflurane and 6/9 (66.7%) patients died [
      • Kofke W.A.
      • Young R.S.
      • Davis P.
      • Woelfel S.K.
      • Gray L.
      • Johnson D.
      • et al.
      Isoflurane for refractory status epilepticus: a clinical series.
      ]. Another series of 5 adults and 2 children presenting RSE, showed that isoflurane and desflurane stopped seizures in 100% of cases, with sustained EEG burst-suppression pattern [
      • Mirsattari S.M.
      • Sharpe M.D.
      • Young G.B.
      Treatment of refractory status epilepticus with inhalational anesthetic agents isoflurane and desflurane.
      ]. Overall, the efficacy of inhalational anesthetics seems to be transient and thus, should be considered as a temporary measure while additional workup is done to establish the etiology and/or adjunctive therapy is administered. The most commonly reported side effect of inhalational anesthetics is hypotension, requiring use of vasopressors. Other common side effects include atelectasis, deep vein thrombosis, infections and paralytic ileus [
      • Shorvon S.
      Super-refractory status epilepticus: an approach to therapy in this difficult clinical situation.
      ], all of which are limiting factors for their use.

      2.2.2 Immune modulators

      In cases of RSE of a presumed autoimmune/inflammatory etiology or in cryptogenic NORSE, clinicians frequently use immunomodulatory therapies as trial in attempts to control seizures. In this scenario, their use is supported by recent discoveries on immunologic (antibodies against neural receptors such as voltage-gated potassium channels and NMDA receptors) and inflammatory (activation of inflammatory signaling pathways such as Interleukin-1 receptor/toll-like receptor pathway) processes that may contribute to their underlying pathophysiology [
      • Shorvon S.
      • Ferlisi M.
      The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol.
      ,
      • Vezzani A.
      • Ruegg S.
      The pivotal role of immunity and inflammatory processes in epilepsy is increasingly recognized: introduction.
      ,
      • Vezzani A.
      • Balosso S.
      • Aronica E.
      • Ravizza T.
      Basic mechanisms of status epilepticus due to infection and inflammation.
      ]. The most commonly used therapies include corticosteroids, IV immunoglobulin (IVIG) and plasmapheresis [
      • van Baalen A.
      • Hausler M.
      • Boor R.
      • Rohr A.
      • Sperner J.
      • Kurlemann G.
      • et al.
      Febrile infection-related epilepsy syndrome (FIRES): a nonencephalitic encephalopathy in childhood.
      ,
      • Ferlisi M.
      • Hocker S.
      • Grade M.
      • Trinka E.
      • Shorvon S.
      • International Steering Committee of the StEp A
      Preliminary results of the global audit of treatment of refractory status epilepticus.
      ,
      • Almaabdi K.H.
      • Alshehri R.O.
      • Althubiti A.A.
      • Alsharef Z.H.
      • Mulla S.N.
      • Alshaer D.S.
      • et al.
      Intravenous methylprednisolone for intractable childhood epilepsy.
      ,
      • Erol I.
      • Alehan F.
      • Yalcin K.
      Refractory status epilepticus owing to human parvovirus B19 encephalitis in a child.
      ,
      • Moreno-Medinilla E.E.
      • Negrillo-Ruano R.
      • Calvo-Medina R.
      • Mora-Ramirez M.D.
      • Martinez-Anton J.L.
      Status epilepticus in paediatrics: a retrospective study and review of the literature.
      ,
      • Kramer U.
      • Chi C.S.
      • Lin K.L.
      • Specchio N.
      • Sahin M.
      • Olson H.
      • et al.
      Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children.
      ]; however, their efficacy remains controversial. A series of 5 young adults with new onset SRSE, showed that early administration of immunotherapy (steroids, IVIG, and/or azathioprine) achieved seizure control in 3 patients with subsequent AEDs, and was associated with good outcomes [
      • Gall C.R.
      • Jumma O.
      • Mohanraj R.
      Five cases of new onset refractory status epilepticus (NORSE) syndrome: outcomes with early immunotherapy.
      ]. Nonetheless, a review including 21 RSE/SRSE cases treated with adjunctive immunomodulatory therapy showed adequate seizure control in only 5% of cases [
      • Ferlisi M.
      • Shorvon S.
      The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy.
      ].
      Plasmapheresis is often used in parallel to other immunotherapies, particularly in RSE/SRSE etiologies such as FIRES, anti-NMDA encephalitis, and autoimmune paraneoplastic encephalitis. A previous series showed the potential benefit of early administration of plasmapheresis in FIRES. In this series, 4 patients received plasmapheresis at days 11, 12, 20 and 30, respectively, after seizure onset. The two patients that received plasmapheresis at days 11 and 12 presented better clinical outcomes than those who received it later [
      • Chevret L.
      • Husson B.
      • Nguefack S.
      • Nehlig A.
      • Bouilleret V.
      Prolonged refractory status epilepticus with early and persistent restricted hippocampal signal MRI abnormality.
      ]. On the contrary, a retrospective case series showed that plasmapheresis was no efficacious in two patients with FIRES [
      • Kramer U.
      • Chi C.S.
      • Lin K.L.
      • Specchio N.
      • Sahin M.
      • Olson H.
      • et al.
      Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children.
      ].
      There are less conventional immune therapies that target pro-inflammatory cytokines, which are considered to play an important role in the etiopathology of resistant epilepsies [
      • Matin N.
      • Tabatabaie O.
      • Falsaperla R.
      • Lubrano R.
      • Pavone P.
      • Mahmood F.
      • et al.
      Epilepsy and innate immune system: a possible immunogenic predisposition and related therapeutic implications.
      ]. Recently, the use of Anakinra has gained attention for the treatment of FIRES [
      • Kenney-Jung D.L.
      • Vezzani A.
      • Kahoud R.J.
      • LaFrance-Corey R.G.
      • Ho M.L.
      • Muskardin T.W.
      • et al.
      Febrile infection-related epilepsy syndrome treated with anakinra.
      ]. Anakinra is an antagonist of the interleukin (IL) 1 receptor type 1, which inhibits the biological actions of IL-1β [
      • Dinarello C.A.
      • Simon A.
      • van der Meer J.W.
      Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases.
      ]. IL-1β is a pro-inflammatory cytokine with ictogenic properties. In animal models with refractory seizures, microglia and astrocytes exhibit overexpression of IL-1β [
      • Dube C.
      • Vezzani A.
      • Behrens M.
      • Bartfai T.
      • Baram T.Z.
      Interleukin-1beta contributes to the generation of experimental febrile seizures.
      ], which makes of Anakinra a potential therapeutic approach for new onset RSE/SRSE.
      Similarly, the potential involvement of toll-like receptors and IL receptors in the role of innate immunity as a precipitating factor of seizures makes inflammatory mediators appealing therapeutic targets. Drugs such as Pralnacasan (inhibitor of IL-1β converting enzyme), Belnacasan (selective inhibitor of the interleukin converting enzyme/caspase-1 family), VX765 (selective inhibitor of interleukin converting enzyme), Resveratrol (suppressor of nuclear factor κB induced by toll like receptors) and Ifenprodil (sensitive blocker of NR2B-contaning NMDA receptors) are experimental inflammatory modulating therapies that deserve further exploration for the treatment of RSE/SRSE [
      • Matin N.
      • Tabatabaie O.
      • Falsaperla R.
      • Lubrano R.
      • Pavone P.
      • Mahmood F.
      • et al.
      Epilepsy and innate immune system: a possible immunogenic predisposition and related therapeutic implications.
      ].

      2.2.3 Other therapies

      Ketogenic diet (KD) is a high-fat, low-carbohydrate, and adequate-protein diet considered a safe and effective optional therapy for patients with drug-resistant epilepsy [
      • Caraballo R.H.
      • Flesler S.
      • Armeno M.
      • Fortini S.
      • Agustinho A.
      • Mestre G.
      • et al.
      Ketogenic diet in pediatric patients with refractory focal status epilepticus.
      ]. It has gained significant attention in recent years for the treatment of SE [
      • Freeman J.M.
      • Vining E.P.
      • Kossoff E.H.
      • Pyzik P.L.
      • Ye X.
      • Goodman S.N.
      A blinded, crossover study of the efficacy of the ketogenic diet.
      ,
      • Bodenant M.
      • Moreau C.
      • Sejourne C.
      • Auvin S.
      • Delval A.
      • Cuisset J.M.
      • et al.
      Interest of the ketogenic diet in a refractory status epilepticus in adults.
      ,
      • Kossoff E.H.
      • Nabbout R.
      Use of dietary therapy for status epilepticus.
      ] as an adjunctive therapy due to its anti-inflammatory and anti-seizure properties. In the pediatric population, small series report a collective efficacy rate of approximately 54% [
      • Farias-Moeller R.
      • Bartolini L.
      • Pasupuleti A.
      Brittany cines RD, kao A, carpenter JL: a practical approach to ketogenic diet in the pediatric intensive care unit for super-refractory status epilepticus.
      ,
      • Appavu B.
      • Vanatta L.
      • Condie J.
      • Kerrigan J.F.
      • Jarrar R.
      Ketogenic diet treatment for pediatric super-refractory status epilepticus.
      ,
      • Chiusolo F.
      • Diamanti A.
      • Bianchi R.
      • Fusco L.
      • Elia M.
      • Capriati T.
      • et al.
      From intravenous to enteral ketogenic diet in PICU: a potential treatment strategy for refractory status epilepticus.
      ,
      • Caraballo R.
      • Noli D.
      • Cachia P.
      Epilepsy of infancy with migrating focal seizures: three patients treated with the ketogenic diet.
      ,
      • Fung E.L.
      • Chang S.K.
      • Yam K.K.
      • Yau P.Y.
      Ketogenic diet as a therapeutic option in super-refractory status epilepticus.
      ]. In a series of 9 children with FIRES, KD was administered with a ratio of fat to combined protein and carbohydrate of 4:1 between days 4 and 55 of seizure onset. Seizure cessation was achieved in 7 of 8 (87.5%) patients that reached ketosis, within 2–4 days of ketonuria. Six of the 7 patients were maintained on the diet and re-experienced mild seizures (∼2 seizures per week) only after few months. The remaining patient returned to RSE after termination of KD, dying 10 days later [
      • Nabbout R.
      • Mazzuca M.
      • Hubert P.
      • Peudennier S.
      • Allaire C.
      • Flurin V.
      • et al.
      Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES).
      ]. Overall, there is heterogeneity regarding timing of implementation of KD, time to ketosis and clinical outcomes [
      • Farias-Moeller R.
      • Bartolini L.
      • Pasupuleti A.
      Brittany cines RD, kao A, carpenter JL: a practical approach to ketogenic diet in the pediatric intensive care unit for super-refractory status epilepticus.
      ,
      • Appavu B.
      • Vanatta L.
      • Condie J.
      • Kerrigan J.F.
      • Jarrar R.
      Ketogenic diet treatment for pediatric super-refractory status epilepticus.
      ,
      • Caraballo R.H.
      • Flesler S.
      • Armeno M.
      • Fortini S.
      • Agustinho A.
      • Mestre G.
      • et al.
      Ketogenic diet in pediatric patients with refractory focal status epilepticus.
      ,
      • Fung E.L.
      • Chang S.K.
      • Yam K.K.
      • Yau P.Y.
      Ketogenic diet as a therapeutic option in super-refractory status epilepticus.
      ,
      • Nabbout R.
      • Mazzuca M.
      • Hubert P.
      • Peudennier S.
      • Allaire C.
      • Flurin V.
      • et al.
      Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES).
      ,
      • Caraballo R.H.
      • Valenzuela G.R.
      • Armeno M.
      • Fortini S.
      • Mestre G.
      • Cresta A.
      The ketogenic diet in two paediatric patients with refractory myoclonic status epilepticus.
      ,
      • Amer S.
      • Shah P.
      • Kommineni V.
      Refractory status epilepticus from NMDA receptor encephalitis successfully treated with an adjunctive ketogenic diet.
      ,
      • Lin J.J.
      • Lin K.L.
      • Chan O.W.
      • Hsia S.H.
      • Wang H.S.
      Intravenous ketogenic diet therapy for treatment of the acute stage of super-refractory status epilepticus in a pediatric patient.
      ,
      • Singh R.K.
      • Joshi S.M.
      • Potter D.M.
      • Leber S.M.
      • Carlson M.D.
      • Shellhaas R.A.
      Cognitive outcomes in febrile infection-related epilepsy syndrome treated with the ketogenic diet.
      ,
      • Cobo N.H.
      • Sankar R.
      • Murata K.K.
      • Sewak S.L.
      • Kezele M.A.
      • Matsumoto J.H.
      The ketogenic diet as broad-spectrum treatment for super-refractory pediatric status epilepticus: challenges in implementation in the pediatric and neonatal intensive care units.
      ,
      • O'Connor S.E.
      • Ream M.A.
      • Richardson C.
      • Mikati M.A.
      • Trescher W.H.
      • Byler D.L.
      • et al.
      The ketogenic diet for the treatment of pediatric status epilepticus.
      ,
      • Sort R.
      • Born A.P.
      • Pedersen K.N.
      • Fonsmark L.
      • Uldall P.
      Ketogenic diet in 3 cases of childhood refractory status epilepticus.
      ]. Moreover, the simultaneous use of pharmacologic and non-pharmacologic therapies challenges the full understanding of the impact of KD efficacy in RSE/SRSE as well as the optimal parameters of administration. An important consideration is the involvement of a dietitian in the multidisciplinary team, as they will be crucial for achieving and maintaining ketosis in these patients. In children who are unable to take enteral feeds, implementation of KD can become complicated. Thus, IV KD can be used in these patients as a temporary measure [
      • Farias-Moeller R.
      • Bartolini L.
      • Pasupuleti A.
      Brittany cines RD, kao A, carpenter JL: a practical approach to ketogenic diet in the pediatric intensive care unit for super-refractory status epilepticus.
      ,
      • Chiusolo F.
      • Diamanti A.
      • Bianchi R.
      • Fusco L.
      • Elia M.
      • Capriati T.
      • et al.
      From intravenous to enteral ketogenic diet in PICU: a potential treatment strategy for refractory status epilepticus.
      ]. Contraindications to KD implementation include carnitine deficiencies, beta-oxidation metabolic defects, pyruvate carboxylase deficiency and porphyria [
      • Kossoff E.H.
      • Zupec-Kania B.A.
      • Amark P.E.
      • Ballaban-Gil K.R.
      • Christina Bergqvist A.G.
      • Blackford R.
      • et al.
      Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group.
      ]. In the absence of a contraindication, KD could be considered in earlier stages of RSE and SRSE management.
      The use of neurosteroids (e.g. allopregnanolone) in RSE/SRSE was initially supported by their action on extrasynaptic GABA-A receptors. These are different to BZDs’ receptors as they do not undergo internalization with prolonged seizures [
      • Trinka E.
      • Brigo F.
      • Shorvon S.
      Recent advances in status epilepticus.
      ], and thus, represented a promising therapy for RSE/SRSE. Their use was reported in adults [
      • Vaitkevicius H.
      • Husain A.M.
      • Rosenthal E.S.
      • Rosand J.
      • Bobb W.
      • Reddy K.
      • et al.
      First-in-man allopregnanolone use in super-refractory status epilepticus.
      ] and two pediatric patients [
      • Broomall E.
      • Natale J.E.
      • Grimason M.
      • Goldstein J.
      • Smith C.M.
      • Chang C.
      • et al.
      Pediatric super-refractory status epilepticus treated with allopregnanolone.
      ], in whom the neurosteroids allowed the general anesthetic infusions to be successfully weaned. Nonetheless, a recent randomized controlled trial in adults and children failed to demonstrate the efficacy of IV allopregnanolone (brexanolone) compared to placebo (43.9% vs. 42.4%; p = 0.877) in the resolution of SRSE, when it was added to the standard care [
      • Rosenthal E.S.W.
      • Mark
      A Study With SAGE-547 for Super-Refractory Status Epilepticus.
      ]. These results highlight the importance of data derived from randomized clinical trials to inform and guide current clinical RSE/SRSE management.
      Therapeutic hypothermia is described mainly for the treatment of TBI. Currently, it is considered as an adjunctive therapy for RSE/SRSE due to its neuroprotective and antiepileptic properties demonstrated in animal studies. Moreover, it has the capacity to reduce cerebral metabolic rate, cerebral edema, inflammation, oxidative stress, and glutaminergic drive [
      • Corry J.J.
      • Dhar R.
      • Murphy T.
      • Diringer M.N.
      Hypothermia for refractory status epilepticus.
      ,
      • Motamedi G.K.
      • Lesser R.P.
      • Vicini S.
      Therapeutic brain hypothermia, its mechanisms of action, and its prospects as a treatment for epilepsy.
      ]. In children, multiple case reports describe resolution of RSE with adjunctive hypothermia [
      • Lin J.J.
      • Lin K.L.
      • Hsia S.H.
      • Wang H.S.
      Therapeutic hypothermia for febrile infection-related epilepsy syndrome in two patients.
      ,
      • Shein S.L.
      • Reynolds T.Q.
      • Gedela S.
      • Kochanek P.M.
      • Bell M.J.
      Therapeutic hypothermia for refractory status epilepticus in a child with malignant migrating partial seizures of infancy and SCN1A mutation: a case report.
      ,
      • Elting J.W.
      • Naalt J.
      • Fock J.M.
      Mild hypothermia for refractory focal status epilepticus in an infant with hemimegalencephaly.
      ,
      • Orlowski J.P.
      • Erenberg G.
      • Lueders H.
      • Cruse R.P.
      Hypothermia and barbiturate coma for refractory status epilepticus.
      ]. In a series of 5 children with RSE, mild hypothermia (32–35 °C) was beneficial in reducing seizure burden, and prevented RSE relapse in all the patients [
      • Guilliams K.
      • Rosen M.
      • Buttram S.
      • Zempel J.
      • Pineda J.
      • Miller B.
      • et al.
      Hypothermia for pediatric refractory status epilepticus.
      ]. Nonetheless, more robust evidence of its efficacy emerged with a multicenter randomized clinical trial comparing therapeutic hypothermia to the standard medical treatment. This study included 270 patients with convulsive SE and concluded that hypothermia was not associated with a lower rate of progression to RSE or SRSE, or improved clinical outcomes [
      • Legriel S.
      • Lemiale V.
      • Schenck M.
      • Chelly J.
      • Laurent V.
      • Daviaud F.
      • et al.
      Hypothermia for neuroprotection in convulsive status epilepticus.
      ]. Important considerations before its implementation include the possible interaction with anesthetics and ASDs clearance [
      • Corry J.J.
      • Dhar R.
      • Murphy T.
      • Diringer M.N.
      Hypothermia for refractory status epilepticus.
      ], as well as awareness of common side effects: deep venous thrombosis, infections, cardiac arrhythmias, electrolyte disturbances, acute intestinal ischemia and coagulation disorders [
      • Bayrlee A.
      • Ganeshalingam N.
      • Kurczewski L.
      • Brophy G.M.
      Treatment of super-refractory status epilepticus.
      ,
      • Zeiler F.A.
      • Zeiler K.J.
      • Teitelbaum J.
      • Gillman L.M.
      • West M.
      Therapeutic hypothermia for refractory status epilepticus.
      ].
      Electroconvulsive therapy (ECT) is also documented for the treatment of SRSE [
      • Ahmed J.
      • Metrick M.
      • Gilbert A.
      • Glasson A.
      • Singh R.
      • Ambrous W.
      • et al.
      Electroconvulsive therapy for super-refractory status epilepticus.
      ] in case series and reports. ECT increases GABA levels, leading to reduction of neuronal metabolic activity and interruption of seizures through the induction of a refractory period [
      • Sackeim H.A.
      The anticonvulsant hypothesis of the mechanisms of action of ECT: current status.
      ,
      • Yang X.
      • Wang X.
      Potential mechanisms and clinical applications of mild hypothermia and electroconvulsive therapy on refractory status epilepticus.
      ,
      • Duthie A.C.
      • Perrin J.S.
      • Bennett D.M.
      • Currie J.
      • Reid I.C.
      Anticonvulsant mechanisms of electroconvulsive therapy and relation to therapeutic efficacy.
      ]. It is considered in children with focal and generalized RSE, with variable etiology (e.g. structural, intractable epilepsy) in whom more than five ASDs have been administered prior to ECT [
      • Morales O.G.
      • Henry M.E.
      • Nobler M.S.
      • Wassermann E.M.
      • Lisanby S.H.
      Electroconvulsive therapy and repetitive transcranial magnetic stimulation in children and adolescents: a review and report of two cases of epilepsia partialis continua.
      ,
      • Griesemer D.A.
      • Kellner C.H.
      • Beale M.D.
      • Smith G.M.
      Electroconvulsive therapy for treatment of intractable seizures: initial findings in two children.
      ,
      • Shin H.W.
      • O’Donovan C.A.
      • Boggs J.G.
      • Grefe A.
      • Harper A.
      • Bell W.L.
      • et al.
      Successful ECT treatment for medically refractory nonconvulsive status epilepticus in pediatric patient.
      ]. In these case reports the patients’ outcomes are variable ranging from transient response to ECT and mild improvement of seizure frequency [
      • Griesemer D.A.
      • Kellner C.H.
      • Beale M.D.
      • Smith G.M.
      Electroconvulsive therapy for treatment of intractable seizures: initial findings in two children.
      ] to no clinical improvement followed by death [
      • Morales O.G.
      • Henry M.E.
      • Nobler M.S.
      • Wassermann E.M.
      • Lisanby S.H.
      Electroconvulsive therapy and repetitive transcranial magnetic stimulation in children and adolescents: a review and report of two cases of epilepsia partialis continua.
      ]. Administering acute ECT is logistically challenging because its availability in some centers is limited. The side effects reported in the literature include transient lethargy or amnesic events [
      • Griesemer D.A.
      • Kellner C.H.
      • Beale M.D.
      • Smith G.M.
      Electroconvulsive therapy for treatment of intractable seizures: initial findings in two children.
      ], though most of the studies fail to document this information.
      Another non-pharmacological option includes the vagus nerve stimulation [
      • Yamazoe T.
      • Okanishi T.
      • Yamamoto A.
      • Yamada T.
      • Nishimura M.
      • Fujimoto A.
      • et al.
      New-onset refractory status epilepticus treated with vagus nerve stimulation: a case report.
      ,
      • De Herdt V.
      • Waterschoot L.
      • Vonck K.
      • Dermaut B.
      • Verhelst H.
      • Van Coster R.
      • et al.
      Vagus nerve stimulation for refractory status epilepticus.
      ,
      • De Benedictis A.
      • Freri E.
      • Rizzi M.
      • Franzini A.
      • Ragona F.
      • Specchio N.
      • et al.
      Vagus nerve stimulation for drug-resistant Epilepsia Partialis Continua: report of four cases.
      ,
      • Howell K.B.
      • Katanyuwong K.
      • Mackay M.T.
      • Bailey C.A.
      • Scheffer I.E.
      • Freeman J.L.
      • et al.
      Long-term follow-up of febrile infection-related epilepsy syndrome.
      ,
      • Winston K.R.
      • Levisohn P.
      • Miller B.R.
      • Freeman J.
      Vagal nerve stimulation for status epilepticus.
      ,
      • Zamponi N.
      • Rychlicki F.
      • Corpaci L.
      • Cesaroni E.
      • Trignani R.
      Vagus nerve stimulation (VNS) is effective in treating catastrophic 1 epilepsy in very young children.
      ]. Similar to ECT, there is certainly no evidence that suggest consistent improvement in seizure control based on the current data.
      Emergency epilepsy surgery should be considered for RSE and SRSE treatment in two scenarios: failure to maximal medical therapy for at least two weeks or when a structural abnormality is identified [
      • Bhatia S.
      • Ahmad F.
      • Miller I.
      • Ragheb J.
      • Morrison G.
      • Jayakar P.
      • et al.
      Surgical treatment of refractory status epilepticus in children: clinical article.
      ]. Although surgery is generally contemplated in the late course of RSE, patients may undergo surgery as early as eight days after SE onset [
      • Alexopoulos A.
      • Lachhwani D.K.
      • Gupta A.
      • Kotagal P.
      • Harrison A.M.
      • Bingaman W.
      • et al.
      Resective surgery to treat refractory status epilepticus in children with focal epileptogenesis.
      ]. Since typical pre-operative diagnostic tools such as cortical mapping are challenging to obtain in an ICU setting, emergency surgery must be carefully weighed. The initial diagnostic approach includes the identification of the epileptogenic focus on EEG. Prior literature in children with RSE treated with surgery showed that common EEG features include generalized or non-focal lateralized discharges [
      • Vendrame M.
      • Loddenkemper T.
      Surgical treatment of refractory status epilepticus in children: candidate selection and outcome.
      ]. However, in some cases these findings can be hindered by the use of barbiturates and BZDs. If that is the case, ancillary testing such as ictal single-photon emission computerized tomography (SPECT), MRI and possibly magneto-encephalogram (MEG) should be utilized. If a structural lesion is identified, the extent of the lesion should be further characterized through the mapping of the eloquent cortex and definition of the epileptogenic zone [
      • Bhatia S.
      • Ahmad F.
      • Miller I.
      • Ragheb J.
      • Morrison G.
      • Jayakar P.
      • et al.
      Surgical treatment of refractory status epilepticus in children: clinical article.
      ].

      3. Outcomes of RSE and SRSE in children

      3.1 Clinical outcomes

      The nature of RSE/SRSE is highly heterogeneous and several factors may contribute to the patients’ prognosis. Mortality estimates in pediatric RSE are 13.7–43.5% [
      • Sahin M.
      • Menache C.C.
      • Holmes G.L.
      • Riviello J.J.
      Outcome of severe refractory status epilepticus in children.
      ,
      • Gilbert D.L.
      • Gartside P.S.
      • Glauser T.A.
      Efficacy and mortality in treatment of refractory generalized convulsive status epilepticus in children: a meta-analysis.
      ,
      • Kim S.J.
      • Lee D.Y.
      • Kim J.S.
      Neurologic outcomes of pediatric epileptic patients with pentobarbital coma.
      ,
      • Lingappa L.
      • Konanki R.
      • Patel R.
      • Vooturi S.
      • Jayalakshmi S.
      Clinical profile and outcome of refractory convulsive status epilepticus in older children from a developing country.
      ], related to etiology, patients’ age (<3 years old), and initial EEG findings (i.e.multifocal or generalized abnormalities) [
      • Sahin M.
      • Menache C.C.
      • Holmes G.L.
      • Riviello J.J.
      Outcome of severe refractory status epilepticus in children.
      ]. The underlying etiology is usually recognized as a primary predictor of outcomes [
      • Eriksson K.
      • Metsaranta P.
      • Huhtala H.
      • Auvinen A.
      • Kuusela A.L.
      • Koivikko M.
      Treatment delay and the risk of prolonged status epilepticus.
      ,
      • Barzegar M.
      • Mahdavi M.
      • Galegolab Behbehani A.
      • Tabrizi A.
      Refractory convulsive status epilepticus in children: etiology, associated risk factors and outcome.
      ,
      • Lingappa L.
      • Konanki R.
      • Patel R.
      • Vooturi S.
      • Jayalakshmi S.
      Clinical profile and outcome of refractory convulsive status epilepticus in older children from a developing country.
      ,
      • Sahin M.
      • Menache C.C.
      • Holmes G.L.
      • Riviello Jr., J.J.
      Prolonged treatment for acute symptomatic refractory status epilepticus: outcome in children.
      ,
      • Mayer S.A.
      • Claassen J.
      • Lokin J.
      • Mendelsohn F.
      • Dennis L.J.
      • Fitzsimmons B.F.
      Refractory status epilepticus: frequency, risk factors, and impact on outcome.
      ]. Patients presenting with RSE due to acute symptomatic etiologies are less likely to return to baseline neurological function and are at higher risk of developing drug-resistant epilepsy [
      • Sahin M.
      • Menache C.C.
      • Holmes G.L.
      • Riviello Jr., J.J.
      Prolonged treatment for acute symptomatic refractory status epilepticus: outcome in children.
      ]. Similarly, existing evidence shows that patients with treatment delays [
      • Gaínza-Lein M.
      • Sánchez Fernández I.
      • Jackson M.
      • et al.
      Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus.
      ], longer RSE duration [
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ,
      • Claassen J.
      • Lokin J.K.
      • Fitzsimmons B.F.
      • Mendelsohn F.A.
      • Mayer S.A.
      Predictors of functional disability and mortality after status epilepticus.
      ], and those who present with non-convulsive SE have worse clinical outcomes [
      • Abend N.S.
      • Wusthoff C.J.
      • Goldberg E.M.
      • Dlugos D.J.
      Electrographic seizures and status epilepticus in critically ill children and neonates with encephalopathy.
      ].
      Not only are patients with RSE/SRSE at risk for higher mortality, they are also at risk for neurological and systemic complications as a consequence of the prolonged length of ICU stay and anesthetic use. While the data for SRSE is scarce, a series of 10 children with SRSE showed a median ICU and hospital length stay of 27 and 62 days, respectively; and a mortality rate of 11.1% [
      • Appavu B.
      • Vanatta L.
      • Condie J.
      • Kerrigan J.F.
      • Jarrar R.
      Ketogenic diet treatment for pediatric super-refractory status epilepticus.
      ]. Another study identified 43 SRSE patients out of 305 children with SE. The patients in the SRSE cohort presented more often with adverse events due to medications. This cohort had a case fatality rate of 21.3% when compared to the 5.1% in all the analyzed SE children [
      • Kravljanac R.
      • Djuric M.
      • Jankovic B.
      • Pekmezovic T.
      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.
      ]. ICU related comorbidities include hypotension, prolonged respiratory failure, sepsis, pneumonia, urinary tract infections and prolonged immobility [
      • Shorvon S.
      • Ferlisi M.
      The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol.
      ]. Moreover, as these patients are often on multiple therapies, systemic complications may arise from interactions between medications or their adverse effects. A study of 171 adult patients with SE evaluated the outcome of patients who were treated with IV anesthetic drugs (37%). After controlling for confounders, the authors found that the use of CIs was associated with increased frequency of infections during SE as well as a 2.9-fold relative risk for death. Additionally, these patients had higher rates of intubation, severe hypotension and poor functional outcome on the Glasgow Outcome Score at long-term follow-up [
      • Sutter R.
      • Marsch S.
      • Fuhr P.
      • Kaplan P.W.
      • Rüeg S.
      Anesthetic drugs in status epilepticus: risk or rescue? A 6-year cohort study.
      ].
      Similarly, there is evidence in children with febrile RSE that induction of therapeutic burst-suppression may lead to increased risk of hemodynamic instability and poor outcomes as compared to electrographic seizure control [
      • Lin J.-J.
      • Chou C.-C.
      • Lan S.-Y.
      • Hsiao H.-J.
      • Wang Y.
      • Chan O.-W.
      • et al.
      Therapeutic burst-suppression coma in pediatric febrile refractory status epilepticus.
      ]. Two retrospective case series showed that recurrence of SE after initiation of pentobarbital was associated with worse neurologic outcomes, suggesting that it should be considered as a poor prognostic factor [
      • Kim S.J.
      • Lee D.Y.
      • Kim J.S.
      Neurologic outcomes of pediatric epileptic patients with pentobarbital coma.
      ,
      • Claassen J.
      • Hirsch L.J.
      • Emerson R.G.
      • Mayer S.A.
      Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review.
      ]. The direct association between CIs use and clinical outcomes in RSE/SRSE warrants further investigation. It remains unclear whether worse outcomes are a result of the administration of CIs and their side effects, the natural progression of a more severe case of RSE/SRSE or a combination of these two. We consider urgent that future studies address the adequate approach to CI administration regarding dosing, up titration versus substituting for another anesthetic infusion, as well as the treatment goals in view of a potential impact on clinical outcomes.

      4. Conclusion

      RSE is a neurological emergency in the pediatric population. Literature on SRSE in children is limited despite the morbidity associated with this disorder. Current clinical practice is challenged by the heterogeneous etiologies and multiple factors involved in the progression from SE to RSE and SRSE. Moreover, there is a need to understand how aggressively RSE/SRSE patients should be treated initially, as the intrinsic risks of treatment and their effect on clinical outcomes should be taken into consideration. A multicenter and multinational collaborative effort is desirable to evaluate epidemiological data on pediatric RSE/SRSE, prevention strategies and available therapeutic options in order to provide more definitive evidence for their efficacy and safety in RSE and SRSE.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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