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New onset refractory status epilepticus (NORSE)

  • Claudine Sculier
    Correspondence
    Corresponding author at: Département de Neurologie, Université Libre de Bruxelles, Hôpital Erasme, Brussels, Belgium.
    Affiliations
    Département de Neurologie, Université Libre de Bruxelles, Hôpital Erasme, Brussels, Belgium

    Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
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  • Nicolas Gaspard
    Affiliations
    Département de Neurologie, Université Libre de Bruxelles, Hôpital Erasme, Brussels, Belgium

    Comprehensive Epilepsy Center, Neurology Department, Yale University School of Medicine, New Haven, CT, USA
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Open ArchivePublished:September 29, 2018DOI:https://doi.org/10.1016/j.seizure.2018.09.018

      Highlights

      • The NORSE definition provides standardized criteria for future multicenter research.
      • Extensive patient-specific investigations are required to find rare causes of NORSE.
      • The etiology is identified in approximatively 50% of adult cases.
      • Recent immunotherapies and ketogenic diet are sometimes efficacious.

      Abstract

      Purpose

      To summarize the clinical features, suggested work-up, treatment and prognosis of new-onset refractory status epilepticus (NORSE), a condition recently defined as the occurrence of refractory status epilepticus (RSE) in a patient without active epilepsy, and without a clear acute or active structural, toxic or metabolic cause; and of the related syndrome of febrile infection-related epilepsy syndrome (FIRES), also recently defined as a subgroup of NORSE preceded by a febrile illness between 2 weeks and 24 h prior to the onset of RSE.

      Method

      Narrative review of the medical literature about NORSE and FIRES.

      Results

      NORSE and FIRES mainly affect school-age children and young adults. A prodromal phase with flu-like symptoms precedes the SE onset in two third of NORSE cases, and by definition in all FIRES. Status epilepticus usually starts with repeated focal seizures with secondary bilateralization. Most cases evolve to super RSE (SRSE) and have unfavorable outcome, with short-term mortality of 12–27%, long-term disability and epilepsy. No specific imaging or laboratory abnormalities have been identified so far that allows an early diagnosis and half of adult cases remain of unknown etiology. A standardized diagnostic algorithm is provided and. Autoimmune encephalitis is the most frequent identified cause. In the absence of specific diagnosis, immunotherapy could be tried in addition to antiepileptic treatment.

      Conclusions

      This review presents the rare but devastating syndrome of NORSE, including the subcategory of FIRES. Early recognition with complete work-up is primordial to identify the underlying cause and promptly start appropriate treatment.

      Keywords

      1. Introduction and new definitions

      New-onset refractory status epilepticus (NORSE) is a rare but devastating condition. Overall, approximately 200 cases of NORSE in adults [
      • Wilder-Smith E.P.V.
      • Lim E.C.H.
      • Teoh H.L.
      • Sharma V.K.
      • Tan J.J.H.
      • Chan B.P.L.
      • et al.
      The NORSE (new-onset refractory status epilepticus) syndrome: defining a disease entity.
      ,
      • Costello D.J.
      • Kilbride R.D.
      • Cole A.J.
      Cryptogenic New Onset Refractory Status Epilepticus (NORSE) in adults-Infectious or not?.
      ,
      • Khawaja A.M.
      • DeWolfe J.L.
      • Miller D.W.
      • Szaflarski J.P.
      New-onset refractory status epilepticus (NORSE)--The potential role for immunotherapy.
      ,
      • 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.
      ,
      • Meletti S.
      • Giovannini G.
      • d’Orsi G.
      • Toran L.
      • Monti G.
      • Guha R.
      • et al.
      New-onset refractory status epilepticus with claustrum damage: definition of the clinical and neuroimaging features.
      ,
      • Gall C.R.E.
      • Jumma O.
      • Mohanraj R.
      Five cases of new onset refractory status epilepticus (NORSE) syndrome: outcomes with early immunotherapy.
      ,
      • Matar R.K.
      • Alshamsan B.
      • Alsaleh S.
      • Alhindi H.
      • Alahmedi K.O.
      • Khairy S.
      • et al.
      New onset refractory status epilepticus due to primary angiitis of the central nervous system.
      ,
      • Marashly A.
      • Lew S.
      • Koop J.
      Successful surgical management of New Onset Refractory Status Epilepticus (NORSE) presenting with gelastic seizures in a 3 year old girl.
      ,
      • Takei J.
      • Takei R.
      • Nozuma S.
      • Nakahara K.
      • Watanabe O.
      • Takashima H.
      Efficacy of potassium bromide in the treatment of drug-resistant epilepsy: a case of new-onset refractory status epilepticus.
      ,
      • Laswell E.M.
      • Chambers K.D.
      • Whitsel D.R.
      • Poudel K.
      New-onset refractory status epilepticus in an adult with an atypical presentation of cat-scratch disease: successful treatment with high-dose corticosteroids.
      ,
      • Shrivastava M.
      • Chouhan S.
      • Navaid S.
      Plasma exchange as a therapeutic modality in a rare case of cryptogenic new onset refractory status epilepticus (NORSE).
      ,
      • Iizuka T.
      • Kanazawa N.
      • Kaneko J.
      • Tominaga N.
      • Nonoda Y.
      • Hara A.
      • et al.
      Cryptogenic NORSE: its distinctive clinical features and response to immunotherapy.
      ] and 200 cases of FIRES in children [
      • Baxter P.
      • Clarke A.
      • Cross H.
      • Harding B.
      • Hicks E.
      • Livingston J.
      • et al.
      Idiopathic catastrophic epileptic encephalopathy presenting with acute onset intractable status.
      ,
      • Mikaeloff Y.
      • Jambaqué I.
      • Hertz-Pannier L.
      • Zamfirescu A.
      • Adamsbaum C.
      • Plouin P.
      • et al.
      Devastating epileptic encephalopathy in school-aged children (DESC): a pseudo encephalitis.
      ,
      • Sakuma H.
      • Awaya Y.
      • Shiomi M.
      • Yamanouchi H.
      • Takahashi Y.
      • Saito Y.
      • et al.
      Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis.
      ,
      • van Baalen A.
      • Häusler M.
      • Boor R.
      • Rohr A.
      • Sperner J.
      • Kurlemann G.
      • et al.
      Febrile infection-related epilepsy syndrome (FIRES): a nonencephalitic encephalopathy in childhood.
      ,
      • 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).
      ,
      • Kramer U.
      • Shorer Z.
      • Ben-Zeev B.
      • Lerman-Sagie T.
      • Goldberg-Stern H.
      • Lahat E.
      Severe refractory status epilepticus owing to presumed encephalitis.
      ,
      • 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.L.
      • Buompadre M.C.
      • Gonzalez M.
      • Fortini S.
      • et al.
      Febrile infection-related epilepsy syndrome: a study of 12 patients.
      ,
      • Patil S.B.
      • Roy A.G.
      • Vinayan K.P.
      Clinical profile and treatment outcome of febrile infection-related epilepsy syndrome in South Indian children.
      ,
      • 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.
      ,
      • Farias-Moeller R.
      • Bartolini L.
      • Staso K.
      • Schreiber J.M.
      • Carpenter J.L.
      Early ictal and interictal patterns in FIRES: the sparks before the blaze.
      ,
      • Gofshteyn J.S.
      • Wilfong A.
      • Devinsky O.
      • Bluvstein J.
      • Charuta J.
      • Ciliberto M.A.
      • et al.
      Cannabidiol as a  potential treatment for febrile infection-related epilepsy syndrome (FIRES) in the acute and chronic phases.
      ,
      • Saitoh M.
      • Kobayashi K.
      • Ohmori I.
      • Tanaka Y.
      • Tanaka K.
      • Inoue T.
      • et al.
      Cytokine-related and sodium channel polymorphism as candidate predisposing factors for childhood encephalopathy FIRES/AERRPS.
      ,
      • 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.
      ,
      • Fox K.
      • Wells M.E.
      • Tennison M.
      • Vaughn B.
      Febrile infection-related epilepsy syndrome (FIRES): a literature review and case study.
      ,
      • Rivas-Coppola M.S.
      • Shah N.
      • Choudhri A.F.
      • Morgan R.
      • Wheless J.W.
      Chronological evolution of magnetic resonance imaging findings in children with febrile infection-related epilepsy syndrome.
      ,
      • Agarwal A.
      • Sabat S.
      • Thamburaj K.
      • Kanekar S.
      Hippocampal changes in febrile infection-related epilepsy syndrome (FIRES).
      ,
      • Mirás Veiga A.
      • Moreno D.C.
      • Menéndez A.I.G.
      • Siscart I.M.
      • Fernández M.D.O.
      • Sánchez E.G.
      • et al.
      Effectiveness of electroconvulsive therapy for refractory status epilepticus in febrile infection-related epilepsy syndrome.
      ] have been reported in the literature.
      This term was used for the first time by Wilder-Smith et al [
      • Wilder-Smith E.P.V.
      • Lim E.C.H.
      • Teoh H.L.
      • Sharma V.K.
      • Tan J.J.H.
      • Chan B.P.L.
      • et al.
      The NORSE (new-onset refractory status epilepticus) syndrome: defining a disease entity.
      ] to describe cases of super refractory status epilepticus (SRSE) without a previous history of epilepsy and with no identifiable underlying cause. However, other definitions have been applied for the term in subsequent studies [
      • Costello D.J.
      • Kilbride R.D.
      • Cole A.J.
      Cryptogenic New Onset Refractory Status Epilepticus (NORSE) in adults-Infectious or not?.
      ,
      • Khawaja A.M.
      • DeWolfe J.L.
      • Miller D.W.
      • Szaflarski J.P.
      New-onset refractory status epilepticus (NORSE)--The potential role for immunotherapy.
      ]. Similar conditions have also been described under various names in children, including severe refractory status epilepticus due to presumed encephalitis [
      • Sahin M.
      • Menache C.C.
      • Holmes G.L.
      • Riviello J.J.
      Outcome of severe refractory status epilepticus in children.
      ], idiopathic catastrophic epileptic encephalopathy presenting with acute onset intractable status [
      • Baxter P.
      • Clarke A.
      • Cross H.
      • Harding B.
      • Hicks E.
      • Livingston J.
      • et al.
      Idiopathic catastrophic epileptic encephalopathy presenting with acute onset intractable status.
      ], devastating epileptic encephalopathy in school-age children (DESC) [
      • Mikaeloff Y.
      • Jambaqué I.
      • Hertz-Pannier L.
      • Zamfirescu A.
      • Adamsbaum C.
      • Plouin P.
      • et al.
      Devastating epileptic encephalopathy in school-aged children (DESC): a pseudo encephalitis.
      ], acute encephalitis with refractory repetitive partial seizures (AERRPS) [
      • Sakuma H.
      • Awaya Y.
      • Shiomi M.
      • Yamanouchi H.
      • Takahashi Y.
      • Saito Y.
      • et al.
      Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis.
      ] and febrile infection-related epilepsy syndrome (FIRES) [
      • van Baalen A.
      • Häusler M.
      • Boor R.
      • Rohr A.
      • Sperner J.
      • Kurlemann G.
      • et al.
      Febrile infection-related epilepsy syndrome (FIRES): a nonencephalitic encephalopathy in childhood.
      ], also called fever-induced refractory epileptic encephalopathy of school-age children [
      • Nabbout R.
      • Vezzani A.
      • Dulac O.
      • Chiron C.
      Acute encephalopathy with inflammation-mediated status epilepticus.
      ] or fulminant inflammatory response epilepsy syndrome [
      • van Baalen A.
      • Vezzani A.
      • Häusler M.
      • Kluger G.
      Febrile infection-related epilepsy syndrome: clinical review and hypotheses of epileptogenesis.
      ]. In the latter, the presence of a febrile episode prior to the onset of SE is by definition required. While fever often precedes the onset of seizures in adults with NORSE [
      • 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.
      ], its presence has never been required to make the diagnosis. Some authors have argued that NORSE and FIRES are distinct entities [
      • Körtvelyessy P.
      • Lerche H.
      • Weber Y.
      FIRES and NORSE are distinct entities.
      ]. However, apart from age and fever, the two syndromes do in fact share many similarities (see below) and most authors now believe they are identical or at least belong to the same category of disease [
      • Ismail F.Y.
      • Kossoff E.H.
      AERRPS, DESC, NORSE, FIRES: multi-labeling or distinct epileptic entities?.
      ,
      • 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.
      ].
      Until recently, the lack of a standardized terminology was a limitation to clinical research. This motivated the introduction of consensus definitions [
      • 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.
      ]. According to this recent proposal, NORSE is defined as a clinical presentation, in a patient without active epilepsy, with new onset of refractory status epilepticus (RSE) without a clear acute 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.
      ]. It includes cases with a known etiology, when it is not easily identified by the recommended initial investigations by imaging (including brain MRI) and lumbar puncture (including PCR for HSV-1), which are typically obtained within 72 h after admission. This definition allows ruling out usual causes of status epilepticus (SE) such as acute strokes, brain masses, drug overdoses, etc. On the other hand, cases due to viral infection of CNS (except HSV1 encephalitis) or auto-immune encephalitis are included [
      • 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 definition of FIRES has also been proposed, defining it as a subgroup of NORSE preceded by a febrile illness between 2 weeks and 24 h prior to the onset of refractory status epilepticus, and removing any age criteria [
      • 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.
      ].
      An etiology is identified in approximatively 50% of adult cases of NORSE. The majority of cases with a known etiology are due to sporadic or paraneoplastic auto-immune encephalitis [
      • 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.
      ]. In case series of children with FIRES, the cause is almost always unknown but the lack of etiological diagnosis was likely an inclusion criteria for these studies, introducing a selection bias [
      • Mikaeloff Y.
      • Jambaqué I.
      • Hertz-Pannier L.
      • Zamfirescu A.
      • Adamsbaum C.
      • Plouin P.
      • et al.
      Devastating epileptic encephalopathy in school-aged children (DESC): a pseudo encephalitis.
      ,
      • van Baalen A.
      • Häusler M.
      • Boor R.
      • Rohr A.
      • Sperner J.
      • Kurlemann G.
      • et al.
      Febrile infection-related epilepsy syndrome (FIRES): a nonencephalitic encephalopathy in childhood.
      ,
      • Caraballo R.H.
      • Reyes G.
      • Avaria M.F.L.
      • Buompadre M.C.
      • Gonzalez M.
      • Fortini S.
      • et al.
      Febrile infection-related epilepsy syndrome: a study of 12 patients.
      ,
      • Patil S.B.
      • Roy A.G.
      • Vinayan K.P.
      Clinical profile and treatment outcome of febrile infection-related epilepsy syndrome in South Indian children.
      ]. Further, those series are small and the diagnostic work-up is variable and often incomplete. Also, many published cases predates the description of encephalitis caused by more recently identified antibodies to neuronal surface antigens, such as anti-gamma-amino-hydroxybutyric acid [GABA](A) receptors [
      • Baxter P.
      • Clarke A.
      • Cross H.
      • Harding B.
      • Hicks E.
      • Livingston J.
      • et al.
      Idiopathic catastrophic epileptic encephalopathy presenting with acute onset intractable status.
      ,
      • Mikaeloff Y.
      • Jambaqué I.
      • Hertz-Pannier L.
      • Zamfirescu A.
      • Adamsbaum C.
      • Plouin P.
      • et al.
      Devastating epileptic encephalopathy in school-aged children (DESC): a pseudo encephalitis.
      ,
      • Kramer U.
      • Shorer Z.
      • Ben-Zeev B.
      • Lerman-Sagie T.
      • Goldberg-Stern H.
      • Lahat E.
      Severe refractory status epilepticus owing to presumed encephalitis.
      ].

      2. Epidemiology of NORSE and FIRES

      NORSE and FIRES most frequently occurs in previously healthy young adults and school-aged children, although adults above 60 can also be affected. There is a female predominance in most adult series [
      • Wilder-Smith E.P.V.
      • Lim E.C.H.
      • Teoh H.L.
      • Sharma V.K.
      • Tan J.J.H.
      • Chan B.P.L.
      • et al.
      The NORSE (new-onset refractory status epilepticus) syndrome: defining a disease entity.
      ,
      • Costello D.J.
      • Kilbride R.D.
      • Cole A.J.
      Cryptogenic New Onset Refractory Status Epilepticus (NORSE) in adults-Infectious or not?.
      ,
      • Khawaja A.M.
      • DeWolfe J.L.
      • Miller D.W.
      • Szaflarski J.P.
      New-onset refractory status epilepticus (NORSE)--The potential role for immunotherapy.
      ,
      • 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.
      ,
      • Iizuka T.
      • Kanazawa N.
      • Kaneko J.
      • Tominaga N.
      • Nonoda Y.
      • Hara A.
      • et al.
      Cryptogenic NORSE: its distinctive clinical features and response to immunotherapy.
      ] while boys are more frequently affected than girls in pediatric series [
      • 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.
      ]. The incidence is unknown but it can be estimated that they represent up to 20% of cases of RSE [
      • Gaspard N.
      Unusual causes of status epilepticus. Status epilepticus.
      ,
      • Gaspard N.
      • Hirsch L.J.
      • Sculier C.
      • Loddenkemper T.
      • van Baalen A.
      • Lancrenon J.
      • et al.
      New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): state of the art and perspectives.
      ]. It is likely that many cases have been previously mislabeled as “possible” or “presumed” viral encephalitis as they often fulfill the diagnostic criteria for these entities [
      • Sahin M.
      • Menache C.C.
      • Holmes G.L.
      • Riviello J.J.
      Outcome of severe refractory status epilepticus in children.
      ,
      • Glaser C.A.
      • Gilliam S.
      • Honarmand S.
      • Tureen J.H.
      • Lowenstein D.H.
      • Anderson L.J.
      • et al.
      Refractory status epilepticus in suspect encephalitis.
      ].

      3. Clinical features and prognosis of NORSE and FIRES

      In adults, a non-specific mild illness with gastro-intestinal, upper respiratory or flu-like symptoms precedes the onset of seizures in two-third of cases [
      • 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.
      ], and in up to 90% of cases of unknown cause [
      • Iizuka T.
      • Kanazawa N.
      • Kaneko J.
      • Tominaga N.
      • Nonoda Y.
      • Hara A.
      • et al.
      Cryptogenic NORSE: its distinctive clinical features and response to immunotherapy.
      ]. Fever is documented in at least a third of adult cases of NORSE [
      • Körtvelyessy P.
      • Lerche H.
      • Weber Y.
      FIRES and NORSE are distinct entities.
      ] and is by definition the rule in FIRES. [
      • van Baalen A.
      • Vezzani A.
      • Häusler M.
      • Kluger G.
      Febrile infection-related epilepsy syndrome: clinical review and hypotheses of epileptogenesis.
      ,
      • 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.
      ,
      • 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.
      ].
      This prodromal phase precedes the onset of seizure and SE by 1–14 days. [
      • van Baalen A.
      • Vezzani A.
      • Häusler M.
      • Kluger G.
      Febrile infection-related epilepsy syndrome: clinical review and hypotheses of epileptogenesis.
      ,
      • 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.
      ,
      • 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.
      ] and the patient may be asymptomatic for a few days during the interval. Seizures are initially brief and infrequent, increasing within a few hours to days in frequency (up to hundreds per day) and evolving into SE, which usually requires ICU admission and anesthesia. The most frequent seizure type is focal seizure with secondary bilateralization [
      • 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.
      ,
      • 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.
      ,
      • 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.
      ].

      3.1 EEG results

      The EEG shows various kinds of sporadic or periodic epileptiform discharges, which can be lateralized, bilateral independent or multifocal, often involving the temporal and frontal regions. Generalized discharges have also been reported [
      • Mikaeloff Y.
      • Jambaqué I.
      • Hertz-Pannier L.
      • Zamfirescu A.
      • Adamsbaum C.
      • Plouin P.
      • et al.
      Devastating epileptic encephalopathy in school-aged children (DESC): a pseudo encephalitis.
      ,
      • 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.
      ].
      Recently, a retrospective analysis suggested that FIRES was characterized by three EEG findings: beta-delta complexes resembling extreme delta brush, seizure onset with prolonged focal fast activity, followed by the gradual appearance of well-formed rhythmic spike or spike-and-wave complexes, and shifting ictal activity [
      • Farias-Moeller R.
      • Bartolini L.
      • Staso K.
      • Schreiber J.M.
      • Carpenter J.L.
      Early ictal and interictal patterns in FIRES: the sparks before the blaze.
      ]. These preliminary findings deserve further study and confirmation.

      3.2 Laboratory and imaging results

      About 70% of cases show an abnormal MRI with T2/FLAIR hypersignal located in limbic and/or neocortical areas, often bilaterally [
      • 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.
      ]. Basal ganglia [
      • Mikaeloff Y.
      • Jambaqué I.
      • Hertz-Pannier L.
      • Zamfirescu A.
      • Adamsbaum C.
      • Plouin P.
      • et al.
      Devastating epileptic encephalopathy in school-aged children (DESC): a pseudo encephalitis.
      ] and peri-insular [
      • Caraballo R.H.
      • Reyes G.
      • Avaria M.F.L.
      • Buompadre M.C.
      • Gonzalez M.
      • Fortini S.
      • et al.
      Febrile infection-related epilepsy syndrome: a study of 12 patients.
      ] involvement have also been reported. When repeated, a diffuse atrophy appears in one third of cases [
      • Kramer U.
      • Shorer Z.
      • Ben-Zeev B.
      • Lerman-Sagie T.
      • Goldberg-Stern H.
      • Lahat E.
      Severe refractory status epilepticus owing to presumed encephalitis.
      ,
      • 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.L.
      • Buompadre M.C.
      • Gonzalez M.
      • Fortini S.
      • et al.
      Febrile infection-related epilepsy syndrome: a study of 12 patients.
      ]. Two recent studies highlighted the presence of peculiar transient bilateral claustral T2/FLAIR changes in adult and children with NORSE or FIRES [
      • Meletti S.
      • Giovannini G.
      • d’Orsi G.
      • Toran L.
      • Monti G.
      • Guha R.
      • et al.
      New-onset refractory status epilepticus with claustrum damage: definition of the clinical and neuroimaging features.
      ,
      • Meletti S.
      • Slonkova J.
      • Mareckova I.
      • Monti G.
      • Specchio N.
      • Hon P.
      • et al.
      Claustrum damage and refractory status epilepticus following febrile illness.
      ]. It is unclear if these findings are specific to these conditions, thus suggesting a specific pathogenic mechanism, or if they are merely the consequence of prolonged ictal activity.
      Half to two-third of the cases of unknown etiology present mild CSF pleocytosis (less than 10 cells/μl) and slightly increased protein level [
      • 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.
      ,
      • 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.
      ],but these findings could result from the intense seizure activity rather than indicate an inflammatory or infectious etiology.

      3.3 Outcome

      Most cases of FIRES and NORSE evolve to SRSE, a category of SE associated with prolonged intensive care unit (ICU) stay and poor outcome [
      • Sakuma H.
      • Awaya Y.
      • Shiomi M.
      • Yamanouchi H.
      • Takahashi Y.
      • Saito Y.
      • et al.
      Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis.
      ,
      • van Baalen A.
      • Häusler M.
      • Boor R.
      • Rohr A.
      • Sperner J.
      • Kurlemann G.
      • et al.
      Febrile infection-related epilepsy syndrome (FIRES): a nonencephalitic encephalopathy in childhood.
      ,
      • 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.
      ,
      • 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.
      ].
      The median duration of ICU stay in FIRES and NORSE ranges from 20 to 40 days in children [
      • Mikaeloff Y.
      • Jambaqué I.
      • Hertz-Pannier L.
      • Zamfirescu A.
      • Adamsbaum C.
      • Plouin P.
      • et al.
      Devastating epileptic encephalopathy in school-aged children (DESC): a pseudo encephalitis.
      ,
      • van Baalen A.
      • Häusler M.
      • Boor R.
      • Rohr A.
      • Sperner J.
      • Kurlemann G.
      • et al.
      Febrile infection-related epilepsy syndrome (FIRES): a nonencephalitic encephalopathy in childhood.
      ,
      • Kramer U.
      • Shorer Z.
      • Ben-Zeev B.
      • Lerman-Sagie T.
      • Goldberg-Stern H.
      • Lahat E.
      Severe refractory status epilepticus owing to presumed encephalitis.
      ,
      • 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.
      ] and 15 days in adults [
      • 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.
      ]. Mortality rate is around 12% in children [
      • 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.
      ] and reaches 16 to 27% in adults [
      • Costello D.J.
      • Kilbride R.D.
      • Cole A.J.
      Cryptogenic New Onset Refractory Status Epilepticus (NORSE) in adults-Infectious or not?.
      ,
      • Khawaja A.M.
      • DeWolfe J.L.
      • Miller D.W.
      • Szaflarski J.P.
      New-onset refractory status epilepticus (NORSE)--The potential role for immunotherapy.
      ,
      • 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.
      ,
      • Gall C.R.E.
      • Jumma O.
      • Mohanraj R.
      Five cases of new onset refractory status epilepticus (NORSE) syndrome: outcomes with early immunotherapy.
      ], with neurological sequelae in most survivors. Long-term outcome is often poor with half to two-third of the survivors developing cognitive impairment and functional disability, including vegetative state, and only a small proportion of patients being able to resume their previous life [
      • Baxter P.
      • Clarke A.
      • Cross H.
      • Harding B.
      • Hicks E.
      • Livingston J.
      • et al.
      Idiopathic catastrophic epileptic encephalopathy presenting with acute onset intractable status.
      ,
      • Sakuma H.
      • Awaya Y.
      • Shiomi M.
      • Yamanouchi H.
      • Takahashi Y.
      • Saito Y.
      • et al.
      Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis.
      ,
      • van Baalen A.
      • Häusler M.
      • Boor R.
      • Rohr A.
      • Sperner J.
      • Kurlemann G.
      • et al.
      Febrile infection-related epilepsy syndrome (FIRES): a nonencephalitic encephalopathy in childhood.
      ,
      • 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.
      ,
      • 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).
      ,
      • Kramer U.
      • Shorer Z.
      • Ben-Zeev B.
      • Lerman-Sagie T.
      • Goldberg-Stern H.
      • Lahat E.
      Severe refractory status epilepticus owing to presumed encephalitis.
      ,
      • 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.L.
      • Buompadre M.C.
      • Gonzalez M.
      • Fortini S.
      • et al.
      Febrile infection-related epilepsy syndrome: a study of 12 patients.
      ,
      • Patil S.B.
      • Roy A.G.
      • Vinayan K.P.
      Clinical profile and treatment outcome of febrile infection-related epilepsy syndrome in South Indian children.
      ]. Drug-resistant epilepsy is the rule in most survivors. Factors associated with worse outcome include the duration of SE and the occurrence of medical complications [
      • 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.
      ]. One large retrospective study found that the use and duration of barbiturate coma was associated with worse outcome in children 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.
      ]. Similarly, one study in adults with NORSE found that the number of anesthetic drugs used was associated with poorer outcome [
      • 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.
      ]. Given the retrospective and observational design of these studies, it is unclear whether this association indicates an independent effect of anesthesia and its complications or is rather due to the variability in severity and refractoriness. Prospective randomized controlled studies are required to settle this question.

      4. Known etiologies and clues to these etiologies

      According to recent definitions, NORSE etiology is either unknown (previously called cryptogenic) or an unusual cause is identified after an extensive work-up. Close to 200 uncommon causes of SE have been reported in the literature [
      • Gaspard N.
      Unusual causes of status epilepticus. Status epilepticus.
      ,
      • Tan R.Y.L.
      • Neligan A.
      • Shorvon S.D.
      The uncommon causes of status epilepticus: a systematic review.
      ] and can be divided in 4 categories: inflammatory and autoimmune encephalitis, uncommon infectious encephalitis, genetic disorders and toxic disorders. As indicated above, the most frequent identified cause is autoimmune encephalitis [
      • Khawaja A.M.
      • DeWolfe J.L.
      • Miller D.W.
      • Szaflarski J.P.
      New-onset refractory status epilepticus (NORSE)--The potential role for immunotherapy.
      ,
      • 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.
      ,
      • Gall C.R.E.
      • Jumma O.
      • Mohanraj R.
      Five cases of new onset refractory status epilepticus (NORSE) syndrome: outcomes with early immunotherapy.
      ], including sporadic and paraneoplastic cases, highlighting the importance of a complete auto-immune workup which should be early set up in case of RSE without a straightforward cause. The most frequently identified antibodies target the N-methyl-D-aspartate (NMDA) receptor and the voltage-gated potassium channel (VGKC) complex. No antibody has been found in pediatric cohort except some anecdotal cases [
      • 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.
      ,
      • Specchio N.
      • Fusco L.
      • Claps D.
      • Vigevano F.
      Epileptic encephalopathy in children possibly related to immune-mediated pathogenesis.
      ,
      • 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).
      ,
      • Milh M.
      • Villeneuve N.
      • Chapon F.
      • Gavaret M.
      • Girard N.
      • Mancini J.
      • et al.
      New onset refractory convulsive status epilepticus associated with serum neuropil auto-antibodies in a school aged child.
      ,
      • van Baalen A.
      • Häusler M.
      • Plecko-Startinig B.
      • Strautmanis J.
      • Vlaho S.
      • Gebhardt B.
      • et al.
      Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES.
      ]. One study found anti-glutamate receptor (GluR) epsilon 2 antibodies in the CSF of a few FIRES cases but their role and significance remain unknown [
      • Sakuma H.
      • Awaya Y.
      • Shiomi M.
      • Yamanouchi H.
      • Takahashi Y.
      • Saito Y.
      • et al.
      Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis.
      ].
      Some clinical features can suggest a specific underlying etiology (Table 1). For instance, paraneoplastic limbic encephalitis, which is exceptional in children but occurs more frequently in adults, is characterized by cognitive impairment, behavioral changes, sleep disturbances, and seizures. Status epilepticus is usually not a prominent manifestation [
      • Gaspard N.
      Unusual causes of status epilepticus. Status epilepticus.
      ,
      • Armangue T.
      • Petit-Pedrol M.
      • Dalmau J.
      Autoimmune encephalitis in children.
      ]. Anti-NMDA receptor encephalitis is the leading cause of autoimmune encephalitis, with 40% of patients being younger than age 18 years [
      • Dalmau J.
      • Gleichman A.J.
      • Hughes E.G.
      • Rossi J.E.
      • Peng X.
      • Lai M.
      • et al.
      Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.
      ] and often starts with febrile illness. Then patients develop psychiatric symptoms, manifesting in children as behavioral disturbances and tantrums. Children are more likely to present movement disorders, seizures and SE than adults. Rapid disintegration of speech and language, hyperactivity, and irritability are often seen, then progression to decreased responsiveness and severe catatonic stage, with typical oro-lingual dyskinesia and autonomic failure [
      • Armangue T.
      • Petit-Pedrol M.
      • Dalmau J.
      Autoimmune encephalitis in children.
      ,
      • Florance N.R.
      • Davis R.L.
      • Lam C.
      • Szperka C.
      • Zhou L.
      • Ahmad S.
      • et al.
      Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents.
      ,
      • Remy K.E.
      • Custer J.W.
      • Cappell J.
      • Foster C.B.
      • Garber N.A.
      • Walker L.K.
      • et al.
      Pediatric Anti-N-Methyl-d-Aspartate receptor encephalitis: a review with pooled analysis and critical care emphasis.
      ]. The EEG shows a specific pattern of ‘extreme delta brushes’ in 50% of cases [
      • Schmitt S.E.
      • Pargeon K.
      • Frechette E.S.
      • Hirsch L.J.
      • Dalmau J.
      • Friedman D.
      Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis.
      ,
      • Haberlandt E.
      • Ensslen M.
      • Gruber-Sedlmayr U.
      • Plecko B.
      • Brunner-Krainz M.
      • Schimmel M.
      • et al.
      Epileptic phenotypes, electroclinical features and clinical characteristics in 17 children with anti-NMDAR encephalitis.
      ]. Encephalitis with anti- VGKC complex (LGI1 or, more rarely Caspr2) antibodies are associated with limbic encephalitis and a syndrome of inappropriate secretion of antidiuretic hormone (SIADH).Pathognomonic facio-brachial dystonic seizures can occur in anti-LGI1 encephalitis. Rare pediatric cases of SE associated with an unspecified anti-VGKC complex antibody have been reported [
      • Suleiman J.
      • Brenner T.
      • Gill D.
      • Brilot F.
      • Antony J.
      • Vincent A.
      • et al.
      VGKC antibodies in pediatric encephalitis presenting with status epilepticus.
      ]. No specific findings have been demonstrated in cryptogenic NORSE cases. They broadly have similar clinical course than patients with NORSE caused by auto-immune encephalitis, albeit with a longer SE duration [
      • 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.
      ]. A retrospective study compared the clinical features of 11 cryptogenic NORSE with anti-NMDA receptor encephalitis and revealed more frequent prodromal fever, symmetric brain MRI abnormalities, had less frequent involuntary movements, absent psychobehavioral symptoms, and had more severe SE with ventilatory support requirement [
      • Iizuka T.
      • Kanazawa N.
      • Kaneko J.
      • Tominaga N.
      • Nonoda Y.
      • Hara A.
      • et al.
      Cryptogenic NORSE: its distinctive clinical features and response to immunotherapy.
      ].
      Table 1NORSE: Prominent presentation features of the most frequent etiologies.
      Categories*Most frequent findingsClinical clues
      Unknown50%No specific findings

      Prodromal mild febrile illness in 65% of cases

      Typically severe and prolonged SE
      Inflammatory and auto-immune encephalitis40%Paraneoplastic limbic encephalitis (Anti-Hu, -Ma2/Ta, -CV2/CRMP-5, -amphiphysin, -VGCC, -mGluR5)Cognitive, especially memory impairment, behavioral changes, temporal lobe seizures, sleep disturbance

      Hu: often more diffuse encephalomyelitis

      Ma2/Ta: hypothalamic dysfunction

      CV2/CRMP5: diffuse encephalomyelitis, chorea
      Surface-binding autoantibodies
      Anti-NMDArMostly young females

      Prodromal fever, short-term memory loss, psychiatric symptoms, hallucinations, oro-lingual dyskinesia, autonomic and respiratory failure

      Children: behavioral changes, movement disorders

      EEG: extreme delta brushes (50%)
      Anti-VGKC complexMostly elderly males

      LGI-1: limbic encephalitis, facio-brachial dystonic seizures, SIADH

      Caspr2: episodic ataxia
      Anti-GABA(B)rLimbic encephalitis
      Anti-GABA(A)rMultifocal neocortical encephalitis
      Anti-AMPArProminent psychiatric symptoms, cerebellar ataxia
      Anti-Glycine-rNo specific features
      Anti-GADNo specific features
      Steroid responsive encephalopathy with autoimmune thyroiditisRapid-onset dementia, myoclonus, stroke-like episodes

      Anti-TPO, anti-TG
      Infectious encephalitis10%HSV1

      Enterovirus

      CMV

      EBV

      VZV

      Mycoplasma pneumoniae

      Bartonella henselae

      Arboviruses (West Nile virus, tick-borne virus etc..)
      Temporal involvement

      Rash, acute lower motor neuron syndrome

      Immunodeficiency: Gastro-intestinal symptoms, retinitis, pneumonitis

      Adenopathies, ataxia

      Immunodeficiency: CNS lymphoma

      Rash

      Respiratory symptoms, EEG: extreme spindles

      Children. Cat-scratch disease with skin lesion and regional adenopathy

      Flu-like episode;

      WNV: parkinsonism, acute lower motor neuron syndrome, EEG: triphasic waves
      Genetic disordersRareSCN1A

      PCDH19

      CADASIL

      Mitochondrial disorders

      MELAS

      POLG1
      Dravet syndrome

      Epilepsy and mental retardation limited to female

      Migraine, strokes, visual problems, cognitive deterioration

      Elevated CSF lactate and stroke-like episodes.

      Occipital seizures, epilepsia partialis continua, liver failure, nystagmus, ataxia.
      *Proportions mainly reflect adult population. There is a lack of data in pediatric population.
      Abbreviations: AMPAalpha-amino-3-hydroxy-5-méthylisoazol-4-propionate; GABA; gamma aminobutyric acid; CADASIL; cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; Caspr2contactin associated protein 2; CMVcytomegalovirus; CNScentral nervous system; CSFcerebrospinal fluid; EBVEpstein-Barr virus; EEGelectroencephalogram; GADglutamic acid decarboxylase; HSVherpes simplex virus; LGI1Leucine-rich glioma inactivated 1; MELASsyndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; NMDA; N-methyl-D-aspartate; PCDHprotocadherin; POLG1mitochondrial DNA polymerase gamma; SIADHsyndrome of inappropriate antidiuretic hormone secretion; SCNneuronal voltage-gated sodium channel; SEstatus epilepticus; TGthyroglobuline; TPOthyroperoxydase; VGKCvoltage gated potassium channel-complex; VZVvaricella-zoster virus; WNVWest-Nile virus.

      5. Current hypothesis for cases with unknown etiology

      Despite an extensive, albeit variable, workup, half of adult NORSE cases remain cryptogenic. However, their clinical features do not differ much from autoimmune cases, suggesting a similar etiology. It is possible that some cryptogenic cases correspond to autoimmune encephalitis associated with antibodies not yet identified. In particular, the prevalence of CSF abnormalities was similar in both cryptogenic cases and cases with an autoimmune or infectious etiology.
      In children, elevated levels of pro-convulsant cytokines (interleukin-6, e.g.) have been documented in the CSF, suggesting an inflammatory cause [
      • Sakuma H.
      • Tanuma N.
      • Kuki I.
      • Takahashi Y.
      • Shiomi M.
      • Hayashi M.
      Intrathecal overproduction of proinflammatory cytokines and chemokines in febrile infection-related refractory status epilepticus.
      ]. Those cytokines could be the consequence of a viral infection, explaining the previous febrile illness, and could occur in the setting of a genetic predisposition [
      • van Baalen A.
      • Vezzani A.
      • Häusler M.
      • Kluger G.
      Febrile infection-related epilepsy syndrome: clinical review and hypotheses of epileptogenesis.
      ,
      • Saitoh M.
      • Kobayashi K.
      • Ohmori I.
      • Tanaka Y.
      • Tanaka K.
      • Inoue T.
      • et al.
      Cytokine-related and sodium channel polymorphism as candidate predisposing factors for childhood encephalopathy FIRES/AERRPS.
      ]. Genetic analyses have also been disappointing so far [
      • Appenzeller S.
      • Helbig I.
      • Stephani U.
      • Häusler M.
      • Kluger G.
      • Bungeroth M.
      • et al.
      Febrile infection-related epilepsy syndrome (FIRES) is not caused by SCN1A, POLG, PCDH19 mutations or rare copy number variations.
      ] but a recent study demonstrated an association with polymorphisms in the interleukin 1 receptor antagonist (IL1RN) gene [
      • Saitoh M.
      • Kobayashi K.
      • Ohmori I.
      • Tanaka Y.
      • Tanaka K.
      • Inoue T.
      • et al.
      Cytokine-related and sodium channel polymorphism as candidate predisposing factors for childhood encephalopathy FIRES/AERRPS.
      ], further suggesting an immune basis.

      6. Diagnosis of NORSE and FIRES

      In the absence of a specific diagnostic test, the diagnosis of NORSE and FIRES is made on clinical grounds after the initial workup rules out obvious causes of RSE, which usually takes 48–72 h.
      Extensive investigations should then be performed to identify a rare cause of SE. These investigations should focus on autoimmune and uncommon infectious etiologies and take into account the specifics of each case. A diagnostic decision tree is available in Fig. 1 and on the NORSE institute website http://www.norseinstitute.org/definitions/.
      Fig. 1
      Fig. 1Adapted from http://www.norseinstitute.org/definitions/http://www.norseinstitute.org/definitions/ [
      Infectious diseases society of america. The management of encephalitis: clinical practice guidelines by the infectious diseases society of america.
      ,
      • Solomon T.
      • Michael B.D.
      • Smith P.E.
      • Sanderson F.
      • Davies N.W.S.
      • Hart I.J.
      Management of suspected viral encephalitis in adults - Association of British Neurologists and British Infection Association National Guidelines.
      ,
      • Kneen R.
      • Michael B.D.
      • Menson E.
      • Mehta B.
      • Easton A.
      • Hemingway C.
      Management of suspected viral encephalitis in children - association of british neurologists and british paediatric allergy, immunology and infection group national guidelines.
      ].
      ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibodies ; B. henselae: bartonella henselae; BUN: blood urea nitrogen; CBC: Complete blood count; C. burnetii: coxiella burnetii; CGH: comparative genomic hybridization; CMV: cytomegalovirus; CNS: central nervous system; C. pneumoniae: chlamydia pneumoniae; C. psittaci: chlamydia psittaci; CRP: C-reactive protein; CSF: cerebrospinal fluid; DNA: deoxyribonucleic acid; EBV: Epstein-Barr virus; EEEV: Eastern equine encephalitis virus; EEG: electroencephalogram; ESR: erythrocyte sedimentation rate; GAD: glutamic acid decarboxylase; HHV: human herpesvirus; HIV: human immunodeficiency virus; HSV: herpes simplex virus; ID: immunodeficiency; LDH: lactate dehydrogenase; LFT: Liver function tests; M. pneumonia: mycoplasma pneumonia; MRA: magnetic resonance angiography; MRI: magnetic resonance imaging; MRV: magnetic resonance veinography; PCR: polymerase chain reaction; PET-CT: positron emission tomography–computed tomography; VLCFA: very long chain fatty acid; VDRL: venereal disease research laboratory; VZV: varicella-zoster virus; WNV: West-Nile virus.
      No validated tests are available to distinguish FIRES from a febrile RSE, a very different entity with good outcome. Theoretically, children with febrile SE present high fever at SE onset while children with FIRES had fever within the two previous weeks.
      Association between FIRES cases and elevated cytokine levels in the CSF or predisposing genetic factors [
      • Sakuma H.
      • Awaya Y.
      • Shiomi M.
      • Yamanouchi H.
      • Takahashi Y.
      • Saito Y.
      • et al.
      Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis.
      ,
      • Saitoh M.
      • Kobayashi K.
      • Ohmori I.
      • Tanaka Y.
      • Tanaka K.
      • Inoue T.
      • et al.
      Cytokine-related and sodium channel polymorphism as candidate predisposing factors for childhood encephalopathy FIRES/AERRPS.
      ] should be confirmed they can be used. Similarly the occurrence of peculiar MRI changes in the claustrum should be further explored as candidate diagnostic tests [
      • Meletti S.
      • Giovannini G.
      • d’Orsi G.
      • Toran L.
      • Monti G.
      • Guha R.
      • et al.
      New-onset refractory status epilepticus with claustrum damage: definition of the clinical and neuroimaging features.
      ].

      7. Treatment of NORSE and FIRES

      Treatment with anti-seizure medications is often disappointing. At least 75% of patients require anesthetics in continuous infusion and prolonged burst-suppression coma is often unavoidable to stop the seizures. Status often resumes once the anesthetics are weaned off [
      • van Baalen A.
      • Vezzani A.
      • Häusler M.
      • Kluger G.
      Febrile infection-related epilepsy syndrome: clinical review and hypotheses of epileptogenesis.
      ,
      • 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.
      ]. At least a third of patients require multiple anesthetic drugs to achieve seizure control [
      • 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.
      ,
      • 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.
      ].
      In adults, some studies have suggested better outcome with immunotherapies. This hypothesis is supported by the fact that half of NORSE cases are caused by auto-immune encephalitis. Early immune therapy is then recommended by experts, as delaying treatment may contributes to worse outcome, as in auto-immune and viral encephalitis [
      • Gaspard N.
      • Hirsch L.J.
      • Sculier C.
      • Loddenkemper T.
      • van Baalen A.
      • Lancrenon J.
      • et al.
      New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): state of the art and perspectives.
      ,
      • Raschilas F.
      • Wolff M.
      • Delatour F.
      • Chaffaut C.
      • De Broucker T.
      • Chevret S.
      • et al.
      Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study.
      ,
      • Titulaer M.J.
      • McCracken L.
      • Gabilondo I.
      • Armangué T.
      • Glaser C.
      • Iizuka T.
      • et al.
      Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study.
      ]. These include first-line (steroids, intravenous immunoglobulins, and plasma exchange) and second-line therapies (e.g., tacrolimus, rituximab, cyclophosphamide, anakinra). However prospective controlled studies are lacking
      In children, immunotherapies seem less effective [
      • Sakuma H.
      • Awaya Y.
      • Shiomi M.
      • Yamanouchi H.
      • Takahashi Y.
      • Saito Y.
      • et al.
      Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis.
      ,
      • van Baalen A.
      • Häusler M.
      • Plecko-Startinig B.
      • Strautmanis J.
      • Vlaho S.
      • Gebhardt B.
      • et al.
      Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES.
      ]. Multiple different therapeutic options have been reported in small case series and none seems to be superior, with the possible exception of the ketogenic diet [
      • 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).
      ,
      • 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.
      ]. Nabbout et al highlighted the efficiency of this therapeutic diet on 8 children, with 7 them showing improvement after 1 to 4 days of ketonuria. This treatment is already known to be efficient in RSE in children of any cause and experts recommend to start it as soon as possible, once FIRES is suspected, e.g., from second day of super-refractory SE [
      • van Baalen A.
      • Vezzani A.
      • Häusler M.
      • Kluger G.
      Febrile infection-related epilepsy syndrome: clinical review and hypotheses of epileptogenesis.
      ]. The efficacy of the ketogenic diet in SRSE in adults, including possible cases of NORSE, has also been suggested [
      • Thakur K.T.
      • Probasco J.C.
      • Hocker S.E.
      • Roehl K.
      • Henry B.
      • Kossoff E.H.
      • et al.
      Ketogenic diet for adults in super-refractory status epilepticus.
      ].
      Cannabidiol (CBD) is a recent potential alternative therapy in epilepsy and has been shown to improve seizure frequency and duration in 6 out of 7 children, mainly in the chronic phase. However only on was seizure free and all had cognitive sequelae [
      • Gofshteyn J.S.
      • Wilfong A.
      • Devinsky O.
      • Bluvstein J.
      • Charuta J.
      • Ciliberto M.A.
      • et al.
      Cannabidiol as a potential treatment for febrile infection-related epilepsy syndrome (FIRES) in the acute and chronic phases.
      ].
      Anakinra, a recombinant version of human Interleukin(Il)-1 receptor antagonist, was successful in a single case of a 32-months-old girl with FIRES who received 5 mg/kg twice daily. The drug was well tolerated and effective, leading to a dramatic seizure reduction on 3 separate occasions in the same patient, however no long-term follow-up is available [
      • 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.
      ,
      • Gaspard N.
      • Hirsch L.J.
      • Sculier C.
      • Loddenkemper T.
      • van Baalen A.
      • Lancrenon J.
      • et al.
      New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): state of the art and perspectives.
      ].
      Those therapeutic options, as well as hypothermia at 33 °C [
      • Lin J.-J.
      • Lin K.-L.
      • Hsia S.-H.
      • Wang H.-S.
      • Chou I.-J.
      • Lin Y.-T.
      • et al.
      Antiglutamic acid decarboxylase antibodies in children with encephalitis and status epilepticus.
      ], ketamine, lidocaine, need to be validated by large and prospective studies. A suggested algorithm for the use of these therapies is presented in Fig. 2, with their suggested dosing.
      Fig. 2
      Fig. 2NORSE treatment algorithm: Commonly used drugs in NORSE and FIRES with most frequently reported doses (expert opinion) [
      • Glauser T.
      • Shinnar S.
      • Gloss D.
      • Alldredge B.
      • Arya R.
      • Bainbridge J.
      Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the american epilepsy society.
      ].
      Adapted from Gaspard et al, 2018 [
      • Gaspard N.
      • Hirsch L.J.
      • Sculier C.
      • Loddenkemper T.
      • van Baalen A.
      • Lancrenon J.
      • et al.
      New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): state of the art and perspectives.
      ] and van Baalen et al, 2017 [
      • Laswell E.M.
      • Chambers K.D.
      • Whitsel D.R.
      • Poudel K.
      New-onset refractory status epilepticus in an adult with an atypical presentation of cat-scratch disease: successful treatment with high-dose corticosteroids.
      ].
      IV = intravenous; IVIG = intravenous immunoglobulin; RSE: refractory status epilepticus, SE: status epilepticus.

      8. Conclusion

      NORSE and FIRES are rare but devastating epileptic disorders, occurring in previously healthy patients. Uncommon but treatable etiologies, such as autoimmune encephalopathies, can be identified in some patients, especially adults, motivating extensive investigations. However a majority of cases remain without a known etiology and little is currently known about the underlying pathologic mechanism, although an inflammatory cause is suspected. Treatment is usually disappointing and outcome is often poor, although a minority of patients may resume their previous life. The ketogenic diet appears promising but requires larger prospective studies. The recent publication of consensus definitions will help future research, with the aims to understand the cause and to improve patient care.

      Conflict of interest

      The authors have no conflict of interest to declare.

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