Received: 12 March 2021 | Revised: 9 May 2021 | Accepted: 11 May 2021 DOI: 10.1111/epi.16950 F U L L - ­L E N G T H O R I G I N A L R E S E A R C H Clinical presentation of new onset refractory status epilepticus in children (the pSERG cohort) Claudine Sculier1,2 | Cristina Barcia Aguilar1,3 | Nicolas Gaspard2,4 | Marina Gaínza-­ Lein1,5,6 | Iván Sánchez Fernández1,7 | Marta Amengual-­Gual1,8 | Anne Anderson9 | Ravindra Arya10 | Brian T. Burrows11,12 | James N. Brenton13 | Jessica L. Carpenter14 | Kevin E. Chapman15 | Justice Clark1 | William D. Gaillard14 | Tracy A. Glauser10 | Joshua L. Goldstein16 | Howard P. Goodkin13 | Mark Gorman1 | Yi-­Chen Lai9 | Tiffani L. McDonough | Mohamad A. Mikati 17 18 | Anuranjita Nayak | Katrina Peariso10 | 9 James Riviello9 | Allison Rusie16 | Katherine Sperberg14 | Coral M. Stredny1 | Robert C. Tasker19 | Dmitry Tchapyjnikov17 | Alejandra Vasquez1,20 | Mark S. Wainwright21 | Angus A. Wilfong22 | Korwyn Williams22 | Tobias Loddenkemper1 | pSERG 1 Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA 2 Department of Neurology, Erasmus Hospital, Free University of Brussels, Brussels, Belgium 3 Department of Child Neurology, La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain 4 Neurology Department, Comprehensive Epilepsy Center, Yale University School of Medicine, New Haven, CT, USA 5 Faculty of Medicine, Institute of Pediatrics, Austral University of Chile, Valdivia, Chile 6 Children's Neuropsychiatry Service, San Borja Arriarán Clinical Hospital, University of Chile, Santiago, Chile 7 Department of Child Neurology, SJD Barcelona Children's Hospital, University of Barcelona, Barcelona, Spain 8 Pediatric Neurology Unit, Department of Pediatrics, Son Espases University Hospital, University of the Balearic Islands, Palma, Spain 9 Section of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA 10 Division of Pediatric Neurology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA 11 Department of Pediatrics, Barrows Neurological Institute, Phoenix Children's Hospital, University of Arizona School of Medicine, Phoenix, AZ, USA 12 Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA 13 Department of Neurology and Pediatrics, University of Virginia Health System, Charlottesville, Virginia, USA 14 Center for Neuroscience, Children's National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC, USA 15 Departments of Pediatrics and Neurology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA 16 Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program, Northwestern University Feinberg, School of Medicine, Chicago, IL, USA 17 Division of Neurology and Epilepsy, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 18 Division of Pediatric Neurology, Duke University Medical Center, Duke University, Durham, NC, USA 19 Department of Neurology, Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA 20 Division of Child and Adolescent Neurology, Mayo Clinic, Mayo Clinic School of Medicine, Rochester, MN, USA 21 Division of Pediatric Neurology, Department of Neurology, University of Washington, Seattle, WA, USA 22 Division of Pediatric Neurology, Department of Child Health, Phoenix Children's Hospital, University of Arizona College of Medicine, Phoenix, AZ, USA Claudine Sculier and Cristina Barcia Aguilar contributed equally. This is an open access article under the terms of the Creative Commons Attribution-­NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy. Epilepsia. 2021;62:1629–1642.  wileyonlinelibrary.com/journal/epi | 1629 1630 |    SCULIER et al. Correspondence Tobias Loddenkemper, Division of Abstract Epilepsy and Clinical Neurophysiology, Objective: We aimed to characterize the clinical profile and outcomes of new onset Harvard Medical School, Boston refractory status epilepticus (NORSE) in children, and investigated the relationship Children's Hospital, 300 Longwood Avenue, Fegan 9, Boston, MA 02115, between fever onset and status epilepticus (SE). USA. Methods: Patients with refractory SE (RSE) between June 1, 2011 and October 1, Email: tobias.loddenkemper@childrens. harvard.edu 2016 were prospectively enrolled in the pSERG (Pediatric Status Epilepticus Research Group) cohort. Cases meeting the definition of NORSE were classified as "NORSE Funding information of known etiology" or "NORSE of unknown etiology." Subgroup analysis of NORSE International Federation of Clinical Neurophysiology of unknown etiology was completed based on the presence and time of fever occur- rence relative to RSE onset: fever at onset (≤24 h), previous fever (2 weeks–­24 h), and without fever. Results: Of 279 patients with RSE, 46 patients met the criteria for NORSE. The me- dian age was 2.4 years, and 25 (54%) were female. Forty (87%) patients had NORSE of unknown etiology. Nineteen (48%) presented with fever at SE onset, 16 (40%) had a previous fever, and five (12%) had no fever. The patients with preceding fever had more prolonged SE and worse outcomes, and 25% recovered baseline neurological function. The patients with fever at onset were younger and had shorter SE episodes, and 89% recovered baseline function. Significance: Among pediatric patients with RSE, 16% met diagnostic criteria for NORSE, including the subcategory of febrile infection-­related epilepsy syndrome (FIRES). Pediatric NORSE cases may also overlap with refractory febrile SE (FSE). FIRES occurs more frequently in older children, the course is usually prolonged, and outcomes are worse, as compared to refractory FSE. Fever occurring more than 24 h before the onset of seizures differentiates a subgroup of NORSE patients with distinc- tive clinical characteristics and worse outcomes. KEYWORDS clinical neurology, epilepsy, febrile infection-­related epilepsy syndrome, new onset refractory status epilepticus, pediatric, refractory status epilepticus, status epilepticus 1 | IN T RO D U C T IO N Key Points New onset refractory status epilepticus (NORSE) is a life-­ • We describe clinical profiles of children with threatening condition characterized by the acute onset of NORSE, FIRES, and refractory FSE based on cur- refractory status epilepticus (RSE) in previously healthy pa- rent NORSE definitions tients. In adults, seizures often progress to prolonged RSE, • Timing of fever onset may help identify separate with mortality rates up to 20%. Chronic, intractable seizures subgroups presenting with different SE severity with neurologic sequelae occur in 60% of these patients.1–­3 In and outcomes one third of patients, a mild febrile illness precedes the onset of • SE duration and age at onset are relevant distinc- status epilepticus (SE). The underlying etiology is identified tive features between FIRES and refractory FSE, in nearly half of the patients, and autoimmune encephalitis is which may contribute to further improvement of the most frequently identified cause.1,4,5 A similar syndrome the current NORSE and FIRES definitions occurs in younger patients, termed febrile infection-­related epilepsy syndrome (FIRES),2 that presents without a clear SCULIER et al.    | 1631 etiology6,7 and with high morbidity and mortality.6,8–­11 The If more than one episode of RSE occurred during the study overall mortality rate in children with superrefractory SE period, only the first was included. including FIRES is approximately 12%,6,12 with up to two thirds of the survivors developing cognitive impairment and functional disability.2,8–­11,13 Pediatric patients with RSE have 2.3 | Definitions a lower mortality rate than adult patients.14 Based on the up- dated ILAE definitions for research, FIRES is a subset of • NORSE: “A clinical presentation, not a specific diagnosis, NORSE; specifically, RSE is preceded by a febrile illness be- in a patient without active epilepsy or other preexisting rel- tween 2 weeks and 24 h before SE onset.2 These definitions evant neurological disorder, with new onset of refractory aim to provide a common framework for clinical research, as status epilepticus, without a clear acute or active structural, prior descriptions of NORSE and FIRES were based on vari- toxic or metabolic cause. The term 'NORSE of unknown able inclusion criteria and terms. etiology' applies to patients with the clinical presenta- In this article, we aimed to evaluate a cohort of children tion of NORSE, but in whom the cause remains unknown with RSE meeting criteria for NORSE and FIRES and to after extensive workup (which may take more than 72 h to assess the effect of fever occurrence on the outcome. To complete).”2 date, outcomes, in particular in the setting of ILAE diag- • FIRES: “A subcategory of NORSE, applicable to all ages, nostic criteria for NORSE and FIRES, have not been well that requires a prior febrile infection starting between described in detail in larger pediatric populations. We, 2 weeks and 24 h prior to onset of refractory status epilep- therefore, aimed to address this gap in the literature by ticus, with or without fever at onset of status epilepticus.”2 characterizing the clinical presentation and outcomes of • FSE: “Status epilepticus that also meets the definition of children with NORSE and FIRES in a prospectively col- febrile seizure (a provoked seizure where the sole acute lected RSE cohort. Children with refractory febrile SE provocation is fever without prior history of afebrile sei- (FSE) were included here, as patients with FSE may meet zures and with no evidence of an acute central nervous sys- current criteria for NORSE. tem [CNS] infection or insult16) in children who have onset of fever <24 h prior to onset of seizures or whose fever is recognized only after the onset of seizures.”2 2 | M ATE R IA L S A N D ME T HODS • RSE: “Status epilepticus persisting despite adequate ad- ministration of BZDs and at least one non-­BZD ASM.”17 2.1 | Study design Data on a subset of RSE patients were prospectively obtained 2.4 | Clinical and outcome variables from 11 centers in the United States within the Pediatric Status Epilepticus Research Group (pSERG).15 This study We acquired information from the pSERG database and was approved by the institutional review board at each in- extracted additional variables for patients with NORSE by stitution. Written informed consent was obtained from the chart review. The prospective pSERG data acquisition tool parents or guardians of each patient. included demographics and clinical information such as pro- dromal history, medical history, family history, type of SE, time of SE onset, SE duration, laboratory, EEG, and mag- 2.2 | Inclusion and exclusion criteria netic resonance imaging (MRI) findings, treatments, and complications. We acquired information on fever (tempera- Inclusion criteria were (1) age from 1 month to 21 years; (2) ture ≥ 38°C), recurrence of seizures, and cognitive function admission to a pSERG institution between June 1, 2011 and at the last follow-­up. Any symptom preceding SE onset by October 1, 2016; and (3) focal or generalized convulsive sei- between 24 h and 15 days was considered a prodromal symp- zures at the onset that continued after administration of at tom. We determined etiology based on available test results least two antiseizure medications (ASMs), including at least performed by the individual centers. Management and treat- one nonbenzodiazepine (non-­BZD) ASM, or the use of an- ment followed best medical practices. esthetics in continuous infusion. Exclusion criteria were (1) We classified patients into two main categories: "NORSE nonconvulsive SE (NCSE) detected on electroencephalogram of known etiology" (genetic, autoimmune, CNS infections) (EEG) lacking convulsive seizure at onset, (2) NCSE with and "NORSE of unknown etiology." The etiology of the first motor manifestations limited to infrequent myoclonic jerks, group was not readily identifiable based on NORSE crite- (3) history of epilepsy, and (4) readily identifiable cause of ria, but the diagnosis was made after extensive evaluations SE easily detected by routine diagnostic tests (e.g., stroke, (infectious, genetic, and autoimmune analyses). We catego- brain lesion, acute medical condition, bacterial meningitis).2 rized NORSE cases of unknown etiology further into three 1632 |    SCULIER et al. subgroups based on the presence and timing of fever occur- with a prior episode of SE). Forty-­three (15%) patients were rence: (1) previous fever: the fever started more than 24 h excluded due to a readily identifiable cause of SE. Forty-­ and less than 15 days before SE onset (and may have been nine children met NORSE criteria. Of these 49 cases, three present or absent at onset of seizures), (2) fever at onset: the additional patients were excluded due to incomplete data. fever started within 24 h of SE onset, and (3) no fever. We de- Thus, 46 cases were included in this study (Figure 1; Table scribed the two main NORSE categories but only performed 1), representing 16% of all the RSE cases. Patients fell into statistical analysis on the three subgroups of NORSE with the following categories: 40 (87%) had NORSE of unknown unknown etiology. Finally, in a supplementary analysis, we etiology and six (13%) had an identified etiology of NORSE evaluated and compared two subcategories of patients ac- (CNS infections [n = 3], autoimmune encephalitis [n = 2], cording to their age, following the definition of febrile sei- and genetic epilepsy [n = 1]). Among the patients with un- zures: (1) 6 years or younger and (2) older than 6 years.18 known etiology, 19 (48%) presented with fever at SE onset, We assessed short-­term outcomes during admission (com- 16 (40%) had a previous fever, and five (12%) had no fever plications such as hypotension) and at the time of discharge. (Figure 1). We categorized findings at discharge into three groups: death, Classifying NORSE patients by age, 29 (73%) were morbidity (development of a neurological deficit), and recov- 6 years or younger and 11 (27%) were older than 6 years. ery (return to baseline, reported by the medical team and the Among the youngest group, 18 (62%) presented with fever at parents). Death and morbidity defined a poor outcome, and onset, nine (31%) had a previous fever, and two (7%) had no return to baseline defined a good outcome. Additionally, we fever. The older group presented more frequently with previ- assessed long-­term outcomes at the last follow-­up evaluating ous fever (64%; Table 2). seizure recurrence, need for ASM, and cognitive abilities as reported by the treating pediatric neurologist. 3.2 | Demographic and clinical characteristics 2.5 | Statistical analysis The median age was 2.4 (IQR = 1.2–­8.6) years, and 25 (54%) Demographic and clinical characteristics were summarized were female. Prodromal symptoms were noted in 28 (61%) with descriptive statistics. We presented continuous vari- patients, including 9 (32%) with headache and 16 (35%) with ables as median (interquartile range [IQR]), and categorical a prior febrile illness. In the unknown etiology group, the variables as count (percent). The univariate analysis high- fever at onset group was younger than both the previous fever lighted differences between the three subgroups of NORSE and no fever groups. Most patients with prodromal headache of unknown etiology by the presence of fever and between were in the previous fever group (88%). The median duration the two age subgroups. We used Fisher exact and Kruskal–­ of SE in the entire population was 24 (IQR = 7–­128) h, and Wallis tests to compare categorical and continuous data, the median intensive care unit (ICU) stay was 3.5 (IQR = respectively, to evaluate the differences between groups in 2–­24) days. The previous fever group experienced longer SE terms of clinical characteristics and outcome. We applied a duration and ICU stays than the fever at onset group (Table correction for multiple testing according to Bonferroni. We 1). performed statistical analyses using R, a language and envi- ronment for statistical computing (R Core Team; RStudio). A p-­value of less than .05 was considered significant. 3.3 | Electroencephalogram An EEG was performed in 42 (91%) patients. Among them, 2.6 | Data availability 13 (31%) had seizures during the EEG monitoring, and 20 (48%) had epileptiform discharges (Table 1). EEG was per- All statistical analyses and results are available in GitHub at formed within 24 h from SE onset in 25 patients, four of them https://crist​inaba​rcia.github.io/pSERG​-­NORSE/. with seizures recorded. EEG was performed later than 24 h in 17 patients, and in nine of these 17 seizures were recorded. Discharges were generalized in 10 (48%), lateralized in 10 3 | R E S U LTS (48%), bilateral independent in two (9%), and multifocal in two (9%). The previous fever group had more frequent epi- 3.1 | Study population and etiologies leptiform abnormalities than the fever at SE onset group. Thirteen patients required a burst suppression coma, includ- Of the 279 patients enrolled in pSERG, 187 (67%) were ex- ing 11 in the previous fever group. The older patients more cluded because of a prior diagnosis of epilepsy (including 35 frequently had epileptiform discharges (Table 2). SCULIER et al.    | 1633 F I G U R E 1 Study population selection diagram. CNS, central nervous system; FIRES, febrile infection-­related epilepsy syndrome; FSE, febrile SE; NMDA, N-­methyl-­d-­aspartate; NORSE, new onset refractory SE; pSERG, Pediatric Status Epilepticus Research Group; SE, status epilepticus; TPO, thyroid peroxidase 3.4 | Imaging of the disease, by increased T2/FLAIR hyperintensities (n = 3) and/or development of cortical atrophy (n = 3). Eight (17%) patients had a computerized tomography Normal MRI was associated with better outcomes (73% vs. only, and all were nonlesional. Thirty-­seven (80%) had 31%, p = .03). Abnormal MRI occurred more frequently in brain MRI, which was abnormal in 20 (54%) patients. patients older than 6 years (Table 2). The most frequent findings were diffuse or focal T2 and fluid-­attenuated inversion recovery (FLAIR) hyperintense changes (n = 16). Hyperintensities were located in the neo- 3.5 | Cerebrospinal fluid cortex (n = 6), mesiotemporal lobe (n = 5), and basal gan- glia (n = 4). Two patients had leptomeningeal T2/FLAIR A lumbar puncture was performed in 41 (89%) patients. enhancement. MRI abnormalities were less frequent in Results were abnormal in 14 (34%); 12 (80%) had an elevated patients with fever at onset. The MRI was repeated in 11 protein level (range = 43–­229 mg/100 ml, median = 72 [IQR patients. One patient with initially normal MRI had subse- = 53–­95] mg/100 ml), and 11 (73%) had an elevated white quent abnormal diffusion-­weighted imaging and T2/FLAIR blood cell count (range = 6–­211/mm3, median = 42 [IQR hyperintensities in bilateral thalamic areas. Four patients = 24.5–­49.7]/mm3). Cerebrospinal fluid (CSF) abnormalities had unchanged or improved results, with a reduction of were more common in the previous fever group compared to FLAIR hyperintensities. Five patients showed progression the fever at onset group (Tables 1 and 3). 1634 |    SCULIER et al. TABLE 1 Characteristics of patients with new onset refractory SE based on etiology and presence of fever NORSE with unknown etiology, n = 40 All cases, Fever ≤24 h prior, Fever >24 h prior, No fever, NORSE with known Characteristic n = 46 FSE, n = 19 FIRES, n = 16 n=5 etiology, n = 6a Age, years 2.4 [1.2–­8.6] 1.2 [.9–­1.7] 5.3 [2.4–­8.9] 10.2 6.3 [3.2–­11.0] [2.3–­10.2] Sex, male 21 (46) 10 (52) 8 (50) 3 (60) 0 (0) Prodromal symptoms 28 (61) 6 (31) 16 (100) 1 (20) 5 (83) Fever still present at SE onset 33 (75) 19 (100) 12 (75) 0 (0) 3 (50) SE duration, h, n = 44 24 [7–­128] 10 [4–­33] 684 [103.5–­1158] 12 [8.2–­17.2] 60 [30–­126] Duration of ICU stay, days 3.5 [2–­24] 2 [1–­3] 49 [24–­64] 1.5 [1–­2] 6 [4–­8] Epileptiform discharges, 20 (48) 3/16 (19) 11/15 (73) 2/5 (40) 4/6 (67) n = 42 Seizures 13 2 8 0 3 Periodic discharges 12 1 10 0 1 Sporadic epileptiform 12 2 5 2 3 discharges Abnormal MRI, n = 37 20 (46) 1/12 (8) 13/16 (69) 2/5 (40) 4 (67) T2/FLAIR hyperintensity 18 0 12 2 3 DWI hyperintensity 12 0 10 0 1 Abnormal CSF, n = 41 14 (39) 1/16 (6) 10/16 (63) 0/3 (0) 3 (50) Elevated protein level 12 0 8 0 3 Elevated white cell count 11 1 8 0 2 Non-­BZD ASM 2 [2–­2] 2 [1–­2] 3 [2–­3] 2 [1–­2] 2 [2–­2] Continuous infusion n (%) 25 (54) 8 (42) 13 (81) 2 (40) 2 (33) Median [IQR] 1 [0–­1] 0 [0–­1] 2 [1–­3] 1 [0–­1] 0 [0–­1] Ketogenic diet 9 (19) 0 9 (56) 0 (0) 0 (0) Immunotherapies 12 (26) 0 11 (69) 1 (20) 0 (0) IV steroids 11 10 1 IVIG 9 9 0 Plasma exchange 3 3 0 Complications, any 20 (43) 3 (16) 13 (81) 1 (20) 3 (50) Good outcome 28 (61) 17 (89) 4 (25) 4 (80) 3 (50) Note: Data are presented as n (%) or median [IQR]. Abbreviations: ASM, antiseizure medication; BZD, benzodiazepine; CSF, cerebrospinal fluid; DWI, diffusion-­weighted imaging; FIRES, febrile infection-­related epilepsy syndrome; FLAIR, fluid-­attenuated inversion recovery; FSE, febrile SE; ICU, intensive care unit; IQR, interquartile range; IV, intravenous; IVIG, intravenous immunoglobulin; MRI, magnetic resonance imaging; NORSE, new onset refractory SE; SE, status epilepticus. a NORSE with known etiology; the etiology was initially unknown but found after extensive investigations. 3.6 | Treatment group (Table 1). Twelve patients (26%) received steroids, intravenous immunoglobulins, and plasma exchange, in- All patients received at least one BZD as first-­line treat- cluding 11 patients in the previous fever group. Nine pa- ment and at least one non-­BZD ASM as second-­line treat- tients started the ketogenic diet, all in the previous fever ment. Fosphenytoin was the most frequent second-­ line group. The outcome was not improved by this treatment option (71%). Fifty-­four percent of patients subsequently (one with good vs. eight with poor outcome). Overall, im- received at least one continuous infusion of anesthetics, munotherapies and ketogenic diet were both more frequent with midazolam being the most common. More ASMs and in the previous fever group and associated with poor out- continuous infusions were required in the previous fever come (Tables 1 and 3). SCULIER et al.    | 1635 T A B L E 2 Characteristics of the new All cases, ≤6 years, >6 years, onset refractory SE group of unknown Characteristic n = 40 n = 29 n = 11 p etiology divided by age (≤6 years or >6 years) Sex, male 19 (48) 13 (45) 6 (55) .72 Prodromal symptoms 23 (58) 16 (55) 7 (66) .72 Fever ≤24 h prior to SE onset 19 (48) 18 (62) 1 (9) .003 Fever >24 h prior to SE onset 16 (40) 9 (31) 7 (64) .07 No fever 5 (13) 2 (7) 3 (27) .11 SE duration, h, n = 32 19 [6–­96.7] 8.5 [4.25–­40] 52 [24–­1200] .008 Duration of ICU stay, days 3 [1.5–­33] 3 [1–­6.2] 42 [3.5–­62] .01 Epileptiform discharges, n = 36 16 (44) 8/25 (32) 8/11 (73) .03 Seizures 10 (25) 6 (21) 4 (36) Periodic discharges 11 (30) 6 (21) 5 (55) Sporadic epileptiform 9 (23) 3 (11) 6 (55) discharges Abnormal MRI, n = 31 16 (40) 8/21 (38) 8/10 (80) .05 T2/FLAIR hyperintensity 14 (35) 8 (38) 6 (60) DWI hyperintensity 9 (23) 5 (24) 4 (40) Abnormal CSF, n = 35 12 (34) 6/24 (25) 6/11 (55) .11 Elevated protein level, n = 33 9 (27) 3 (13) 6 (55) Elevated white cell count, 9 (27) 6 (25) 3 (27) n = 34 ASMs 2 [1.7–­2.2] 2 [2–­2] 2 [1.5–­3] .69 Continuous infusion Median [IQR] 1 [0–­1] 0 [0–­1] 1 [1–­2.5] .05 n (%) 25 (63) 15 (52) 10 (91) Ketogenic diet 9 (23) 5 (17) 4 (36) .22 Immunotherapies 12 (30) 6 (21) 6 (55) .05 IV steroids 11 (28) 5 (17) 6 (54) IVIG 9 (26) 5 (17) 4 (3) Plasma exchange 3 (8) 2 (7) 1 (9) Complications, any 17 (43) 10 (35) 7 (64) .15 Good outcome 25 (63) 22 (76) 3 (27) .009 Note: Data are presented as n (%) or median [IQR]. Abbreviations: ASM, antiseizure medication; CSF, cerebrospinal fluid; DWI, diffusion-­weighted imaging; FLAIR, fluid-­attenuated inversion recovery; ICU, intensive care unit; IQR, interquartile range; IV, intravenous; IVIG, intravenous immunoglobulin; MRI, magnetic resonance imaging; SE, status epilepticus. 3.7 | Outcome Functional outcome at follow-­up was available in 41 pa- tients. At last follow-­up (range = 5 months–­5 years) from SE Twenty-­ eight (61%) patients returned to baseline at dis- onset, 22 of 41 patients had normal cognitive performance, in- charge, including 17 of 19 (89%) in the fever at onset group cluding 15 of 19 in the fever at onset group, two of 12 in the and four of 16 (25%) in the previous fever group. Patients previous fever group, and two of four in the no fever group. in the fever at onset group had fewer medical complications Follow-­up data on seizure recurrence were available in 39 pa- than the previous fever group, and these were often related to tients. Twenty-­one were seizure-­free (with or without ASM) therapies used to treat SE (such as hypotension in the setting in the entire cohort, including 13 of 18 patients in the fever of continuous infusion therapy). Three (6%) patients died at onset group, three of four patients in the no fever group, during admission, all in the previous fever group. Previous and one of 11 in the previous fever group. Among 12 previous fever cases with longer SE durations had worse outcomes fever patients with abnormal MRI, one died, eight had residual (p < .05). epilepsy, and follow-­up was not available in three patients. 1636 |    SCULIER et al. T A B L E 3 Results of statistical tests for comparisons between In the subanalysis by age, 22 of 29 (76%) of the young- the three NORSE subgroups of unknown etiology after Bonferroni est patients returned to baseline, and 17 (72%) of these were correction (statistically significant p-­values [p < .05]) in the fever at onset subgroup. However, three of 11 (27%) patients older than 6 years returned to baseline at discharge. FSE No fever Among the previous fever patients, four of nine (44.4%) from Age FIRES .047 NS the youngest group and none from the oldest group returned No fever .034 –­ to baseline. SE duration FIRES .015 NS No fever NS –­ Duration of ICU stay FIRES <.001 .005 3.8 | NORSE of unknown etiology No fever NS –­ without fever Epileptiform discharges FIRES .030 NS on EEG No fever NS –­ Five patients had NORSE of unknown etiology without fever. We present individual characteristics in Table 4. Three pa- Abnormal MRI FIRES .002 NS tients (60%) had abnormal MRI findings, two (40%) had in- No fever .026 –­ terictal discharges on EEG, and one (20%) had elevated CSF Abnormal CSF FIRES .006 NS protein levels. The outcome was favorable in four (80%). No fever NS –­ ASM FIRES .053 NS No fever NS –­ 4 | D IS C U SS ION Continuous infusion FIRES .026 NS 4.1 | Summary No fever NS –­ Ketogenic diet FIRES <.001 NS NORSE cases represented 16% of the 279 prospectively No fever NS –­ collected children with an episode of RSE. Children with Immunotherapies FIRES <.001 NS NORSE of unknown etiology were divided into three patient No fever NS –­ subgroups: (1) fever at SE onset (FSE), (2) previous fever Complications, any FIRES <.001 NS (FIRES), and (3) no fever. FIRES patients had prolonged No fever NS –­ SE and worse outcomes, with 25% recovering baseline func- Good outcome FIRES <.001 NS tions. Refractory FSE patients were younger and had shorter No fever NS –­ SE episodes, and 89% recovered baseline function. Fever oc- curring more than 24 h before the onset of SE may identify Abbreviations: ASM, antiseizure medication; CSF, cerebrospinal fluid; EEG, electroencephalogram; FIRES, febrile infection-­related epilepsy syndrome; FSE, a subgroup with different clinical characteristics and worse febrile SE; ICU, intensive care unit; MRI, magnetic resonance imaging; NS, not outcomes. significant, SE, status epilepticus. 4.2 | Differences between previous fever and residual epilepsy, and 77% with a functional decline. Poor fever at SE onset groups outcomes in the prior study may have been in part attrib- uted to selection bias, as superrefractory or prolonged NORSE of unknown etiology had different profiles across cases of SE were specifically included. An inclusion crite- the three subgroups. NORSE with previous fever (FIRES) rion in the prior cohort was the diagnosis of “acute onset differed from NORSE with fever at onset (refractory catastrophic SE,” as defined by continuation of seizures FSE). FIRES cases were older, had more frequent CSF following the first treatment cycle of burst suppression and MRI abnormalities, and had a more severe clinical coma or by multiple seizures per day for more than 1 week course. FIRES patients required more aggressive treat- despite treatment.6 In our study, this group was defined as ment (higher rates of continuous infusions, ketogenic diet, NORSE with a previous febrile episode, without any crite- and immunotherapy). This clinical presentation of NORSE ria for duration or superrefractoriness of SE, thus shifting of unknown etiology with previous fever is consistent selection based on treatment response to clinical criteria with prior reports on FIRES.6,9–­11,19 In a FIRES cohort early in the presentation. of 77 patients, an 11% mortality rate was reported, 93% NORSE with fever at onset had a different clinical profile, of patients presented with residual epilepsy, and 66% had suggesting at least overlap or congruence with FSE.16,20 All subsequent mild to severe mental delay.6 Comparatively, patients except one were younger than 5 years with favorable our FIRES cohort revealed a mortality of 18%, 94% with outcomes and most often normal results in complementary SCULIER et al.    | 1637 TABLE 4 Clinical characteristics of the new onset refractory SE of unknown etiology without fever cases Characteristic 1 2 3 4 5 Age, years 10 2 10 13 2 Gender Male Female Male Male Female Comorbidities –­ –­ –­ Hearing loss –­ Prodromal symptoms –­ –­ –­ –­ URTI Fever at status epilepticus onset NA No No No No Epileptiform EEG Yes No No Yes No Seizures –­ –­ Periodic discharges –­ –­ Sporadic epileptiform discharges Lateralized Multifocal MRI Abnormal Abnormal Abnormal None None T2/FLAIR hyperintensity Left hippocampus Left hippocampus Right thalamus Abnormal CSF Yes None No No None Elevated protein level Yes, 72 mg/dl Elevated white cell count No, 4/mm3 ASMs 2 3 2 1 1 Continuous infusion 0 0 1 1 0 Ketogenic diet 0 0 0 0 0 Immunotherapies 1, steroids 0 0 0 0 ICU duration, days 2 1 1.5 4 1 SE duration, h 24 NA 15 9 6 Convulsive time, min 120 1320 150 177 90 Complications No No No Yes, No hypotension Good outcome Yes No Yes Yes Yes Abbreviations: ASM, antiseizure medication; CSF, cerebrospinal fluid; EEG, electroencephalogram; FLAIR, fluid-­attenuated inversion recovery; ICU, intensive care unit; MRI, magnetic resonance imaging; NA, not available; SE, status epilepticus; URTI, upper respiratory tract infection. TABLE 5 Key clinical features for the differential diagnosis between FSE, FIRES, and NORSE without fever NORSE of unknown etiology NORSE without Clinical features FSE FIRES fever Time from fever onset to SE onset <24 h >24 h No fever Age 1 month–­6 years School-­aged Variable <2 years in 79% >2 years in 81% >2 years in 80% SE duration Most <48 h (90%) Most >48 h (86%) All <48 h Abnormal findings on MRI, CSF, or EEG None in CSF and MRI At least one abnormal finding: 90% Variable EEG: focal/diffuse slowing in 47% CSF 63% MRI 69% EEG 80% Outcome Generally good Generally poor Variable Abbreviations: CSF, cerebrospinal fluid; EEG, electroencephalogram; FIRES, febrile infection-­related epilepsy syndrome; FSE, febrile SE; MRI, magnetic resonance imaging; NORSE, new onset refractory SE; SE, status epilepticus. studies. Moreover, the comparison of the subgroups by age with the current definition of febrile seizures. The fever at supported the higher frequency of FSE (62% vs. 9%) and onset group represents our largest subgroup (40%) of NORSE more favorable outcomes in the youngest group, consistent cases, in line with prior studies highlighting FSE as the most 1638 |    SCULIER et al. common cause of the first episode of SE, being at least twice study confirms that pediatric NORSE cases are mostly rep- as frequent as acute symptomatic SE.21 FSE is refractory in resented by FIRES if we differentiate FSE cases. In the larg- 10%–­20% of patients, whereas acute symptomatic SE is re- est series of FIRES, almost all patients had a prior febrile fractory in 20%–­40%.21,22 Therefore, our large proportion of illness.6 Whether cases of NORSE with unknown etiology refractory FSE (40%) may be explained by the exclusion of without fever are similar to FIRES is unclear, as the fever acute symptomatic cases. could sometimes be missed, or perhaps other unidentified The refractory FSE profile appears distinct from the usual triggers may lead to a similar presentation. Although the description of NORSE, but the proposed definitions include small size of our cohort prevented any statistically significant those patients within the NORSE entity. The different evolution differences, three of these cases (Cases 1, 3, and 4) seemed to of FIRES and FSE may be explained by an alternative underly- differ from FIRES, based on older age, shorter SE duration, ing etiology. In children with FIRES, elevated levels of procon- fewer MRI and CSF abnormalities, and more favorable out- vulsant cytokines (e.g., interleukin-­6) have been documented in comes. The fifth case had a clinical course compatible with the CSF, suggesting an inflammatory cause, potentially in the FSE, but no fever was noted. setting of a genetic predisposition. An underlying immune cause NORSE with previous fever (FIRES) frequently pre- is also supported by the association with polymorphisms in the sented with abnormal EEG (80%), neuroimaging (69%), interleukin-­1 receptor antagonist (IL1RN) gene.23,24 The time or CSF (63%) findings. The combination of these find- limit of fever onset in the current definitions of FSE and FIRES ings, including prior febrile episodes and RSE, raises remains arbitrary and may not prevent the risk of initial misdi- suspicion for autoimmune or infectious encephalitis.34–­36 agnosis in clinical practice. Thus, additional criteria should be One patient presented with clinical symptoms of men- considered, to better distinguish these entities early in the disease ingitis, including headache and neck pain. However, course. Based on our findings, age (>2 years) and electroclin- the severe, monosymptomatic course including seizures ical duration of SE (>48 h) could potentially be considered as only, and lack of response to first-­line immunotherapy in complementary factors in future diagnostic approaches, as they FIRES, may help separate these entities, making an au- were the most distinctive features. Eighty-­two percent of FIRES toimmune etiology less likely.1,6,37 Rather, recent studies patients were older than 2 years, and 79% of FSE patients were suggest a key role of innate immune system dysfunction in younger. Similarly, SE duration was longer than 48 h in 86% of FIRES patients.38 The most frequent imaging abnormal- FIRES and shorter in 89% of FSE cases (Table 5). Other fea- ities were seen in the FIRES subgroup (69%), including tures such as the seizure semiology (generalized/focal), onset T2/FLAIR hyperintensities in the mesial temporal lobe, characteristics (abrupt single SE episode vs. a flurry of seizures neocortical regions, or basal ganglia. In the largest prior of increasing frequency), and presence of a fever-­free interval FIRES series, 45% of MRIs were abnormal, mainly with before SE may also warrant further investigation. bi-­or unilateral hippocampal, peri-­insular, or basal gan- In our study, FIRES cases had longer SE duration and glia T2/FLAIR hyperintensities.6 However, proportions worse outcomes than refractory FSE. Etiology is often of abnormal imaging findings are variable among FIRES the main determinant of outcome related to SE, possibly studies, ranging from 0 to 58%,8,13,19,33,39 even if MRI was playing a larger role than the SE episode and related treat- systematically performed at the “acute phase” of the dis- ment,25–­27 but others highlighted the independent prognos- ease. When repeated after several weeks, additional T2/ tic role of SE duration.28–­31 We were unable to address this FLAIR hyperintensities or diffuse atrophies were often issue in our subset of patients, as most episodes of NORSE noted.6,8,39 Furthermore, a recent study showed revers- of unknown etiology lasted more than 2 days, whereas all ible bilateral claustral MRI T2 hyperintensity in adults episodes of FSE lasted less than 1 day, and therefore, du- and children with NORSE.40 The proportion of abnormal ration may have confounded outcomes. FIRES cases were findings in our FIRES group is higher than in prior stud- more frequently treated with immunotherapies and the ies, and this may have been related to relatively late MRI ketogenic diet than others, which was not associated with imaging during the disease. better outcomes. Notably, the application of therapies to patients with more severe disease courses and hence worse outcomes may have led to confounding by indication. 4.4 | Discussion of NORSE definition The current NORSE definition is largely based on the ability 4.3 | NORSE of unknown to quickly identify the cause of the SE. It is thus expected that etiology and FIRES the incidence of NORSE of unknown etiology will decrease with time as our understanding of the underlying causes Previous pediatric studies have focused on FIRES,8–­11,32,33 improves and the availability of faster diagnostic methods whereas NORSE series have included mostly adults.1,5 Our increases. Our study focused on patients with unknown SCULIER et al.    | 1639 etiology after extensive workup. This subgroup might cor- separate FIRES and FSE, our cohort was not sufficiently respond to a single disease and may be independent of the large to test other time windows. Therefore, this time window speed of testing or an assessment within 72 h, warranting remains arbitrary. Furthermore, a clearer distinction between more detailed evaluation. FSE and NORSE definitions, or related subcategories, may Our analyses provide suggestions for improvements in be helpful. the definition, such as the consideration of fever onset, SE duration, and age. These factors, among others, may help distinguish the previously well-­defined FSE group, which is 5 | CONCLUSIONS currently included in the current larger NORSE definition. Our data support that refractory FSE is a separate clinical en- Approximately 16% of RSE patients present as NORSE. tity based on clinical presentation and course, and should be Our study identifies the time of the onset of fever as a rel- excluded from the NORSE diagnosis, or distinguished within evant factor identifying three subgroups of patients within NORSE subcategories to acknowledge the different clinical NORSE of unknown etiology and supports the current age presentation, age spectrum, and clinical course, which may cutoff for FSE. In approximately 40% of cases, a febrile ill- also be reflected in etiological differences. Further represen- ness precedes SE onset by up to 2 weeks, and these patients tation of the clinical characteristics may help improve acute meet FIRES criteria. FIRES patients are usually older, pre- patient assessments and may reduce the importance of etio- sent with prolonged SE, have more abnormal MRI and CSF logic diagnosis in the current definitions. However, similar findings, and often have an unfavorable outcome. Our study to other SE presentations, etiological findings remain crucial provides clinical differences between these groups, confirm- for prognosis and more specific treatment selection. ing separate clinical features in refractory FSE, which may help improve diagnostic criteria. An additional distinction between NORSE and refractory FSE definitions may offer 4.5 | Challenges diagnostic and prognostic opportunities. Further research is needed to improve our understanding of pediatric NORSE, Given the observational nature of this study, the selection of FIRES, and FSE. patients is not random but includes consenting patients meet- ing inclusion criteria. Only cases treated in selected pSERG ACKNOWLEDGMENTS centers were included, and although we used a standardized This study and consortium were funded by the Epilepsy data acquisition tool, clinical information may have been Research Fund, the Epilepsy Foundation of America (EF-­ collected differently between centers, introducing a potential 213583, Targeted Initiative for Health Outcomes), the center-­based selection and information bias. American Epilepsy Society/Epilepsy Foundation of America Diagnosis and treatment were guided by physicians' judg- Infrastructure Award, and the Pediatric Epilepsy Research ment and standard of care, without standardized diagnostic Foundation. or treatment protocols. The efficiency of drugs cannot be as- sessed given the large heterogeneity of treatment on a small CONFLICT OF INTEREST group of patients. In addition, the subanalysis of patients with C.S. is funded by the International Federation of Clinical refractory and superrefractory SE was limited by the sample Neurophysiology. C.B.A. is funded by the Fundación Alfonso size. EEG and MRI results are not comparable if obtained at Martín Escudero. I.S.F. is funded by the Epilepsy Research different time points, as results are likely to change with time. Fund and was funded by the Fundación Alfonso Martín MRI results were not available in all patients at the time of Escudero and the HHV6 Foundation. M.A.-­G. was funded data collection. Information on MRI timing, protocol, or the by the Fundación Alfonso Martín Escudero. J.N.B. is funded equipment utilized was not reported in our dataset. Moreover, by National Institutes of Health (NIH) National Institute of complete autoimmune, infectious, and genetic workup was Neurological Disorders and Stroke 1K23NS116225. He also not systematically performed, which could have increased the served as a consultant for Novartis. W.D.G. is an editor for number of NORSE of unknown etiology cases in this series. Epilepsia and Epilepsy Research. T.A.G. is funded by NIH Also, outcomes were not assessed by official scales of mea- grants 2U01-­NS045911, U10-­NS077311, R01-­NS053998, surement, and follow-­up time was variable. This highlights R01-­NS062756, R01-­NS043209, R01-­LM011124, the importance of more standardized protocols in future stud- R01-­NS065840, U24 NS107200, and 1U01TR002623. He ies. The strengths of this study are the prospective design and has received consulting fees from Supernus, Sunovion, Eisai, multicenter large cohort. Prior studies have not highlighted and UCB. He also serves as an expert consultant for the US the detailed relationship of previous fever or fever at SE onset. Department of Justice and has received compensation for There is no diagnostic test for NORSE. Although our work as an expert on medicolegal cases. He receives royal- data support the cutoff time for fever occurrence of 24 h to ties from a patent license. D.T. has received research funding 1640 |    SCULIER et al. from Children's Miracle Network Hospitals and Duke Forge. Cristina Barcia Aguilar participated in drafting and revising the He has also received consultation fees from Gerson Lehrman manuscript for content, including medical writing, study con- Group, Guidepoint, IQVIA, and bioStrategies Group. cept and design, data acquisition, analysis and interpretation M.S.W. serves as a scientific consultant and on the clinical of data, statistical analysis, and study supervision or coordina- advisory board for Sage Pharmaceuticals. A.A.W. receives tion. Nicolas Gaspard participated in drafting and revising the research funding from Novartis, Eisai, Pfizer, UCB, Acorda, manuscript for content, including medical writing, study con- Lundbeck, GW Pharma, Upsher-­Smith, and Zogenix and cept and design, data acquisition, analysis and interpretation of receives publication royalties from UpToDate. T.L. serves data, statistical analysis, and study supervision or coordination. on the board of the NORSE Institute, on the council (and Marina Gaínza-­Lein participated in revising the manuscript for as past president) of the American Clinical Neurophysiology content, including medical writing, study concept and design, Society, as committee chair at the American Epilepsy data acquisition, and study supervision or coordination. Iván Society (Investigator Workshop Committee), as founder Sánchez Fernández participated in revising the manuscript for and consortium principal investigator of the pediatric sta- content, including medical writing, study concept and design, tus epilepticus research group, as an associate editor for data acquisition, and study supervision or coordination. Marta Wyllie's Treatment of Epilepsy 6th and 7th editions. He is Amengual-­Gual participated in revising the manuscript for part of pending patent applications to detect, treat, and pre- content, including medical writing, study concept and design, dict seizures and to diagnose epilepsy. He receives research data acquisition, and study supervision or coordination. Anne support from the NIH, Patient-­Centered Outcomes Research Anderson participated in revising the manuscript for content, Institute, Epilepsy Research Fund, Epilepsy Foundation of including medical writing, study concept and design, data ac- America, Epilepsy Therapy Project, and Pediatric Epilepsy quisition, and study supervision or coordination. Ravindra Arya Research Foundation, and has received research grants from participated in revising the manuscript for content, including Lundbeck, Eisai, Upsher-­ Smith, Mallinckrodt, Sage, and medical writing, study concept and design, data acquisition, Pfizer. He has served in the past as a consultant for Zogenix, and study supervision or coordination. Brian T. Burrows partic- UCB, Engage, Amzell, Upsher-­Smith, Eisai, and Sunovion. ipated in revising the manuscript for content, including medical He performs video-­electroencephalographic long-­term and writing, study concept and design, data acquisition, and study ICU monitoring, electroencephalograms, and other electro- supervision or coordination. J. Nicholas Brenton participated physiological studies at Boston Children's Hospital and affili- in revising the manuscript for content, including medical writ- ated hospitals and bills for these procedures, and he evaluates ing, study concept and design, data acquisition, and study su- pediatric neurology patients and bills for clinical care. He pervision or coordination. Jessica L. Carpenter participated in has received speaker honorariums from national societies revising the manuscript for content, including medical writing, including the American Academy of Neurology, American study concept and design, data acquisition, and study supervi- Epilepsy Society, and American Clinical Neurophysiology sion or coordination. Kevin E. Chapman participated in revis- Society, and for grand rounds at various academic centers. ing the manuscript for content, including medical writing, study T.L. is a coinventor of the TriVoxHealth technology. In the concept and design, data acquisition, and study supervision or future, this technology may be sold commercially. If this coordination. Justice Clark participated in revising the manu- were to occur, T.L. and Boston Children's Hospital might script for content, including medical writing, study concept and receive financial benefits in the form of compensation. As design, data acquisition, and study supervision or coordination. in all research studies, the hospital has taken steps designed William D. Gaillard participated in revising the manuscript to ensure that this potential for financial gain does not en- for content, including medical writing, study concept and de- danger research subjects or undercut the validity and integ- sign, data acquisition, and study supervision or coordination. rity of the information learned by this research. His wife, Dr. Tracy A. Glauser participated in revising the manuscript for Karen Stannard, is a pediatric neurologist, and she performs content, including medical writing, study concept and design, video-­electroencephalographic long-­term and ICU monitor- data acquisition, and study supervision or coordination. Joshua ing, electroencephalograms, and other electrophysiological L. Goldstein participated in revising the manuscript for con- studies and bills for these procedures and she evaluates pedi- tent, including medical writing, study concept and design, data atric neurology patients and bills for clinical care. None of acquisition, and study supervision or coordination. Howard P. the other authors has any conflict of interest to disclose. Goodkin participated in revising the manuscript for content, including medical writing, study concept and design, data ac- AUTHOR CONTRIBUTIONS quisition, and study supervision or coordination. Mark Gorman Claudine Sculier participated in drafting and revising the man- participated in revising the manuscript for content, including uscript for content, including medical writing, study concept medical writing, study concept and design, data acquisition, and design, data acquisition, analysis and interpretation of and study supervision or coordination. Yi-­Chen Lai partici- data, statistical analysis, and study supervision or coordination. pated in revising the manuscript for content, including medical SCULIER et al.    | 1641 writing, study concept and design, data acquisition, and study Iván Sánchez Fernández https://orcid. supervision or coordination. Tiffani L. McDonough partici- org/0000-0002-4313-002X pated in revising the manuscript for content, including medical Marta Amengual-­Gual https://orcid. writing, study concept and design, data acquisition, and study org/0000-0002-6887-3495 supervision or coordination. Mohamad A. Mikati participated Ravindra Arya https://orcid.org/0000-0003-0873-9718 in revising the manuscript for content, including medical writ- William D. Gaillard https://orcid. ing, study concept and design, data acquisition, and study su- org/0000-0001-5709-0033 pervision or coordination. Anuranjita Nayak participated in Yi-­Chen Lai https://orcid.org/0000-0002-9450-5506 revising the manuscript for content, including medical writing, Mohamad A. Mikati https://orcid. study concept and design, data acquisition, and study supervi- org/0000-0003-0363-8715 sion or coordination. Katrina Peariso participated in revising the manuscript for content, including medical writing, study R E F E R E NC E S concept and design, data acquisition, and study supervision or 1. Gaspard N, Foreman BP, Alvarez V, Cabrera Kang C, Probasco coordination. James Riviello participated in revising the manu- JC, Jongeling AC, et al. New-­ onset refractory status epilep- script for content, including medical writing, study concept and ticus: etiology, clinical features, and outcome. Neurology. 2015;85(18):1604–­13. design, data acquisition, and study supervision or coordination. 2. 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