Clinical presentation of new onset refractory status epilepticus in children (the pSERG cohort)

doi:10.1111/epi.16950

. 2021 Jul;62(7):1629-1642.

doi: 10.1111/epi.16950. Epub 2021 Jun 6.

Clinical presentation of new onset refractory status epilepticus in children (the pSERG cohort)

Claudine Sculier^{1

2}, Cristina Barcia Aguilar^{1

3}, Nicolas Gaspard^{2

4}, Marina Gaínza-Lein^{1

5

6}, Iván Sánchez Fernández^{1

7}, Marta Amengual-Gual^{1

8}, Anne Anderson⁹, Ravindra Arya¹⁰, Brian T Burrows^{11

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 McDonough¹⁷, Mohamad A Mikati¹⁸, Anuranjita Nayak⁹, Katrina Peariso¹⁰, James Riviello⁹, Allison Rusie¹⁶, Katherine Sperberg¹⁴, Coral M Stredny¹, Robert C Tasker¹⁹, Dmitry Tchapyjnikov¹⁷, Alejandra Vasquez^{1

20}, Mark S Wainwright²¹, Angus A Wilfong²², Korwyn Williams²², Tobias Loddenkemper¹; pSERG

Affiliations

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.

PMID: 34091885
PMCID: PMC8362203
DOI: 10.1111/epi.16950

Clinical presentation of new onset refractory status epilepticus in children (the pSERG cohort)

Claudine Sculier et al. Epilepsia. 2021 Jul.

. 2021 Jul;62(7):1629-1642.

doi: 10.1111/epi.16950. Epub 2021 Jun 6.

Authors

Affiliations

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.

PMID: 34091885
PMCID: PMC8362203
DOI: 10.1111/epi.16950

Abstract

Objective: We aimed to characterize the clinical profile and outcomes of new onset refractory status epilepticus (NORSE) in children, and investigated the relationship between fever onset and status epilepticus (SE).

Methods: Patients with refractory SE (RSE) between June 1, 2011 and October 1, 2016 were prospectively enrolled in the pSERG (Pediatric Status Epilepticus Research Group) cohort. Cases meeting the definition of NORSE were classified as "NORSE of known etiology" or "NORSE of unknown etiology." Subgroup analysis of NORSE of unknown etiology was completed based on the presence and time of fever occurrence 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 median 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 distinctive 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.

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Conflict of interest statement

C.S. is funded by the International Federation of Clinical Neurophysiology. C.B.A. is funded by the Fundación Alfonso Martín Escudero. I.S.F. is funded by the Epilepsy Research Fund and was funded by the Fundación Alfonso Martín Escudero and the HHV6 Foundation. M.A.‐G. was funded by the Fundación Alfonso Martín Escudero. J.N.B. is funded by National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke 1K23NS116225. He also served as a consultant for Novartis. W.D.G. is an editor for Epilepsia and Epilepsy Research. T.A.G. is funded by NIH grants 2U01‐NS045911, U10‐NS077311, R01‐NS053998, R01‐NS062756, R01‐NS043209, R01‐LM011124, R01‐NS065840, U24 NS107200, and 1U01TR002623. He has received consulting fees from Supernus, Sunovion, Eisai, and UCB. He also serves as an expert consultant for the US Department of Justice and has received compensation for work as an expert on medicolegal cases. He receives royalties from a patent license. D.T. has received research funding from Children's Miracle Network Hospitals and Duke Forge. He has also received consultation fees from Gerson Lehrman Group, Guidepoint, IQVIA, and bioStrategies Group. M.S.W. serves as a scientific consultant and on the clinical advisory board for Sage Pharmaceuticals. A.A.W. receives research funding from Novartis, Eisai, Pfizer, UCB, Acorda, Lundbeck, GW Pharma, Upsher‐Smith, and Zogenix and receives publication royalties from UpToDate. T.L. serves on the board of the NORSE Institute, on the council (and as past president) of the American Clinical Neurophysiology Society, as committee chair at the American Epilepsy Society (Investigator Workshop Committee), as founder and consortium principal investigator of the pediatric status epilepticus research group, as an associate editor for Wyllie's Treatment of Epilepsy 6th and 7th editions. He is part of pending patent applications to detect, treat, and predict seizures and to diagnose epilepsy. He receives research support from the NIH, Patient‐Centered Outcomes Research Institute, Epilepsy Research Fund, Epilepsy Foundation of America, Epilepsy Therapy Project, and Pediatric Epilepsy Research Foundation, and has received research grants from Lundbeck, Eisai, Upsher‐Smith, Mallinckrodt, Sage, and Pfizer. He has served in the past as a consultant for Zogenix, UCB, Engage, Amzell, Upsher‐Smith, Eisai, and Sunovion. He performs video‐electroencephalographic long‐term and ICU monitoring, electroencephalograms, and other electrophysiological studies at Boston Children's Hospital and affiliated hospitals and bills for these procedures, and he evaluates pediatric neurology patients and bills for clinical care. He has received speaker honorariums from national societies including the American Academy of Neurology, American Epilepsy Society, and American Clinical Neurophysiology Society, and for grand rounds at various academic centers. T.L. is a coinventor of the TriVoxHealth technology. In the future, this technology may be sold commercially. If this were to occur, T.L. and Boston Children's Hospital might receive financial benefits in the form of compensation. As in all research studies, the hospital has taken steps designed to ensure that this potential for financial gain does not endanger research subjects or undercut the validity and integrity of the information learned by this research. His wife, Dr. Karen Stannard, is a pediatric neurologist, and she performs video‐electroencephalographic long‐term and ICU monitoring, electroencephalograms, and other electrophysiological studies and bills for these procedures and she evaluates pediatric neurology patients and bills for clinical care. None of the other authors has any conflict of interest to disclose.

Figures

**FIGURE 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

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References

1. Gaspard N, Foreman BP, Alvarez V, Cabrera Kang C, Probasco JC, Jongeling AC, et al. New‐onset refractory status epilepticus: etiology, clinical features, and outcome. Neurology. 2015;85(18):1604–13. - PMC - PubMed
1. Hirsch LJ, 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. Epilepsia. 2018;59(4):739–44. - PubMed
1. Costello DJ, Kilbride RD, Cole AJ. Cryptogenic new onset refractory status epilepticus (NORSE) in adults—infectious or not? J Neurol Sci. 2009;277(1–2):26–31. - PubMed
1. Khawaja AM, DeWolfe JL, Miller DW, Szaflarski JP. New‐onset refractory status epilepticus (NORSE)—the potential role for immunotherapy. Epilepsy Behav. 2015;47:17–23. - PubMed
1. Gall CRE, Jumma O, Mohanraj R. Five cases of new onset refractory status epilepticus (NORSE) syndrome: outcomes with early immunotherapy. Seizure. 2013;22(3):217–20. - PubMed

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[1] Gaspard N, Foreman BP, Alvarez V, Cabrera Kang C, Probasco JC, Jongeling AC, et al. New‐onset refractory status epilepticus: etiology, clinical features, and outcome. Neurology. 2015;85(18):1604–13. - PMC - PubMed

[2] Gaspard N, Foreman BP, Alvarez V, Cabrera Kang C, Probasco JC, Jongeling AC, et al. New‐onset refractory status epilepticus: etiology, clinical features, and outcome. Neurology. 2015;85(18):1604–13. - PMC - PubMed

[3] Hirsch LJ, 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. Epilepsia. 2018;59(4):739–44. - PubMed

[4] Hirsch LJ, 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. Epilepsia. 2018;59(4):739–44. - PubMed

[5] Costello DJ, Kilbride RD, Cole AJ. Cryptogenic new onset refractory status epilepticus (NORSE) in adults—infectious or not? J Neurol Sci. 2009;277(1–2):26–31. - PubMed

[6] Costello DJ, Kilbride RD, Cole AJ. Cryptogenic new onset refractory status epilepticus (NORSE) in adults—infectious or not? J Neurol Sci. 2009;277(1–2):26–31. - PubMed

[7] Khawaja AM, DeWolfe JL, Miller DW, Szaflarski JP. New‐onset refractory status epilepticus (NORSE)—the potential role for immunotherapy. Epilepsy Behav. 2015;47:17–23. - PubMed

[8] Khawaja AM, DeWolfe JL, Miller DW, Szaflarski JP. New‐onset refractory status epilepticus (NORSE)—the potential role for immunotherapy. Epilepsy Behav. 2015;47:17–23. - PubMed

[9] Gall CRE, Jumma O, Mohanraj R. Five cases of new onset refractory status epilepticus (NORSE) syndrome: outcomes with early immunotherapy. Seizure. 2013;22(3):217–20. - PubMed

[10] Gall CRE, Jumma O, Mohanraj R. Five cases of new onset refractory status epilepticus (NORSE) syndrome: outcomes with early immunotherapy. Seizure. 2013;22(3):217–20. - PubMed

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Clinical presentation of new onset refractory status epilepticus in children (the pSERG cohort)

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Clinical presentation of new onset refractory status epilepticus in children (the pSERG cohort)

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