Accepted: 10 January 2018

DOI: 10.1111/epi.14016

CRITICAL REVIEW AND INVITED COMMENTARY

Proposed consensus definitions for new-onset refractory status

epilepticus (NORSE), febrile infection-related epilepsy syndrome
(FIRES), and related conditions

Lawrence J. Hirsch1 | Nicolas Gaspard2 | Andreas van Baalen3 | Rima Nabbout4 |

Sophie Demeret5 | Tobias Loddenkemper6 | Vincent Navarro7 | Nicola Specchio8 |
Lieven Lagae9 | Andrea O. Rossetti10 | Sara Hocker11 | Teneille E. Gofton12 |
Nicholas S. Abend13 | Emily J. Gilmore1 | Cecil Hahn14 | Houman Khosravani15,16 |
Felix Rosenow17 | Eugen Trinka18,19

1
Comprehensive Epilepsy Center, Department of Neurology, Yale University, New Haven, CT, USA
2
Department of Neurology, Universit
e Libre de Bruxelles – H^opital Erasme, Bruxelles, Belgium
3
Department of Neuropediatrics, Christian-Albrechts University, University Medical Center Schleswig-Holstein, Kiel, Germany
4
Reference Center for Rare Epilepsies, Department of Child Neurology, Necker Enfants Malades Hospital, AP-HP, Paris Descartes University, Paris,
France
5
AP-HP, Neurological Intensive Care Unit, Piti
e-Salp^etriere Hospital, Paris, France
6
Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital & Harvard Medical School, Boston, MA,
USA
7
AP-HP, GH Pitie-Salp^etriere-Charles Foix, Epilepsy Unit, Brain and Spine Institute, Sorbonne University, UPMC University, Paris, France
8
Department of Neuroscience, Bambino Gesu Children’s Hospital, IRCCS, Rome, Italy
9
Department of Development and Regeneration, Section of Pediatric Neurology, University Hospitals Leuven, Leuven, Belgium
10
Department of Neurology, CHUV and University of Lausanne, Lausanne, Switzerland
11
Division of Critical Care Neurology, Department of Neurology, Mayo Clinic, Rochester, MN, USA
12
Department of Clinical Neurological Sciences, Western University, Schulich School of Medicine and Dentistry, London, ON, Canada
13
Departments of Neurology and Pediatrics, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, USA
14
Division of Neurology, The Hospital for Sick Children and Department of Paediatrics, University of Toronto, Toronto, ON, Canada
15
Division of Neurology and Interdepartmental Division of Critical Care, Department of Medicine, Sunnybrook Health Sciences Centre, University of
Toronto, Toronto, ON, Canada
16
Interdepartmental Division of Critical Care, Department of Medicine, University of Toronto, Toronto, ON, Canada
17
Epilepsy Center Frankfurt Rhine-Main, Center of Neurology and Neurosurgery, Goethe-University Frankfurt, Frankfurt/Main, Germany
18
Department of Neurology, Christian Doppler Medical Center, Paracelsus Medical University, Center for Cognitive Neuroscience, Salzburg, Austria
19
Institute of Public Health, Department of Public Health, Health Services and HTA, UMIT, Hall in Tirol, Austria

Correspondence
Lawrence J. Hirsch, Division of Epilepsy
and EEG, Comprehensive Epilepsy
Center, Critical Care EEG Monitoring
Program, Yale University School of
Medicine, New Haven, CT, USA.
Email: Lawrence.Hirsch@Yale.edu
Summary
We convened an international group of experts to standardize definitions of New-
Onset Refractory Status Epilepticus (NORSE), Febrile Infection-Related Epilepsy
Syndrome (FIRES), and related conditions. This was done to enable improved com-
munication for investigators, physicians, families, patients, and other caregivers.
Consensus definitions were achieved via email messages, phone calls, an in-person
consensus conference, and collaborative manuscript preparation. Panel members

Epilepsia. 2018;59:739–744. wileyonlinelibrary.com/journal/epi Wiley Periodicals, Inc. | 739

© 2018 International League Against Epilepsy
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| HIRSCH ET AL.

were from 8 countries and included adult and pediatric experts in epilepsy, elec-
troencephalography (EEG), and neurocritical care. The proposed consensus defini-
tions are as follows: NORSE is a clinical presentation, not a specific diagnosis, in a
patient without active epilepsy or other preexisting relevant neurological disorder,
with new onset of refractory status epilepticus without a clear acute or active struc-
tural, toxic or metabolic cause. FIRES is a subcategory of NORSE, applicable for
all ages, that requires a prior febrile infection starting between 2 weeks and
24 hours prior to onset of refractory status epilepticus, with or without fever at onset
of status epilepticus. Proposed consensus definitions are also provided for Infantile
Hemiconvulsion-Hemiplegia and Epilepsy syndrome (IHHE) and for prolonged,
refractory and super-refractory status epilepticus. This document has been endorsed
by the Critical Care EEG Monitoring Research Consortium. We hope these consen-
sus definitions will promote improved communication, permit multicenter research,
and ultimately improve understanding and treatment of these conditions.

KEYWORDS
autoimmune, cryptogenic, encephalitis, febrile infection-related epilepsy syndrome, febrile status
epilepticus, infantile hemiconvulsion-hemiplegia and epilepsy syndrome, new-onset refractory status
epilepticus, prolonged febrile convulsions, refractory status epilepticus, super-refractory status
epilepticus

1 | INTRODUCTION
When an adult patient presents with refractory status
epilepticus that remains unexplained after initial evaluation,
the term NORSE (New-Onset Refractory Status Epilepti-
cus) is often used in clinical practice; NORSE is commonly
preceded by an unremarkable febrile infection.1,2 When a
child presents with the same scenario after a febrile infec-
tion, the term FIRES (Febrile Infection-Related Epilepsy
Syndrome) is preferred by most pediatric clinicians.3–8
These terms have been used with variable definitions in the
literature. The relationship between NORSE and FIRES
remains unclear,9,10 and their nosology has been a matter
of debate. Lack of standardized terminology complicates
multicenter investigations and may impact clinical manage-
ment. For example, there is evidence that a substantial por-
tion of these cases are either caused by or worsened by
immune activation.1,6,11–13 Some preliminary evidence, par-
ticularly in adults, suggests that early immunotherapy may
be beneficial even when a definite immune etiology has
not been identified.12,14–16 Yet many centers are not admin-
istering immunotherapy for adults with NORSE unless a
definitive etiology has been identified.17 As another exam-
ple, in children with FIRES, the ketogenic diet may be par-
ticularly effective,4,18 but it is administered inconsistently
and often very late in the course. Many other aspects of
the etiologies and management of these patients remain
understudied and uncertain.
Key Points
• We convened an international, multidisciplinary
group of experts to develop proposed consensus
definitions for NORSE, FIRES, and related con-
ditions and terms. These definitions were
endorsed by the Critical Care EEG Monitoring
Research Consortium
• NORSE is a clinical presentation, not a specific
diagnosis, in a patient without active epilepsy or
other preexisting relevant neurological disorder,
with new onset of refractory status epilepticus
without a clear acute or active structural, toxic or
metabolic cause
• FIRES is a subcategory of NORSE, applicable
for all ages, that requires a prior febrile infection
starting between 2 weeks and 24 hours prior to
onset of refractory status epilepticus, with or
without fever at onset of status epilepticus
• These consensus definitions should allow
improved communications and more effective
multicenter research
To standardize the use of these terms, we convened a
multinational expert panel at the occasion of the 6th Lon-
don-Innsbruck Colloquium on Status Epilepticus and Acute
HIRSCH ET AL.
Seizures in Salzburg, Austria (www.statusepilepticus.eu).
The panel consisted of 18 experts from 8 countries, most of
whom are established status epilepticus investigators and all
of whom have a special interest in this topic. Seven panel
members are pediatric specialists. The conference was sup-
ported by The Norse Institute (www.norseinstitute.org).
2 | OBJECTIVE
To standardize terminology and agree on working defini-
tions in order to:
• Permit multicenter studies.
• Improve communication for clinical care and research.
• Provide a name for this clinical presentation so that (1)
patients and families can learn about it, and (2) care-
givers can identify related literature using electronic lit-
erature searches.
• Improve early recognition of NORSE/FIRES to help
with early management and identification of more speci-
fic diagnoses. This requires using practical terms that
can be applied early in the clinical course; thus, the defi-
nitions must not require extensive etiologic testing that
may take weeks to complete.
• Help with fundraising for research.
• Avoid conflicting with any existing consensus defini-
tions or guidelines whenever possible, including the
status epilepticus classification developed by the Interna-
tional League Against Epilepsy (ILAE).19
3 | METHODS
An initial draft was created by the medical advisory board
of The Norse Institute (www.norseinstitute.org; co-chairs:
authors LJH and NG). This was followed by extensive
email discussions with the full panel, followed by a face to
face meeting of 9 members (4 pediatric: AvB, RN, TL,
NS; and 5 adult: LJH, NG, SD, VN, ET) from 6 countries
in Salzburg, Austria on April 5th, 2017. The definitions
were then presented in an open half-day symposium on the
same day, with additional edits and clarifications based on
feedback, questions, and subsequent email discussions. A
final draft was then circulated to all members for additional
email discussion and to ensure consensus.
4 | RESULTS
4.1 | Consensus definition of new-onset
refractory status epilepticus
New-onset refractory status epilepticus is a clinical pre-
sentation, not a specific diagnosis, in a patient without
| 741
active epilepsy or other preexisting relevant neurological
disorder, with new onset of refractory status epilepticus
without a clear acute or active structural, toxic, or meta-
bolic cause.
4.1.1 | Explanatory notes
• Most of the common acute or active structural, toxic, or
metabolic etiologies can be identified in the first few
hours, but it may take up to 72 hours to rule out some
structural lesions, drug overdoses, and metabolic condi-
tions due to delays in obtaining imaging and laboratory
results.
• NORSE includes patients with viral infections (including
herpes simplex virus-1 [HSV-1]) and autoimmune syn-
dromes of new onset, even if these are diagnosed in the ini-
tial 72 hours (including anti-NMDA encephalitis). Thus,
these more specific diagnoses can present as NORSE.
o Although we initially planned to exclude HSV-1,
research has shown that HSV-1 only rarely (if ever)
presents with refractory status epilepticus. For exam-
ple, in the California Encephalitis Project, of 1151
cases of encephalitis, only 43 (4%) had refractory sta-
tus epilepticus, and none of those had HSV-1
detected.20 We decided not to exclude any specific
viruses as we do not want the definition to vary
based on the ability to identify viruses in different
centers, or to vary over the years as we improve our
ability to detect viruses. In addition, the causal role
of positive testing for certain viruses may be unclear.
Thus, patients with these positive results can present
as NORSE and should still be included in research
on NORSE.
o The reasoning was similar for including patients with
autoimmune syndromes, regardless of how quickly
they are diagnosed. Most cannot be diagnosed
quickly enough to affect early management decisions.
We do not want the determination of the clinical pre-
sentation of NORSE to depend on the speed and
accuracy of the local laboratories, or to change over
the years as these results are obtained more quickly
or as more antibodies are discovered. Furthermore,
the direct causal role of many of these antibodies
remains unclear and should be studied further (eg,
anti-thyroid peroxidase, low titer anti-glutamic acid
decarboxylase, or anti-voltage-gated potassium chan-
nel complex without anti-leucine-rich, glioma inacti-
vated 1 protein or contactin-associated protein-like 2).
Thus, these antibodies can be associated with (and
potentially cause) the clinical presentation of NORSE.
Finally there is evidence that NORSE that remains
742
| HIRSCH
unexplained and NORSE found to have an autoim-
mune etiology are similar in most aspects, including
cerebrospinal fluid (CSF) profiles, at least based on 1
study of 125 cases.1
• NORSE includes patients with remote brain injuries and
patients with resolved epilepsy (seizure-free for 10 years
and off medication for >5 years21). Those with active
epilepsy are excluded.
• A determination of NORSE requires imaging, CSF anal-
ysis, toxicology assessment, and other blood tests as rec-
ommended for evaluation of status epilepticus in other
guidelines and reviews.19,22–24
• NORSE typically presents as super-refractory status
epilepticus (see definition below), but this is not required
to qualify as NORSE.
• “Cryptogenic NORSE” or “NORSE of unknown etiol-
ogy” subgroup: This term applies to patients with the
clinical presentation of NORSE, but in whom the cause
remains unknown after extensive workup (which may
take several weeks to complete). This term is already in
use in the literature in this manner.16,25–27
• NORSE does not include refractory status epilepticus
with fully retained consciousness such as epilepsia par-
tialis continua.
4.2 | Consensus definition of febrile infection-
related epilepsy syndrome
Febrile infection-related epilepsy syndrome is a subcate-
gory of NORSE that requires a prior febrile infection, with
fever starting between 2 weeks and 24 hours prior to onset
of refractory status epilepticus, with or without fever at
onset of status epilepticus.
4.2.1 | Explanatory notes
• FIRES includes all ages.
• This definition of FIRES excludes most cases of feb-
rile status epilepticus in children (prolonged febrile
convulsions), as febrile seizures usually occur in chil-
dren who have onset of fever <24 hours prior to onset
of seizures or whose fever is recognized only after the
onset of seizures.28 Although this definition may
include some unusual cases of “febrile status epilepti-
cus” when fever has been present for >24 hours and
the status epilepticus is refractory, this situation may
reflect a pathophysiology similar to that of other cases
presenting with NORSE, albeit on the mild end of the
spectrum. Further research is necessary to determine if
these self-limited cases and more typical cases of
NORSE have distinct or overlapping etiologies and
pathophysiologies.
ET AL.
4.3 | Consensus definition of infantile
hemiconvulsion-hemiplegia and epilepsy
syndrome
Infantile hemiconvulsion-hemiplegia and epilepsy syn-
drome is a specific syndrome in a patient <2 years old,
presenting as NORSE with unilateral motor seizures, high-
grade fever at the time of onset of refractory status epilepti-
cus, and unilaterally abnormal acute imaging, followed by
hemiparesis lasting at least 24 hours, and excluding definite
infectious encephalitis.
4.3.1 | Explanatory note
• As this syndrome of IHHE presents as NORSE and has
no clear definition in the literature, we felt it would be
useful to include a proposed definition in this manu-
script.
4.4 | Consensus definitions for status
epilepticus subtypes
The following terms have been defined previously, but
sometimes in variable ways. We have kept the most com-
monly used definitions, and put them in this document for
convenience as they are closely related to the definition of
NORSE. We also newly define the term “prolonged” as a
modifier for refractory SE and super-refractory SE.
• Refractory SE (RSE): SE persisting despite administra-
tion of at least 2 appropriately selected and dosed par-
enteral medications including a benzodiazepine. There is
no specific seizure duration required.
• Super-Refractory SE (SRSE): SE persisting at least
24 hours after onset of anesthesia, either without inter-
ruption despite appropriate treatment with anesthesia;
recurring while on appropriate anesthetic treatment; or
recurring after withdrawal of anesthesia and requiring
anesthetic reintroduction. This is consistent with the
recent literature.29,30 “Anesthesia” includes commonly
used agents such as midazolam, propofol, pentobarbital,
thiopental, ketamine, and others, so long as they are
used at anesthetic doses.
• Prolonged RSE (PRSE): RSE that persists for at least
7 days despite appropriate management, but without use
of anesthetics.
• Prolonged SRSE (PSRSE): SRSE that persists for at least
7 days, including ongoing need for anesthetics.
The definitions in this manuscript were reviewed and
fully endorsed by the Critical Care EEG Monitoring
Research Consortium (CCEMRC) on 11/15/2017. The
HIRSCH ET AL.
CCEMRC is an international consortium of more than 50
member centers dedicated to multicenter research to
improve diagnosis and treatment of critically ill adults and
children by harnessing neurophysiologic monitoring. See
https://www.acns.org/research/critical-care-eeg-monitoring-
research-consortium-ccemrc for further details on the
CCEMRC.
5 | CONCLUSION
We hope these definitions will improve communication for
clinicians, researchers, families, and patients. We expect
that these definitions will broaden the use of these terms to
some degree, such as including less refractory cases (refrac-
tory, but not super-refractory). This will help enable inves-
tigators to answer questions such as why some patients
become super-refractory; whether NORSE preceded by a
febrile infection (ie, FIRES) is different than other cases of
NORSE; whether etiologies and responses to treatments
differ by age; if and when early immune treatment is bene-
ficial; and many other questions.
ACKNOWLEDGMENTS
We would like to thank Nora and Raymond Wong and The
Norse Institute (www.norseinstitute.org) for providing moti-
vation and financial support for the meeting in Salzburg.
DISCLOSURES
None of the authors has any conflict of interest to disclose.
We confirm that we have read the Journal’s position on
issues involved in ethical publication and affirm that this
report is consistent with those guidelines.
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