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Accepted: 19 January 2018

DOI: 10.1111/epi.14022


New-onset refractory status epilepticus (NORSE) and febrile

infection–related epilepsy syndrome (FIRES): State of the art
and perspectives

Nicolas Gaspard1,2 | Lawrence J. Hirsch2 | Claudine Sculier1,3 |

3 4
Tobias Loddenkemper | Andreas van Baalen | Judette Lancrenon5 | Michel Emmery5 |
Nicola Specchio6 | Raquel Farias-Moeller7 | Nora Wong8 | Rima Nabbout9

Service de Neurologie et Centre de Reference pour le Traitement de l’Epilepsie Refractaire, Universite Libre de Bruxelles – H^opital Erasme,
Bruxelles, Belgique
Department of Neurology, Comprehensive Epilepsy Center, Yale University School of Medicine, New Haven, CT, USA
Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA,
Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany
Association Paratonnerre – European Association of Persons Affected by F.I.R.E.S, Lyon, France
Rare and Complex Epilepsies Unit, Department of Neuroscience, Bambino Gesu Children’s Hospital, IRCCS, Rome, Italy
Center for Neuroscience, Children’s National Health System, George Washington University, Washington, DC, USA
NORSE Institute, New Haven, CT, USA
Department of Pediatric Neurology, Centre de Reference Epilepsies Rares, Necker-Enfants Malades Hospital, Inserm U1129, Imagine Institute, Paris
Descartes University, Paris, France

Nicolas Gaspard, Service de Neurologie, Summary
Universite Libre de Bruxelles – H^opital We report the proceedings of the First International new-onset refractory status
Erasme, Bruxelles, Belgique.
epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES)
Email: Nicolas.Gaspard@erasme.ulb.ac.be
Symposium. To promote awareness of this condition and foster research efforts,
we conveyed the First International new-onset refractory status epilepticus
(NORSE) and febrile infection-related epilepsy syndrome (FIRES) Symposium.
The conference was supported by The NORSE Institute (http://www.norseinsti
tute.org). This article summarizes the discussions that were held during the Sym-
posium and presents our strategy to unravel the cause of these disorders and to
improve patient care. The standardized definitions for these disorders that have
been developed, are required to improve communication and facilitate the devel-
opment of multicenter registries and biobanks. A distinction between childhood-
and adult-onset forms of the syndrome is not supported by strong scientific
evidence and it is argued that both should be studied together. Although the
pathophysiology remains elusive, nascent evidence suggests a role for a postinfec-
tious cytokine-mediated mechanism, which should be further investigated. It also
appears important to develop tools for their early recognition and prompt treat-
ment. Recent evidence suggests that specific electroencephalography (EEG) fea-
tures might be helpful. The optimal treatment options remain to be determined;

Epilepsia. 2018;59:745–752. wileyonlinelibrary.com/journal/epi Wiley Periodicals, Inc. | 745

© 2018 International League Against Epilepsy

immune therapies are usually disappointing, but the ketogenic diet has proved
effective in uncontrolled trials. NORSE and FIRES represent a very delicate clini-
cal situation with specific communication issues between physicians and with
patients and families. Standardized consensus definitions and a multidisciplinary
multicenter strategy will help research efforts and improve clinical care for
patients with NORSE and FIRES.

acute encephalitis with refractory repetitive partial seizures, febrile infection–related epilepsy
syndrome, new-onset refractory status epilepticus

Key Points
The cause of status epilepticus (SE) is often easily identi-
fied with a standardized approach.1 A careful history tak- • New-onset refractory status epilepticus (NORSE)
and febrile infection-related epilepsy syndrome
ing, neurological examination, and basic laboratory tests
(FIRES) are a clinical challenge
might identify the most common etiologies of SE, such as
nonadherence or changes in antiseizure treatment, intoxica- • The lack of a unified terminology for these disor-
ders hampers clinical care, communication with
tion, central nervous system (CNS) infections, acute or
families, and research
remote structural brain injury, acute metabolic imbalances,
and alcohol withdrawal.2 • To promote awareness of this condition and fos-
ter research efforts, we conveyed the First Inter-
In up to 20% of cases, however, this initial work-up
national NORSE and FIRES Symposium
may be unrevealing, and the clinician is left with the
difficulty of pinpointing one of the many uncommon • The adoption of a standardized terminology and
of a multidisciplinary multicenter strategy is
causes of SE.3,4 In the management of acute seizures
required to help research efforts and to improve
and SE, we invariably prioritize the control of seizures
patient care
over the determination and treatment of the underlying
cause. However, finding the etiology of SE has both
therapeutic and prognostic implications, perhaps even
more importantly when dealing with refractory SE. Diag- presence of a preceding febrile illness in most cases further
nostic and therapeutic delay contributes to poor outcome complicates the matter. This entity has received various
in a variety of diseases that can cause SE,5 and seizure names and acronyms in the past, such as new-onset refrac-
control might only be achieved provided the underlying tory status epilepticus (NORSE) in adults12–14 and idio-
cause is known and treated. With close to 200 uncom- pathic catastrophic epileptic encephalopathy,15 febrile
mon disorders that can cause SE,3 there is a need to infection or febrile illness-related epilepsy syndrome
define this clinical situation and to develop guidelines (FIRES),16,17 acute encephalitis with refractory repetitive
for a rational and efficient workup. partial seizures (AERRPS),18 or devastating epilepsy in
In a small but nonnegligible group of patients—mostly school-age children (DESC)19 in children. The lack of a
previously healthy young adults and children—an extensive unified terminology for these disorders prevents their early
diagnostic workup fails to reveal the cause of SE. This diagnosis, triggering unnecessary treatment; hampers com-
group may represent up to 60% of cases of de novo refrac- munication between clinicians and between clinicians and
tory SE.2,6 It is often misclassified as “possible encephali- families; and limits clinical and biological research.
tis” in epidemiological studies, as diagnostic criteria for
autoimmune and infectious encephalitis do not require the
formal identification of the causative antibody or patho- 2 | CONSENSUS DEFINITIONS OF
gen.7,8 Prolonged seizure activity can cloud consciousness NORSE AND FIRES (LAWRENCE J.
and alter cognition, and cause focal neurological deficits, HIRSCH)
as well transient magnetic resonance imaging (MRI) and
cerebrospinal fluid (CSF) changes,9–11 all carrying the risk To address this issue, a multinational expert panel set out
of being mistaken for evidence of encephalitis. The to standardize definitions of NORSE and FIRES. This was

done via emails, phone calls, and an in-person consensus with FIRES,16 whereas it is absent in one-third of NORSE
conference on April 5, 2017, in Salzburg, Austria, prior to cases.14 It is possible, however, that this dissimilarity could
the 6th Colloquium on Status Epilepticus and Acute Sei- be due simply to reporting bias (the parents of a sick child
zures. There were 18 panel members from 8 countries, are more likely to report symptoms than the sometimes dis-
including adult and pediatric experts in epilepsy, electroen- tant relatives of a sick adult) or publication bias (fever is a
cephalography (EEG), and neurocritical care. The confer- prerequisite for FIRES—even if not always clearly reported
ence was supported by The NORSE Institute (http://www. —while it is not necessary for NORSE). These differences
norseinstitute.org), and the definitions were endorsed by between NORSE and FIRES seem to be in large part due
the Critical Care EEG Monitoring Research Consortium to the use of arbitrary criteria (age groups, presence of a
(CCEMRC; https://www.acns.org/research/critical-care-eeg- preceding documented febrile illness) that are not backed
monitoring-research-consortium-ccemrc). up by solid scientific evidence and introduce selection and
Consensus definition of New-Onset Refractory Status reporting bias. Second, although there is a male predomi-
Epilepticus (NORSE): a clinical presentation, not a specific nance in FIRES in children, NORSE in adults more often
diagnosis, in a patient without active epilepsy or other pre- affects women.14,16 However, this does not exclude that
existing relevant neurological disorder, with new onset of FIRES and NORSE are the same condition, as changes in
refractory status epilepticus without a clear acute or active gender bias with age have been reported in other disorders.
structural, toxic, or metabolic cause. This includes patients Furthermore, in many other key aspects, NORSE and
with viral or autoimmune causes. If no cause is found after FIRES appear largely similar. Both conditions occur in
extensive evaluation, this is considered “cryptogenic patients without a previous history of epilepsy and often
NORSE” or “NORSE of unknown etiology.” present as a progressive build-up of seizures that evolve to
Consensus definition of Febrile Infection-Related Epi- prolonged refractory SE. Nonspecific CSF and imaging
lepsy Syndrome (FIRES): a subcategory of NORSE that findings are found in both with a similar frequency, and
requires a prior febrile infection, with fever starting cerebral biopsy, when available, does not provide any
between 2 weeks and 24 hours prior to onset of refractory specific findings that can distinguish one condition from
SE, with or without fever at onset of SE. This applies to the other.13 The outcome is similarly poor as well, with
all ages. There may or may not be fever at the time of severe neurological sequelae, mortality in up to one-fifth of
onset of SE. patients, and refractory epilepsy.
Complete definitions of these terms plus the definitions Hence, there have been arguments in favor of reconcil-
of Infantile Hemiconvulsion-Hemiplegia and Epilepsy syn- ing the 2 syndromes.21–23 By applying the same definition
drome (IHHE), refractory SE, and super-refractory SE are across the lifespan, we aim to facilitate inclusive research
available in a separate report in this issue of Epilepsia by and comparison between different age groups. Further elu-
Hirsch et al.20 cidation of the causes and natural history etiologies may
The rest of this article summarizes the other discussions permit further separation or merging of underlying condi-
that were held at the First International NORSE and FIRES tions in the future.
Symposium following the smaller, invitation-only consen-
sus definition conference. The first part describes recent
developments in the description and pathophysiology of 4 | PATHOPHYSIOLOGICAL
NORSE and FIRES. The second part presents ongoing HYPOTHESIS: A GENETICALLY
efforts to improve public advocacy, clinical research, and DETERMINED, POSTINFECTIOUS,
care of patients with these uncommon but devastating CYTOKINE-MEDIATED DISORDER?

3 | NORSE IN ADULTS AND FIRES Cryptogenic NORSE and FIRES are characterized by the
IN CHILDREN: SIMILAR OR rapidly progressive onset of seizures and encephalopathy
DIFFERENT CONDITIONS that evolve into prolonged superrefractory SE over a few
days. In FIRES, this is preceded by a minor febrile infec-
By consistently using the terms NORSE and FIRES in dif- tion. Unlike chronic epilepsy with explosive onset, the
ferent age groups (adults and children, respectively), the single episode of SE in NORSE and FIRES can last for
existing literature suggests that they represent different con- weeks and, unlike encephalitis, drug-resistant epilepsy fol-
ditions. Beyond the age distinction, available case series lows without a latent period.19,22 At first sight, crypto-
provide data pointing to 2 other possible differences genic NORSE and FIRES may appear to share some
between the 2 disorders. First, a preceding fever is the rule commonalities with well-described fever-sensitive epilepsy

syndromes, such as Dravet syndrome, or with inborn stop seizure activity in the acute phase, although seizures
errors of metabolism in which fever and infections may often recur as soon as they are discontinued, and there has
precipitate seizures, such as mitochondrial disorders. How- been no evidence that long-term outcomes were improved.
ever, in cryptogenic NORSE and FIRES, SE often starts Given the putative causal role of inflammation in crypto-
not during but after the febrile episode, and therefore after genic FIRES and NORSE, immune therapies have been
the main infectious and resulting metabolic stress. In addi- tried. These include first-line (eg, steroids, intravenous
tion, patients with cryptogenic NORSE and FIRES experi- immunoglobulins [IVIG], and plasma exchange) and sec-
ence only 1 episode of SE.19,22 These observations argue ond-line therapies (eg, tacrolimus, rituximab, cyclophos-
against a metabolic disease or a fever-sensitive epilepsy phamide, and anakinra), although the experience with the
syndrome. Furthermore, in a few tested cases, mutations latter is limited, as well as therapies with a broad action
were not found in the SCN1A, POLG1, and PCDH19 that may include an antiinflammatory component (keto-
genes.24 A unifying mechanism that could account for the genic diet [KD], cannabidiol, and hypothermia). Overall,
all the specific features of cryptogenic NORSE and there are 225 cases of cryptogenic FIRES and 101 cases of
FIRES is still lacking. It is, however, tempting to specu- cryptogenic NORSE reported in the literature of patients
late that it might be caused by a fulminant inflammatory who received immune therapies either in the acute or the
response in the CNS.25 An intrathecal overproduction of chronic phase (Table 1).12–14,16,19,30–37 No randomized con-
proinflammatory cytokines and chemokines has been trolled trial is available, and data come from single case
described in children with FIRES, and was not observed reports and small uncontrolled series, which are prone to
in the CSF of controls with other inflammatory and non- report bias. There is currently no consensus regarding the
inflammatory neurological conditions.26 Several of these use of immune therapies in NORSE, but they are nonethe-
molecules have proconvulsant activity. This accumulation less often used, including by some of the authors. Similar
could be the product of the activation of T cells, perivas- to autoimmune encephalitis, first-line immune therapies are
cular cells, and glia and could take several days, perhaps the most commonly used but typically show a low
explaining the latency between the febrile episode and the response rate (Table 1). Suggested dosages are presented in
onset of SE. However, it is currently unclear whether Table 1. Too little information is available on the
intrathecal inflammation is the cause or the consequence adequate dosage of other treatments to formulate any
of the prolonged episode of refractory SE (RSE), as con- recommendation.
trols with RSE of noninflammatory origin were not stud- The KD is an established treatment for drug-resistant
ied. Furthermore, whether this cytokine storm is sufficient epilepsy, with both anti-seizure and anti-inflammatory
to explain a long-lasting severe episode of SE is also effects. In animal models, it is associated with a reduction
unclear, and additional mechanisms such as mitochondrial of plasma levels of pro-inflammatory cytokines.38 There
dysfunction or synaptic plasticity may occur. Individual have been reports of a dramatic response (approximately
predisposition may be determined by allelic variations in 50%) to KD in children with FIRES, but this needs to be
HLA subtypes or cytokine pathways, as in other postin- confirmed in prospective controlled studies.39
fectious neurological disorders.27,28 Further studies to con- Cannabidiol (CBD) is a recent potential alternative ther-
firm these hypotheses are ongoing. apy in epilepsy and has been shown to improve seizure fre-
Given the rarity of the disease and the complexity of quency and duration in the acute or chronic phase of
the underlying mechanisms, further collaborative work, infection in 6 of 7 reported patients with FIRES.40
including a multinational clinical registry and biorepository Anakinra is a recombinant version of human interleu-
and partnership with immunology and genetic research kin-1 (Il-1) receptor antagonist, which inhibits the biolog-
groups, is required to confirm these preliminary hypothe- ical actions of Il-1 beta. Increased expression of Il-1 beta
ses. in microglia and astrocytes is observed in in various
forms of drug-resistant epilepsy. A single case has been
reported of a 32-month-old girl with FIRES who received
5 | THE ROLE OF IMMUNE 5 mg/kg twice daily.41 After 6 months of seizure free-
THERAPIES IN CRYPTOGENIC dom, weaning attempts to 1 daily dose were unsuccess-
NORSE AND FIRES (NICOLA ful. The drug was well tolerated and effective, leading to
SPECCHIO) a dramatic seizure reduction on 3 separate occasions in
the same patient; however, no long-term follow-up is
There is currently no specific therapy for cryptogenic available.42
FIRES and NORSE, and conventional antiseizure medica- Finally, therapeutic hypothermia exhibits neuroprotec-
tions show very limited success.14,16,29 Continuous intra- tive and anti-inflammatory properties in vivo after perinatal
venous anesthetics, including barbiturates, can temporarily asphyxia and adult cardiac arrest, by reducing

T A B L E 1 Summary of patients who receive immune therapies or therapies that might have an antiinflammatory effect
Cryptogenic FIRES (N = 225) Cryptogenic NORSE (N = 101)
Positive effects (some Positive effects (some
Number of cases only transient) Number of cases only transient)
Therapies Suggested dosage treatments (%) treatments (%)
Steroids IV methyldprednisolone 1000 mg per day 63 11 (17) 40 15 (38)
for 3-5 d (adults)
IV methyldprednisolone 10 to 30 mg/kg
(up to 1000 mg) per day for 3-5 d
Sometimes followed by oral prednisone
1 mg/kg per day
Intravenous 1.2 to 2 g/kg over 3-5 d 94 5 (5) 17 5 (30)
Ketogenic diet N/A 35 19 (54) 12 8 (67)
Plasmapheresis 3 to 5 exchanges, one every other day 18 2 (11) 15 6 (40)
Hypothermia N/A 5 3 (60) 4 2 (40)
Rituximab N/A 3 1 (33) 0 NA
Azathioprine N/A 1 0 (0) 0 NA
Tacrolimus N/A 1 0 (0) 0 NA
Cyclophosphamide N/A 1 0 (0) 0 NA

proinflammatory cytokine levels and protecting the integ- frequently observed. Whether or not these findings show
rity of the blood–brain barrier. In 2 cases of FIRES, moder- any specificity to NORSE and FIRES is still unclear, and
ate therapeutic hypothermia at 33°C resulted in fast and they deserve further study and confirmation, including in
sustained control of SE. the adult NORSE population and in larger multicenter


The diagnosis of FIRES and NORSE is typically given EMMERY, RIMA NABBOUT, AND
late, if at all, in a patient’s clinical course, which may NICOLAS GASPARD)
hinder clinical care and research. The development of a
specific diagnostic test for their early identification is The creation of a FIRES and NORSE registry poses several
needed. There is currently no available CSF or serological challenges. On the one hand, there is a need to collect in-
marker. Brain MRI may disclose suggestive findings,43 depth clinical details and to create a repository of biologi-
but they are usually absent in the early phase and repeat- cal samples. At the same time, FIRES and NORSE are rel-
ing imaging is not always practical. On the other hand, atively uncommon entities and a multicenter approach is
EEG can be performed early and continuously throughout required. The NORSE Institute is planning a prospective
the course of SE. In a retrospective analysis of children registry through 2 preexisting research networks, the
with FIRES, 3 commonalities were noted.44 First, seizures CCEMRC and the Pediatric Status Epilepticus Research
were initially brief and relatively infrequent, with a grad- Group (pSERG; http://www.pserg.org), which together
ual evolution to SE. Second, beta-delta complexes resem- comprise over 50 academic medical institutions. The reg-
bling extreme delta brush were observed. Finally, seizures istry initially aims to enroll 100 consecutive patients with
had a characteristic electrographic pattern, typically begin- cryptogenic NORSE (including FIRES) over 2 years. It
ning with prolonged focal fast activity, followed by the will collect clinical data, spanning from early critical care
gradual appearance of well-formed rhythmic spike or to long-term functional, cognitive and epilepsy outcome, as
spike-and-wave complexes. Shifting ictal activity was well as brain imaging, EEG, and biological samples (DNA,

serum, CSF, and brain tissue, whenever available). Partner- incomplete because it is a diagnosis of exclusion and there
ships with genetic and immunological experts have been are yet few empirical data. More effective communication
established. The registry will entail a heavy workload, lim- must begin at the doctor level. Doctors should share infor-
iting participation to a relatively small group of large medi- mation across institutions and areas of expertise. Because
cal centers. Data will be collected by clinicians during NORSE and FIRES are so uncommon, each specialist has
patient contacts, and long-term cognitive and quality-of-life treated only a limited number of patients. Sharing knowl-
endpoints will be investigated. The registry will also be edge by participating in meetings, inviting outside special-
restricted to a relatively narrow recruitment basis. ists, and fostering multidisciplinary communication and
To address these limitations, the NORSE Institute is collaboration is vital.
planning a family- and patient-based registry in partner- Doctors should also communicate fully with other
ship with the Paratonnerre association (http://associationpa medical teams within the hospital. This seems obvious,
ratonnerre.org). Paratonnerre is a European association but the crisis environment and the rotation schedules of
supporting children affected by FIRES. Its objectives are the medical teams make it difficult. Doctors can hold
the following: (1) to gather families and facilitate experi- regular, interdisciplinary programs within their hospitals
ence-sharing; (2) to inform about FIRES; (3) to represent to discuss the multifaceted challenges of diagnosing and
persons affected by FIRES; and (4) to encourage scien- treating NORSE and other disorders with the same level
tific research. Created in 2012, it now comprises 160 of complexity and uncertainty. Doctors should hold ongo-
individual members and 3 organizations (Fondation ing, candid medical conferences with the family. General
L’Oreal—Airbus staff council—Desautel), mobilized recommendations about physician-family interactions
around 20 children affected by FIRES in France. The apply.45 The team should designate case leaders to coor-
association is also in contact with 150 families world- dinate and integrate patient care and communication. The
wide. With the support of a scientific committee, Para- team itself should include members of the intensive care
tonnerre offers to coordinate a working group with unit (ICU) and epilepsy teams, as well as nurses, social
patients, clinicians, and researchers interested in develop- workers, and palliative care specialists. Conferences
ing a patient- and family-oriented registry of individuals should be held periodically because the families will not
with NORSE and FIRES. Families and patients have a be able to comprehend and accept all the information at
strong desire to better understand these syndromes and once. Moreover, the patient’s condition may change sig-
are thus eager to contribute to such a registry. On the nificantly over time.
other hand, doctors and researchers worldwide strive to Conferences should be held in a quiet, private room.
increase scientific knowledge on these rare syndromes, During conversations, doctors should discuss the working
usually with limited resources. Concerted action between diagnosis and the prognosis, using layman’s language and
all stakeholders is now critical to make such a registry openly acknowledging the uncertainty of the diagnosis and
exist. Coordination is indeed key to build on existing prognosis, discuss the treatment plan as well as the alterna-
experiences and achievements, to make sure that the reg- tives, outline the trajectory of the infection while still in
istry will match expectations and come as a user-friendly the hospital, and well before discharge, outline what fami-
and accessible tool, based on the European Commission lies might expect when they leave the hospital. It should
Expert Group on Rare Diseases (ECEGRD) core recom- never be assumed that someone else on the team has
mendations, as well as to facilitate fundraising for the already informed the family. Some doctors may be reluc-
registry itself and for subsequent research. Today, there tant to adopt this depth of communication because it is
seems to be a momentum: the creation of the EPICARE time-consuming and uncomfortable. But as uncomfortable
ERN (European Network of Reference for Rare Epilep- as these discussions are, there are greater burdens that
sies) and the collaboration with the NORSE Institute result from silence. Obviously, families bear the greatest
coincide to make the development of the NORSE and burden. Families need time to prepare themselves for death
FIRES registry more attainable than ever. or to begin a new life with their loved ones who most
likely will be very different from whom they were before.
Families need to know the name of the disorder. Just as
8 | COMMUNICATING ABOUT scientists need consensus definitions around which to orga-
NORSE AND FIRES (NORA WONG) nize their thinking and research, families need to know
what hurt their loved ones. Without a name, there is no
Although we attempt to unravel the causes of NORSE and closure. Knowing the name of the disorder allows families
FIRES and improve patient care, we must build better ways to find a community in which to share their grief, pool
to communicate with colleagues, patients, and families. their knowledge, and to direct their actions and their
Communication about NORSE is often delayed and resources. It is the community of patients and families that

will participate in medical registries. It is the community of 6. Jayalakshmi S, Vooturi S, Sahu S, et al. Causes and outcomes of
families that will fund research. Professionals and families new onset status epilepticus and predictors of refractoriness to
can find NORSE information at www.norseinstitute.org. therapy. J Clin Neurosci. 2016;26:89–94.
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None of the authors has any conflict of interest to disclose.
a multicenter study on 77 children. Epilepsia. 2011;52:1956–65.
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Claudine Sculier http://orcid.org/0000-0001-5500-4090
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Raquel Farias-Moeller http://orcid.org/0000-0001-8717-
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