Zeitschrift für

Epileptologie
Leitthema
Z. Epileptol. 2022 · 35:322–331
https://doi.org/10.1007/s10309-022-00533-5
Accepted: 23 September 2022
FIRES—Pathophysiology,
Published online: 17 November 2022
© The Author(s) 2022 therapeutical approach, and
outcome
Diana Reppucci1 · Alexandre N. Datta2,3
1
Department of Pediatric Intensive Care, University Children’s Hospital Basel, Basel, Switzerland
2
Department of Pediatric Neurology and Developmental Medicine, University Children’s Hospital Basel,
Basel, Switzerland
3
Department of Clinical Research, University of Basel, Basel, Switzerland

Abstract

In this article Background: The acronym FIRES stands for febrile infection-related epileptic syndrome,
which is a rare epileptic syndrome in the pediatric population. The initial presentation
– Introduction of FIRES is similar to febrile seizures (FS). Both start after a febrile episode; however,
– Definition in FIRES the epileptic seizure evolves into a super refractory status epilepticus within
– Incidence days despite appropriate treatment. FIRES needs to be diagnosed early and treated
– Clinical features by a multidisciplinary team to control the status epilepticus (SE) as fast as possible.
– Diagnosis Limiting the duration of the SE is paramount for the prevention of catastrophic
– Etiology sequelae such as severe neurologic disabilities or even death.
– Differential diagnosis Objective/Conclusion: We describe possible pathophysiological mechanisms and
– Therapeutic options summarize important clinical features of FIRES. The aim of this review is to raise
Primary treatment goal and referral awareness, foster early recognition and improve neurologic long-term outcomes.
·
to specialized center Acute phase: Moreover, we propose a diagnostic approach and list therapeutic options providing an
·
suppressing seizures First-line and algorithm.
·
second-line treatments Alternative
treatment options (see . Fig. 1 algorithm Keywords

chronic phase
·
graph: treatment) Treatment during FIRES · Febrile seizure · Super refractory status epilepticus · Catastrophic outcome · Death

– Practical conclusion

Febrile infection-related epileptic syn- Introduction

drome (FIRES) is a rare epileptic syn-
drome in the pediatric population with
an estimated incidence of 1 in 1 million.
The initial presentation of FIRES is sim-
ilar to febrile seizures (FS). In contrast
to mostly benign and self-limiting FS,
in patients with FIRES, seizures evolve
into a refractory status epilepticus. The
course of the disease is therefore com-
plicated and the outcome much worse.
Here, we highlight possible pathophys-
iological mechanisms and the clinical
symptoms, propose a diagnostic ap-
proach, and review the therapeutic op-
tions. Our aim is to raise awareness and
foster early recognition of FIRES in order
to improve neurologic outcome.
Scan QR code & read article online
More than 60 years ago, 16 cases [31] of
acute encephalopathy of obscure origin
in infants and children after a febrile
infection were described for the first time.
During the following years similar cases
using different names were published:
devastating epileptic encephalopathy in
school-aged children (DESC); acute en-
cephalitis with refractory, repetitive partial
seizures (AERRPS); or catastrophic epilep-
tic encephalopathy presenting with acute
onset of intractable seizures [23]. The
lack of standard terminology made early
recognition of the disease difficult, which
resulted in delayed diagnosis.
Definition
In 2010 the ACRONYM FIRES was coined by
a German group [41] and 8 years later an

322 Zeitschrift für Epileptologie 4 · 2022

 History:
• Previously healthy

HISTORY
• all ages (peak school age)
• no gender predilection
• no family hx of epilepsy

Current hx: febrile illness 2 weeks to 24 h ago

At Emergency Department:
• Recurrent brief seizures
• +/- Fever
PRESENTATION

=> evolving into SE refractory to conventional ASD

Definition FIRES
Febrile infection-related epilepsy syndrome is a
subcategory of NORSE that requires a prior febrile
suspect infection, with fever starting between 2 weeks

Leitthema
and 24 hours prior to onset of refractory status
FIRES ? epilepticus, with or without fever at onset of SE.

EEG

MRI Brain

Lumbar puncture
• Cell count: normal to mild pleocytosis
DIAGNOSIS

• Culture and encephalitis panel negative

• Cytokines, Chemokines

Serum: infectious agents, metabolic, cytokines, chemokines

Autoimmune-antibodies

Genetic
Consider Biopsy
t
1st line Immuno-Treatment:

ASD Steroids
Methylprednisolone
(multiple) 10-30 mg/kg/d 3-5 days

IVIG Simultaneously consider

0.4 g/kg or 1.2 to 2 g/kg 2-5 days alternative treatment:
Therapeutic Hypothermia
Afterward Consider PLEX
TREATMENT

(3-5 exchanges on alternate day)

NO
improvement

BCS 2nd line Immuno-Treatment:

• Cycle duration 7 days
• may be repeated
Anakinra (IL-1-RA)
KETOGENIC 4:1 DIET

up to 5 mg/kg bid

Tocilizumab (IL-6-R)
4 mg/kg sc per week Alternative treatment:
MgSO4, Ketamine, Lidocaine,
Single case reports inhalational anesthetics, ECT
Rituximab, Cyclophosphamide,
Tacrolimus

CBD Intensive Care Unit

• Mechanical Ventilation
• Consider early tracheostomy!
MONITORING

• Sedation and Anti-Seizure Effect (Midazolam, Propofol)

Continuous EEG / AEG

Repeat MRI Brain

Adverse Drug Effects?

NVS Early Rehabilitation:

• Physiotherapy / Speech therapy / Ergotherapy

Fig. 1 8 Algorithm graph for FIRES. ASD antiseizure drugs, BCS burst coma suppression, CBD cannabidiol, hx history, NVS va-
gal nerve stimulation, IVIG immunoglobulin, PLEX plasma exchange, ECT electroconvulsive therapy, SE status epilepticus

Zeitschrift für Epileptologie 4 · 2022 323

Leitthema
Table 1 Studies of FIRES patients published from 1961 to 2022.Before the ACRONYM “FIRES” was set in 2010 several terms were used
Author Year Patients (N) Gender Comments
Lyon et al. 1961 16 No data Firstly described as
the acute encephalopathies of obscure origin in infants and children
Sahin M et al. 2001 8 No data Refractory status epilepticus
Ito H et al. 2002 1 M AERRPS, autoantibody to glutamate receptor GluE2
Baxter P et al. 2003 6 M>W Idiopathic catastrophic epileptic encephalopathy presenting with
acute-onset intractable status
Kramer U et al. 2005 8 No data Severe Refractory Status Epilepticus
Mikaeloff Y et al. 2006 14 M>W DESC
Okanishi T et al. 2007 1 M AERRPS
Shyu CS et al. 2008 14 M=W AERRPS
Lin JJ et al. 2009 9 M>W AERRPS, specifically therapeutic hypothermia
Fugate J et al. 2010 1 W Refractory SE, isoflurane therapy
Van Baalen et al. 2010 22 M>W ACRONYM “FIRES” firstly used
Sakuma H et al. 2010 29 M>W AERRPS
Specchio N et al. 2010 8 M>W AERRPS
Specchio N et al. 2011 1 W Mimicking FIRES, PCDH19 gene mutation
Okumura A et al. 2011 2 W AERRPS
Geva-Dayan K et al. 2012 9 No data Severe childhood epilepsy including FIRES
Howell K et al. 2012 7 M FIRES, long-term follow-up
Lin JJ et al. 2012 2 M=W FIRES, specifically therapeutic hypothermia
Kobayashi K et al. 2012 1 M AERRPS, SCN2A mutation
Wakamoto H et al. 2012 1 M AERRPS, CSF: antibodies against the GluRe2 subunit
Caraballo R et al. 2013 12 M>W FIRES
Nozaki F et al. 2013 1 M FIRES, reversible splenic lesion
Singh R et al. 2014 2 M=W FIRES, specifically ketogenic diet
Byler D et al. 2014 1 M FIRES
Cherian P et al. 2014 1 No data FIRES
Matsuzono K et al. 2014 1 M AERRPS, ketogenic diet
Ueda Ret al. 2015 6 M>W AERRPS, effect of levetiracetam
Capizzi G et al. 2015 1 W FIRES, specifically lidocaine treatment
Chou I et al. 2015 1 W FIRES, specifically lidocaine and MgSO4 therapy
Ogawa C et al. 2016 1 M AERRPS, autopsy findings
Sato Y et al. 2016 1 M AERRPS; CSF: anti-glutamate receptor e2 antibodies
Uchida T et al. 2016 1 M AERRPS
Kenney-Jung D et al. 2016 1 W FIRES, specifically anakinra therapy
Alparslan C et al. 2017 1 M FIRES, specifically immunomodulation therapy
Miras Veiga A et al. 2017 1 M FIRES, electroconvulsive therapy
Gofshteyn J et al. 2017 7 M>W FIRES, specifically cannabidiol treatment
Kaufman T et al. 2017 1 M FIRES and Moyamoya
Fox Ket al. 2017 1 W FIRES
James A et al. 2017 1 W FIRES

international group of experts proposed
a consensus definition [14]. FIRES was de-
fined as a subcategory of new-onset refrac-
tory status epilepticus (NORSE). In contrast
to NORSE, patients suffering from FIRES al-
ways present with a preceding febrile in-
fection starting between 2 weeks and 24 h
prior to onset of SE (see . Fig. 1 Algorithm
Graph: History), with or without fever at
onset of SE [14]. Hence, fever remains
a sine qua non for the diagnosis. Nev-
ertheless, most patients with NORSE also
present with fever [10, 14] and in 60% of
NORSE patients a mild preceding infection
is present. In the past the term NORSE was
reserved for adults and FIRES for children
with fever. Today, the diagnosis FIRES is
used across all ages.
Incidence
The annual incidence of FIRES in a German
population was estimated as 1 case per
1,000,000 [42]. In a multicenter American
study, 16 out of 92 patients with refractory
SE and no previous history of epilepsy met
the criteria of FIRES [37]. In smaller coun-
tries like Switzerland and Austria, the num-

324 Zeitschrift für Epileptologie 4 · 2022

 Table 1 (Continued)
Author
CONSENSUS DEFINITION for FIRES and NORSE in 2018 by Hirsch LJ et al. Epilepsia 59:739–744
Tan AP et al.
Lee HF et al.
Caputo D et al.
Dahl A et al.
Peng P et al.
Arayakarnkul P et al.
L’Erario M et al.
Wen Jing Li et al.
Lou Tian et al.
Serrano A et al.
Year Patients (N) Gender Comments
2018 1 W FIRES, specifically with multifocal subcortical infarcts
2018 29 M<W FIRES, specifically therapeutic complication and follow-up
2018 1 W FIRES, specifically with GABAA R antibodies
2018 1 W Drug-related eosinophilia with systemic symptoms in FIRES
2019 7 M>W FIRES, ketogenic diet
2019 3 M Pediatric super-refractory status epilepticus
2021 1 M FIRES, specifically sevoflurane, PLEX, anakinra
2021 1 M FIRES; specifically ketogenic diet in acute phase
2021 1 M FIRES, vagus nerve stimulation
2022 5 M<W FIRES, tocilizumab and anakinra in the chronic phase

Leitthema
Acampora R et al. 2022 1 M FIRES in a young adult
Kurimoto T et al. 2022 1 M FIRES
Jain V et al. 2022 7 M>W FIRES
AERRPS acute encephalitis with refractory, repetitive partial seizures, DESC devastating epileptic encephalopathy in school-aged children, PLEX plasma
exchange

ber of FIRES patients is limited to 5–8 cases
per year. For better guidance, an algorithm
may support the treating team in not only
makingthediagnosis butalso choosingthe
best treatment option. So far more than
220 cases have been published (. Table 1:
FIRES cases from 1961 to 2022).
Clinical features
The syndrome starts with a febrile illness
between 2 weeks and 24 h prior to onset
of SE in previously healthy children (see
Algorithm Graph: History). Unlike FIRES,
children with FS [37] are younger and the
time onset between fever and epileptic
seizure is usually less than 24 h. Moreover,
body temperature in FIRES is lower, the SE
lasts longer (more than 48 h) and is usu-
ally refractory to multiple antiseizure drugs
(ASD). FIRES mostly occurs in children at
a median age of 6–8 years [23, 32, 43].
To date, no affected siblings have been
reported. Rarely family members have
epilepsy [20, 41]. FIRES is characterized by
three phases. A prodromal phase lasting
for 13 days with febrile illness; mostly of the
respiratory tract followed by gastrointesti-
nal infection [20, 23]. Beyond that seizures
develop and get more frequent, evolving
into refractory SE (see . Fig. 1 Algorithm
Graph: Clinical Presentation). At the time
of SE, most FIRES children have recovered
from their initial illness. Fever might still
be present but often a fever-free interval
occurs. The third phase is a lifelong chronic
stage with patients being on multiple ASD
and having different grades of disability.
Seizures are usually multifocal or general-
ized [43] with full or impaired awareness
evolving into super refractory SE count-
ing up to several hundred seizures a day.
Clinically, there is a frontotemporal pre-
dominance in both cerebral hemispheres
[23, 41]. Common EEG features as possi-
ble biomarkers for early recognition have
been published [8]:
1. Initial seizures are brief, infrequent and
gradually evolve to SE.
2. Beta delta complexes resemble ex-
treme delta brushes.
3. Seizures generally begin with pro-
longed focal (. Fig. 2) fast activity,
followed by gradual appearance of
well-formed rhythmic spikes or spike
wave complexes (. Fig. 3a–c).
Diagnosis
FIRES remains a clinical diagnosis because
no biological markers or genetic testing
exists. Ideally, it should be recognized
within the first 48–72 h. FIRES is a diagno-
sis of exclusion hence extensive work-up
is needed (see . Fig. 1 Algorithm Graph:
Diagnosis) to rule out other differential
diagnoses such as epilepsy, encephalitis,
and encephalopathy [43]. The prerequi-
sites for the diagnosis include no central
nervous system infection or autoimmune
encephalitis, no structural cause, and the
absence of a genetic condition [21]. To
encourage early recognition, several diag-
nostic flowcharts have been proposed ([20,
21, 34]; see . Fig. 1 Algorithm graph: Di-
agnosis). The CSF is usually unremarkable
with few exemptions showing mild pleocy-
tosis [20, 43] but no pathogen [14, 20, 42].
Initial brain magnetic resonance imaging
(MRI) is normal in more than half of the
cases [5, 20, 23]. During the acute stage,
25% [5] have signal abnormalities in the
temporal lobe and rarely other abnormali-
ties in the basal ganglia and in the thalami.
Over time there is a progression to diffuse
atrophy of the cerebrum and cerebellum
with sclerosis of the hippocampi [5, 20, 43]
and subsequent ventriculomegaly. Brain
biopsy is rarely performed showing mostly
gliosis and seldom leptomeningeal inflam-
matory infiltrates [23, 41]. Whole-exome
and HLA sequencing in FIRES did not iden-
tify any pathogenic variant in established
genes for epilepsies or any prominent HLA
alleles [13].
Etiology
The etiology of FIRES remains unknown.
Over the past few decades, the follow-
ing hypotheses have been discussed:
(a) infections, (b) autoimmune-mediated,
(c) inflammation-mediated, (d) genetic,
or (e) metabolic [14, 20, 23, 43].

Zeitschrift für Epileptologie 4 · 2022 325

Leitthema
Fig. 2 8 aEEG: Series of short focal seizures on the right (red arrow) and on the left (blue arrow) hemisphere
A few cases tested positive for my-
coplasma or adenovirus, although these
pathogens were not primary responsible
for the current disease; however, in most of
the cases no pathogens are found. Further-
more, CSF protein might also be increased
as a breakdown of the blood–brain barrier
(BBB). Infection as the underlying reason
for FIRES therefore seems unlikely.
Elevated autoimmune antibodies have
been reported in FIRES cases [18, 20, 23]
suggesting an autoimmune-mediated ori-
gin [43]. However, these patients might
instead fit the diagnosis of NORSE [10].
One of the largest systematic reviews [20]
found 11.4% of the patients to be positive
for either anti-glutamate receptor antibod-
ies or anti-GAD antibody and IL6/IL8 in CSF.
Single case reports detected PCDH19, anti-
SMA, and SCN2A [20]. The brief time gap
between febrile illness and SE [23] and the
disappointing response to immunother-
apy [20, 41, 43] does not support the
aforementioned theory.
The time delay [14] is more sugges-
tive of a post-infectious triggering pro-
cess than an infectious disease itself [23].
An inflammation-mediated mechanism as
the leading process was also hypothesized
[20, 23, 41]; however, a lack of response to
immune modulators [43] and the absence
of inflammation on CSF, MRI, and brain
biopsy speaks against it.
Proinflammatory molecules (cytokines,
chemokines) during febrile illness might
lower the seizure threshold by modifying
ion channel functions and promoting neu-
ronal excitability with a certain delay [23,
43]. These molecules prime the activation
of innate immunity mechanisms in glia
cells, neurons, and cellular components
of the BBB in seizure-prone areas, giv-
ing rise to a neuroinflammatory cascade.
This process reflects the aforementioned
326 Zeitschrift für Epileptologie 4 · 2022
time delay. In short, FIRES represents an
inflammatory but not autoimmune-medi-
ated encephalopathy with an immune re-
sponse leading to intractable seizures [43].
An imbalance between pro- and anti-in-
flammatory molecules with increased in-
trathecal cytokines and chemokines has
been postulated for the time delay [23,
43].
A double hit process between (a) an im-
mune response to a febrile illness affecting
the brain and (b) an intrinsic predisposition
toward an auto-sustaining epileptogenic
process was later proposed [38]. Themech-
anistic model of epileptogenesis for FIRES
includes a systemic infection that activates
the immune system. This again releases
pro-inflammatory molecules and lowers
seizure threshold. Then, SE not only re-
leases pro-inflammatory cells, turning into
a vicious circle, but also leads to chronic
tissue damage ending in chronic epilepsy.
Seizures trigger neuroinflammation and
contribute to more seizure activities. This
acts concomitantly to an acquired or ge-
netic predisposed factor.
FIRES shows a proinflammatory alter-
ation in CSF cytokine profiles with elevated
interleukin IL-6, C-X-X motif chemokine
ligand 8 (CXCL8), and C-C motif ligand
L3 and 4 (CCL4 and CCL3; [11, 20, 22]).
The IL-6 was more elevated in CSF than
in serum [11], suggesting a CNS-specific
inflammation. It remains unclear whether
this alteration is primary or secondary to
SE. The proinflammatory cytokine IL-1β
is upregulated in brain tissue from drug-
resistant epilepsy but not consistently el-
evated in CSF or serum [20]. The clinical
utility of these cytokines in predicting re-
sponse to immune therapy needs to be
studied further.
Inconsistently elevated IL-1 receptor
antagonist (IL-1RA) levels in serum and
CSF of FIRES means that IL-1RA is function-
ally compromised [4]. The IL-1RA gene
mutations may play a role as a predispos-
ing factor. In contrast to FIRES, a reduced
level of IL-1RA was found in febrile SE,
which might explain a genetic involve-
ment in the production and function of
this specific cytokine of FIRES.
An autoinflammatory thesis by an ex-
cessive activation of the microglial NLRP3
inflammasome /IL1 axis creating a proin-
flammatory and proconvulsive milieu has
been discussed [29]. This might provoke
a vicious cycle between inflammation and
seizures. Children with FIRES also have
impaired TLR3, TLR4, TLR7/8, and TLR9
responses that are related to weakened
phagocytosis and lower T-regulatory cells
[16]. These patients may benefit from im-
munomodulatory therapy (steroids, intra-
venous immunoglobulins [IVIG]).
Differential diagnosis
Several differential diagnoses should be
taken into consideration: FS, infectious en-
cephalitis, posterior reversible encephalo-
pathic syndrome (PRES), Dravet syndrome,
familial acute necrotizing encephalopathy
(ANE1) associated with a ran-binding pro-
tein2 (RNP2) mutation [27], Hashimoto’s
disease, Alpers disease, and metabolic dis-
eases [43]. To rule out some of these diag-
noses, diagnostic tests are performed such
as lumbar puncture, metabolic screening,
genetic testing, thyroid hormone, and neu-
roimaging (see . Fig. 1 Algorithm Graph:
Diagnosis). The biphasic course and the re-
fractory or rather challenging SE of FIRES
patients makes the diagnosis of an en-
cephalitis improbable. PCDH19 epilepsy
can mimic FIRES [20] but can be distin-
guished by age, gender (usually younger
and females), and by a good response
 Leitthema
a

Fig. 3 8 a aEEG: Delta brushes in FIRES: paroxysmal beta–delta complex consisting of 15–18-Hz beta activity superimposed
over 1–3 Hz delta (black arrows). b aEEG: Beginning of a right hemispheric seizure (red arrow) and later a left hemispheric
seizure (blue arrow). c aEEG: Continuation of both right (red arrow) and left (blue arrow) independent focal seizures

Zeitschrift für Epileptologie 4 · 2022 327

Leitthema
to intravenous benzodiazepine. In both,
a preceding viral illness can occur but
PCDH19-affected children are character-
ized by a predominance of autism [23].
DRAVET syndrome shares similarities with
FIRES but occurs much earlier in life, usually
before the age of 1 year. In contrast to FIRES
patients [35] who do not have a SCNA1
mutation, 75–80% of DRAVET patients are
positive for the mutation [12, 35]. They of-
ten present with cluster of seizures rather
than SE [14] with a normal EEG in the first
2 years. An intellectual disability was also
reported after 1–3 years. In cases of POLG1
mutation, seizures are occipital and have
a unilateral predominance in contrast to
FIRES where seizure activity is frontotem-
poral and in both cerebral hemispheres
[23, 42]. In summary, SCNA1-, PDCH19-,
and POLG1-associated epilepsies have an
earlier age of onset and SE is less severe.
FIRES remains a diagnosis of exclusion.
To rule out the aforementioned diseases,
an extensive work-up including blood and
CSF samples for infectious, autoimmune,
metabolic, and genetic testing is required
(see . Fig. 1 Algorithm Graph: Diagnosis).
Genetic testing normally takes some time,
and therefore at the beginning children are
treated independently of these results. In
previous published case reports, however,
genetic testing is often missing [20]. As
there is still no specific biomarker for its
diagnosis, the population might still be
heterogenous.
Therapeutic options
Primary treatment goal and referral
to specialized center
Today there is still no specific treatment
available since evidence is lacking in guid-
ing the choice, dosing, and timing [11,
33]. For each individual patient the best
therapeutic option must be discovered by
perhaps even trying several drugs with-
out getting any effect. Primary goal of
treatment [20, 33, 34, 37] is to control
the SE and to avoid iatrogenic complica-
tions. Affected children should be referred
to a specialized center with a multidisci-
plinary team of neuropediatricians, inten-
sivists, neuroradiologists, and pharmacol-
ogists. Hospitalization time can vary from
14 to 208 days [25]. Most children need
328 Zeitschrift für Epileptologie 4 · 2022
mechanical ventilation (median duration:
41 days; [23, 25]) and are admitted to the
intensive care unit with a median stay from
20 to 40 days [37].
Acute phase: suppressing seizures
The acute phase is the most frustrating
and vulnerable one for family members
and the medical team. It also impacts the
long-term outcome.
The fundamental approach is to sup-
press clinical and subclinical epileptic
seizures by the adjustment of first- and
second-line ASD (see . Fig. 1 Algorithm
Graph: Treatment) based on continuous
EEG. Up to four to six ASD per day are often
insufficient to stop seizures. Common re-
ported adverse events of ASD are hepatic
dysfunction and DRESS [20]. One third of
children [10] end up requiring multiple
anesthetics to achieve seizure control as
conventional ASD are not enough [11,
23]. A high dose of barbiturate to induce
burst coma suppression (BCS) seems to
be the only effective therapeutic option
[20, 23]. Multiple cycles up to 7 days are
usually required [11, 20] and after taper-
ing, seizures often reoccur. Commonly
used anesthetics are midazolam infusion,
propofol, thiopentone, pentobarbital, and
ketamine. Prolonged burst suppression
is associated with longer ICU stay, intu-
bation, higher rate of complications, and
worst cognitive outcome [23, 39]. Poten-
tial serious side effects of barbiturate such
as hypotension, acidosis, infection, ileus,
and change in potassium concentration
must be monitored. Due to awareness of
propofol infusion syndrome, this alterna-
tive option has been pushed to the back
[2].
First-line and second-line treatments
Anti-inflammatory drugs are subdivided
into first line (steroid, IVIG and PLEX) and
second line (anakinra, cyclophosphamide,
rituximab; [11, 20, 33]) showing mixed
results [20, 43].
First-line treatment (see . Fig. 1
algorithm graph: treatment)
Dosage recommendations are: steroid
10–30 mg/kg/day for 3–5 days, IVIG
0.4–2 g/kg over 3–5 days, and plasma
exchange (PLEX) 2–4 exchanges on every
other day [11, 20, 38]. Ritter et al. [34]
suggest starting with i.v. methylpred-
nisolone, then PLEX, followed by IVIG if
there is no improvement. A treatment
proposal from the latest workshop [21]
agreed to start with methylprednisolone
and/or IVIG. Starting simultaneously [20,
34, 43] with pulse steroids and ketogenic
diet (KD) statistically improves outcome
compared to PLEX and IVIG. The patient
is contemporaneously on multiple ASD.
Even if immunosuppressive treatments
are applied early among FIRES, they show
disappointing effects [14].
If no improvement after first-line
treatment
If no improvement is noted, second-
line treatment such as with anakinra
can be administered for a minimum of
3–4 weeks. Whereas immune modulators
such as tocilizumab or canakinumab may
be considered after persisting seizures de-
spite therapy with anakinra. Drugs were
allocated to categories of effective (KD,
cannabidiol, phenobarbital, clobazam)
versus partial or ineffective (perampanel,
vagal nerve stimulation [VNS], lacosamide)
after SE [20]. As burst suppression is as-
sociated with worse outcome, GABAergic
therapy, immune therapy, mild hypother-
mia, and KD are recommended during
the acute phase.
Ketogenic diet
Ketogenic diet was shown to have a dra-
matic efficacy in FIRES since it is anti-in-
flammatory and anticonvulsant for acute
and long-term epilepsy [1, 20]. In 2010,
a positive response of a 4:1 KD was first
achieved after an onset of 4–6 days and
confirmed later by weaning off anesthetics
within 15 days [14, 20]. This effect [20, 43]
could not be replicated in the subsequent
study. It remains unclear why KD is effi-
cacious in FIRES. Nevertheless, KD should
be considered as first-line treatment and
started early [20, 21, 43] with close moni-
toring of lipids and liver function [8]. The
concomitant use of propofol and KD [2]
remains a contraindication.
Therapeutic hypothermia
Since fever exacerbates seizure activity,
controlling body temperature with thera-
peutic hypothermia (TH) may be beneficial
to suppress convulsion [23]. By protecting
the BBB integrity and reducing pro-inflam-
matory cytokines, TH may work toward the
control of SE [11]. In a retrospective Tai-
wanese [17] study, seven patients with
FIRES were managed for a few days with
hypothermia (34–35°) and showed a signif-
icantly shorter duration of seizures, a better
long-term outcome, and lower incidence
of later refractory chronic epilepsy. Com-
plications of hypothermia were bradycar-
dia and electrolyte imbalance. Only two
FIRES patients treated [20] with moder-
ate hypothermia showed mild cognitive
impairment.
Other adjunctive non-medical
options
Other adjunctive non-medical options in-
clude VNS and electroconvulsive therapy
(ECT). In DRAVET VNS revealed a seizure
reduction of more than 50% in nearly
half of the patients [6]. Similar results
were confirmed in a pediatric retrospec-
tive study [7] of more than 140 children.
Observed VNS complications entail hoarse-
Hier steht eine Anzeige.
K
ness, deep infection requiring device re-
moval, pneumothorax, and superficial in-
fections. In FIRES, to date one patient
has reached seizure control with VNS af-
ter 42 days [30]. A toddler underwent
ECT and needed 14 sessions of progres-
sive doses ranging from 40 to 200 J to be-
come seizure free. At 1 year follow-up, she
had severe retardation and diffuse atrophy.
[20]. Six FIRES patients were treated with
add-on intrathecal steroids after measur-
ing cytokines before and after treatment
[15]. Before treatment, several levels of
cytokines and chemokines were elevated,
although only CXLC10 and neopterin de-
creased after dexamethasone. After a me-
dian of 5.5 days, anesthetics could be
weaned off, hence leading to a reduc-
tion in the ICU stay and the duration of
intubation.
Second-line treatment (see . Fig. 1
algorithm graph: treatment)
In an international cohort, 25 FIRES pa-
tients [24] were treated with anakinra to
achieve control of seizure after other treat-
ments had failed. Anakinra was started at
a median of 20 days after seizure onset
with a dose of 3–5 mg/kg/day for 1 day
up to 420 days. In almost three quarters
of patients, a seizure reduction of over
50% was observed. As a recombinant
analogue of the human endogenous an-
tagonist of IL-1 receptor type 1, it inhibits
IL-1B (proinflammatory cytokine), which is
involved in autoinflammatory disease [43].
One case report showed normalization in
IL-8 and IL-6 levels along with a reduction
in seizure frequencies after anakinra [20].
Because its association with a shorter du-
Leitthema
ration of mechanical ventilation, length of
ICU/hospital stay, and seizure reduction,
it should be implemented early if first-
line medication fails [21, 24, 44]. Known
adverse events are infection, DRESS, and
cytopenia (neutropenia). The beneficial
response of anakinra supports a hyperac-
tive IL-1-beta activity and/or functional
IL-1ra deficiency as potential causes of
FIRES. Anakinra has also been effective
during the chronic phase [24] Neverthe-
less, seizures reoccurred after stopping
the drug. Another second-line drug op-
tion is tocilizumab, a humanized mono-

clonal antibody IL-6 receptor [19] showing
anti- and pro-seizures effects [9]. In FIRES
[3], two children treated with tocilizumab
had a positive response. Also in NORSE,
six of seven patients reached resolution
of SE within 2–10 days after 2 weeks of
treatment [19] and IL-6 levels in CSF and
serum normalized. Reported side effects
included leukopenia and severe infections
[19, 26]. The IL-6 concentration may be
increased in seizures but its role in ictogen-
esis remains unclear. Tocilizumab does not
cross the BBB, but prolonged seizures may
disrupt this and increase its permeability.
It remains unclear whether inflammation is
primary or secondary to seizures. In FIRES,
inflammatory cytokines and interleukins
are superior compared to in afebrile SE
and refractory epilepsies, supporting the
presence of neuroinflammation [20, 22].
Evidence taken from the febrile SE litera-
ture suggests a possible correlation with
outcomes [40].
Alternative treatment options (see
. Fig. 1 algorithm graph: treatment)
Continuous magnesium-sulfate infusion
[43] up to 30 mg/kg/h used as rescue
treatment in two FIRES cases showed de-
creased seizure frequency in one of them.
Other single cases have been published
on drugs such as perampanel, lidocaine
infusion, and ketamine infusion [20]. It
remains elusive if the effect of perampanel
is coincidental or normal to the disease
course [28].
Treatment during chronic phase
The chronic phase of FIRES resembles the
“difficult to treat” epilepsy, and children
rarely become seizure free. Cannabidiol
and anakinra are recommended for this
phase [24, 43]. By decreasing glutamate
and gamma-aminobutyric acid synaptic
transmission in the brain, cannabidiol also
showed an improvement in seizure fre-
quency and duration during the acute
phase [11]. Other options involve ritux-
imab and epilepsy surgery. Each drug
or therapeutic modality is added on an
already established therapy [26]. The con-
comitant use of different treatment modal-
ities and their questionable effectiveness
330 Zeitschrift für Epileptologie 4 · 2022
Zusammenfassung
FIRES – Pathophysiologie, therapeutischer Ansatz und Folgen
Hintergrund: Das Akronym FIRES steht für „febrile infection-related epileptic
syndrome“ und gehört zu den seltenen Epilepsiesyndromen im Kindesalter. Wie bei
Fieberkrämpfen (FK) kommt es auch bei FIRES initial zu einem fieberassoziierten Anfall,
der innerhalb von wenigen Tagen zu einem supertherapierefraktären Status epilepticus
(SE) führt – trotz adäquater Therapie. FIRES sollte rasch diagnostiziert werden und von
einem multidisziplinären Team betreut werden, um den SE frühzeitig unter Kontrolle
zu bringen und somit mögliche schwerwiegende neurologische Folgen oder Tod zu
vermeiden.
Ziel und Schlussfolgerung: Für die Sensibilisierung und somit Früherkennung
dieser Krankheit wurden in der vorliegenden Arbeit mögliche pathophysiologische
Mechanismen und die wichtigen klinischen Symptome zusammengefasst. Ein
diagnostischer Ansatz und mögliche therapeutische Optionen wurden in einer
algorithmisch illustrierten Grafik dargestellt.
Schlüsselwörter
FIRES · Fieberkrämpfe · Supertherapierefraktärer Status epilepticus · Schwerwiegende Folgen ·
Tod
make a clear therapeutic recommendation borderline, and one died
difficult.
Despite the disappointing effect of first-
line immunotherapies, they should be con- Corresponding address
sidered during the first week [36, 43] fol- PD Dr. Alexandre N. Datta, MD
lowed by second-line drugs if the former Department of Pediatric Neurology and
fail. Developmental Medicine, University Children’s
Hospital Basel
Spitalstraße 33, 4056 Basel, Switzerland
Practical conclusion Alexandre.Datta@ukbb.ch
4 Febrile infection-related epileptic syn-
drome (FIRES) is associated with high
mortality and morbidity. The mortal-
Funding. Open access funding provided by Univer-
ity rate during acute and chronic phase
sity of Basel
ranges from 10 to 12%. Causes of death
are multiorgan failure, hypotension, in-
tracranial hemorrhage, acute hepatitis,
respiratory failure, sepsis, and cardiac ar- Declarations
rest
4 Individual outcome is difficult to predict Conflict of interest. D. Reppucci and A.N. Datta
declare that they have no competing interests.
but, in most cases, chronic epilepsy with-
out a silent period occurs. More than
half of FIRES children are on multiple For this article no studies with human participants
or animals were performed by any of the authors. All
antiseizure drugs, but only few become studies mentioned were in accordance with the ethical
seizure free standards indicated in each case.
4 Cognitive impairment can range from
mild to severe with neuropsychological Open Access. This article is licensed under a Creative
deficits such as attention, speech, and Commons Attribution 4.0 International License, which
executive functioning issues. permits use, sharing, adaptation, distribution and re-
4 Young age and longer burst coma sup- production in any medium or format, as long as you
pression were associated with poor cog- give appropriate credit to the original author(s) and
the source, provide a link to the Creative Commons li-
nitive outcome and a more severe course
cence, and indicate if changes were made. The images
of disease. By contrast, a good outcome or other third party material in this article are included
was seen in children treated early with in the article’s Creative Commons licence, unless in-
ketogenic diet. dicated otherwise in a credit line to the material. If
4 In a long-term follow-up study, all seven material is not included in the article’s Creative Com-
patients with FIRES had refractory seizures, mons licence and your intended use is not permitted
while four of them had moderate-to-se- by statutory regulation or exceeds the permitted use,
vere intellectual impairment, two were you will need to obtain permission directly from the
copyright holder. To view a copy of this licence, visit
http://creativecommons.org/licenses/by/4.0/.
References
1. Appavu B, VanattaL, CondieJetal(2016)Ketogenic
diet treatment for pediatric super-refractory status
epilepticus. Seizure 41:62–65
2. BaumeisterF, OberhofferR, LiebhaberGetal(2004)
Fatal propofol infusion syndrome in association
with ketogenic diet. Neuropediatrics 35:250–252
3. Cantarín-Extremera V, Jiménez-Legido M, Duat-
Rodríguez A et al (2020) Tocilizumab in pediatric
refractory status epilepticus and acute epilepsy:
Experience in two patients. J Neuroimmunol
340:577142
a boy with fever-induced refractory epileptic
encephalopathy in school-age children (FIRES).
Develop Med Child Neuro 53:1053–1057
19. Jun JS, Lee ST, Kim R et al (2018) Tocilizumab treat-
ment for new onset refractory status epilepticus.
Ann Neurol 84:940–945
20. Kessi M, Liu F, ZhanYetal(2020)Efficacyofdifferent
treatment modalities for acute and chronic phases
of the febrile infection-related epilepsy syndrome:
a systematic review. Seizure 79:61–68
21. Koh S, Wirrell E, Vezzani A et al (2021) Proposal
to optimize evaluation and treatment of febrile
infection-related epilepsy syndrome (FIRES): a
report from FIRES workshop. Epilepsia Open
6:62–72
22. Kothur K, Bandodkar S, Wienholt L et al (2019)
Etiology is the key determinant of neuroinflamma-
tion in epilepsy: elevation of cerebrospinal fluid
37. Sculier C, Gaspard N (2019) New onset refractory
status epilepticus (NORSE). Seizure 68:72–78
38. Serino D, Santarone ME, Caputo D et al (2019)
Febrile infection-related epilepsy syndrome
(FIRES): prevalence, impact and management
strategies. Neuropsychiatr Dis Treat 15:1897
39. Shorvon S, Ferlisi M (2012) The outcome of
therapies in refractory and super-refractory con-
vulsive status epilepticus and recommendations
for therapy. Brain 135:2314–2328
40. Tan THL, Perucca P, O’brien TJ et al (2021)
Inflammation, ictogenesis, and epileptogenesis:
an exploration through human disease. Epilepsia
62:303–324
41. Van Baalen A, Häusler M, Boor R et al (2010) Febrile
infection–related epilepsy syndrome (FIRES): a
nonencephalitic encephalopathy in childhood.
Epilepsia 51:1323–1328

4. Clarkson BD, Lafrance-Corey RG, Kahoud RJ et
al (2019) Functional deficiency in endogenous
interleukin-1 receptor antagonist in patients with
febrile infection-related epilepsy syndrome. Ann
Neurol 85:526–537
5. Culleton S, Talenti G, Kaliakatsos M et al (2019)
The spectrum of neuroimaging findings in febrile
infection-related epilepsy syndrome (FIRES):
a literature review. Epilepsia 60:585–592
6. Dibue-Adjei M, Fischer I, Steiger H-J et al (2017)
Efficacy of adjunctive vagus nerve stimulation in
patients with Dravet syndrome: a meta-analysis of
68 patients. Seizure 50:147–152
7. Elliott RE, Rodgers SD, Bassani L et al (2011) Vagus
nerve stimulation for children with treatment-
resistantepilepsy: aconsecutiveseriesof141cases.
J Neurosurg Pediatr 7:491–500
8. Farias-Moeller R, Bartolini L, Staso K et al (2017)
Early ictal and interictal patterns in FIRES: the
sparks before the blaze. Epilepsia 58:1340–1348
9. Gaspard N (2019) A new hose to Extinguish the
fires? Epilepsy Curr 19:86–87
10. Gaspard N, Foreman BP, Alvarez V et al (2015)
New-onset refractory status epilepticus: etiology,
clinical features, and outcome. Neurology
85:1604–1613
11. Gaspard N, Hirsch LJ, Sculier C et al (2018)
New-onset refractory status epilepticus (NORSE)
and febrile infection–related epilepsy syndrome
(FIRES): state of the art and perspectives. Epilepsia
59:745–752
12. Harkin LA, Mcmahon JM, Iona X et al (2007) The
spectrum of SCN1A-related infantile epileptic
encephalopathies. Brain 130:843–852
13. Helbig I, Barcia G, Pendziwiat M et al (2020) Whole-
exome and HLA sequencing in Febrile infection-
related epilepsy syndrome. Ann Clin Transl Neurol
7:1429–1435
14. Hirsch LJ, Gaspard N, Van Baalen A et al (2018)
Proposed consensus definitions for new-onset
refractory status epilepticus (NORSE), febrile
infection-related epilepsy syndrome (FIRES), and
related conditions. Epilepsia 59:739–744
15. Horino A, Kuki I, Inoue T et al (2021) Intrathecal
dexamethasone therapy for febrile infection-
related epilepsy syndrome. Ann Clin Transl Neurol
8:645–655
16. Hsieh M-Y, Lin J-J, Hsia S-H et al (2020) Diminished
Toll-like receptor response in febrile infection-
related epilepsy syndrome (FIRES). Biomed J
43:293–304
17. Hsu M-H, Kuo H-C, Lin J-J et al (2020) Therapeutic
hypothermia for pediatric refractory status
epilepticusMayAmelioratepost-statusepilepticus
epilepsy. Biomed J 43:277–284
18. Illingworth MA, Hanrahan D, Anderson CE et
al (2011) Elevated VGKC-complex antibodies in
Leitthema
cytokines and chemokines in febrile infection- 42. Van Baalen A, Häusler M, Plecko-Startinig B et al
related epilepsy syndrome and febrile status (2012)Febrileinfection-relatedepilepsysyndrome
epilepticus. Epilepsia 60:1678–1688 without detectable autoantibodies and response
23. Kramer U, Chi CS, Lin KL et al (2011) Febrile infec- to immunotherapy: a case series and discussion
tion–related epilepsy syndrome (FIRES): patho- of epileptogenesis in FIRES. Neuropediatrics
genesis, treatment, and outcome: a multicenter 43:209–216
study on 77 children. Epilepsia 52:1956–1965 43. Van Baalen A, Vezzani A, Häusler M et al (2017)
24. Lai YC, Muscal E, Wells E et al (2020) Anakinra usage Febrile infection–related epilepsy syndrome:
in febrile infection related epilepsy syndrome: clinical review and hypotheses of epileptogenesis.
an international cohort. Ann Clin Transl Neurol Neuropediatrics 48:5–18
7:2467–2474 44. Yang JH, Nataraj S, Sattar S (2021) Successful
25. Lam S-K, Lu W-Y, Weng W-C et al (2019) The short- treatment of pediatric FIRES with Anakinra. Pediatr
term and long-term outcome of febrile infection- Neurol 114:60–61
related epilepsy syndrome in children. Epilepsy
Behav 95:117–123
26. Lee H-F, Chi C-S (2018) Febrile infection-related
epilepsy syndrome (FIRES): therapeutic complica-
tions, long-term neurological and neuroimaging
follow-up. Seizure 56:53–59
27. Levine JM, Ahsan N, Ho E et al (2020) Genetic
acute necrotizing encephalopathy associated with
RANBP2: clinical and therapeutic implications in
pediatrics. Mult Scler Relat Disord 43:102194
28. Lim GY, Chen CL, Shih CWD (2021) Utility and safety
of perampanel in pediatric FIRES and other drug-
resistant epilepsies. Child Neurol Open 8:2329048
29. LinWS,HsuTR(2021)Hypothesis: Febrileinfection-
related epilepsy syndrome is a microglial NLRP3
inflammasome/IL-1 axis-driven autoinflammatory
syndrome. Clin Transl Immunol 10:e1299
30. Luo T, Wang Y, Lu G et al (2022) Vagus nerve
stimulation for super-refractory status epilepticus
in febrile infection–related epilepsy syndrome:
a pediatric case report and literature review. Childs
Nerv Syst 38:1401–1404
31. Lyon G, Dodge PR, Adams R (1961) The acute
encephalopathies of obscure origin in infants and
children. Brain 84:680–708
32. Nausch E, Schaffeldt L, Tautorat I et al (2022)
New-onset refractory status epilepticus (NORSE)
and febrile infection-related epilepsy syndrome
(FIRES) of unknown aetiology: a comparison of the
incomparable? Seizure 96(2002):18–21
33. Payne ET, Koh S, Wirrell EC (2020) Extinguishing
febrile infection-related epilepsy syndrome: pipe
dream or reality? In: Seminars in neurology.
Thieme, Stuttgart, pp 263–272
34. Ritter LM, Nashef L (2021) New-onset refrac-
tory status epilepticus (NORSE). Pract Neurol
21:119–127
35. Rojo DC, Harvey AS, Iona X et al (2012) Febrile
infection-related epilepsy syndrome is not caused
by SCN1A mutations. Epilepsy Res 100:194–198
36. SakumaH, HorinoA, Kuki I(2020)Neurocriticalcare
and target immunotherapy for febrile infection-
related epilepsy syndrome. Biomed J 43:205–210

Zeitschrift für Epileptologie 4 · 2022 331