Seizure: European Journal of Epilepsy 111 (2023) 215–222

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Seizure: European Journal of Epilepsy

journal homepage: www.elsevier.com/locate/seizure

Review

Febrile infection-related epilepsy syndrome in childhood: A clinical review

and practical approach
Andreas van Baalen
Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Kiel University (CAU), Arnold-Heller-Street 3, House C, Kiel 24105, Germany

A R T I C L E I N F O A B S T R A C T

Keywords: Febrile infection-related epilepsy syndrome (FIRES) of unknown aetiology is an extremely rare but severe epi­
FIRES lepsy syndrome. It is characterized by a nonspecific febrile infection a few days before the onset of super-
Childhood refractory status epilepticus, followed by refractory epilepsy and high morbidity in previously healthy chil­
Cryptogenic
dren and young adults. To date, FIRES is incurable and irreversible. The clinical course may depend more on time
Status epilepticus
than on therapy, while the outcome may depend more on the clinical spectrum than on therapy.
Therapy
Based on a literature search, retrospective data analysis, and personal observations, this review aimed to
explore the clinical spectrum and therapeutic options for FIRES to improve outcomes by optimized and more
standardized diagnosis and therapy, including adapted immunotherapy and a less aggressive approach to
manage seizures, as seizure-freeness is difficult to achieve and, therefore, not the primary goal for cryptogenic
FIRES.

1. Definition seizures [3]. Hence, seizures seem to be ‘the tip of the iceberg’ of an un­
derlying pathophysiologic process. According to the former FIRES
Febrile infection-related epilepsy syndrome (FIRES) is currently definition, children can experience recurring seizures that do not evolve
classified by the International League Against Epilepsy (ILAE) as an into status epilepticus [4]. Nevertheless, severe seizure activity contrasts
epilepsy syndrome with progressive neurological deterioration begin­ with the preceding mild febrile illness in previously healthy patients. In
ning in childhood [1]. FIRES has a highly characteristic multiphasic FIRES, status epilepticus seems self-sustaining and presents as
course (Fig. 1). super-refractory status epilepticus (SRSE), persisting for at least 24 h
To date, FIRES is a subcategory of new-onset refractory status epi­ after the commencement of anaesthetics, or more typically, as prolonged
lepticus (NORSE). Since 2018, NORSE has been the umbrella term for SRSE persisting for a minimum of 7 days, necessitating continuous
FIRES (Fig. 2) and has been uniformly defined as a clinical presentation anaesthetic administrations [2]. A recent review termed this progression
rather than a specific diagnosis. It appears in patients without active ‘from bush fires to firestorms’ [5].
epilepsy or relevant previous neurological diseases, without a clear Using standardized terms and definitions improves communication,
acute or active structural, toxic, or metabolic cause. FIRES can affect facilitates the conduct of multicentre studies, and promotes under­
individuals of any age and necessitates a prior febrile infection that standing of NORSE and FIRES [2]. It also improves parents’ counselling
occurs between 2 weeks and 24 h before the onset of refractory status [6], preparing them with an understanding of a potentially extended
epilepticus (where status epilepticus persists despite the administration course and an often unfavourable outcome despite exhaustive thera­
of at least two appropriately selected and dosed par-enteral medications, peutic interventions. This enables parents to understand the specific
including benzodiazepines; no specific seizure duration is required). The clinical condition afflicting their child, even though the underlying
presence of persistent fever at the onset of status epilepticus is not cause remains unknown in most cases [7]. FIRES may represent distinct
obligatory [2]. Although nearly all patients develop status epilepticus, clinical disorders, and given that it can also impact predominantly
recurring brief seizures rather than status epilepticus marks the onset of young adults, an extension of the phenotypic term is rational [8].
epileptic activity. These seizures exhibit a gradual increase in seizure Otherwise, the homogeneity of the phenotype and consistent unidenti­
frequency and are accompanied by a profound clinical encephalopathy fied aetiologies point to a singular clinical entity. To date, FIRES remains
between seizures, the cause of which cannot be attributed to subclinical one of the most enigmatic clinical presentations without any known

E-mail address: andreas.vanbaalen@uksh.de.

https://doi.org/10.1016/j.seizure.2023.09.008
Received 24 May 2023; Received in revised form 4 September 2023; Accepted 6 September 2023
Available online 7 September 2023
1059-1311/© 2023 Published by Elsevier Ltd on behalf of British Epilepsy Association. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
A. van Baalen Seizure: European Journal of Epilepsy 111 (2023) 215–222

aetiology [9], originally described in children. Therefore, paediatric

FIRES of unknown aetiology is reviewed in this study.

2. Methods

This study obtained the data from a retrospective data analysis of

140 children and adolescents with cryptogenic FIRES across four con­
tinents (Table 1). Additionally, treatment and collegial consultations
were conducted with over two dozen children with FIRES, representing
the personal observations. A continuous literature search was performed
using PubMed [search terms: FIRES epilepsy, NORSE, and status epi­
lepticus] and Google Scholar [search terms: NORSE status epilepticus,
FIRES febrile infection] databases, evaluating more than 130 scientific
publications on NORSE and FIRES (annotated reference list: htt
ps://www.norseinstitute.org/references). Furthermore, membership in
the international NORSE consensus and experts group contributed to the
additional insights. The ethics committee of the Faculty of Medicine at
Kiel University approved this observational study (D 470/20), and
written informed consents were obtained.

3. Epidemiology
Fig. 2. New-onset refractory status epilepticus (NORSE). The visualization of
actual definitions of the umbrella term NORSE and its subtype FIRES (IHHE =
FIRES is one of the most severe epileptic encephalopathies, because Infantile hemiconvulsion-hemiplegia and epilepsy syndrome).
the seizures are extremely refractory and frequent. Global brain atrophy
often occurs within a few weeks and is usually associated with a poor
occurrence of seizures and absence of response to first-line immuno­
outcome [10]. FIRES is extremely rare (‘one in a million disease’), with
therapy are characteristic for FIRES of unknown aetiology, and the latter
slight male predominance and no association with heredity factors. Prior
can also be considered as a diagnostic criterion. In addition, the sudden
to experiencing FIRES, the affected children were generally in good
onset of epileptic seizures with a high frequency and marked resistance
health and were primarily of preschool or elementary school age. No
to therapy without further symptoms, such as behavioural and psychi­
definite seasonal occurrence was observed [11].
atric disturbances or movement disorders, is particularly characteristic
of monosymptomatic FIRES and not of viral or autoimmune
4. Diagnosis encephalitis.
Encephalopathy begins after a seemingly benign, more or less
Based on our retrospective data analysis, owing to the characteristic feverish infection or illness. Frequently, after the children experience an
multiphasic course, it is possible and recommended to consider FIRES improvement in their condition, they may resume normal activities for
within a few days of the onset of seizure activity to tailor the appropriate approximately half a day or slightly longer. FIRES doesn´t typically
therapy, especially if cerebrospinal fluid (CSF) and magnetic resonance commence with a seizure; rather, children tend to become fatigued or
imaging (MRI) show no evidence of encephalitis and the first-line confused before the first seizure occurs. The frequency of recurrent
immunotherapy (steroids and immunoglobulins) is not effective. seizures increases over a few hours or days, evolving into prolonged
Hence, the most important differential diagnoses of viral and autoim­ SRSE. Fever does not necessarily have to reappear. Parents invariably
mune encephalitis are less likely, particularly because the isolated

Fig. 1. Febrile infection-related epilepsy syndrome (FIRES). The highly characteristic multiphasic course of FIRES.

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Table 1 structural cause for this persistent or self-sustaining cortical

Descriptive analysis of the available data from the retrospective cohort of 140 hyperexcitability?
children and adolescents with cryptogenic FIRES. The normal CSF findings, indicating an intact blood-brain barrier,
Demographics and baseline clinical characteristics the initial normal MRI findings in most cases, despite status epilepticus,
Demographics
and the lack of response to first-line immunotherapy argue against a
Median age of onset, years (range), n = 119 6 (1 – 19) causative hyperinflammation. However, in contrast to viral encephalitis,
Sex increased concentrations of cytokines and chemokines can be detected
Female, n (%) 45/120 (37.5) [13]; thus, the positive effect of intrathecal dexamethasone adminis­
Male, n (%) 75/120 (62.5)
tration in the first case series in children with FIRES is conclusive [14].
Initial CSF and MRI findings
Abnormal CSF, n (%) 8/22 (36.6) The release of cytokines and chemokines requires the activation of
Abnormal MRI, n (%) 20/31 (64.5) perivascular and glial T-cells, which may cause latency between the first
Status epilepticus signs of infection and first seizure [6].
Median duration of status epilepticus (range) 3 weeks (1 day–5 The current hypothesis for epileptogenesis is a functional deficiency
months)
Treatments
in the endogenous IL-1 receptor, which can explain the response to the
Anaesthetics, n (%) 77/117 (65.8) IL-1 receptor antagonist, anakinra [15]. Nevertheless, FIRES may be a
First-line immunotherapies, n (%) 18/28 (64.3) cerebral cytokine release syndrome; hence, the previously proposed
Second-line immunotherapy (anakinra), n (%) 15/120 (12.5) term ‘fulminant inflammatory response epilepsy syndrome’ may be more
Ketogenic diet, n (%) 54/112 (48.2)
accurate from the pathophysiological point of view [16]. A diminished
Cannabidiol, n (%) 15/110 (13.6)
Vagus nerve stimulation, n (%) 15/120 (12.5) toll-like receptor response was found in five children with FIRES [17],
Median number of antiseizure medications (range), n 7 (2–17) and the hypothesis of overactivation of the microglial
= 93 inflammasome/IL-1 axis as a pivotal event was formulated [18].
Outcomes Recently, a hyperinflammatory monocytic response to bacterial patho­
Median follow-up period, years (range), n = 114 8 (0–28)
gens was reported in a child with FIRES [19].
Aphasia, n (%) 4/14 (28.6)
Behavioural disturbances, n (%) 6/14 (42.9) The age of onset after infancy argues against both metabolic and
Seizure control genetic causes. Consequently, metabolic studies were inconclusive, and
Seizure-free with or without antiseizure medication, n 3/28 (10.7) the yield of genetic testing was 0% Thus, negative genetic testing may be
(%)
a diagnostic criterion [9,20]. While mitochondrial disorders (e.g., due to
Refractory seizures, n (%) 24/27 (88.9)
Second episode of refractory status epilepticus, n (%) 5/88 (5.7) POLG1 or DNM1L mutations), Dravet syndrome, PCDH19 epilepsy, and
Functional outcome other genetic variants linked to FIRES may have FIRES-like pre­
Good outcome (mRS 0–3, GOS 4–5), n (%) 12/31 (38.7) sentations, their clinical courses with prior developmental delay are
Poor outcome (mRS 4–6, GOS 1–3), n (%) 19/31 (61.3) usually distinct from cryptogenic FIRES that occurs in previously
Brain atrophy, n (%) 23/31 (74.2)
healthy children.
Death, n (%) 17/123 (13.8)
Median age at death, years (range) 14 (1–29)
Median duration from FIRES onset to death, years 3 (9 days–19 years) 6. Diagnostic procedures
(range)
Sudden unexpected death in epilepsy, n (%) 1/123 (0.8)
6.1. CSF and MRI
Numbers, percentages, medians and ranges are based on cases with non-missing
data or sub-group analyses. mRS, modified Rankin Scale; GOS, Glasgow Based on our retrospective data, normal findings in both CSF and
Outcome Score; FIRES, febrile infection-related epilepsy syndrome; MRI, mag­ MRI despite status epilepticus are indicative for FIRES. Mild CSF pleo­
netic resonance imaging; CSF, cerebrospinal fluid. cytosis and mild T2/fluid-attenuated inversion recovery (FLAIR)
changes are more the consequences than the causes of high seizure ac­
recall the date of the first seizure because it happened ‘out of the blue’, tivity. Accordingly, T2/FLAIR changes correlate locally and temporally
therefore, a French parent’s association of children with FIRES calls it­ with EEG [21]. CSF and serum should also be examined for unknown
self Paratonnerre (which translates to ‘lightning conductor’). neuronal autoantibodies. In future, cytokine and chemokine profiles in
the CSF and serum should be added to the diagnostic procedures [22,
5. Pathophysiology 23].

Therefore, FIRES is more than seizures, marked by encephalopathy 6.2. EEG: ‘The sparks before the blaze’ [3]
leads to seizures as the prominent feature. However, the seizures are
only the surface of an underlying pathomechanism without known Global slowing and focal discharges with bilateral frontotemporal
aetiology that can be treated accordingly. The frequently observed predilection, often changing hemispheres over a few seconds, were
global slowing in the electroencephalogram (EEG) indicates a funda­ typical observations in our retrospective cohort. Increasing seizure fre­
mental underlying neuronal and glial dysfunction, alongside the quency, extreme delta brushes, prolonged rapid focal activity at seizure
occurrence of ‘extreme delta brushes’ [3], which are also detectable in onset, and shifting between hemispheres during a seizure (Fig. 3) have
anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, suggesting been observed, and can be used as early biomarkers if continuous EEG
synaptic dysfunction. FIRES of unknown aetiology seems not to be monitoring is feasible [3]. Thus, continuous EEG is recommended as it
caused by neuronal autoantibodies, as they were not detectable despite may facilitate early diagnosis and treatment.
an extended search for unknown neuronal autoantibodies in CSF and
serum, even in the acute phase [12]. Additionally, the lack of response to 6.3. Seizures
first-line immunotherapy contradicts the diagnosis of autoimmune
encephalitis. In the observed cases, seizures typically involved the unilateral focal
Various, often unremarkable, peripheral infections lead to a uniform clonic or tonic activity of the mouth and face (hemifacial twitching),
and severe cerebral clinical scenario. Therefore, FIRES seems to be which may evolve into generalized tonic-clonic seizures, such as benign
infection-triggered. As the disease progresses, the clinical focus is more self-limited Rolandic epilepsy syndrome. This may explain why the
on excitation rather than inflammation, which remarkably persists for antiseizure medications sulthiame and clobazam, which are effective in
days to weeks. The key question arises here: What is the functional or those cases, are often effective in FIRES, though much higher dosages

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Fig. 3. Ictal shifting from one hemisphere to the contralateral. A and B segments show 40 s of continuous EEG recording of a 6-year-old girl from our FIRES cohort:
hemispheric shifting of the ictal activity from the right parietal region (P4) (asterisk in the upper segment) to the left temporal region (T3) (arrow in the lower
segment). EEG settings: referential montage, sensitivity 150 µV/mm, low-frequency filter 0.1 Hz, high-frequency filter 70 Hz, notch filter off.

are required. 7.1. Acute phase

6.4. Brain biopsy The typical therapy resistance of status epilepticus in FIRES requires
an aggressive treatment, usually coma therapy, which is associated with
Brain biopsies have revealed predominantly reactive changes a poorer outcome. However, this may also reflect more severe disease
resulting from an extraordinarily high number of seizures [4]. Recently, activity [27]. Recently, the success of a less aggressive therapy with the
a brain biopsy showed sporadic CD8-positive T-lymphocytes, indicating acceptance of brief seizures in a 9-year-old child with FIRES was re­
sustained activation of the innate immune response [21]. Future studies ported. In this case, phenobarbital at high doses and clobazam were
should examine brain tissue in a targeted manner, for which the NORSE administered as less-sedating antiseizure medications, and phenobar­
INSTITUTE provides support through a collaborative biorepository bital bolus and lorazepam were administered only for generalized sei­
(www.norseinstitute.org/research) [24]. A more consistent investiga­ zures that lasted for >5 min. While writing is certainly easier than
tion of brain specimens may ultimately be the only way to elucidate the witnessing when a child repeatedly seizes, trying to avoid anaesthesia
pathophysiology of FIRES and guide specific treatment if neuropatho­ for each seizure may improve acceptance by parents and medical staff,
logical findings support an adapted immunotherapy [25]. facilitate interaction with the child, and increase hope for positive
outcomes [28].
7. Therapy
7.1.1. Antiseizure medications
Owing to the extreme rarity of FIRES, gaining experience and Empirically, gamma-aminobutyric-acid (GABA)ergic (phenobar­
expertise is difficult. Additionally, any therapy recommendation is bital, benzodiazepines), acidosis (sulthiame), and ketosis (ketogenic
based only on case reports, small case series, or personal observations. diet)-inducing agents are the most effective but not causally effective in
Therefore, reports of therapeutic success in paediatric status epilepticus FIRES (Table 2). High-dose phenobarbital may help avoid thiopental
independent of FIRES were included in this review. An international anaesthesia and its significant potential side effects. Empirically, a
group of experts agreed on readable recommendations to optimise and phenobarbital dose of 30 mg/kg/day in three divided doses resulted in a
standardise diagnosis and treatment to improve the outcomes of FIRES high serum concentration that should be at least >80 mg/L or even
[26]. Given the challenging therapy, early recognition of FIRES in the >180 mg/L in mega-dose therapy [16]. Owing to personal observations
clinical course can facilitate rapid transfer to a large tertiary centre. In of hemifacial twitching in several children with FIRES, which is similar
addition, regular consultations with other centres to coordinate therapy to Rolandic epilepsy syndrome, sulthiame was added, often with a sig­
are recommended [6]. nificant seizure-reducing effect. Owing to its effect as a carbonic anhy­
drase inhibitor, attention must be paid to possible interactions with
co-medications and a ketogenic diet. Similarly, clobazam, given

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Table 2 option. A very high-dose use has been described for the cytokine storm
Acute phase of FIRES. characteristic of hemophagocytic lymphohistiocytosis (HLH) or macro­
Therapeutic options phage activation syndrome [39] and refractory CNS-HLH [40], despite
these being off-licence indications and routes of administration. How­
First choice (GABAergic, acidosis or, ketosis-inducing mechanisms of action):
- Phenobarbital: high dose infusion (1 × 10 mg/kg over 15 min, followed by 1 mg/kg/ ever, these data and the severity of the disease support the rationale for
h, and subsequently increased every 6 h by 0.5 mg/kg/h up to a maximum of 3 mg/ very high-dose of intravenous anakinra as a first-line treatment for
kg/h; plasma levels: 100–180 mg/L) under EEG control according to standardized FIRES.
protocol [64] The intrathecal administration of anakinra has only been studied in
- Sulthiame: 10–30 mg/kg/day (personal observations in several cases)
- Clobazam: 10–60 mg/day in status epilepticus [29]
animal models. Because CSF findings are usually normal, an intact
- Lorazepam: calculated conversion from midazolam infusion to enteral lorazepam in blood-brain barrier is more likely to be overcome by intrathecal
four daily doses [30] administration of dexamethasone, which has been reported in a small
- Midazolam: 0.12–1.92 mg/kg/h in refractory status epilepticus [65] case series of six children with FIRES [14]. Additionally, because
- Ketogenic diet [46,47,66–68]
anakinra-refractory cases, despite a high dose of 20 mg/kg/day, have
Immunotherapy:
- Anakinra: 2 × 5 mg/kg/day subcutaneously, or possibly more effective but off-label: been observed [41], intrathecal dexamethasone administration may be
100 mg IV bolus, followed by 2 mg/kg/h as continuous 72-h infusion [35,39,40] the primary immunotherapy in the future unless intrathecal anakinra
- Dexamethasone: 0.15–0.25 mg/kg intrathecally, repeated four times or more every administration is also introduced in humans. Notably, the intrathecal
1–6 weeks [14] delivery of corticosteroids may maintain a more persistent therapeutic
- Tocilizumab (in anakinra-refractory cases or instead of anakinra): 8 mg/kg [23] or
12 mg/kg [42] at intervals of 2 weeks with four doses for 8 weeks or 4 mg/kg with a
effect than intravenous delivery; therefore, the locus of delivery may
second dose after 1 week [43,69] matter more than the specific corticosteroid. This indicated that
Options without sufficient evidence but favourable effects in cases series: continuous systemic dexamethasone or methylprednisolone infusion
- Cannabidiol: up to 25 mg/kg/day [50,53] phenocopies the intrathecal effect. Therefore, future studies should
- Hypothermia [56]
consider these therapeutic approaches [19].
Further options:
- Ketamine: 2.5–10 mg/kg/h in SRSE [70] Currently, tocilizumab, an IL-6 receptor antagonist, is indicated for
- Chloral hydrate: e.g., 4–8 × 1000 mg/day (personal observations in several cases) anakinra-refractory cases [42] or used instead of anakinra [43]. How­
- Levetiracetam: 50–60 mg/kg/day [71] ever, instead of single-factor therapies, such as anakinra or tocilizumab,
- Brivaracetam: IV [51] the multifaceted mechanistic effect of dexamethasone may be a key
- Lacosamide: enterally in FIRES [72], 10 mg/kg IV loading, or first dose in new-onset
component for simultaneously reducing inflammatory factors [19].
status epilepticus [73]
- Perampanel: 4–12 mg/day [74]
- Lidocaine [75] 7.1.3. Ketogenic diet: ‘The fat is in the fire’ [44]
- MgSO4 [76] A ketogenic diet should be started as early as possible before the
- Inhalation anaesthetics: Positive case report of sevoflurane combined with
onset of anaesthesia-related intestinal complications and can also be
simultaneous plasma exchange [77]; negative case report of isoflurane, possibly due
to neurotoxicity [78] started intravenously, as shown clearly in a practical guide [45]. Cases
- Electroconvulsive therapy [79] of improved cognitive outcomes after the early initiation of a ketogenic
- Vagus nerve stimulation [53,80] diet have been reported [46]. A systematic literature review has re­
ported positive outcomes associated with using a ketogenic diet during
the acute phase [47]. Otherwise, the outcome can be poor [48], and the
sporadically in Rolandic epilepsy syndrome, is effective in both the acute
status epilepticus resolution time appears longer in cryptogenic cases
and chronic phases [29]. Enteral lorazepam can be a weaning substitute
than in cases with an identified aetiology [49]. Mitochondrial disorders
for intravenous midazolam, and the early introduction of enteral lor­
should be carefully considered in cases with FIRES-like presentations
azepam is associated with a reduced duration of hospital stay [30].
characterized by prior developmental delay and an early age of onset.
Furthermore, midazolam and the NMDA receptor antagonist ketamine
This consideration is crucial owing to the potential risk of inducing fatal
have fewer severe side effects than thiopental in patients with
liver failure through the use of a ketogenic diet in these patients.
benzodiazepine-refractory status epilepticus.
7.1.4. Cannabidiol
7.1.2. ‘The nuances of immunotherapy’ [31]
Cannabidiol is believed to have anti-excitatory and anti-
First-line immunotherapy (steroids, immunoglobulins, and plasma­
inflammatory effects, which may explain the increasing number of
pheresis) is usually ineffective, with few exceptions [32]; therefore,
positive case reports on FIRES [50–53]. However, consensus was
response to first-line immunotherapy is an exclusion criterion. Under the
reached among international experts that the current evidence does not
current hypothesis that FIRES is an autoinflammatory process [33], and
clearly support the usefulness of cannabidiol as a first-line treatment
based on an increasing number of case reports about positive effects,
[54,55], which is consistent with our retrospective data, where canna­
second-line immunotherapy should be considered as a new first-line
bidiol was only administered to a minority of patients and had a positive
immunotherapy for FIRES. Second-line immunotherapy is possibly the
effect in <10% of cases. Special attention should be paid to drug-drug
only available causal therapeutic approach at present; therefore, it
interactions with cannabidiol [55].
should be used as early as possible, demanding proficiency in its
administration. The beneficial effect of anakinra, a human IL-1 receptor
7.1.5. Optimised environmental conditions
antagonist commonly used in paediatric rheumatology, was reported
Elevated body temperature, noise, and touch may additionally
most frequently [34–36]. Anakinra should be administered for a mini­
trigger seizures; therefore, mild therapeutic hypothermia [56] and
mum of 21 days [26,37]. Successful treatment for several months has
stimulus reduction, which is difficult in the intensive care unit, should
also been reported [35]. However, despite treatment with anakinra,
be sought, although a strong consensus was reached among interna­
ongoing seizures and long-term neurocognitive impairment were
tional experts that evidence does not support the use of therapeutic
observed in all six children with FIRES [38].
hypothermia as a first-line treatment [54,55].
The penetration of anakinra through the intact blood-brain barrier is
suboptimal owing to its molecular weight (~17.3 kDa); therefore, suf­
7.2. Chronic phase
ficiently high doses and alternative routes of administration are
required. Anakinra is regularly administered subcutaneously twice a day
Given the dramatic onset, the research focus is on acute management
at the beginning, although intravenous administration is also a possible
and identification of the underlying pathophysiology. However, the

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chronic phase lasts much longer than the acute phase. Additionally, the 8. Outcome: ‘Winning the battle but losing the war?’ [58]
chronic phase of treatment is extraordinarily difficult, and multiple
long-term issues, such as neuropsychological outcomes, must be The outcomes of FIRES are poor [27]. This retrospective study
addressed. Moreover, the number of acute-phase survivors is increasing. revealed an overall mortality rate of 13%. Death occurred between 9
Therefore, collaborative efforts are important to improve care during the days and 9 years after disease onset (median, 3 years). Age, season of
chronic phase. The post-acute and chronic phases of FIRES are charac­ onset, infection phenotype (cause, body temperature, use of ibuprofen
terized by refractory epilepsy; thus, freedom from seizures is not a and acetaminophen, severity, and duration of illness), number of days
realistic goal. Our retrospective data showed that high-dose polytherapy between fever onset and first seizure, asymptomatic interval, fever at
is nearly universal in the post-acute phase. Therapeutic drug monitoring first seizure, type and duration of first seizure, and antiseizure medica­
is indicated because of multiple and difficult-to-predict pharmacokinetic tions were not predictive of the outcome after the acute phase, with the
interactions. Antiseizure medications that are more effective in FIRES exception of longer intubation duration, which was significantly asso­
and additional therapeutic options are listed in Table 3. Empirically, ciated with a poor outcome (p < 0.01). Therapy failure is probably
sulthiame and clobazam, possibly in combination with phenobarbital, because of the particularly severe course of the disease. Hence, parents
have been shown to reduce seizures in several cases (personal should be informed about the severity of the disease in time [7].
observations). Although functional outcomes can improve even after weeks or months
A therapeutic effect has been reported in single cases with almost all of coma therapy [6], our retrospective data from 10 children with coma
antiseizure medications, such as oxcarbazepine, rufinamide, stiripentol, therapy longer than 60 days showed poor outcomes in all patients.
lacosamide, zonisamide, pregabalin, perampanel, brivaracetam, felba­ The outcome was normal or borderline normal (for example,
mate, bromide, and vigabatrin, and vagus nerve stimulation has also learning disabilities) in approximately one-third of our survivors; one-
been reported [55]. The positive effects of cannabidiol and ketogenic third had mild to moderate cognitive impairment, and one-third were
diet have been reported several times. In contrast, our retrospective severely mentally and motor-disabled or in a vegetative state. Virtually
study showed fewer clear effects. Additionally, a ketogenic diet can all children experience drug-resistant and long-term seizures. Behav­
cause a loss of appetite. ioural disorders, including autistic disorders, are common and difficult
In our retrospective cohort, behaviour and cognition disturbances to treat. Both seizures and antiseizure medications may exacerbate
were commonly observed in cases of FIRES and were probably the learning and behavioural disorders [38]. Several patients had residual
consequences of the underlying disease process, seizures, antiseizure aphasia.
medications, or a combination of all the above. Therefore, particular Poor clinical outcomes are correlated with brain atrophy, as dis­
attention should be paid to the further deterioration of behaviour and cussed by Culleton et al. [59]. In our paediatric sample population,
cognition due to often-sedative antiseizure medications. However, global brain atrophy often occurred after a few weeks but was not al­
despite its high and potentially sedative doses, single cases may benefit ways associated with poor outcomes. In contrast, learning disorders are
from clobazam. Furthermore, specific therapies for behavioural distur­ possible despite normal MRI findings. Brain atrophy can progress
bances have been indicated. Classical first-line immunotherapy (ste­ throughout the disease. Whether this was due to the refractory epilepsy,
roids, immunoglobulins, or plasmapheresis) may only be useful in a the polytherapy, the underlying disease process, or a combination of
single case, especially if it was effective in the acute phase. Second-line these remains unknown [38]. Children rarely develop symptoms of de­
immunotherapies such as anakinra and tocilizumab, should also be mentia, probably as a result of refractory epilepsy. In most cases, seizure
considered, as several positive cases have been reported [57]. The sei­ activity stabilized within several years; hence, several days of seizure
zures are largely multifocal; therefore, epilepsy surgery is not a realistic freedom could be achieved, and polytherapy could be reduced. Seizures
option for treating FIRES. tended to occur in clusters, and in rare cases, they evolved into status
epilepticus again, for example, during a febrile illness, which required a
new intensive therapy. Sudden unexpected death in epilepsy was re­
ported only once in our retrospective cohort study.
In summary, FIRES is characterized by high morbidity, irrevers­
Table 3
ibility, and incurability. Survivors of FIRES have a high seizure burden
Chronic phase of FIRES.
and poor quality of life [60]; therefore, the question ‘winning the battle
Therapeutic options: but losing the war?’ was proposed [58]. However, improvements in
First choice: seizure activity and functional outcomes are achievable, and healing has
- Sulthiame: at least 10 mg/kg/day if tolerated, up to 10 – 30 mg/kg/day in the case of been reported in single cases.
polytherapy (personal observations in several cases)
- Clobazam: up to 2 × 0.5 mg/kg/day (personal observations in several cases)
- Phenobarbital: possibly worse for cognition than clobazam 9. Conclusions
- Cannabidiol: 7–25 mg/kg/day [50,51]
- Ketogenic diet can still be effective even in the chronic phase [81] According to the current ILAE classification, the clinical course,
Immunotherapy:
seizures, EEG, CSF, and MRI findings collectively characterized FIRES as
- Anakinra: therapy > 12 months [34] and beneficial use despite the start of therapy,
even many years after FIRES onset [21,57], have been reported; the duration and an epilepsy syndrome with progressive neurological deterioration
method of withdrawal are currently unknown beginning in childhood. A suspected diagnosis can and should be made
- Tocilizumab after ineffectiveness of anakinra [57] as early as possible to adjust the status epilepticus therapy and initiate
Further options: targeted immunotherapy as early as possible. This may improve the
- Lamotrigine: especially in behavioural disturbances
- Valproate, phenytoin, oxcarbazepine, levetiracetam, lacosamide, perampanel,
outcome, especially in cryptogenic cases with typical presentations,
vigabatrin, bromide, rufinamide, and zonisamide: Only effective in single cases but which were the focus of this review. Nonetheless, the course of the
mostly ineffective disease may depend more on individual vulnerability than on therapy,
Neurostimulation: and the time to spontaneous remission of the initial high epileptic ac­
- Vagus nerve stimulation: Very little available data [55,82]; not effective in every case
tivity rather than therapy may influence the course of the disease.
(own retrospective data)
- Responsive neuro stimulation or deep brain stimulation: first positive case reports Recently, a promising in vitro FIRES model for selecting clinically
[83,84] effective antiseizure medications was published [61]. The NORSE
Optional for seizure cluster (personal observations): Institute established an open NORSE/FIRES biorepository with stan­
- Clobazam, phenobarbital, chloral hydrate (e.g., 4–8 × 1000 mg/day), and dardized procedures for biospecimens collection, promoting multicentre
clonazepam
research to identify biomarkers and provide a better understanding of its

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