Received: 24 September 2022

| Revised: 21 March 2023

| Accepted: 21 March 2023

DOI: 10.1111/epi.17591

B R I E F C O M M U N I C AT I O N

Treatment of new onset refractory status epilepticus/febrile

infection-­related epilepsy syndrome with tocilizumab in a
child and a young adult

Marie-­Laure Girardin1 | Thomas Flamand2 | Ombeline Roignot1 |

Marie-­Thérèse Abi Warde3,4 | Véronique Mutschler5 | Paul Voulleminot5 |
Max Guillot2 | Vera Dinkelacker4,5 | Anne De Saint-­Martin3,4

1
Department of Pediatric Intensive
Care Unit, Hôpitaux Universitaires de Abstract
Strasbourg, Strasbourg, France New onset refractory status epilepticus (NORSE) is a rare and devastating condi-
2
Department of Intensive Care Unit, tion occurring in a previously healthy patient. It is called febrile infection-­related
Hôpitaux Universitaires de Strasbourg,
Strasbourg, France
epilepsy syndrome (FIRES) when preceded by a febrile infection. It often leads to
3
Department of Neuropediatrics, intensive care treatment, including antiseizure drugs in combination with anes-
Hôpitaux Universitaires de Strasbourg, thetic agents, and sometimes ketogenic diet. The mortality rate is high, and severe
Strasbourg, France
epileptic and neuropsychiatric sequelae are usually observed. Based on the pos-
4
Reference Center for Rare Epilepsies,
sible role of neuroinflammation, intravenous immunoglobulin, corticosteroids,
Hôpitaux Universitaires de Strasbourg,
Strasbourg, France and immunomodulatory treatment (anti-­IL1, IL6) can be added. We describe
5
Department of Neurology, Hôpitaux here a child and a young adult with FIRES, both treated with tocilizumab. We ob-
Universitaires de Strasbourg, served a rapid positive response on the status epilepticus and good tolerance, but
Strasbourg, France
different neurological outcomes for our two patients. Further prospective studies
Correspondence may be necessary both to confirm the efficacy and the safety of this promising
Anne De Saint-­Martin, Department
treatment and to optimize the immunomodulatory strategy in FIRES/NORSE.
of Neuropediatrics, Hôpitaux
Universitaires de Strasbourg,
KEYWORDS
Strasbourg, France.
Email: anne.desaintmartin@chru- FIRES, inflammatory epilepsy, NORSE, pediatric neurology, status epilepticus, superrefractory
strasbourg.fr status, tocilizumab

by a febrile infection.1 NORSE/FIRES typically presents as

1 | I N T RO DU CT ION
New onset refractory status epilepticus (NORSE) is a rare
and devastating condition occurring in adults and children
without active epilepsy or preexisting relevant neurolog-
ical disorders, and without a clear acute or active struc-
tural, toxic, or metabolic cause identified in the first few
days. Febrile infection-­related epilepsy syndrome (FIRES)
represents a subgroup of patients with NORSE preceded
superrefractory status epilepticus, is resistant to first-­ and
second-­line antiseizure medications (ASMs) and to intra-
venous continuous anesthetics, and often requires >24 h
of general anesthesia for seizure control.2 This condition
is life-­threatening, and severe epileptic and neuropsy-
chiatric sequelae are usually observed when the patient
survives. The pathophysiology remains uncertain; how-
ever, increasing evidence underscores the role of neuroin-
flammation.3,4 Hence, a variety of immunomodulatory

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© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Epilepsia. 2023;64:e87–e92.  wileyonlinelibrary.com/journal/epi   | e87

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e88    GIRARDIN et al.

treatments have been proposed over the past years: ste-
roids, intravenous immunoglobulin, plasmapheresis, and
more recently monoclonal antibodies such as anti-­CD20,
rituximab, and anti-­cytokine receptors, notably anakinra
(anti-­IL1) or tocilizumab (anti-­IL6).5 A cohort of seven
adults, successfully treated by tocilizumab, was reported
in 2018 by Jun et al.,6 and two pediatric patients were re-
ported in 2020 by Cantarín-­Extremera et al.7 We present
here two cases of FIRES in a child and a young adult who
responded to an add-­on treatment with tocilizumab.
2 | C A S E RE PORT 1
A previously healthy 9-­year-­old boy was referred to the in-
tensive care unit (ICU) for persistent focal motor seizures,
preceded by 5 days of fever, headaches, asthenia, and
vomiting. His family history was unremarkable except
for his father suffering from lupus erythematosus. The
boy rapidly presented with generalized status epilepticus,
and alteration of consciousness (Day 1). He was intubated
for airway protection and placed in pharmacologically
induced coma. Daily video electroencephalograms (EEGs)
and continuous EEG monitoring evidenced a diffuse delta
activity, and persistent multifocal nonconvulsive seizures
(Figure 1). The initial brain magnetic resonance imag-
ing (MRI; Day 1) was normal. A second one (Day 10) re-
vealed bilateral enhanced T2 fluid-­attenuated inversion
recovery (FLAIR) signal of the hippocampi (Figure 1).
Cerebrospinal fluid (CSF) analysis on Day 1 found only
pleocytosis (35 lymph/mm3). The infectious workup was
negative in blood and CSF (cultures, herpes simplex virus,
Epstein–­Barr virus, cytomegalovirus, QuantiFERON).
The metabolic, autoimmune, and neuronal autoantibody
plasma and CSF screening was negative. Plasma levels of
cytokines (IL1, IL6, interferon) were normal on Day 4 and
Day 17 (see Appendix) and were not assessed in the CSF.
The status epilepticus was refractory to a combination
of ASMs (clonazepam, fosphenytoin, levetiracetam, phe-
nobarbital, lacosamide), anesthetics (midazolam, propo-
fol, ketamine), and ketogenic diet. Due to the underlying
inflammatory and noninfectious process, those symptom-
atic treatments were completed with immunomodulatory
therapy: intravenous methylprednisolone started on Day

F I G U R E 1 Presentation and treatment timeline of Case 1. The electroencephalogram (left upper panel) showed diffuse delta activity
and multifocal nonconvulsive seizures. Brain magnetic resonance imaging on Day 10 evidenced bilateral enhanced T2 fluid-­attenuated
inversion recovery signal of hippocampi (right upper panel). Treatment with tocilizumab was administered on Day 17 and Day 23, visible
within the chronological timeline of treatments (lower panel). CZP, clonazepam; D, day; IVIg, intravenous immunoglobulin; K DIET,
ketogenic diet; KET, ketamine; LCM, lacosamide; LEV, levetiracetam; MDZ, midazolam; MTPRED, methylprednisolone; NORSE, new onset
refractory status epilepticus; PB, phenobarbital; PHT, phenytoin; PL EXC, plasmatic exchange; PRO, propofol; TOCI, tocilizumab.

GIRARDIN et al.
3 for 5 days, intravenous immunoglobulin (IVIg) started
on Day 7 for 2 days, and six plasma exchanges from Day
11 to Day 16. The level of consciousness improved, as the
number of seizures decreased during plasma exchanges.
Due to the incomplete control of seizures, after a mul-
tidisciplinary meeting, tocilizumab (4 mg/kg) was admin-
istered on Day 17 and Day 23. Mechanical ventilation was
interrupted at Day 19, and the seizures stopped on Day 21.
Tolerance was good, without any infection. A 24-­h EEG
recording performed on Day 27 revealed normal back-
ground activity, without any seizures. The child rapidly
recovered his previous language level and motor abilities.
At Day 30, apart from a little disinhibition, the neuropsy-
chological evaluation did not evidence any cognitive or ex-
ecutive dysfunction. He was discharged at Day 45 from the
hospital and returned to his normal daily life. After 1 year,
the boy experienced brief monthly focal seizures, treated
with three ASMs, and his EEG showed rare left tempo-
ral slow waves. He is attending a regular primary school
and his neuropsychological evaluation is normal, except a
small attention deficit. A control MRI scan 4 months after
onset showed no hippocampal atrophy.
In summary, after a partial response to plasmapher-
esis, our 9-­year-­old patient recovered from the onset of
tocilizumab treatment on Day 17 and Day 23 and was dis-
charged from the ICU at day 27. His evolution is favor-
able after 1 year, with neuropsychological and behavioral
recovery, albeit focal epilepsy controlled with three ASMs.
3 | C A S E RE PORT 2
A 22-­year-­old man was admitted to the emergency depart-
ment on Day 1 for three generalized tonic–­clonic seizures,
preceded by fever, asthenia, possible ophthalmoplegia,
and stiffness for 7 days. His medical background was
rheumatoid purpura at the age of 4 years, no recent travel,
and up-­to-­date vaccination, including anti-­SARS-­CoV-­2
2 months prior. The patient was treated with a combina-
tion of propofol, levetiracetam, and fosphenytoin and in-
tubated, due to the alteration of consciousness.
The first EEG, prior to intubation, showed diffuse
high-­amplitude delta activity, predominating on the right
hemisphere, without seizures. After 5 days, his EEG de-
teriorated to persistent status epilepticus (Figure 2) with
prolonged focal fast activity and shifting seizures, as de-
scribed by Farias-­Moeller in FIRES.8 The brain MRI on
Day 1 found a cytotoxic lesion of corpus callosum. A third
brain MRI on Day 5 showed regression of this lesion but
bilateral T2 hyperintensity of the claustrum and hippo-
campi (Figure 2). The CSF analysis, on Day 2, revealed
normal findings (biology, virology, herpes simplex virus,
arbovirus panel, bacteriology). No sign of an evolutionary
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   e89
process or paraneoplastic lesion was noticed (whole body
computed tomography scan, testicular ultrasound, bone
marrow biopsy). Metabolic and neuronal antibody screen-
ing was negative in blood and CSF samples. Antinuclear
antibodies showed a 1/320 clearance, with no specificity.
High rates of IL6 and IL10 in blood and CSF were sugges-
tive of a major inflammatory process (see Appendix).
Epileptic seizures were uncontrolled despite the use
of 10 antiseizure treatments (propofol, levetiracetam, fo-
sphenytoin, lacosamide, carbamazepine, phenobarbital,
ketamine, topiramate, perampanel, and ketogenic diet).
A first line of immunomodulatory treatment consisted
of 3 days of methylprednisolone overlapping with 5 days
of IVIg, followed by five sessions of plasma exchange. No
clinical improvement was shown despite the decrease of
IL6 and IL10 rate in the CSF on Day 12. Additional treat-
ment included 4 days of thiopental coma with burst sup-
pression, but at the weaning of thiopental, shifting focal
fast activity seizures recurred. Then, given the persistent
status epilepticus, tocilizumab was administered on Days
12 and 21 at a dose of 8 mg/kg, with good tolerance and
ensuing gradual reduction of electroclinical seizures. On
Day 28, the sedation was stopped, and the patient woke
up, able to talk and interact. The ventilatory weaning was
possible on Day 31 without seizure recurrence, and the
EEG improved. His neurological examination revealed
major short-­term memory curtailing and cerebellar ataxia.
On Days 44 and 45, the patient suffered from auditory
hallucinations concomitant to bilateral perisylvian and tem-
porolateral hypermetabolism on positron emission tomog-
raphy. He further showed irritability and anxiety associated
with generalized and focal seizures. Therefore, an interdis-
ciplinary team decided to administer a third dose of tocili-
zumab. Symptoms were brought under control, enabling the
patient to be transferred to the neurology department. On
Day 60, centroparietal activity and subclinical focal seizures
were recorded on 24-­h EEG. Clinically, the patient was still
amnesic, and showed deficits in praxis, and attentive and ex-
ecutive functions, as well as ataxia. On Day 90, the patient
received a fourth dose of tocilizumab. At discharge to a reha-
bilitation unit, he remained under ASM polytherapy (cloba-
zam, levetiracetam, phenobarbital, topiramate).
At seizure recurrence in the rehabilitation unit, the na-
tional board of neuroinflammation experts recommended a
fifth dose of tocilizumab. This dose entailed severe neutropenia
warranting cessation of this treatment. Within the following
6 months, his memory markedly improved, but he continued
to have focal seizures and developed depressive symptoms.
After 9 months from onset, MRI showed moderate bilateral
hippocampal atrophy without enhanced T2 FLAIR signal.
Taken together, this 22-­year-­old patient showed no
significant electroclinical improvement prior to tocili-
zumab treatment. Following the second dose on Day 21,
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e90    GIRARDIN et al.

F I G U R E 2 Presentation and treatment timeline of Case 2. The electroencephalogram (left upper panel), performed during general
anesthesia, showed superrefractory status epilepticus with intermittent shifting seizures with right predominance. Magnetic resonance
imaging scans on Day 5 (right upper panel) revealed T2 fluid-­attenuated inversion recovery hypersignal in bilateral claustrum and
hippocampi. Tocilizumab was administered on Days 12 and 21 after symptoms onset as illustrated in the chronological timeline (lower
panel). CBZ, clobazam; D, day; IVIg, intravenous immunoglobulin; K DIET, ketogenic diet; KET, ketamine; LCM, lacosamide; LEV,
levetiracetam; MDZ, midazolam; MTPRED, methylprednisolone; NORSE, new onset refractory status epilepticus; PB, phenobarbital; PHT,
phenytoin; PL EXC, plasma exchange; PRO, propofol; PRP, perampanel; TOCI, tocilizumab; TPM, topiramate; TPT, thiopental.

he emerged rapidly to a satisfying neurological status. He
was discharged from the ICU at Day 45. As the epilepsy
relapsed, he received a total of five doses of tocilizumab.
Severe amnesia was the most debilitating neurological
deficit but improved gradually. He is still treated with an
ASM polytherapy for drug-­resistant focal epilepsy.
4 | DI S C USSION
In this report, we have described a boy and a young adult who
both developed FIRES. Despite failure of multiple ASMs, ke-
togenic diet, and anesthetic agents, both patients responded
to immunomodulatory therapy with tocilizumab, with cessa-
tion of seizures, 2 days after the first injection for the child, and
within 1 week after the second injection for the adult, which
allowed the weaning of anesthetic agents and ventilatory sup-
port. This treatment was administered quite early in the evo-
lution, in comparison to the previous publications. The first
injections were well tolerated in our patients. However the
fifth dose in Patient 2 caused severe neutropenia, and severe
infections were previously reported in two adults.6,7
Tocilizumab is an anti-­IL6 receptor humanized mono-
clonal antibody, already known to improve refractory auto-
immune neurologic diseases, such as neuromyelitis optica8
and autoimmune encephalitis.9 It has been proposed for
refractory seizures, as an elevation of IL6 levels is often
observed in this condition.5,10 This cytokine is involved in
neuroinflammation and may exacerbate the seizure activ-
ity. We have highlighted elevated IL6 plasma and CSF lev-
els in the adult patient, but not for the boy (see Appendix).
In children, the immunomodulatory strategy for FIRES/
NORSE is still debated, with the promoted use of IL1 recep-
tor antagonist anakinra.11 In a large retrospective study of
children treated with anakinra, the responder rate (reduc-
tion of seizures achieved > 50%) was 11 of 25, but no seizure
freedom was achieved.12 Moreover, successful treatment
with tocilizumab has been reported in a child with status
epilepticus refractory to anakinra13 and in a young woman
refractory to classic immunomodulatory therapies.14

GIRARDIN et al.
The long-­term neurological outcome of FIRES is
usually severe, with chronic refractory epilepsy, brain
damage, and persistent neurocognitive and psychiatric
impairment. After the cessation of the status epilepticus,
the neuropsychological and epileptic outcome of the child
case was favorable, whereas the adult patient experienced
several weeks of severe amnesia.
Regarding the limitations of our study, it needs to be
acknowledged that the response to tocilizumab in these
two cases occurred within a complex regimen of ASM and
immunological treatment. The spontaneous evolution
may also constitute a confounding factor, which precludes
concluding with certainty on the efficacy of tocilizumab
alone. Notwithstanding, in both cases clinical improve-
ment was noted within days of tocilizumab adminis-
tration. As suggested by Wickstrom et al.,5 we therefore
consider that tocilizumab should be included in the im-
munomodulatory armamentarium of FIRES/NORSE.
Finally, most studies report on short-­term seizure ces-
sation allowing weaning of the anesthetic agents, ventila-
tory support, and the reduction of ICU length stay. Yet, the
most important endpoint is obviously the long-­term bur-
den of neurological sequelae. More studies are warranted
to consolidate whether early acute administration of to-
cilizumab promotes a more favorable long-­term outcome
of this rare and devastating condition.
AUTHOR CONTRIBUTIONS
Marie-­Laure Girardin: Conceptualization (lead); writing–­
original draft (lead); formal analysis (lead); writing–­review
and editing (equal). Thomas Flamand: Writing–­review and
editing (equal). Ombeline Roignot: Writing–­review and
editing (equal). Marie-­Thérèse Abi Warde, Véronique
Mutschler, Paul Voulleminot, Max Guillot: Review and
editing (equal). Vera Dinkelacker: Writing–­original draft
(supporting); writing–­review and editing (equal). Anne De
Saint-­Martin: Conceptualization (lead); writing–­original
draft (supporting); writing–­review and editing (equal).
ACKNOWLEDGMENTS
We thank both patients and their families.
CONFLICT OF INTEREST STATEMENT
All authors declare that there is no conflict of interest in
this article.
ORCID
Anne De Saint-­Martin https://orcid.
org/0000-0003-4666-5369
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How to cite this article: Girardin M-L, Flamand
T, Roignot O, Abi Warde M-T, Mutschler V,
Voulleminot P, et al. Treatment of new onset
refractory status epilepticus/febrile infection-­
related epilepsy syndrome with tocilizumab in a
child and a young adult. Epilepsia. 2023;64:e87–
e92. https://doi.org/10.1111/epi.17591
 |

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e92    GIRARDIN et al.

APPENDIX

Case 1.
Dates Day 4 Day 18 Day 41 Day 78
Blood IL6, pg/mL (.6–­5.9), ELISA 1.2 0 19.1
Blood IL1, pg/mL (<0–­1 pg/mL) 2 .3 .2

Abbreviation: ELISA, enzyme-­linked immunosorbent assay.

Case 2.
Dates Day 2 Day 7 Day 12 Day 36
Blood IL-­6, pg/mL (.6–­5.9), ELISA 2.5 165 49.9
CSF IL-­6, pg/mL (0–­13) 200 4.1 9.8
Blood IL-­10, pg/mL (0–­3) 4.1 38.4 6.3
CSF IL-­10, pg/mL (0–­13) 9.6 1.7 67.9
Abbreviations: CSF, cerebrospinal fluid; ELISA, enzyme-­linked immunosorbent assay.