The expanding spectrum of febrile infection-related epilepsy syndrome (FIRES).
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ABSTRACT: We conducted a nationwide multicenter study in Japan to elucidate the clinical and laboratory characteristics of acute encephalitis with refractory, repetitive partial seizures (AERRPS). Clinical and laboratory features, treatment, and outcome were assessed using a structured questionnaire. Twenty-nine children were enrolled in the study. Refractory and repetitive partial seizures accompanied by fever were the cardinal clinical features. Partial seizures consisted principally of eye deviation or facial twitching, being periodically repeated during the acute phase. These seizures were refractory to conventional anticonvulsants and were only suppressed by high-dose intravenous barbiturate administration. Rhythmic activities on electroencephalography and non-specific cerebral atrophy on neuroimaging were common. Serum or cerebrospinal antibodies against GluRepsilon2 were positive in six patients. General prognosis was unfavorable due to intractable epilepsy and cognitive deficits. Based on the peculiar and homogenous features, AERRPS can be regarded as a distinct clinical entity.Acta Neurologica Scandinavica 12/2009; 121(4):251-6. · 2.47 Impact Factor
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ABSTRACT: P>Encephalitis is generally presumed, even when seizures follow banal febrile infection, and pathogen detection in cerebrospinal fluid fails. This retrospective multicenter case series reports on 22 previously healthy children aged 3-15 years (median 6.5 years) with prolonged or recurrent seizures occurring 2-14 days (median 5 days) after fever onset (19 children with respiratory or nonspecific infections). Cerebrospinal fluid studies revealed 2-42 cells/mu l (median 5 cells/mu l) and no pathogens. Electroencephalography showed diffuse slowing or multifocal discharges. Neuroimaging demonstrated normal findings in 10 children. Brain biopsies were performed in seven children showing gliosis but no inflammation. Anesthetic barbiturates were used in 14 children with refractory status epilepticus, and immunotherapy in 9. Two children died, eight remained in a state of impaired consciousness, eight developed therapy-refractory epilepsies, two had behavioral disturbances, and two recovered. The lack of evidence for encephalitis suggests another infection-related pathogenesis of this disastrous epileptic encephalopathy. Therefore, we propose the term "febrile infection-related epilepsy syndrome" (FIRES).Epilepsia 03/2010; 51(7):1323-1328. · 3.96 Impact Factor
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ABSTRACT: To characterise a homogeneous group of patients with new-onset refractory status epilepticus (NORSE syndrome). This is a descriptive, semiprospective review of all cases of NORSE syndrome seen between 2000 and 2004 at a tertiary care public hospital in Singapore. A review of the literature was performed to identify possible additional similar cases for comparison. Seven patients with NORSE syndrome were identified. Characterising features were female gender, young age, previous good health, cerebrospinal fluid pleocytosis (in 4), antecedent febrile illness (in 5), extraordinarily prolonged status epilepticus (average 32 days), failure of extensive investigations to reveal an underlying cause, catastrophic outcome as well as temporal lobe and leptomeningeal abnormality on brain magnetic resonance imaging. A review of the literature identified 12 similar patients, comprising both adults and children. Based on our patients and those described in the literature, we characterise the NORSE syndrome. Increased recognition of this clinical entity is needed to help delineate the underlying aetiology of this unique severe illness.Annals of the Academy of Medicine, Singapore 09/2005; 34(7):417-20. · 1.36 Impact Factor
The expanding spectrum of febrile infection-related epilepsy syndrome (FIRES)
Pedro J. Serrano-Castro*, Pablo Quiroga-Subirana, Manuel Paya ´n-Ortiz, Javier Fernandez-Perez
Neurology and Neurophysiology Unit, Complejo Hospitalario Torreca ´rdenas, Almeria, Spain
In recent years, a number of phenomena included in the group
of probable epileptic encephalopathies of autoimmune origin have
been described. Their common denominator is abrupt onset,
usually after a self-limited febrile illness, and a clinical picture of
repetitive seizures or difficult-to-control status epilepticus. These
symptoms occur mostly in children and have received a wide range
of names, despite their highly similar presentations with minor
distinctive aspects. Such denominations include acute encephalitis
with refractory repetitive partial seizures (AERRPS),1febrile
infection-related epilepsy syndrome (FIRES)2or new-onset refrac-
tory status epilepticus (NORSE).3
Recently, several authors have advocated a simplification of this
heterogeneous range of diagnoses, with Ismail and Kossoff4
suggesting the definition of a single post-infectious syndrome
with common characteristics.
We report a case of acute encephalopathy after a febrile illness
with complete remission of symptoms following antiepileptic and
steroid treatment. We conducted an extensive workup including
Video-EEG monitoring and speculate on the nature and classifica-
tion of these syndromes and their growing clinical spectrum.
2. Case report
The patient was a 19-year-old female with no relevant personal
or family history. She was born after normal pregnancy
and delivery and she also had normal acquisition of psychomotor
developmental milestones. There were no significant comorbid
In the week prior to admission, the patient experienced a flu-
like illness with fever, myalgia and malaise. Within a week, she
developed sudden-onset paroxysmal episodes of a painful
‘‘cramping’’ affecting the right arm and hand, and occasionally
the right leg, with Jacksonian progression to the face, dysarthria,
salivation, and clustering (up to 30–40 episodes in 1 day). She
remained conscious throughout the episodes and could remember
them. This situation was also present 3 days prior to admission.
Brain MRI performed 3 days after seizure onset showed a
hyperintense area in both insular regions, more evident on the
right (Fig. 1). These MRI findings are suggestive of an inflammatory
process involving cortical areas although they have also been
described as a consequence of repeated seizures.5
Video-EEG monitoring showed abundant seizure episodes
similar to those described by the patient, even during sleep. The
nocturnal episodes coincided with irritative activity composed of
spikes and sharp waves starting in the temporal regions bilaterally
and reflected clinically as versive head deviation, as well as oral
Seizure 22 (2013) 153–155
A R T I C L E
I N F O
Received 23 October 2012
Received in revised form 15 November 2012
Accepted 16 November 2012
Febrile infection-related epilepsy
Fig. 1. MR imaging in acute phase. Axial FLAIR sequences. Hyperintense area in both
insular regions, more evident on the right.
* Corresponding author. Tel.: +34 671562365; fax: +34 950016284.
E-mail address: email@example.com (P.J. Serrano-Castro).
Contents lists available at SciVerse ScienceDirect
jou r nal h o mep age: w ww.els evier .co m/lo c ate/ys eiz
1059-1311/$ – see front matter ? 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
and swallowing automatisms (Supplementary Video 1). There was
no secondary generalization.
Supplementary material related to this article found, in the
online version, at http://dx.doi.org/10.1016/j.seizure.2012.11.006.
CSF analysis showed 6 cells and normal glucose and protein
levels. No immunoreactivity was detected to intracytoplasmic
neural antigens (Hu, Ri, Yo, Amphiphysin) or to surface antigens
(NMDAR, LGI1 or other potassium channels). Serological and PCR
tests for neurotropic viruses (including herpes group viruses and
HIV) were negative.
A neuroimaging screen for occult neoplasms, including a
specific search for ovarian teratomas, was also negative.
IV levetiracetam, clonazepam and methylprednisolone pulses
(1000 mg/day for 5 consecutive days) were administered. There
was dramatic improvement both from the clinical and neuroim-
aging standpoint. One month after onset, the patient was
asymptomatic and receiving eslicarbazepine acetate as secondary
The clinical spectrum of epileptic encephalopathies of autoim-
mune origin has expanded greatly in the last 30 years.6
Traditionally, limbic encephalitis was the prototype of these
diseases, which were typically conceived as paraneoplastic
syndromes associated with antibodies directed against intracellu-
lar targets (onconeural antigens) and usually had a poor outcome
despite immunomodulatory therapy.7
The following years saw the description of a number of
antibodies directed against extracellular targets (known as surface
antigens) representing neural protein domains in their native
conformation,8especially those directed against voltage-gated
potassium channels (VGKC) and, more recently, those directed
against receptors of the N-methyl-D-aspartate (NMDA) complex.9
The common denominator of these manifestations was the
presence of limbic encephalitis, clinically defined by the triad of
amnesia, disorientation and complex partial seizures. Over the last
two years, the subgroup of patients with limbic encephalitis
associated with VGKC antibodies has been subdivided by virtue of
our ability to identify specific ligands within the receptor. Thus, we
have identified syndromes associated with the presence of
antibodies against the leucine-rich, glioma-inactivated protein
(LGI1) (related to limbic encephalitis with acute dystonic
faciobrachial seizures) and with contactin-associated protein 2
(CASPR2) or contactin-2, which are more related to peripheral
nervous system impairment of the neuromyotonia or Morvan
In recent years, another subtype of syndromes has been defined,
also presumed to be autoimmune in nature, but with two common
features: febrile infection in the weeks prior to the acute onset of
an extraordinary high seizure activity most difficult to treat.
These include the so-called febrile infection-related epilepsy
syndrome (FIRES). van Baalen et al.2and Kramer et al.10published
the most important series describing this phenomenon to date and
outlined the clinical profile of FIRES. Symptoms were most
prevalent in patients under the age of 15, and there was a slight
male predominance. All patients had suffered an infection in the
week prior to the onset of symptoms. Respiratory tract infections
were the most common (more than 50%). The natural history of
FIRES is typically biphasic, with a seizure-free period between
the resolution of fever and the onset of symptoms ranging from
2 to 14 days. Thereafter, the acute period of the disease develops,
lasting from 1 to 12 weeks (mean, 3 weeks). Most cases had a poor
prognosis; the mortality rate was 9% and many patients were left
with cognitive sequelae, which were occasionally severe.
Apart from antibody-related encephalitis, other pathogenetic
mechanisms have been proposed for FIRES. These alternative
hypotheses grant a special role to the innate immune system11or
even to a genetic predisposition.12
Our case meets the diagnostic criteria for FIRES, with several
characteristics that seem relevant.
The first concerns its localization in terms of the epileptogenic
region. In most cases of FIRES described hitherto, the epileptogenic
zone identified is limited to the medial temporal lobe. In our case,
however, acute phase MRI studies identify hyperintensities located
in bilateral insular areas without evidence of hippocampal
damage. Four cases previously reported by van Baalen and
Kramer2,10also showed unilateral or bilateral insular involvement.
We clarify that patients with insular involvement in both series are
the same. Any case, insular damage must be considered a rare
location in FIRES as it has been described in less than 9% of cases
reported in the most relevant series.
The second difference concerns prognosis. Our patient was
asymptomatic after the acute phase and after one year of follow-
up. Most patients in previous series did not obtain positive
outcomes despite the use of immunomodulatory therapy (i.e.
methylprednisolone pulses or intravenous immunoglobulin).
Nevertheless, around 15% of the patients had a good medium-
term evolution despite the fact that FIRES is considered a
‘‘catastrophic syndrome’’ (Table 1). In addition, 7 out of 14
patients who showed good evolution had not received any type of
immunosuppressive therapy. Moreover, our case suggests the
existence of a benign subgroup of patients with FIRES. Table 1
shows that these patients tend to be older than those with worse
evolution (9.4 years old vs. 7.5 years old). This may be explained by
the fact that an older brain is also a fully mature brain. Our patient
was 19 years old and, therefore, probably had more possibilities of
obtaining a good outcome.
Our case serves as a warning sign of the increasing recognition
of febrile infection-related epileptic encephalopathies that are not
necessarily confined to children or localized to the medial
temporal lobe. The prognosis of FIRES may be better in adults.
Revision of the previous series of FIRES concerning to the outcome and immunosuppressive treatments. IvIg, intravenous immunoglobulin; y-o, years old; and MP,
methylprednisolone pulses. Patient of series by van Baalen are included in the series by Kramer.
Patients with normal
Median age (range) in normal
outcome patients vs cognitive
impairment patients or death
treatment (IS) in normal
IS in the patients with
patients or death
9.3 y-o (range 2–15)
vs 7.6 y-o (range 2–17)
No treatment 5/12 (41.6%)
IS treatment, 7/12 (58.4%)
No treatment 8/65 (12.3%)
IS treatment 26/65 (40%)
IvIg 1/12 (8.3%)
MP 2/12 (16.6%)
MP + IgIV 4/12
IvIG 11/65 (16.9%)
MP 4/65 (6.1%)
MP + IvIg 11/65
Unknown 31/65 (47.7%)
No treatment 10/20 (50%)
IS treatment 10/20 (50%)
10 y-o (range 9–11)
vs 7.5 y-o (range 3–15)
No treatment 2/2 (100%)
P.J. Serrano-Castro et al. / Seizure 22 (2013) 153–155
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