Epilepsia, 52(11):e172e175, 2011
doi: 10.1111/j.1528-1167.2011.03193.x
BRIEF COMMUNICATION
Acute-onset epilepsy triggered by fever mimicking FIRES
(febrile infectionrelated epilepsy syndrome): The role of
protocadherin 19 (PCDH19) gene mutation
Nicola Specchio, Lucia Fusco, and Federico Vigevano
Division of Neurology, Bambino Gesu Childrens Hospital IRCCS, Rome, Italy
SUMMARY
To report differences and similarities between febrile
infectionrelated epilepsy syndrome (FIRES) and epilepsy
in female patients with protocadherin 19 (PCDH19) muta-
tion. These are two recently described epileptic condi-
tions characterized by drug-resistant epilepsy and
cognitive impairment. We report, as exemplification, one
of our patients with acute-onset epilepsy triggered by
Febrile infectionrelated epilepsy syndrome (FIRES) is
a severe condition characterized by acute onset of status
epilepticus during a febrile illness and subsequent refractory
epilepsy in patients with previous normal development (van
Baalen et al., 2010). Cognitive outcome is variable, but in
most of cases, mental retardation and behavioral distur-
bances become evident during the course of epilepsy. Etiol-
ogy remains unknown. This condition has been already
described as idiopathic catastrophic epileptic encephalopa-
thy presenting with acute-onset intractable status (Baxter
et al., 2003), devastating epileptic encephalopathy in
school-aged children (DESC) (Mikaeloff et al., 2006), acute
encephalitis with refractory, repetitive partial seizures
(AERRPS) (Sakuma et al., 2010), and childhood refractory
focal epilepsy following acute febrile encephalopathy
(Specchio et al., 2010). Clinical, neurophysiologic, imaging
features, and treatment strategies have also been reported,
based mainly on its possible pathogenetic mechanisms
(Nabbout et al., 2011). The hypothesis on its etiology
ranges from immune-mediated (Specchio et al., 2010) to
inflammation-mediated mechanisms (Nabbout et al., 2011).
Possible differential diagnosis has been made with limbic
Accepted June 8, 2011; Early View publication July 21, 2011.
Address correspondence to Nicola Specchio, M.D., Division of Neurol-
ogy, Bambino Ges Childrens Hospital IRCCS, P.za S. Onofrio, 4 00165
Rome, Italy. E-mail: nicola.specchio@opbg.net
Wiley Periodicals, Inc.
2011 International League Against Epilepsy
e172
fever with clinical course resembling FIRES, but with a
missense mutation of PCDH19 gene. The clinical charac-
teristics of this patient are similar to those reported for
FIRES. We believe that female patients with febrile acute-
onset epilepsy resembling FIRES are potential PCDH19
mutation carriers.
KEY WORDS: FIRES, PCDH19, Acute onset epilepsy,
Febrile onset, Encephalopathy.
encephalitis (Meyer et al., 1995) and Alpers disease
(El Sabbagh et al., 2010).
Moreover, a similar acute onset, precipitated by a feb-
rile illness, is observed in female patients affected by
infantile-onset epilepsy associated with mental retardation
or behavioral disorders due to mutations of protocadherin
19 (PCDH19) gene located at Xq22 (Specchio et al.,
2011), which determine a calcium-dependent cellcell
adhesion molecule dysfunction (Dibbens et al., 2008).
The clinical boundary between the two conditions can be
subtle and each form can be mistaken for the other.
Within nine published and unpublished PCDH19 patients
(Marini et al., 2010; Specchio et al., 2011) followed at
Bambino Ges Childrens Hospital in Rome, three
patients presented (with) epilepsy onset during an acute
febrile illness with repetitive seizures or status epilepticus,
followed by chronic epilepsy, resembling FIRES. We
describe in detail one case to summarize the similarities
and the differences between FIRES and epilepsy due to
PCDH19 gene mutation.
Case Report
This is a 10-year-old girl born at term after an uneventful
pregnancy. Family history was unremarkable. At the age of
8 months during febrile rotavirus gastroenteritis she pre-
sented high frequency focal seizures that quickly evolved
toward status epilepticus. Seizure recording revealed both
asynchronous bilateral temporal and parietal seizure
onset, characterized by left or right eye deviation, bilateral
 e173
Epilepsy Due to PCDH19 Resembling FIRES

blinking, sometimes limbs automatisms, and evolving to
secondarily generalization. Subclinical ictal discharges
were also recorded. Interictal electroencephalography
(EEG) showed asynchronous bilateral central and posterior
slow waves, intermingled with rare posterior temporal epi-
leptiform abnormalities. Periodic lateralized epileptiform
discharges (PLEDs) were also evident over the posterior
right hemisphere. This acute phase lasted for 20 days during
which the patient presented as accompanying symptoms
fever, visual attention deficit, and soporous state. Brain
magnetic resonance imaging (MRI) was normal including
diffusion weighted images sequences. Blood samples were
obtained, and cerebrospinal fluid (CSF) analyses were per-
formed. Viral tests included herpes simplex virus (HSV) 1
and 2, rotavirus, enterovirus, varicella-zoster virus (VZV),
rubella, cytomegalovirus (CMV), parvovirus B19, toxo-
plasma, EpsteinBarr virus (EBV), enterovirus, human
herpesvirus 6 (HHV-6), and mumps. All virologic studies
were performed using DNA polymerase chain reaction
(PCR) and were normal except for rotavirus positivity.
Oligoclonal immunoglobulin (Ig)G bands (OBs), checked
with isoelectric focusing, were present. Blood examination,
moreover, revealed high titers of antibodies to b2-glyco-
protein and anticardiolipin. Metabolic examination
including lactic acid, organic acid, and amino acids were
normal.
During the follow-up the patient continued to present
focal seizures, sometimes evolving to secondary generaliza-
tion. Seizures recurred in clusters lasting several days every
35 months, and were characterized by screams, sometimes
fear expression of the face, psychomotor arrest, and motor
automatisms (head and eye deviation followed by right or
left focal motor seizures were sometimes also reported).
Interictal EEG showed bilateral asynchronous slow abnor-
malities and spikes-and-wave complexes over parietal, tem-
poral, and occipital areas. Ictal EEG showed left or right
frontal or temporal discharges characterized by rhythmic
focal low voltage theta activity increasing in amplitude
and decreasing in frequency. The following antiepileptic
medications were ineffective: carbamazepine, topiramate,
phenobarbital, valproate, levetiracetam, phenytoin, and
clobazam. During clusters only intravenous continuous
infusion of midazolam was useful. She was also treated with
intravenous immunoglobulin and methylprednisone with
inconstant results.
Soon after epilepsy onset cognitive and motor regression
was noted. Serial cognitive evaluations during the first
3 years of life revealed a mental developmental index
(MDI) of 68 at 9 months, <50 at 22 months, and remained
stable at 29 and 33 months, indicative of a moderate-
severe mental retardation. She also presented a pervasive
developmental disorder (PDD) characterized by autistic

Table 1. Summary of clinical findings and diagnostic examinations in FIRES and PCDH19 patients
Epilepsy with PCDH19 mutation FIRES
Age at onset 3 months to 3.5 years 315 years
Sex Restricted to female Male preponderance
Conditions that precede onset Viral illness sometimes Viral illness constant (respiratory infection)
Fever at onset Most of cases Always
Number of seizures at onset Repetitive/status epilepticus Repetitive/status epilepticus
Type of seizures Focal with SG Focal with SG
Requiring ICU admission Not constant Almost constant
and intubation
Interictal EEG onset Bilateral SW, rare focal Diffuse SW, multifocal of focal
epileptiform abnormalities epileptiform abnormalities
Ictal EEG onset Diffuse or frontal and Mainly frontal and temporal discharges
temporal focal discharges (both hemispheres)
(both hemispheres)
MRI onset Normal Normal or increased T2 signal intensity in
bilateral temporomesial structures or insula
Treatment onset Benzodiazepine more effective AED ineffective (barbiturate induced coma
(barbiturate induced coma rare) frequent)
Drug resistance follow-up Frequent but prolonged seizure-free Constant
periods are reported in some patients
Seizure frequency follow-up Variable (weekly/monthly/yearly) Variable (weekly/monthly)
Cluster reported as main feature Cluster reported
Type of seizures follow-up Focal sometimes with SG, absences, myoclonia Focal sometimes with SG
Interictal EEG follow-up Normal, bilateral SW, rare epileptiform Asynchronous bilateral SW and epileptiform
abnormalities abnormalities (frontal, temporal, multifocal)
Cognitive outcome Cognitive deficit, autistic features, behavioral Severe cognitive deficits, behavioral disturbances
disturbances, normal cognitive outcome also
reported
ICU, Intensive care unit; SG, secondary generalization; SW, slow waves; AED, antiepileptic drug.

Epilepsia, 52(11):e172e175, 2011

doi: 10.1111/j.1528-1167.2011.03193.x
e174
N. Specchio et al.
features and language delay. At the age of 7 years PCDH19
sequencing disclosed the new de novo missense hetero- diseases. Regarding cognitive and motor skills during the
zygous c.1129G>C (p.Asp377His) mutation. Partial data of
this patient have been already reported (Marini et al., 2010,
Patient 7).
Discussion
The clinical features of epilepsy onset and evolution in
the patient described could be suggestive of FIRES. This is,
however, one of the possible phenotypes of PCDH19
presentation. Other two different phenotypes have been
described (Marini et al., 2010): The first is characterized by
focal epilepsy and the second by epileptic encephalopathy
with Dravets syndromelike features. The FIRES-like
clinical picture might be a third phenotype of PCDH19
presentation. In our series a similar febrile acute onset of
the disease was recognized in 30% of patients (three of
nine).
Similarities between the two conditions should be
acknowledged. Febrile acute onset with repetitive high fre-
quency seizures is clearly reported in patients with FIRES
(van Baalen et al., 2010), and also with PCDH19 mutations
(Marini et al., 2010; Specchio et al., 2011). In the acute
phase, antiepileptic drugs (AEDs) are ineffective both in
FIRES and PCDH19 patients, whereas intravenous midazo-
lam continuous infusion might be effective in PCDH19
patients. In chronic phase, seizures tend to decrease sponta-
neously, despite the treatment. Neuroimaging is most of the
time normal in both conditions: In some patients, tempo-
romesial or insular hyperintensity has been reported for
FIRES, but these data are inconstant (van Baalen et al.,
2010). An encephalitic process is suspected in both condi-
tions, despite normal CSF examination, because of febrile
onset, sometimes associated with soporous state and interic-
tal EEG slow waves.
Seizures semiology might be similar in the two condi-
tions, but some differences should be acknowledged.
In FIRES, although mainly tonicclonic generalized
seizures have been reported (van Baalen et al., 2010), focal
seizures with eye deviation and sometimes automatisms
(Specchio et al., 2010), or chewing movements have also
been described (Nabbout et al., 2011). In PCDH19 patients,
seizures are mainly focal with or without motor component,
but a generalized onset has been noted. On the other side
myoclonic seizures have been observed in PCDH19 patients
(Marini et al., 2010) but not in FIRES. In both diseases
seizures arise, independently from right and left hemi-
spheres and tend to appear isolated or in clusters.
The main differences between these two clinical condi-
tions are: age at onset, ranging between 6 and 38 months in
PCDH19 patients and between early childhood and the sec-
ond decade in FIRES patients. In FIRES, apparently a male
predominance is evident (van Baalen et al., 2010), whereas
PCDH19 patients are all female. Table 1 summarizes the
Epilepsia, 52(11):e172e175, 2011
doi: 10.1111/j.1528-1167.2011.03193.x
clinical characteristics and differences between these two
follow-up, FIRES has mostly a severe disease course with
cognitive regression and motor deficits, whereas autistic
features seem to predominate in PCDH19 patients. Normal
cognitive development has also been reported in PCDH19
patients (Marini et al., 2010; Specchio et al., 2011). At
onset, the main clinical findings might overlap and some
differences could indeed be evident during the follow-up.
Considering the data reported, we believe that female
patients with febrile acute-onset epilepsy resembling
FIRES are potential mutation carriers. Female patients
with these clinical findings should be tested for PCDH19
mutation, as molecular diagnosis is relevant for the
patients management in order to find better therapeutic
strategies, to help avoiding useless invasive and expensive
diagnostic testing, and to improve genetic counseling.
Acknowledgments
We thank Mrs. Sylvia Fanfani for her help in the English editing of the
text.
Disclosure
The authors have nothing to disclose. We confirm that we have read the
Journals position on issues involved in ethical publication and affirm that
this report is consistent with those guidelines.
References
Baxter P, Clarke A, Cross H, Harding B, Hicks E, Livingston J, Surtees R.
(2003) Idiopathic catastrophic epileptic encephalopathy presenting with
acute onset intractable status. Seizure 12:379387.
Dibbens LM, Tarpey PS, Hynes K, Bayly MA, Scheffer IE, Smith R, Bomar
J, Sutton E, Vandeleur L, Shoubridge C, Edkins S, Turner SJ, Stevens
C, OMeara S, Tofts C, Barthorpe S, Buck G, Cole J, Halliday K, Jones
D, Lee R, Madison M, Mironenko T, Varian J, West S, Widaa S, Wray
P, Teague J, Dicks E, Butler A, Menzies A, Jenkinson A, Shepherd R,
Gusella JF, Afawi Z, Mazarib A, Neufeld MY, Kivity S, Lev D,
Lerman-Sagie T, Korczyn AD, Derry CP, Sutherland GR, Friend K,
Shaw M, Corbett M, Kim HG, Geschwind DH, Thomas P, Haan E,
Ryan S, McKee S, Berkovic SF, Futreal PA, Stratton MR, Mulley JC,
Gcz J. (2008) X-linked protocadherin 19 mutations cause female-
limited epilepsy and cognitive impairment. Nat Genet 40:776781.
El Sabbagh S, Lebre AS, Bahi-Buisson N, Delonlay P, Soufflet C, Boddaert
N, Rio M, Rtig A, Dulac O, Munnich A, Desguerre I. (2010) Epileptic
phenotypes in children with respiratory chain disorders. Epilepsia
51:12251235.
Marini C, Mei D, Parmeggiani L, Norci V, Calado E, Ferrari A, Moreira A,
Pisano T, Vigevano F, Specchio N, Battaglia D, Guerrini R. (2010)
Protocadherin 19 mutations in girls with infantile onset epilepsy.
Neurology 75:646653.
Meyer JJ, Bulteau C, Adamsbaum C, Kalifa G. (1995) Paraneoplastic ence-
phalomyelitis in a child with neuroblastoma. Pediatr Radiol 25(s1):
99101.
Mikaeloff Y, Jambaqu I, Hertz-Pannier L, Zamfirescu A, Adamsbaum C,
Plouin P, Dulac O, Chiron C. (2006) Devastating epileptic encephalop-
athy in school-aged children (DESC): a pseudo encephalitis. Epilepsy
Res 69:6779.
Nabbout R, Vezzani A, Dulac O, Chiron C. (2011) Acute encephalopathy
with inflammation-mediated status epilepticus. Lancet Neurol 10:99
108.

Sakuma H, Awaya Y, Shiomi M, Yamanouchi H, Takahashi Y, Saito Y,
Sugai K, Sasaki M. (2010) Acute encephalitis with refractory, repetitive
partial seizures (AERRPS): a peculiar form of childhood encephalitis.
Acta Neurol Scand 121:251256.
Specchio N, Fusco L, Claps D, Trivisano M, Longo D, Cilio MR,
Valeriani M, Cusmai R, Cappelletti S, Gentile S, Fariello G,
Specchio LM, Vigevano F. (2010) Childhood refractory focal epilepsy
following acute febrile encephalopathy. Eur J Neurol 18:952
961.
e175
Epilepsy Due to PCDH19 Resembling FIRES
Specchio N, Marini C, Terracciano A, Mei D, Trivisano M, Sicca F, Fusco
L, Cusmai R, Darra F, Dalla Bernardina B, Bertini E, Guerrini R, Vige-
vano F. (2011) Spectrum of phenotypes in females with epilepsy due to
protocadherin 19 mutations. Epilepsia doi: 10.1111/j.1528-1167.2011.
03063.x.
van Baalen A, Husler M, Boor R, Rohr A, Sperner J, Kurlemann G, Panzer
A, Stephani U, Kluger G. (2010) Febrile infection-related epilepsy
syndrome (FIRES): a nonencephalitic encephalopathy in childhood.
Epilepsia 51:13231328.
Epilepsia, 52(11):e172e175, 2011
doi: 10.1111/j.1528-1167.2011.03193.x