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Acute-onset epilepsy triggered by fever mimicking FIRES (febrile infection relatedepilepsy syndrome): The role of protocadherin 19 ( PCDH19 ) gene mutation

1. Nicola Specchio,

2. Lucia Fusco and

3. Federico Vigevano

Article first published online: 21 JUL 2011

DOI: 10.1111/j.1528-1167.2011.03193.x

Wiley Periodicals, Inc. 2011 International League Against Epilepsy

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Epilepsia

Volume 52 , Issue 11 , pages e172 e175 , November 2011

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Abstract Article References Cited By

Enhanced Article (HTML) Get PDF (54K) Keywords:

FIRES;

PCDH19;

Acute onset epilepsy;

Febrile onset;

Encephalopathy

Summary

To report differences and similarities between febrile infection related epilepsy syndrome (FIRES) and epilepsy in

female patients with protocadherin 19 ( PCDH19 ) mutation. These are two recently described epileptic conditions

characterized by drug-resistant epilepsy and cognitive impairment. We report, as exemplification, one of our patients

with acute-onset epilepsy triggered by fever with clinical course resembling FIRES, but with a missense mutation

of PCDH19 gene. The clinical characteristics 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.

Febrile infection related 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

disturbances become evident during the course of epilepsy. Etiology remains unknown. This condition has been

already described as idiopathic catastrophic epileptic encephalopathy 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 encephalitis (Meyer et al., 1995 ) and Alpers disease (El Sabbagh et al., 2010 ).Moreover, a similar acute onset, precipitated by a febrile 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 cell cell 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.,

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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 presented 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 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 ra re posterior temporal

epileptiform 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 performed. Viral tests included herpes simplex virus (HSV) 1 and 2, rotavirus, enterovirus, varicella-

zoster virus (VZV), rubella, cytomegalovirus (CMV), parvovirus B19, toxoplasma, Epstein Barr 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

2 -glycoprotein 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 generalization.

Seizures recurred in clusters lasting several days every 3 5 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

abnormalities and spikes-and-wave complexes over parietal, temporal, and occipital areas. Ictal EEG showed left or

right frontal or temporal discharges characterized by rhythmic focal low voltage theta activity increasing in amplitudeand 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.

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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, 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 syndrome like 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 frequency

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 midazolam continuous infusion might be effective in PCDH19 patients. In

chronic phase, seizures tend to decrease spontaneously, despite the treatment. Neuroimaging is most of the time

normal in both conditions: In some patients, temporomesial 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 conditions, despite

normal CSF examination, because of febrile onset, sometimes associated with soporous state and interictal EEG

slow waves.

Seizures semiology might be similar in the two conditions, but some differences should be acknowledged. In FIRES,

although mainly tonic clonic 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 hemispheres

and tend to appear isolated or in clusters.

The main differences between these two clinical conditions are: age at onset, ranging between 6 and 38 months

in PCDH19 patients and between early childhood and the second 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 clinical characteristics and differences between these two diseases. Regarding

cognitive and motor skills during the follow-up, FIRES ha s mostly a severe disease course with cognitive regression

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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.

Epilepsy with PCDH19 mutation FIRES

1. ICU, Intensive care unit; SG, secondary generalization; SW, slow waves; AED, antiepileptic drug.

Age at onset 3 months to 3.5 years 3 15 years

Sex Restricted to female Male preponderance

Conditions that precede

onsetViral illness sometimes Viral illness constant (respiratory infection)

Fever at onset Most of cases Always

Number of seizures at

onsetRepetitive/status epilepticus Repetitive/status epilepticus

Type of seizures Focal with SG Focal with SG

Requiring ICU admission

and intubation Not constant Almost constant

Interictal EEG onset Bilateral SW, rare focal epileptiform abnormalitiesDiffuse SW, multifocal of focal epileptiform

abnormalities

Ictal EEG onsetDiffuse or frontal and temporal focal discharges (both

hemispheres)

Mainly frontal and temporal discharges (both

hemispheres)

MRI onset Normal Normal or increased T 2 signal intensity in bi

temporomesial structures or insula

Treatment onset Benzodiazepine more effective (barbiturate induced coma rare) AED ineffective (barbiturate induced coma frequent)

Drug resistance follow-upFrequent but prolonged seizure-free periods are reported in

some patientsConstant

Seizure frequency follow-

up

Variable (weekly/monthly/yearly) Cluster reported as main

featureVariable (weekly/monthly) Cluster reported

Type of seizures follow-

upFocal sometimes with SG, absences, myoclonia Focal sometimes with SG

Interictal EEG follow-up Normal, bilateral SW, rare epileptiform abnormalities Asynchronous bilateral SW and epileptiform

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Epilepsy with PCDH19 mutation FIRES

abnormalities (frontal, temporal, multifocal)

Cognitive outcomeCognitive deficit, autistic features, behavioral disturbances,

normal cognitive outcome also reportedSevere cognitive deficits, behavioral disturban

Table 1. Summary of clinical findings and diagnostic examinations in FIRES and PCDH19 patients