Fever as a seizure precipitant factor in Panayiotopoulos syndrome:
A clinical and genetic study
Duccio Maria Cordellia,b, Anna Aldrovandia, Valentina Gentilea, Caterina Garonea, Sara Contia,
Arianna Acetic, Elena Gennarod, Federico Zarad, Emilio Franzonia,*
aChild Neurology and Psychiatry Unit, University of Bologna, S. Orsola-Malpighi Hospital, via Massarenti 11, 40138 Bologna, Italy
bPhD School in Applied Neurological Sciences, University of Siena, Viale Bracci 16, Siena, Italy
cDepartment of Pediatrics, University of Bologna, S. Orsola-Malpighi Hospital, via Massarenti 11, 40138 Bologna, Italy
dLaboratory of Human Genetics, Galliera Hospital, via Volta 6, 16128 Genova, Italy
Panayiotopoulos syndrome (PS) is a ‘‘benign age-related focal
seizure disorder occurring in early and mid childhood. It is
characterized by seizures, often prolonged, with predominantly
autonomic symptoms, and by an EEG that shows shifting and/or
multiple foci, often with occipital predominance’’.1,2Autonomic
seizures in PS consist of episodes characterized by emetic
symptoms usually accompanied by other autonomic features
(colour changes, especially pallor, pupillary changes, cardiorespi-
ratory and thermoregulatory alterations) and more conventional
ictal clinical manifestations such as unilateral deviation of the eyes
and convulsions.1,2PS starts at a peak age of 3–6 years, with no
apparent sex or race prevalence, and affects about 6% of children
with seizures aged 1–15 years.3An increased rate of febrile
seizures is reported in patients with PS3; also, it has been reported
that in patients with PS, autonomic seizures can occur during a
febrile illness.4,5In these patients, mutations of the sodium
channel, voltage-gated, type I, alpha subunit gene (SCN1A) have
The aim of the present study is to examine the role of fever as a
triggering factor for autonomic seizures in patients with PS, and to
evaluate the pathogenetic role of SCN1A gene in PS patients with
seizures triggered by fever.
2. Patients and methods
The medical records of patients referred to the Child Neurology
and Psychiatry Unit of S. Orsola-Malpighi Hospital, Bologna, for
seizures from January 2000 to June 2008 were reviewed. All the
patients who fulfilled the following diagnostic criteria for
Panayiotopoulos syndrome were enrolled in the study: (a) age
at the onset of epilepsy from 1 to 14 years; (b) presence of at least
one autonomic seizure of unequivocal epileptic origin; (c) normal
neurological and mental status; and (d) normal brain imaging.
Seizure 21 (2012) 141–143
A R T I C L E
I N F O
Received 5 August 2011
Received in revised form 27 September 2011
Accepted 28 September 2011
A B S T R A C T
Purpose: To examine fever as a precipitating factor for focal seizures in patients with Panayiotopoulos
syndrome (PS) and evaluate the role of SCN1A in PS patients with seizures triggered by fever.
Methods: From January 2000 to June 2008, we identified patients referred for seizures who fulfilled the
criteria of PS. Patients were divided into two groups, according to the presence (group A) or the absence
(group B) of seizures triggered by fever. Electroclinical features of the two groups were compared. In
addition, an analysis of SCN1A in patients of group A was performed.
Results: Thirty patients fulfilled the inclusion criteria. Eleven patients (36%) had at least one focal
autonomic seizure triggered by fever (group A). In group A, 7/11 patients (63.5%) had the first focal
autonomic seizure during a febrile illness. Two of these 7 patients were misdiagnosed at the onset of PS.
The median age at the onset of PS was slightly lower in group A than in group B (p = .050). Moreover,
patients in group A more frequently had a positive familial history of febrile seizures (FS) (p = .047). No
mutations of SCN1A were found in any of the 10 patients screened.
Conclusion: Fever is a common trigger for focal autonomic seizures in PS. Knowing that an autonomic
manifestation during fever can be an epileptic seizure could facilitate diagnosis and prevent unnecessary
investigations and erroneous treatments. Moreover, our data show that SCN1A gene does not contribute
significantly to susceptibility to autonomic seizures during fever in patients with PS.
? 2011 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +39 051 6363994; fax: +39 051 304839.
E-mail address: email@example.com (E. Franzoni).
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1059-1311/$ – see front matter ? 2011 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Patients with paroxysmal autonomic manifestations of none-
pileptic origin were excluded. Symptomatic epilepsy and preex-
isting neurodevelopmental abnormalities were considered as
exclusion criteria. EEG features were not considered as inclusion
or exclusion criteria due to the current evidence that PS is a
multifocal epileptic syndrome with a significant EEG variability.3
The following data were collected: familial history of seizures;
pre- and perinatal antecedents; neurologic development; epileptic
history; semiology of seizures; EEG features; brain magnetic
resonance imaging (MRI); and treatment. Outcome was assessed
only for patients that had ?3 years of follow-up.
The patients enrolled were then divided into two groups,
according to the presence (group A) or absence (group B) of
seizures triggered by fever. For the purpose of this study, a seizure
was considered as triggered by fever only if it occurred during a
febrile illness of documented origin. Specifically, group A included
PS patients who had at least one seizure during febrile illness,
while group B included PS patients who had never had seizures
triggered by fever.
Demographic variables, familial history of febrile seizures (FS)
and/or epilepsy, age at onset, the occurrence of misdiagnosis,
secondary generalization, duration of seizures, number of seizures,
EEG features at the onset of the disease, therapy with antiepileptic
drugs (AEDs) and outcome in the two groups were compared.
In group A, the number of patients who had a focal autonomic
seizure during fever at the onset of PS, the rate of focal autonomic
seizures during fever, and the etiology of febrile illnesses were also
2.1. Genetic analysis
In patients of group A, SCN1A mutational screening was
performed by denaturing high-performance liquid chromatogra-
phy (DHPLC) and multiplex ligation probe amplification (MLPA).
The study protocol was approved by the Ethical Committee of S.
Orsola-Malpighi Hospital in Bologna (protocol code: PAN 2010,
trial no. 37/2010/O/Tess).
Written, informed consent was obtained from the patients’
parents or caregivers.
2.2. Statistical analysis
Statistical analysis was performed by Statistical Package for the
Social Sciences (SPSS) 16.0 (SPSS Inc., Chicago, IL, USA) for
Windows. Categorical variables were compared by chi-square
test, while continuous variables were compared by Mann–
Whitney test. The level of significance was set at p ? 0.05.
3.1. Demographic and clinical data
Thirty patients (14 males and 16 females) fulfilled the inclusion
Eleven patients (36%) had at least one focal autonomic seizure
triggered by fever, and thus were included in group A; four of these
11 patients had, in addition, one or more seizures triggered by
fever described as generalized tonic clonic seizure (GTCS). The
remaining 19 patients (64%), who were included in group B, had no
history of seizures during febrile illness.
The male/female ratio was comparable between the two
groups. No significant difference was found between the two
groups regarding: the number of seizures; the occurrence of
secondary generalization and of autonomic status epilepticus; EEG
features at the onset of disease; the use of AEDs; and outcome.
The median age at the onset of PS was slightly lower in group A
than in group B (p = .050). Moreover, patients in group A more
frequently had a positive familial history of FS (p = .047), while no
differences in familial history of epilepsy were found between the
two groups. In group A, 7 patients (63.5%) had their first focal
autonomic seizure during a febrile illness. Two of these 7 patients
were misdiagnosed at the onset of PS. One patient was diagnosed
and treated for febrile gastroenteritis, while the other patient had a
febrile autonomic status at the onset simulating encephalitis and
underwent several diagnostic procedures, including a lumbar
puncture. Patients in group A had overall 97 focal autonomic
seizures, 19 (19.5%) of which occurred during fever. In 16 cases, the
fever was due to viral infections (12 upper airway infections, 3
exanthematic diseases, 1 enteritis), while in 3 cases the fever was
due to bacterial infections (pneumonia, bronchitis, and otitis).
3.2. Genetic analysis
Genetic analysis of SCN1A was performed in 10 out of the 11
patients included in group A (the parents of one patient did not
give their consent to DNA analysis). No mutation was found in any
of the patients.
Results are summarized in Table 1.
Fever is currently not considered a seizure precipitant factor in
PS. However, an increased rate of febrile seizures3and isolated
cases of PS associated with SCN1A mutations have been recently
This is the first attempt to investigate the relationship between
fever and PS in a large and selected population. Our study shows
that fever is a common seizure precipitant factor in PS: in our
cohort, we found that 36% of the patients had at least one focal
autonomic seizure triggered by fever.
Thermoregulatory alterations are possible autonomic manifes-
tations of seizures in patients with PS6,7; to reduce misinterpreta-
tions, we considered a seizure to be triggered by fever only if it
occurred during a febrile illness of documented origin.
PS is often misdiagnosed at onset because emetic and other
autonomic manifestations are not recognized as seizure events.
Autonomic symptoms may suggest nonepileptic conditions, such
as atypical migraine, gastroenteritis, syncope, encephalitis, or
intoxication.8Our experience suggests that misdiagnosis is more
likely if autonomic seizures occur during fever. Seven of our
patients had their first focal autonomic seizure during a febrile
illness, and 2 of those 7 patients were misdiagnosed with febrile
gastroenteritis and encephalitis. We believe that considering
epileptic seizures in the differential diagnosis of autonomic
manifestations during fever can facilitate early diagnosis of PS
and prevent unnecessary investigations and erroneous treatments.
The epilepsy features and EEG characteristics of our population
were comparable with literature data.9,10
The median age at the onset of PS was slightly lower in the
patients of group A. This could suggest a higher, age-related,
predisposition to seizures triggered by fever in patients with early
onset of PS. Furthermore, we found that patients in group A more
frequently had a positive familial history of FS, supporting the
hypothesis of a genetically based higher predisposition to seizures
triggered by fever. For this reason and following recent reports,4,5
we performed the analysis of SCN1A gene in patients with a history
of at least one seizure during fever.
OurdatashowthatSCN1Agenedoes notcontribute significantlyto
susceptibility to autonomic seizures during fever in patients with PS.
Therefore, weadvise againstroutine screeningforSCN1Amutations in
patients with focal autonomic seizures triggered by fever.
D.M. Cordelli et al. / Seizure 21 (2012) 141–143
5. Conclusion Download full-text
Our data show that fever is a common trigger for focal
autonomic seizures in PS. Knowing that an autonomic manifesta-
tion during fever can be an epileptic seizure could facilitate
diagnosis and prevent unnecessary investigations and erroneous
treatments. Moreover, SCN1A gene does not seem to contribute
significantly to autonomic seizures susceptibility during fever in
patients with PS. However, more studies are needed to better
understand the complex genetic background of PS.
Conflicts of interest
None of the authors has any conflict of interest to disclose.
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Population (n, 30)
Group A (n, 11)
Group B (n, 19)
Positive familial history for FS; n (%)
Positive familial history for epilepsy; n (%)
Months of age at the onset; median (range)
Number of seizures; median (range)
Overall focal autonomic seizures (n)
During fever n (%)
Pts with focal autonomic seizures during fever at onset of PS; n (%)
Pts with misdiagnosis at onset of PS; n (%)
Pts with autonomic status epilecticus n (%)
Interictal EEG abnormalities at onset; n (%)
Therapy with AEDs; n (%)
Follow-up; median (range)
Pts with ?3 years of follow-up (n)
Months of age
At first seizure; median (range)
At last seizure; median (range)
At last visit; median (range)
FS: febrile seizures; PS: Panayiotopoulos syndrome; Pts: patients; AEDs: antiepileptic drugs.
aEach patient can have more than one localization of EEG abnormalities.
D.M. Cordelli et al. / Seizure 21 (2012) 141–143