Brain & Development xxx (2018) xxx–xxx

www.elsevier.com/locate/braindev

Original article

Association of developing childhood epilepsy subsequent to

febrile seizure: A population-based cohort study
Lin-Mei Chiang a,1, Go-Shine Huang b,1, Chi-Chin Sun c,d, Ying-Li Hsiao e,
Chung Kun Hui f, Mei-Hua Hu g,h,⇑
a
Department of Pediatric, Keelung Branch, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
b
Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, Taiwan
c
Department of Ophthalmology, Keelung Branch, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
d
Department of Chinese Medicine, Chang Gung University, Taoyuan, Taiwan
e
Department of Medical Research and Development, Keelung Branch, Chang Gung Memorial Hospital, Taiwan
f
Department of Anesthesiology, Keelung Branch, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
g
Division of Pediatric General Medicine, Chang Gung Memorial Hospital, LinKou Branch, College of Medicine,
Chang Gung University, Taoyuan, Taiwan
h
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan

Received 5 April 2017; received in revised form 15 June 2017; accepted 9 May 2018

Abstract

Purpose: Epilepsy is an important neurological condition that frequently associated with neurobehavioral disorders in child-
hood. Our aim was to identify the risk of developing epilepsy subsequent to febrile seizure and the association between epilepsy risk
factors and neurobehavioral disorders.
Subjects and methods: This longitudinal population-based cohort data included 952 patients with a febrile seizure diagnosis and
3808 age- and sex-matched controls. Participants were recruited for the study from 1996 to 2011, and all patients were followed up
for maximum 12.34 years.
Results: The association of epilepsy was significantly higher (18.76-fold) in individuals that experienced febrile seizure compared
to controls. Further, of those individuals who experienced febrile seizure, the frequency of subsequent development of epilepsy was
2.15-fold greater in females, 4.846-fold greater in patients with recurrent febrile seizure, and 11.26-fold greater patients with comor-
bid autism.
Conclusions: Our study showed that being female, comorbid autism with febrile seizure and recurrent febrile seizure had an
increased association with development of epilepsy. Increased recognition the association for epilepsy might be warranted in those
febrile seizure children with certain characteristics.
Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Keywords: Epilepsy; Autism; Comorbidity; Recurrent febrile seizure

⇑ Corresponding author at: Division of Pediatric General Medicine,

1. Introduction
Chang Gung Memorial Hospital, LinKou Branch, College of
Medicine, Chang Gung University, 12L, No.5, Fu-Shin Street, Epilepsy is an important spectrum of neurological
Kwei-shan 333, Taoyuan, Taiwan. condition that frequently associated with cognitive
E-mail address: p65952@gmail.com (M.-H. Hu). impairment and neurobehavioral disorders in childhood.
1
These authors are contributed equally to this work.

https://doi.org/10.1016/j.braindev.2018.05.006
0387-7604/Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: Chiang L-M et al. Association of developing childhood epilepsy subsequent to febrile seizure: A population-
based cohort study. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.05.006
2 L.-M. Chiang et al. / Brain & Development xxx (2018) xxx–xxx

With the increasing recognition of epilepsy, many inves-
tigators have attempted to identify factors that increase
the risk of developing epilepsy [1]. More than 50 million
people worldwide have epilepsy [2], and 10–20% of epi-
lepsy patients have had a febrile seizure (FS). FS is the
most common convulsion that occurs in childhood; FS
affects 2–5% of all children and usually appears between
6 months and 6 years of age [3,4]. Although some studies
have found a higher risk of developing epilepsy after FS
[5–8], the association between FS and subsequent epi-
lepsy has not been the subject of adequate numbers of
population-based studies. Furthermore, the association
between epilepsy risk factors and neurobehavioral disor-
ders comorbid with FS has not been investigated in a
population-based study.
In the present study, we aimed to determine the asso-
ciation between comorbidities and the subsequent risk
of epilepsy in febrile seizure. Therefore, we performed
an association study on comorbidities in children with
a history of FS and subsequent epilepsy development.
Using the National Health Insurance Research Data-
base (NHIRD), we conducted a nationwide
population-based study to investigate the relationship
between FS and subsequent epilepsy incidence.
2. Subjects and methods
The NHIRD included 99% of the 23 million residents
of Taiwan. The National Health Insurance (NHI) pro-
gram provides for approximately 90% of medical cover-
age and examinations by board-certified medical
physicians and institutions. Therefore, information
regarding diseases diagnoses, medication, and familial
incomes are accessible. However, the Personal Informa-
tion Privacy Act required that each patient’s original
identification number be encrypted in the cohort data.
To our knowledge, the NHIRD database is one of
the largest nationwide population-based databases in
the world, and its use has resulted in publication of
many scientific manuscripts. Our data included
1,000,000 randomly sampled NHIRD insurant regis-
tered in 2005, either during hospitalization or subse-
quent outpatient department visits. These cohort data
also included each patient’s longitudinal medical records
following registration. This study was approved by the
Institutional Review Board (IRB-103-0779B) of Chang
Gung Medical Hospital.
The study cohort consisted of individuals aged 6
months to 6 years who were diagnosed with FS (Interna-
tional Classification of Diseases, Ninth Revision; ICD-
9: code 78031) between January 1996 and December
2011. Exclusion criteria included: previous epilepsy
(ICD-9 code: 345x), previous cerebral palsy (343x), or
within one month of being diagnosed or concurrently
diagnosed with meningitis (320x, 047x, 049x) or
encephalitis (062x, 323x). The control group was ran-
domly sampled and selected four times according to
the same criteria used for the study cohort, and was
matched according to age, sex, and index year (Fig. 1).
The primary outcome of the study was the occurrence
of decision-making claims of epilepsy (ICD-9-CM code:
345x) as the main diagnosis and anticonvulsant medica-
tion prescribed for at least 3 months by a board-certified
physician.
Recurrent FS (ICD-9 code: 78031) was defined as the
occurrence of FS more than once in the same patient

Fig. 1. Research design flow chart of the present study. ICD-9: International Classification of Diseases, Ninth Revision.

Please cite this article in press as: Chiang L-M et al. Association of developing childhood epilepsy subsequent to febrile seizure: A population-
based cohort study. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.05.006
 L.-M. Chiang et al. / Brain & Development xxx (2018) xxx–xxx 3

over an at least 5-day interval. Comorbidities included
autism (ICD-9: 299x), attention deficit hyperactivity dis-
order (ADHD; ICD-9: 314x), Tourette syndrome/tic
disorder (ICD-9: 30720, 30721, 30722, 30723, 3333),
asthma (ICD-9: 493x), allergic rhinitis (ICD-9: 477x),
and atopic dermatitis (ICD-9: 6918). All patients were
followed-up until December 31, 2011.
Statistical analyses were performed using Statistical
Package for the Social Sciences (SPSS) software, version
18 (SPSS, Inc.). A stratified Cox proportional hazards
regression analysis was performed to examine the risk
of new-onset epilepsy during the follow-up years in
patients with and without FS. All patient data were
recorded from the index date until epilepsy presentation
or December 31, 2011. Relative risk ratio and 95% con-
fidence intervals (CIs) were calculated to indicate the
risk of epilepsy. A P value <0.05 (two-tailed) was con-
sidered to indicate statistical significance. The Kaplan-
Meier method was used to calculate time-to-event end
point, and a log-rank test was used to compare the
cohorts.
3. Results
In total, 952 patients from the NHIRD fulfilled the
inclusion criteria. Non-FS patients were age- and sex-
matched, and included 3808 individuals (Fig. 1). The
distributions of the demographic variables and comor-
bidities of the FS and non-FS cohorts are shown in
Table 1. The mean index age of the FS and non-FS
cohorts was 2.697 ± 1.217 years, with most individuals
(51.79%) being 2–4 years old. Patient with newly
diagnosed FS had more autism (odds ratio: 2.018,
p = 0.019), ADHD (odds ratio: 1.39, p = 0.011), asthma
(odds ratio: 1.397, p < 0.0001), allergic rhinitis (odds
ratio: 1.334, p = 0.0002), and atopic dermatitis (odds
ratio: 1.236, p = 0.0006) than non-FS subjects. The
medications used for seizure treatment for patients with
FS included diazepam (18.48%), phenobarbital (2.73%),
and lorazepam (1.89%).
During a maximum 12.34 years’ follow up (mean 5.
96 ± 1.51 years), 32 (3.36%) of the FS patients were
diagnosed with epilepsy, and 7 non-FS subjects
(0.18%) were diagnosed with epilepsy. Fig. 2 exhibits
the results of a Kaplan-Meier analysis and the log-
rank test showed that febrile seizure had significantly
higher incidence of epilepsy than non-FS subjects (P <
0.001). The annual incidence rate of epilepsy in the FS
cohort (537.81/100,000 person-years) was significantly
higher than the control cohort (28.66/100,000 person-
years), yielding an incidence rate ratio of 18.76 between
these two groups (Table 2).
In patients with a history of FS, the incidence of epi-
lepsy in females was 2.15-fold greater than that in males
(95% CI: 1.019–4.545). Furthermore, 373 children
(39.2%) with FS had recurrent FS, and those with recur-
rent FS had a 4.846-fold greater risk of epilepsy com-
pared with those without recurrent FS (95% CI: 2.07–
11.344). Additionally, multivariate analysis revealed
that comorbid autism significantly increased the rate
of subsequent epilepsy in patients with FS (HR: 11.26,
95% CI: 2.513–50.469). However, neither comorbidities
(ADHD, asthma, allergic rhinitis, atopic dermatitis),
nor therapy with anticonvulsant medications was associ-
ated with epilepsy occurrence after adjusting for the
duration of FS since diagnosis (Table 3).

Table 1
Demographic characteristic of children with febrile seizure and the control group.
Variable Febrile seizure (n = 952) Control Odds ratio P value
(n = 3808)
Total % Total %
Age (Mean ± SD) 2.697 ± 1.217 2.697 ± 1.217
<2 year 307 32.25 1228 32.25 N/A
2–<4 years 493 51.79 1972 51.79 N/A
=4 years 152 15.97 608 15.97 N/A
Gender (M) 552 57.98 2208 57.98 N/A
Comorbidities
Autism 17 1.79 34 0.89 2.018 0.019
ADHD 87 9.14 257 6.75 1.39 0.0111
Tourette/Tic disorder 21 2.21 57 1.5 1.485 0.1251
Asthma 481 50.53 1608 42.23 1.397 <0.0001
Allergic rhinitis 656 68.91 2377 62.42 1.334 0.0002
Atopic dermatitis 326 34.24 1129 29.65 1.236 0.0006
Medications
Diazepam 176 18.48
Phenobarbital 26 2.73
Lorazepam 18 1.89
FS, febrile seizure; SD, standard deviation; CI, confidence interval; M, male; N/A, not applicable; ADHD, attention deficit hyperactivity disorder.

Please cite this article in press as: Chiang L-M et al. Association of developing childhood epilepsy subsequent to febrile seizure: A population-
based cohort study. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.05.006
4 L.-M. Chiang et al. / Brain & Development xxx (2018) xxx–xxx

increased age of FS onset. Furthermore, being female,

Fig. 2. Kaplan-Meier estimates of survival free of epilepsy events in
subjects categorized by febrile seizure. The event-free survival rates
were significantly different in two groups (P value <0.001 by log-rank
test).
4. Discussion
This is the first study of the association between epi-
lepsy development and FS comorbidities in a nationwide
cohort dataset in Taiwan. The current study revealed
that FS was associated with an increased association
of future epilepsy development in this cohort after a
maximum of 12.34 years of follow-up. Additionally, a
decreased risk of epilepsy was associated with an
experiencing recurrent FS, and autism comorbidity
increased the incidence rate of subsequent epilepsy.
Our study results demonstrated that FS patients car-
ried an 18.76-fold increased association of developing
epilepsy compared with the non-FS group. This finding
supports previous reports that FS may be an indepen-
dent risk factor for epilepsy [9]. Although the results cer-
tainly showed causal relationship between epilepsy
following FS, the direct cause of epilepsy remains
unknown from the present study. FS may be associated
with, or cause brain damage; or alternatively, they may
be the first expression of a genetic or lesion predisposi-
tion to epilepsy. For the same reason, autism and other
neurodevelopmental disorders, which are often accom-
panied with epilepsy, may not be the cause of epilepsy
but the result from the same etiology.
The pathophysiology of epilepsy and FS remain
unclear. Multiple risk factors—including genetic suscep-
tibility, defects in iron channel function and associated
proteins, modulation of cytokine-related processes,
oxidative stress, regulation of neuronal excitability, vac-
cination, and exogenous agents such as viruses—are
thought to play a role in epilepsy development after
FS [10–12]. Genetic association studies showed that
SCN1A, IL-1b, CHRNA4, and GABRG2 were most
commonly associated with both FS and epilepsy [13].
Similar to previous studies, our longitudinal nation-
wide study revealed that FS had an increased

Table 2
Incidence of epilepsy in febrile seizure and control cohorts.
Patient numbers Person-Years Epilepsy events Incidence rate IRR 95%CI p-value
Control cohort 3808 24,421 7 28.66 reference reference
Febrile seizure 952 5950 32 537.81 18.76 (8.28–42.51) <0.0001
IRR, incidence rate ratio; CI, confidence interval.

Table 3
Risk of subsequent epilepsy in patients with febrile seizure.
Variable Epilepsy (n = 32) Non epilepsy (n = 920) Univariate analysis Multivariate analysis P
Total % Total % HR (95% CI) HR (95% CI)
Age (Mean ± SD) 2.31 ± 1.14 2.71 ± 1.22 0.575 (0.33–1.001)
<2 year 16 50 291 31.6 2.076 (1.038–4.152) 2.083 (0.599–7.25) 0.247
2–<4 years 13 40.6 480 52.2 0.627 (0.309–1.269) 0.997 (0.28–3.549) 0.999
=4 years 3 9.4 149 16.2 0.573 (0.175–1.883) N/A
Gender (Male) 13 40.6 539 58.6 0.497 (0.246–1.007) 0.465 (0.22–0.981) 0.044
(Female) 19 59.4 381 41.4 2.011 (0.993–4.073) 2.15 (1.019–4.545) 0.044
Recurrent Febrile seizures 25 78.1 348 37.8 2.51 (1.671–3.77) 4.846 (2.07–11.344) 0.0003
Comorbidities
Autism 3 9.4 14 1.5 8.902 (2.45–32.25) 11.26 (2.513–50.469) 0.0016
ADHD 3 9.4 84 9.1 0.676 (0.166–2.753) 0.492 (0.107–2.259) 0.362
Asthma 16 50 465 50.5 0.989 (0.527–1.859) 0.831 (0.394–1.753) 0.628
Allergic rhinitis 25 78.1 631 68.6 1.438 (0.918–2.253) 1.682 (0.692–4.089) 0.251
Atopic dermatitis 12 37.5 314 34.1 1.826 (0.893–3.374) 1.143 (0.546–2.389) 0.723
Anticonvulsant usage 13 40.6 245 26.6 1.434 (0.822–2.503) 1.073 (0.513–2.245) 0.851
HR, hazard ratio; CI, confidence interval; SD, standard deviation; N/A, not applicable; ADHD, attention deficit hyperactivity disorder.

Please cite this article in press as: Chiang L-M et al. Association of developing childhood epilepsy subsequent to febrile seizure: A population-
based cohort study. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.05.006
 L.-M. Chiang et al. / Brain & Development xxx (2018) xxx–xxx
association with allergic comorbidities, including
asthma, allergic rhinitis, and atopic dermatitis, when
compared with the non-FS group [14]. Dysregulation
of inflammatory cytokines plays a role in neuromodula-
tory functions and contributes to neuronal hyperex-
citability in FS [15,16]. However, these comorbidities,
or therapy with anticonvulsant medications were not
found to be associated with the risk of epilepsy after
adjustment for the duration of FS since diagnosis. This
finding suggests FS or certain underlying comorbidities,
not anticonvulsant agents, are more important determi-
nants of future risk of developing epilepsy.
We found that 39.2% of children with FS experienced
a recurrence after their first episode of FS, which led to a
4.846-fold greater risk of developing subsequent epilepsy
compared with individuals without recurrent FS. Our
results and those of others suggest that an increased risk
of subsequent epilepsy in recurrent FS might be due to
genetic susceptibility, multifactorial seizure mechanisms,
or brain damage due to recurrent FS [17].
This study revealed an increased association between
FS and neuropsychiatric diseases in children, including
autism and ADHD, when compared with non-FS chil-
dren. Furthermore, comorbid autism increased the risk
of subsequent epilepsy in FS patients. Children with epi-
lepsy had relatively lower performance abilities or sparse
verbal abilities, suggesting shared mechanisms with neu-
rodevelopmental disorders [18,19]. Several case-control
studies revealed that iron deficiency might be related
to the pathophysiology of autism or FS [20,21]. Animal
studies showed that iron deficiency resulted in slower
myelination, reduced affinity of dopamine D2 receptors,
and alterations in neural metabolites in the hippocam-
pus, which may be responsible for abnormal cognitive
or behavioral performance [22]. Moreover, previous
studies showed that KCC2-dependent GABA signaling,
SCN1A mutation, or abnormal electroencephalogram
may contribute to autism or idiopathic generalized epi-
lepsy [23–25]. Further studies that investigate autism
comorbidity with FS as an important factor that influ-
ences the association of subsequent epilepsy may be
warranted.
Our population-based cohort study revealed that
females with FS had a higher risk of epilepsy. Previous
studies revealed that a number of X-linked epilepsies
have been described in which females are exclusively
affected [26]. In females, because of random X-
inactivation, which result in cellular interference, where
the two classes of cell have aberrant interactions result-
ing in a more severe phenotype in female [27]. Childhood
absence epilepsy is 2- to 5-fold more common in females,
juvenile absence epilepsy is 3-fold more common among
females, and juvenile myoclonic epilepsy is about 2.9-
fold more common in females [28–30]. The effect of gen-
der on epilepsy is unclear and so further studies are war-
ranted. Future cohort studies focused on early
Please cite this article in press as: Chiang L-M et al. Association of developing childhood epilepsy subsequent to febrile seizure: A population-
based cohort study. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.05.006
5
identification of subsequent epilepsy are necessary and
should include variables such as genetic background.
This study had a number of strengths. First, this was
a population-based study of FS, and the control group
was selected from patients who did not develop FS dur-
ing the study period. The study cohort included sampled
99% of the registered population; all comorbidities and
medications prescribed by board-certificated physicians
and medical clinics or hospitals during the study were
obtained for analysis. This participant sampling allowed
us to avoid issues with patients visiting other clinics or
hospitals that occurs in most longitudinal studies and
minimized the possibility of recall bias.
However, there were several limitations to our study.
First, the diagnoses of FS and epilepsy were identified
using the ICD-9 code in the database, which lacked
information on family history of FS or epilepsy, dura-
tion of the febrile seizure, simple or complex FS, cases
of febrile status epilepticus, focal or generalized epilep-
sies, or descriptions of etiology, genetic study, neu-
roimaging study, cytokine level, serum iron level,
causative pathogens, degree of fever in the initial FS,
or electroencephalogram data. Second, some patients
with epilepsy might have been misclassified or miscoding
could have occurred; however, board-certified physi-
cians diagnosed the patients included in our study.
5. Conclusions
Our study provides population-based cohort data
suggesting that the risk of subsequent epilepsy is higher
following FS. Risk factors, including being female,
comorbid autism with FS, and recurrent FS, had an
increased association with development of epilepsy.
However, we found that use of anticonvulsant agents
had no beneficial effects for preventing development of
epilepsy. Further therapeutic strategies should be inves-
tigated for the prevention of epilepsy.
Acknowledgement
This work was supported by grant CLRPG2C0021
and CLRPG2C0022 from the Keelung Chang Gung
Memorial Hospital.
Data sharing statement
Our study is based on the National Health Insurance
Research Database provided by the Bureau of National
Health Insurance of Taiwan.
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