Brain & Development 43 (2021) 768–774

www.elsevier.com/locate/braindev

Original article

Body temperature predicts recurrent febrile seizures in the

same febrile illness
Jun Kubota a,b,⇑, Norimichi Higurashi b, Daishi Hirano b, Shiro Okabe a,b,
Kento Yamauchi a,b, Rena Kimura a,b, Haruka Numata a,b, Takayuki Suzuki a,b,
Daisuke Kakegawa a,b, Akira Ito a,b, Shin-ichiro Hamano c
a
Department of Pediatrics, Atsugi City Hospital, Kanagawa, Japan
b
Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan
c
Division of Neurology, Saitama Children’s Medical Center, Saitama, Japan

Received 13 November 2020; received in revised form 9 February 2021; accepted 10 March 2021

Abstract

Background: The incidence of recurrent febrile seizures during the same febrile illness (RFS) is 14–24%. A pilot study found that
body temperature and male sex were predictors of RFS. This study sought to validate body temperature as a predictor of RFS,
calculate the optimal cut-off body temperature for predicting RFS, and identify the other predictors of RFS.
Methods: This prospective cohort study enrolled children with febrile seizures aged 6–60 months who visited the emergency
department at Atsugi City Hospital, Japan, between March 1, 2019, and February 29, 2020. Children who had multiple seizures,
diazepam administration before the emergency department visit, seizures lasting >15 min, underlying diseases, or who could not
be followed up were excluded. The optimal cut-off body temperature was determined using a receiver-operating characteristic curve.
Results: A total of 109 children were enrolled, of whom 13 (11.9%) had RFS. A lower body temperature was significantly asso-
ciated with RFS (P = 0.02). The optimal cut-off body temperature for predicting RFS was 39.2 °C. Children with RFS also had
significantly lower C-reactive protein and blood glucose levels (P = 0.01 and 0.047, respectively), but none of the other factors con-
sidered were significantly associated with RFS.
Conclusions: This large prospective study confirmed that body temperature is a predictor of RFS. The optimal cut-off body tem-
perature for predicting RFS was 39.2 °C. Low C-reactive protein level and blood glucose level might be predictors of RFS, but this
needs to be confirmed in prospective multicenter studies.
Ó 2021 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Keywords: Blood glucose; Body temperature; C-reactive protein; Febrile seizures; Recurrent seizures

1. Introduction
Febrile seizures (FSs) are a common type of child-
hood seizures globally, with an incidence reaching 2–
⇑ Corresponding author at: Department of Pediatrics, Atsugi City
Hospital, 1-16-36 Mizuhiki, Atsugi City, Kanagawa 243-8588, Japan.
E-mail address: junkubota13@gmail.com (J. Kubota).
11% [1–3]. Although most children with FSs have only
one seizure during the same febrile illness, the incidence
of recurrent FSs during the same febrile illness (RFS)
within 24 h of the initial FS is 14–24% [1,4,5]. Two chal-
lenges regarding the management of RFS are the need to
distinguish them from other acute causes of childhood
seizures, which are serious central nervous system infec-
tions such as bacterial meningitis and acute encephalitis/

https://doi.org/10.1016/j.braindev.2021.03.002
0387-7604/Ó 2021 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
 J. Kubota et al. / Brain & Development 43 (2021) 768–774
encephalopathy, and the need to hospitalize children
with FSs for observation or supportive care [6,7]. How-
ever, serious central nervous system infections are rarely
found in children with RFS. Repeated hospital visits
and hospitalizations cause a burden on children, their
families, and medical staff, and increase healthcare costs.
Therefore, identifying predictors of RFS may enable the
prevention of RFS and reduce the associated burden
and healthcare costs.
A previous study [8] and our pilot study [9] reported
an association between body temperature and RFS. Our
pilot study found that the majority of children with FS
have a body temperature below the cut-off of 39.9 °C
[9], limiting the clinical utility of this value as a cut-off.
The pilot study had a retrospective design and a limited
sample size; therefore, a large prospective cohort study
is required to confirm the association between body tem-
perature and RFS, and to determine the optimal cut-off
body temperature.
The aims of this prospective study were: (1) to vali-
date body temperature as a predictor of RFS; (2) to cal-
culate the optimal cut-off body temperature for
predicting RFS; and (3) to identify the other predictors
of RFS.
2. Methods
2.1. Design and participants
We conducted a prospective study at Atsugi City
Hospital in Kanagawa, Japan. Patients with FS who vis-
ited the emergency department (ED) between March 1,
2019 and February 29, 2020, were enrolled in the study.
An FS was defined according to the criteria of the Japa-
nese Society of Child Neurology as ‘‘a seizure accompa-
nied by fever (body temperature
38.0 °C), without
central nervous system infection, that occurs in infants
and children 6 through 60 months of age.” [10] Children
with FS over the course of different febrile illnesses, were
eligible to enrol for each illness, and each enrolment was
considered separately in the analysis.
Exclusion criteria of this study were the following:
multiple seizures before visiting the ED; status epilepti-
cus (seizures lasting > 15 min); use of anticonvulsant
drugs to treat seizures; diazepam administered before
visiting the ED; and the presence of underlying dis-
eases/conditions, such as epilepsy, chromosomal abnor-
malities, inborn errors of metabolism, perinatal
abnormalities, delayed psychomotor development, gas-
troenteritis, brain tumors, intracranial hemorrhage,
hydrocephalus, or a history of intracranial surgery. In
addition, children were only enrolled if a parent/
guardian provided informed consent and follow-up
was possible.
769
2.2. Procedures
Three categories of parameters were recorded on
enrolment in the study: (1) baseline characteristics and
variables associated with the fever, including sex, age
(months), time from fever to seizure onset (hours), axil-
lary temperature (°C) on arrival at the ED. Children
with a body temperature of more than 38.0 °C before
visiting the ED were diagnosed with FS even if their
axillary temperature on arrival at the ED was less than
38.0 °C; (2) variables associated with seizures, including
duration of the seizure (minutes), time from seizure
onset to arrival at the ED (minutes), seizure type (gener-
alized or focal), level of consciousness during the ED
visit according to the Japan Coma Scale (0, alert con-
sciousness; 1–3, wakeful without any stimuli; 10–30,
arousal by some stimuli; 100–300, coma) [11,12], total
number of past FSs, family history of FSs in first-
degree relatives (parents and siblings), acetaminophen
and antihistamine (e.g., d-chlorpheniramine, cyprohep-
tadine, and ketotifen) administration before the FS;
and (3) laboratory test results, including blood cell
count, biochemistry, and venous blood gas analysis.
Parents were instructed to bring their child back to the
hospital immediately if the child experienced an RFS.
Since acetaminophen use has been reported to poten-
tially prevent seizure recurrence, instead of focusing
only on the participants with risk factors for FS recur-
rence, we instructed all the participants’ parents regard-
ing the use of acetaminophen (10 mg/kg, every 6 h, for
24 h after the onset of the FS if the child’s fever
remained >38.0 °C) to ensure consistency among the
participants [1]. All participants were followed up using
an outpatient service or telephone calls for at least 24 h
after the FS to determine whether they developed RFS
and/or serious central nervous system infections such
as bacterial meningitis and acute encephalitis/
encephalopathy.
2.3. Data and measures
Clinical and laboratory data were collected from par-
ticipants’ electronic medical records using a structured
data capture form, and a structured questionnaire was
used to collect information from each child’s parent/-
guardian regarding the child’s medical history, history
of the current illness, and follow-up information regard-
ing RFS.
The primary and secondary outcome measures were
body temperature on arrival at the ED (as a predictor
of RFS based on our pilot study [9]) and optimal body
temperature cut-off for predicting RFS (assuming that
body temperature was validated as a predictor of
RFS), respectively.
770 J. Kubota et al. / Brain & Development 43 (2021) 768–774
We used the axillary method to measure body tem-
perature for two reasons: First, Teller et al. [13] reported
that even though axillary temperature was always lower
than rectal temperature, it was adequate for fever
screening. Second, axillary temperature is more com-
monly measured than rectal temperature in Japan. An
afebrile state was defined as maintaining a body
temperature < 37.5 °C for more than 24 h without using
acetaminophen. RFS was defined as the occurrence of a
second seizure prior to reaching an afebrile state.
The types of seizures, their duration, and total num-
ber of past FSs were determined by interviewing the par-
ents/guardians. The types of seizures were categorized
into generalized seizures, including generalized motor
seizures (tonic, clonic, and tonic-clonic), and focal sei-
zures. Administration of antihistamines, such as d-
chlorpheniramine, cyproheptadine, and ketotifen,
before the FS was assessed because their effects on seda-
tion are stronger than those of other antihistamines sug-
gested by the Japanese guidelines for the management of
febrile seizures [10].
The cause of fever was determined based on the
results of rapid antigen-based tests for adenovirus,
influenza virus, respiratory syncytial virus, and strepto-
coccal infections and the final diagnosis by the
pediatrician.
The laboratory test results (complete blood cell
count, biochemical examination of blood serum, and
blood gas analysis) included the tests that are routinely
used to rule out acute symptomatic diseases, such as
acute hepatitis, organophosphate poisoning, Reye syn-
drome, and rhabdomyolysis, which are treated in the
Atsugi City Hospital ED. As in our pilot study [9], we
calculated estimated glomerular filtration rate (eGFR)
and osmotic pressure using the following formulas:
eGFR ¼ 107:3=ðcreatinine½mg=dLÞ=Q;
where: Q for males = 0.21 + 0.057  age (years)
– 0.0075  age2 +
0:00064  age3  0:000016  age4 ;
and Q for females = 0.23 + 0.034  age
– 0.0018  age2 + 0.00017 
age3  0:0000051  age4 ;
osmotic pressure = sodium  2 + blood glucose/18
+ blood urea nitrogen/2.8.
2.4. Statistical analysis
R version 3.6.1 (R Foundation for Statistical Com-
puting, Vienna, Austria) was used for the sample size
calculation, and all other analyses were performed using
Stata version 15.1 (StataCorp., College Station, TX,
USA). P values <0.05 were considered statistically
significant.
We determined the sample size based on the area
under the curve of the receiver-operating characteristic
(ROC) of a patient’s body temperature to be 0.7672
based on our pilot study [9]. A total sample size of 83
participants was found to be required by assuming a
10% incidence of RFS with acetaminophen administra-
tion. The estimate of 10% was rounded up from 9.1%
[1] (one-sided test, power = 80%, and type Ⅰ error = 5%)
[14,15]. The study period was set to be at least one year
in order to eliminate seasonal bias.
Continuous variables were expressed as the median
and interquartile range (IQR), and categorical variables
were expressed as frequencies. Comparisons between the
two groups were made using the Mann-Whitney U test
for continuous variables, and the chi-square or Fisher’s
exact test for categorical variables. The optimal cut-offs
for dichotomizing continuous variables were determined
using the Youden index (the maximum value of [sensi-
tivity – (1 – specificity)]) based on the ROC curve [16].
The data from our pilot study was validated using a
body temperature cut-off of [9].
2.5. Ethics
This study was conducted in accordance with the eth-
ical principles of the Declaration of Helsinki and
according to the ethical guidelines for epidemiological
studies issued by the Ministry of Health, Labor and
Welfare of Japan. This study was approved by the
Atsugi City Hospital Institutional Review Board (H30-
06). Informed consent was obtained from the parents
or guardians.
3. Results
3.1. Patient characteristics
A total of 210 patients with an FS visited the ED dur-
ing the study period. Of the 210 patients, 101 (48.1%)
were excluded for the following reasons: the parent/-
guardian did not provide consent (n = 38); multiple sei-
zures had occurred before visiting the ED (n = 18);
status epilepticus (n = 15); gastroenteritis (n = 13); dia-
zepam administration before visiting the ED (n = 11);
not followed up (n = 2); unknown time of onset
(n = 2); extremely low birth weight and mental retarda-
tion (n = 1); and trisomy 21 with epilepsy (n = 1). After
these exclusions, there were 109 patients who fulfilled
the inclusion criteria. Five patients visited twice and
two patients visited three times during the study period.
Basic patient characteristics and laboratory test results
are shown in Tables 1 and 2, respectively. (A more com-
prehensive listing of all laboratory results is provided in
Supplemental Table 1) Most participants had a Japan
Coma Scale score of 0 (fully awake and alert). Fever
was present at the time of occurrence of FS in 12
 J. Kubota et al. / Brain & Development 43 (2021) 768–774 771

Table 1
Baseline characteristics of study patients.
Recurrent FS (n = 13) Single FS (n = 96) P value
Male, n (%) 7 (53.8) 59 (61.5) 0.60
Age (mo), median (IQR) 22.0 (15.0–28.0) 21.0 (16.0–34.5) 0.86
Body temperature (°C), median (IQR) 38.9 (38.7–39.4) 39.6 (39.1–40.1) 0.02
Body temperature at second seizure (°C), median (IQR) 39.8 (39.4–40.3) 0.045à
Time from onset of fever to seizure (h), median (IQR) 13.5 (1.5–22.0) 8.6 (2.9–21.5) 0.55
Duration of seizure (min), median (IQR) 3 (3–5) 2 (1–5) 0.18
Time from onset of seizure to arrival at the ED (min), median (IQR) 37 (30–43) 33 (27–38) 0.06
Type of seizure, n (%) 0.40
Generalized 12 (92.3) 93 (96.9)
Focal 1 (7.7) 3 (3.1)
Number of previous FSs†, median (IQR) 1 (1–1) 1 (1–2) 0.36
Family history of FSs in first degree relatives, n (%) 8 (61.5) 32 (33.3) 0.07
Family history of epilepsy in first degree relatives, n (%) 0 (0) 4 (4.2) >0.99
Acetaminophen administration before FS, n (%) 3 (23.1) 20 (20.8) >0.99
Antihistamine administration before FS, n (%) 1 (8.3) 10 (10.4) >0.99
Cause of fever
Exanthema subitum, n (%) 4 (30.8) 9 (9.4)
Hand, foot, and mouth disease, n (%) 1 (7.7) 18 (18.8)
Influenza type A infection, n (%) 1 (7.7) 7 (7.3)
Adenovirus infection, n (%) 1 (7.7) 4 (4.2)
Streptococcal infection, n (%) 1 (7.7) 4 (4.2)
Herpangina, n (%) 1 (7.7) 2 (2.1)
Croup, n (%) 0 (0.0) 2 (2.1)
Acute otitis media, n (%) 0 (0.0) 2 (2.1)
Postvaccination, n (%) 0 (0.0) 1 (1.0)
Pharyngitis, n (%) 3 (23.1) 21 (21.9)
Upper respiratory tract infection, n (%) 1 (7.7) 14 (14.6)
Unknown, n (%) 0 (0.0) 12 (12.5)
ED, emergency department; FS, febrile seizure; IQR, interquartile range.
†
Including the FS that led to the child’s hospital visit; à when compared with the body temperature at first seizure in the recurrent FS group.

Table 2
Laboratory results of study patients.
Recurrent FS (n = 13) Single FS (n = 96) P value
White blood cells (/mL), median (IQR) 7100 (4500–11,600) 10,950 (7400–14,000) 0.06
Neutrophils (%), median (IQR) 72.6 (65.4–77.7) 70.7 (64.3–77.8) 0.86
Lymphocytes (%), median (IQR) 15.8 (12.0–24.1) 19.7 (12.3–24.7) 0.65
Sodium (mEq/L), median (IQR) 134 (132–136) 134 (133–135) 0.92
CRP (mg/dL), median (IQR) 0.19 (0.09–0.53) 0.74 (0.19–1.48) 0.01
Blood glucose (mg/dL), median (IQR) 106 (100–122) 116 (107–131) 0.047
CRP, C-reactive protein; FS, febrile seizures; IQR, interquartile range.

patients (11.0%). The body temperature of one patient
on arrival at the ED was 37.7 °C.
3.2. Incidence of recurrent febrile seizures during the same
febrile illness
Of the 109 participants, 13 (11.9%) had RFS. The
median interval between the onset of the first seizure
and the second seizure was 5.3 h (IQR: 4.0–14.0 h).
All participants had their second FS within 24 h of the
first FS. Three participants had their second FS without
having received acetaminophen. Twelve participants
(92.3%) were hospitalized, but no participants had seri-
ous central nervous system infections during the follow-
up period.
3.3. Body temperature
Body temperature on arrival at the ED had a statisti-
cally significant association with RFS in the univariate
analysis (P = 0.02) (Table 1). In addition, the body tem-
perature at second seizure was significantly higher than
that at first seizure in the RFS group (P = 0.045)
(Table 1). The area under the ROC curve of body tem-
perature was 0.7047 (Fig. 1). The optimal cut-off for
dichotomizing body temperature based on ROC curve
analysis was 39.2 °C.
Using this cut-off value resulted in a sensitivity, speci-
ficity, positive predictive value, and negative predictive
value of 55.6% (95% confidence interval [CI], 26.5–
81.1%), 76.2% (95% CI, 61.5–86.5%), 33.3% (95% CI,
772 J. Kubota et al. / Brain & Development 43 (2021) 768–774
Fig. 1. The receiver-operating characteristic curve of body temperature. The AUC for body temperature was 0.7047. The cut-off corresponded to a
body temperature of 39.2 °C. AUC, area under the curve.
15.2–58.3%), and 88.9% (95% CI, 74.7–95.6%),
respectively.
3.4. Other potential predictors of recurrent febrile seizures
during the same febrile illness
Lower C-reactive protein (CRP) and blood glucose
levels were significantly associated with RFS in the uni-
variate analysis (P = 0.01 and 0.047, respectively)
(Table 2), but there was no statistically significant asso-
ciation between RFS and any of the other factors con-
sidered, including patient characteristics and
laboratory test results (Table 1 and Supplemental
Table 1).
4. Discussion
This prospective study confirmed that body tempera-
ture was a predictor of RFS. This study estimated that
the optimal cut-off body temperature for predicting
RFS was 39.2 °C. In addition, CRP and blood glucose
levels were associated with RFS. In contrast to the pilot
study, male sex was not a predictor of RFS.
In this study, the association between body tempera-
ture and RFS is consistent with the totality of the evi-
dence. While our pilot study [9] and another previous
study [8] found an association between body tempera-
ture and RFS, a study by Jeong et al. [17] did not. There
are two possible reasons why their study did not find an
association between body temperature and RFS. First,
the majority of patients were afebrile on discharge from
the ED (mean body temperature, 37.5 °C), and second,
they included patients who had gastroenteritis and/or
had received anticonvulsant drugs. This study had an
adequate sample size to estimate the optimal cut-off
for predicting RFS. The cut-off of 39.2 °C found in this
study has greater clinical utility than the cut-off of 39.9 °
C found in our pilot study [9]. The specificity (76.2%;
95% CI, 61.5–86.5%) and negative predictive value
(88.9%; 95% CI, 74.7–95.6%) of this cut-off may be used
to guide the selection of patients for prophylactic anti-
convulsant therapy. Although there is individual varia-
tion in the body temperature threshold associated with
FS [18,19], children with a lower body temperature at
FS onset may have a low FS threshold.
In this study, we found that a low CRP level and low
blood glucose were both associated with RFS. Previous
studies have also shown that the CRP of children with
FSs was significantly lower than that of children with
fever without seizures [20,21]. In a study by Liu et al.
[20], there was no significant difference in the level of
CRP between children with simple and complex FS,
but they did not compare the incidence of simple and
RFS according to the CRP level. Three previous studies
have investigated the association between FS and blood
glucose level. A large retrospective study by Valerio
 J. Kubota et al. / Brain & Development 43 (2021) 768–774
et al. [22] found that children with FS were significantly
more likely to have stress hyperglycemia (blood
glucose
150 mg/dL) than the controls. However,
Lee et al. [23] and Costea et al. [24] found no significant
association between RFS and stress hyperglycemia. The
sample size of this study was too small to evaluate
whether low CRP and blood glucose levels are indepen-
dently associated with RFS. Therefore, further larger
studies are needed to determine whether low CRP and
blood glucose levels are independent predictors of RFS.
Contrary to our pilot study, male sex was not a pre-
dictor of RFS in this study [9]. Several other studies
have reported that FSs were more common in males
[1,4,21,25], and only a few of them have shown that
the incidence of FS had significantly higher in males
than in females [20,26]. The relationship between sex
and FS is uncertain. The conflicting results between this
study and our pilot study could be attributed to the dif-
ferent sample sizes. Therefore, sex may not be a predic-
tor of RFS.
None of the patients with RFS in this study and our
pilot study had serious central nervous system infections
[9]. These results raise the question whether RFS should
be included as a criterion for diagnosing complex FSs.
The classification of complex FSs was originally estab-
lished by Nelson and Ellenberg [27] based on risk factors
for subsequent epilepsy. However, in clinical practice,
especially in emergency settings, the most important
consideration regarding the management of complex
FSs is to diagnose serious central nervous system infec-
tions, rather than to estimate the risk of subsequent epi-
lepsy. In order to differentiate between serious central
nervous system infections and RFS in children with
FSs, consideration should be given to removing ‘‘two
seizures during the same febrile illness” from the criteria
of complex FSs in children with no neurological symp-
toms during the interictal phase. Grill and Ng [28]
reported RFS as a new term ‘‘simple febrile seizures
plus.” Therefore, we suggest reviewing the classification
of FSs taking into consideration the need for emergency
intervention and the risk of subsequent epilepsy.
This study had six main limitations. First, this study
was conducted at a single facility. To address this limita-
tion, the results of this study warrant confirmation in a
multicenter study. Second, consent was not obtained
from the parents or guardians of 18.1% (38/210) of the
patients with FS. However, there were no differences
in sex, age, or body temperature between the included
patients and those excluded because consent was not
obtained (data not shown). Third, the number of events
of RFS in this study was 13, and the number of patients
in the RFS group was too small to perform a multivari-
ate analysis. Additionally, we could not evaluate the
effect of confounders on the association between CRP,
blood glucose level, and RFS. In addition, the sample
size of this study was less than the estimated sample sizes
773
(136 and 206) based on the ROC curves of CRP and
blood glucose levels to calculate cut-offs for predicting
RFS. Therefore, we concluded that further studies with
larger sample sizes are needed to validate the association
between CRP level, blood glucose level, and RFS.
Fourth, we used axillary temperature as a measure of
body temperature. However, it has been reported that
even though axillary temperature was always lower than
rectal temperature, it was adequate for fever screening
[13]. We included patients with an axillary body temper-
ature of
38.0 °C in our study. This meant that the rec-
tal temperature of the included patients was more than
38.0 °C. Fifth, we measured body temperature only once
(on arrival at the ED). Finally, this study only included
Asian children. Therefore, the results have limited gen-
eralizability to children of other races; further studies
are needed to overcome this limitation.
5. Conclusions
This was a large prospective study to identify predic-
tors of RFS and confirmed that a lower body tempera-
ture on arrival at the ED was a predictor of RFS. The
optimal cut-off body temperature was calculated to be
39.2 °C. In addition, we identified low CRP and blood
glucose levels as possible predictors of RFS, but this
needs to be confirmed in future multicenter studies.
Declaration of competing interest
The authors declare no competing interests.
Acknowledgments
We thank Sho Takahashi for the assistance with the
statistical analysis. We also thank Hirotaka Isono,
Takaya Honda, Satoru Ishikawa, Takuma Mori, Yuki-
toshi Tanabe, Masatoshi Iijima, Reiji Ito, Manabu
Yoshihashi and Takeru Ito for helping with the clinical
research.
Funding source
This study was financially supported by the Center
for Baby Science, Doshisha University (Joint Usage/
Research Center accredited by the Ministry of Educa-
tion, Culture, Sports, Science and Technology). The
remaining authors have no financial relationships rele-
vant to this article to disclose.
Appendix A. Supplementary data
Supplementary data to this article can be found
online at https://doi.org/10.1016/j.braindev.2021.03.
002.
774 J. Kubota et al. / Brain & Development 43 (2021) 768–774
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