Seizure: European Journal of Epilepsy 75 (2020) 70–74

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Seizure: European Journal of Epilepsy

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Change in the strategy for prophylactic diazepam use for febrile seizures and T
the impact on seizure recurrence within 24 h
Masataka Inoue, Shunichi Adachi, Isao Kawakami, Hiroshi Koga*
Department of Pediatrics, National Hospital Organization Beppu Medical Center, 1473 Oaza-Uchikamado, Beppu, Oita 874-0011, Japan

A R T I C LE I N FO A B S T R A C T

Keywords: Purpose: To investigate the association between reduced prophylactic diazepam usage and short-term recurrence
Anticonvulsant of febrile seizures (FSs) after the FS practice guideline was updated in Japan.
Rectal administration Method: In this single-center, retrospective study, children (6–60 months of age) with FS who were transported
Seizure to our center by ambulance from January 2011 through December 2018 were included. Rectal administration of
Recurrence
diazepam (0.3-0.5 mg/kg) after the first seizure and seizure recurrence within 24 h were compared between
Treatment outcome
2011–2015 (pre-guideline revision) and 2016–2018 (post-guideline revision).
Results: Among the total of 509 children, 297 were transported to our hospital in 2011–2015 and 212 in
2016–2018. Rectal diazepam administration was decreased in 2016–2018 (17 %) compared to 2011–2015 (53
%, P < 0.0001), while seizure recurrence was increased in 2016–2018 (20 %) compared to 2011–2015 (12 %,
P = 0.0087). Similarly, hospital revisits (23 %) and hospital admissions (26 %) were increased in 2016–2018
compared to 2011–2015 (15 %, P = 0.031 and 18 %, P = 0.026, respectively). Multiple logistic regression
analyses showed that prophylactic diazepam administration was the only factor related to preventing seizure
recurrence. FS recurrence after the initial seizure was significantly less frequent with diazepam use (6 %) than
without diazepam use (21 %, P < 0.0001; relative risk reduction, 70 %; number needed to treat, 6.8 children).
Conclusion: The FS practice guideline revision was associated with reduced prophylactic diazepam usage and
increased FS recurrence within 24 h in Japan. Prophylactic diazepam use should be determined based on clinical
safety, local health infrastructure, and parental anxiety.

1. Introduction revision of the practice guideline for FS.

Febrile seizures (FSs) are the most common seizures among children
6 months to 5 years of age, accompanied by fever (≥100.4 °F or 38 °C)
without central nervous system infection [1]. The cumulative incidence
of FS is estimated to be 2–4 % in the United States and 8–10 % in Japan
[2,3]. The risk of recurrence during the same febrile illness has been
reported as around 15 % [4,5], and recurrence usually occurs within
24 h [6,7]. Prophylactic diazepam was previously widely administered
to children with FS according to the clinical practice guideline for FS in
Japan [8]. However, that guideline was revised in 2015 by the Japanese
Society of Child Neurology [9]. The new guideline does not recommend
routine use of diazepam suppositories if FS has stopped, and diazepam
administration has since reduced nationwide [10]. However, we pos-
tulated that recurrence of FSs during a single febrile episode may in-
crease with reduced diazepam usage. The aim of this study was to
compare the risk of seizure recurrence between before and after
2. Methods
2.1. Study design and participants
A retrospective observational study of children who were trans-
ported to a single pediatric center in Japan for FS was conducted.
Children who were transported to Beppu Medical Center by ambulance
between January 2011 and December 2018 were reviewed. In ac-
cordance with the international criteria for FS [1], those children
meeting both of the following criteria were included: 1) children be-
tween 6 and 60 months who were transported to Beppu Medical Center
by ambulance due to the onset of a seizure; and 2) fever ≥38.0 °C
confirmed on arrival or during transportation. To prevent inclusion of
children with afebrile seizures in this study, children with fever <
38.0 °C detected both throughout transportation and on arrival at

Abbreviations:FS, febrile seizure

⁎
Corresponding author.
E-mail address: koga.hiroshi.ab@mail.hosp.go.jp (H. Koga).

https://doi.org/10.1016/j.seizure.2019.12.021
Received 13 August 2019; Received in revised form 20 December 2019; Accepted 21 December 2019
1059-1311/ © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
M. Inoue, et al.
hospital were not included. Children with signs of meningeal irritation
underwent lumbar puncture to exclude meningitis. Children with epi-
lepsy, chromosomal abnormality, inborn errors of metabolism, hydro-
cephalus, brain tumor, intracranial hemorrhage, or a history of in-
tracranial surgery were also excluded.
Throughout the study period, patients meeting the indications for
prophylactic diazepam use were given a 0.3- to 0.5-mg/kg diazepam
suppository on arrival if FS had stopped, and diazepam was adminis-
tered intravenously by a pediatrician if the seizure had lasted > 5 min
and was continuing on arrival [8,9]. If a prophylactic diazepam sup-
pository had already been administered before arrival, caregivers were
instructed to administer another diazepam suppository 8 h after the first
use. During 2011–2015, patients without prophylactic indications were
also given a diazepam suppository on arrival if this was considered
warranted by the pediatrician. Children given intravenous diazepam or
other antiepileptic drugs were excluded from this study.
Diazepam was widely used during 2011–2015 in accordance with
the former guideline for FS and was used in a limited fashion during
2016–2018 in accordance with the new guideline in Japan [10]. The
new guideline for FS was published on March 29th, 2015 in Japan and
has been used in clinical practice since January 2016 in our institution.
The new guideline defined the indications for prophylactic diazepam
suppositories as follows: 1) children with a history of prolonged FS ≥
15 min; and 2) children with a history of repeated FS and ≥2 of the 6
identified risk factors (preexisting neurological abnormality or devel-
opmental delay; focal or repeated seizures within 24 h; family history of
FS or epilepsy; age < 12 months; seizure within 1 h after onset of fever;
and seizure with body temperature < 38.0 °C) [9]. The criteria for
prophylactic administration of diazepam suppository in the former
guideline were nearly the same as those in the new guideline except for
2 risk factors: seizure within 1 h after onset of fever; and seizure oc-
curring with body temperature < 38.0 °C. However, the new guideline
states that routine diazepam suppository use is not needed on arrival at
the emergency department if seizures have stopped [9], while the
former guideline did not define how to use diazepam suppository on
arrival [8] and the use depended on the judgment of the pediatrician.
The former and new guidelines thus differ in how to use diazepam
suppositories on arrival for children in whom FS has stopped. Nation-
wide surveillance in Japan has revealed that diazepam suppositories
were administered in the emergency room in 52 % of pediatric in-
stitutions during 2013–2014 (former guideline era), compared to 37 %
in 2016 (new guideline era) [10].
Caregivers were instructed to visit our center if the seizure recurred
during the same febrile period to evaluate the need for diagnostic
workup and rescue therapy and, consequently, to confirm FS recur-
rence. FS recurrence within 24 h was checked by reviewing medical
records. Baseline characteristics, including sex, age, neurodevelop-
mental condition, past history of FS, family history of FS, diarrheal
symptoms during the febrile episode, seizure type (general or focal),
duration between onset of fever ≥38.0 °C and FS, duration of seizure,
and temperature, were recorded on arrival. Laboratory testing, in-
cluding white blood cell counts and concentrations of C-reactive pro-
tein, sodium, and blood glucose, was performed for children with no
history of FS, prolonged seizure ≥15 min, or seizure recurrence during
a single febrile episode. Baseline information, laboratory data, hospital
revisits during the same febrile episode, and hospital admission were
also obtained from medical records. During the study period, admin-
istration of acetaminophen (10 mg/kg/dose at 6-h intervals) as an an-
tipyretic was not restricted if fever remained ≥38.5 °C.
This study protocol was approved by the ethics committee at Beppu
Medical Center. Informed consent was obtained from parents.
2.2. Statistical analysis
JMP version 14 software (SAS Institute Inc., Cary, NC) was used for
all statistical analyses. Values of P < 0.05 were considered significant.
71
Seizure: European Journal of Epilepsy 75 (2020) 70–74
The main outcome measure was seizure recurrence within 24 h. Patient
characteristics, laboratory data, and seizure recurrence within 24 h
were compared between visits during 2011–2015 and during
2016–2018. Comparisons were made using the Mann-Whitney U test
for continuous variables and using Pearson’s chi-squared test or Fisher’s
exact test for categorical variables. Logistic regression analysis was used
to evaluate the relationship between rectal diazepam administration
and seizure recurrence within 24 h. The multivariate model was ad-
justed for potential confounders on univariate analysis (P < 0.05) and
for the relevant risk factors of seizure recurrence reported in the pre-
vious studies [7,11–14], such as age, family history of FS, neurodeve-
lopmental abnormality, focal or prolonged (≥15 min) seizure, low
temperature (< 39.0 °C), short duration (< 1 h) of fever before seizure
onset, and low serum sodium level (< 135 mEq/L).
3. Results
During the study period from 2011 to 2018, a total of 1932 children
were transported by ambulance to our hospital. Of these children, 543
met the inclusion criteria, and 34 were excluded (28 for intravenous
administration of antiepileptic drugs, 3 for hydrocephalus, 2 for epi-
lepsy, and 1 for intracranial hemorrhage). Subsequently, a total of 509
children were considered eligible for this study. Of these 509 children,
297 (58 %) visited our hospital in 2011–2015 (former guideline era)
and 212 (42 %) in 2016–2018 (the new guideline era). Blood tests were
performed in 359 children (71 %), diagnostic lumbar puncture in 27
(5.3 %), brain CT or MR imaging in 56 (11 %), and electro-
encephalography in 19 (3.7 %). No abnormal results were seen from
cerebrospinal fluid examinations. Of the 19 electroencephalographic
studies, abnormal findings were identified in 3 children (16 %) during
2011–2015, including focal epileptiform discharges in 2 and a gen-
eralized spike-and-wave complex in 1. Diazepam suppositories were
administered to 193 children (38 %), with no serious adverse effects
identified in any children.
In a total of 78 children (15 %), seizure recurrences were observed
within 24 h. Of the 78 children with recurrent FS within 24 h, the FS
recurred within 8 h in 67 (86 %). Regarding risk factors for FS recur-
rence [7,11,12], family history of FS was observed in 21 (27 %) of the
78 children with FS recurrence within 24 h and in 85 (20 %) of the 431
children without FS recurrence within 24 h (relative risk [RR] 1.40; 95
% confidence interval [CI] 0.89–2.20, P = 0.15), neurodevelopmental
abnormality in 2 (2.6 %) and in 8 (1.9 %) (RR 1.31; 95 %CI 0.37–4.61,
P = 0.65), focal seizure in 5 (6.4 %) and in 10 (2.3 %) (RR 2.26; 95 %CI
1.07–4.76, P = 0.064), prolonged (≥15 min) seizure in 5 (6.4 %) and
in 16 (3.7 %) (RR 1.59; 95 %CI 0.72–3.52, P = 0.35), low temperature
(< 39.0 °C) on arrival in 20 (26 %) and in 98 (23 %) (RR 1.14; 95 %CI
0.72–1.82, P = 0.58), and short duration (< 1 h) of fever before seizure
onset in 12 (15 %) and in 73 (17 %) (RR 0.91; 95 %CI 0.51–1.60,
P = 0.74), respectively.
Sources of fever were clinically diagnosed based on physical find-
ings, imaging study, rapid antigen test, and specific antibody test.
Etiologies were compared between groups with and without FS recur-
rence within 24 h as follows: upper respiratory tract infection in 35 (45
%) of 78 patients with FS recurrences within 24 h and in 266 (62 %) of
431 patients without recurrence, lower respiratory tract infection in 11
(14 %) and 39 (9.0 %), exanthem subitum in 11 (14 %) and 12 (2.8 %),
influenza virus infection in 5 (6.4 %) and 29 (6.7 %), adenovirus in-
fection in 3 (3.8 %) and 6 (1.4 %), herpangina in 2 (2.6 %) and 14 (3.2
%), infectious gastroenteritis in 2 (2.6 %) and 10 (2.3 %), hand-foot-
and-mouth disease in 2 (2.6 %) and 1 (0.2 %), group A streptococcal
infection in 1 (1.3 %) and 7 (1.6 %), urinary tract infection in 0 (0 %)
and 2 (0.5 %), mumps in 0 (0 %) and 2 (0.5 %), varicella in 0 (0 %) and
1 (0.2 %), cellulitis in 0 (0 %) and 1 (0.2 %), and unknown source of
fever in 6 (7.7 %) and 41 (9.5 %).
Basic patient characteristics and laboratory data are shown in
Table 1. On univariate analyses, significant relationships were
M. Inoue, et al. Seizure: European Journal of Epilepsy 75 (2020) 70–74

Table 1
Univariate analysis comparing the periods before and after revision of the practice guideline (2011–2015 and 2016–2018).
2011–2015 2016–2018 Relative risk P value
n = 297 n = 212 (95 % confidence interval)

Sex – male, n (%) 159 (54) 136 (64) 1.20 (1.04–1.39) 0.017
Age – months, median (IQR) 22 (17–32) 22 (16–32) 0.81
Age < 12 months, n (%) 19 (6.4) 11 (5.2) 0.81 (0.39–1.67) 0.57
Pre-existing neurodevelopmental abnormality, n (%) 9 (3.0) 1 (0.5) 0.16 (0.02–1.22) 0.051
Past history of FS, n (%) 112 (38) 71 (33) 0.89 (0.70–1.13) 0.33
Family history of FS, n (%) 62 (21) 44 (21) 0.99 (0.70–1.40) 0.97
Diarrhea during febrile episode, n (%) 13 (4.4) 7 (3.3) 0.75 (0.31–1.86) 0.54
Focal seizure, n (%) 6 (2.0) 9 (4.3) 2.10 (0.76–5.82) 0.14
Temperature on arrival − °C, median (IQR) 39.4 (38.7–39.8) 39.5 (39.0–40.0) 0.031
Temperature on arrival < 39 °C, n (%) 86 (29) 32 (15) 0.52 (0.36–0.75) 0.0003
Interval between fever and FS – h, median (IQR) 7 (2–13) 7 (2–18) 0.38
Interval between fever and FS < 1 h, n (%) 49 (17) 36 (17) 1.03 (0.70–1.52) 0.89
Duration of seizure – min, median (IQR) 3 (1–5) 3 (1–5) 0.68
Prolonged FS ≥ 15 min, n (%) 10 (3.4) 11 (5.2) 1.54 (0.67–3.56) 0.31
Rectal diazepam administration, n (%) 156 (53) 37 (17) 0.33 (0.24–0.45) < 0.0001
Recurrence of FS within 24 h, n (%) 35 (12) 43 (20) 1.72 (1.14–2.59) 0.0087
Interval between first and second FS – h, median (IQR) 4 (0.5–8) 3 (0.5–6) 0.38
Laboratory data
WBC count − /μL, median (IQR) 10,770 (7390–14,650) 10,780 (8173–14,048) 0.96
C-reactive protein – mg/L, median (IQR) 5.4 (2.2–12.7) 5.5 (1.9–13.5) 0.96
Sodium – mEq/L, median (IQR) 135 (134–136) 135 (133–137) 0.53
Blood glucose – mg/dL, median (IQR) 116 (104–133) 118 (106–137) 0.30
Lumbar puncture, n (%) 14 (4.7) 13 (6.1) 1.30 (0.62–2.71) 0.48
Brain imaging study
CT, n (%) 28 (9.4) 21 (9.9) 1.05 (0.61–1.80) 0.86
MRI, n (%) 6 (2.0) 1 (0.5) 0.23 (0.03–1.93) 0.25
Electroencephalography, n (%) 10 (3.4) 9 (4.3) 1.26 (0.52–3.05) 0.61
Hospital revisit during same febrile episode, n (%) 45 (15) 48 (23) 1.49 (1.04–2.16) 0.031
Hospital admission, n (%) 54 (18) 56 (26) 1.45 (1.04–2.02) 0.026

CT, computed tomography; FS, febrile seizure; IQR, interquartile range; MRI, magnetic resonance imaging; WBC, white blood cell.

identified between the two periods (2011–2015 or 2016–2018) and sex, % (number needed to treat, 6.8 children).
temperature on arrival, diazepam administration, FS recurrence within
24 h, hospital revisits during the same febrile episode, and hospital
admission. With the guideline revision, rectal diazepam administration 4. Discussion
was reduced from 53 % in 2011–2015 to 17 % in 2016–2018, and FS
recurrence within 24 h was increased from 12 % in 2011–2015 to 20 % This study is the first to investigate the impact of reduced rectal
in 2016–2018. diazepam usage in Japan after the practice guideline for FS was up-
To evaluate the association between seizure recurrence and the re- dated by the Japanese Society of Child Neurology, advocating more
lated factors, multiple logistic regression analysis was performed limited use of rectal diazepam following simple FS. In this study,
(Table 2). FS recurrence within 24 h was associated with rectal dia- compared to 2011–2015, rectal diazepam administration was sig-
zepam administration on arrival and was no longer associated with the nificantly decreased, and the frequency of seizure recurrence within
other risk factors or potential confounding factors. Comparing rectal 24 h was significantly increased in 2016–2018. Logistic regression
diazepam use (n = 193) and non-use (n = 316) after the initial seizure, analysis suggested that diazepam suppository use contributed to pre-
the frequency of FS recurrence was significantly lower with diazepam venting short-term seizure recurrence. Our findings suggest that strict
use (6 %) than without diazepam use (21 %; RR 0.30; 95 %CI adherence to the updated guideline in Japan, which is based on the
0.17–0.54, P < 0.0001), representing an absolute risk reduction of 15 international recommendations, may lead to an increase in short-term
recurrence of FS.
The present investigation demonstrated that prophylactic diazepam
Table 2 administration actually decreased in our center, as in many other in-
Multivariate logistic regression analysis for predicting febrile seizure recurrence
stitutions in Japan, after the publication of the new guideline [10].
within 24 h.
However, FS recurrences within 24 h increased within the same period.
Odds ratio P value Although this study involved a single center that consistently complied
(95 % confidence with the guideline for FS, clinical guidelines were not firmly adhered to
interval)
in general. Nationwide surveillance has demonstrated that the guide-
Diazepam suppository 0.24 (0.12–0.50) 0.0001 line for FS was used in clinical practice by 32 % of pediatricians in the
Serum sodium < 135 mEq/L 1.46 (0.83–2.57) 0.19 United States [15] and by 55 % of pediatricians in Japan [10]. If the
Focal seizure 2.28 (0.66–7.81) 0.19 new guideline for FS can be more broadly adhered to in Japan, pro-
Family history of FS 1.55 (0.80–3.03) 0.20
Sex, male 1.32 (0.74–2.34) 0.34
phylactic use of rectal diazepam may decrease further and short-term
Pre-existing neurodevelopmental 2.02 (0.35–11.84) 0.44 recurrence of FS may increase throughout Japan. Indeed, routine use of
abnormality diazepam suppositories following FS is not recommended, given the
Temperature on arrival < 39 °C 1.25 (0.65–2.39) 0.50 benign nature of FS, but the indication for prophylactic diazepam use
Interval between fever and FS < 1 h 0.82 (0.37–1.85) 0.64
should be considered based on the individual condition, with admin-
Prolonged FS ≥ 15 min 1.29 (0.41–4.08) 0.66
Age < 12 months 1.19 (0.40–3.56) 0.76 istration applied where the benefits outweigh the risks.
The present study showed that diazepam suppository use had the
FS, febrile seizure. potential to reduce the risk of FS recurrence within 24 h. This is

72
M. Inoue, et al.
consistent with the finding of Hirabayashi et al. [4], who assessed the
efficacy of diazepam suppository at 0.5 mg/kg/dose on arrival, com-
paring the recurrence of FS during the same febrile episode between a
diazepam use group (n = 95; single administration in 81 and additional
administrations 8 h after first use in 14) and a non-use group (n = 108).
In that study, seizure recurrence was significantly reduced in the dia-
zepam use group compared to the non-use group (2.1 % vs. 14.8 %,
P = 0.0021). After single administration of a diazepam suppository
(0.5 mg/kg) to children at a mean age of 15 months, plasma con-
centration reached the effective range (> 150 ng/mL) within 30 min
and was maintained within this effective range for 8 h following ad-
ministration [16]. In our study, 86 % of short-term FS recurrences oc-
curred within 8 h after initial FS. Use of diazepam suppository thus
appears to have some potential to prevent short-term FS recurrence.
Prophylactic diazepam use can also prevent revisiting hospital and
hospital admissions and, as a result, can contribute to decreasing
healthcare costs and reducing the psychological or physical stress of
caregivers. Levels of parental anxiety were not measured in this study,
but were presumed to be strong enough for them to call emergency
medical services. The trend toward nuclear families and escalating
child-rearing anxiety in Japan may have contributed to the increasing
ambulance calls by parents nationwide. Actually, the annual number of
children transported by ambulance in this study was greater in
2016–2018 than in 2011–2015.
The neurological outcome of FS is usually good [17], and anti-
seizure drugs are not commonly required for children with simple FS. In
addition, diazepam administration causes mild adverse effects such as
sedation, ataxia, lethargy, and irritability in 10–47 % of children
[18,19], which raises the concern that adverse effects may obscure the
symptoms of serious infection, particularly meningitis and encephalitis.
Actually, prolonged FS due to serious underlying etiology was stopped
by diazepam use and the antiseizure activity appeared to be stronger
after intravenous administration than rectal administration [20].
However, the common adverse effects of diazepam were self-limiting
sedative events and no serious events leading to neurological sequelae
or death have been reported [4,16,18,19]. Prophylactic diazepam use
should be decided carefully on the basis of local health infrastructure,
accessibility to hospital, strong parental anxiety, and the possibility of
underlying central nervous infection.
There is longstanding concern about possible central nervous system
infection in children with FS, particularly in the case of complex FS.
Observational studies in the United States identified no bacterial me-
ningitis in 260 children with simple FS who underwent lumbar punc-
tures [21], and bacterial meningitis was identified in only 3 (0.9 %) of
340 children with complex FS who underwent lumbar puncture [22].
Of those 3 children with bacterial meningitis, all involved Streptococcus
pneumoniae and two had not received pneumococcal conjugated vac-
cines [22]. The clinical practice guideline for simple FS published by
the American Academy of Pediatrics has recommended that lumbar
puncture be performed in children with meningeal signs and considered
as an option in children who have been pretreated with antibiotics or
who have not received Haemophilus influenzae type b or Streptococcus
pneumoniae immunizations [1]. Since the introduction of Haemophilus
influenzae type b vaccine and pneumococcal conjugated vaccine, the
incidence of bacterial meningitis in children has been decreasing in
Japan [23], as in the United States. Given the safety concerns, a diag-
nostic workup of underlying serious etiologies is necessary prior to the
use of prophylactic diazepam if a child presenting with complex FS,
especially with meningeal signs, neurological deficit, impaired con-
sciousness, no history of vaccinations, or antibiotic pretreatment. If
present, underlying central nervous system infection should be treated
aggressively.
Younger onset age [11,12], focal or prolonged seizure [7,11], short
duration between fever and FS [12], lower temperature at onset [12],
and family history of FS [11,12] have been considered as risk factors for
long-term FS recurrence during subsequent febrile episodes. Although
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Seizure: European Journal of Epilepsy 75 (2020) 70–74
temperature at seizure onset was not identified in the present study,
temperature on arrival was lower in 2011–2015 than in 2016–2018.
This was partly attributable to the presence of 3 children with abnormal
electroencephalographic findings only in 2011–2015. However, FS re-
currence within 24 h was more frequent in 2016–2018 than in
2011–2015. This observation raised concerns about the possible effects
of high fever on short-term FS recurrence, but no such effect was
identified in multivariate analysis. Our findings agree with recent stu-
dies with large sample sizes that showed no association between serum
sodium level and FS recurrence within 24 h [13,14]. Although sex was
associated with FS recurrence on the present univariate analysis, no
such association was found on multiple logistic regression analysis. No
sex predominance for FS recurrence has been observed in previous
studies [4,5,12].
Murata et al. evaluated the efficacy of acetaminophen in preventing
short-term FS recurrences [5]. That open, randomized, controlled trial
compared FS recurrence during a single febrile episode between a
group with regular use of rectal acetaminophen at 10 mg/kg/dose
(every 6 h–24 h after initial FS; n = 219) and a non-use group
(n = 204). In that study, seizure recurrence was significantly lower in
the rectal acetaminophen regular use group than in the non-use group
(9.1 % vs. 23.5 %, P < 0.001), and no serious complications related to
acetaminophen were observed. Nonetheless, no international consensus
on the preventive effect of acetaminophen has been reached, because
no other studies have shown the efficacy of antipyretics against recur-
rence of FS [19,24]. In addition, no comparative studies have examined
prophylactic effects against short-term FS recurrence between rectal
acetaminophen and rectal diazepam. The relative effects of acet-
aminophen and diazepam in reducing FS recurrence should be eval-
uated in future research. If acetaminophen is confirmed to offer the
same effectiveness as diazepam for the prevention of FS recurrence,
routine use of prophylactic acetaminophen following FS may be re-
commended.
Some limitations to our study merit consideration. First, all study
subjects were transported to our center by ambulance. Cases of rela-
tively severe FS were thus thought to be included in this study.
However, duration of seizures, frequency of prolonged seizure, and
multiple recurrences within 24 h were similar to values reported in
previous reports [4,5]. Second, this study involved a single center in
Japan. Since the cumulative incidence of FS differs between Japan and
the United States [2,3], the generalizability of the study results to non-
Japanese children may be limited. Third, acetaminophen use was not
evaluated in this study. Acetaminophen administration was not re-
stricted in this study and could have influenced FS recurrence. Acet-
aminophen is widely used for febrile children in Japan, since anti-
pyretics are available over the counter in this country, so close
monitoring of acetaminophen administration is difficult in retrospective
studies. Finally, the causative pathogens of fever were not completely
identified in our study. The recurrence of FS may be affected by the
causative pathogens.
5. Conclusion
In the present study, FS recurrences within 24 h were shown to have
increased, potentially due to the limited use of rectal diazepam since
the publication of the new clinical practice guideline for FS in Japan. As
described in the guideline, routine use of diazepam cannot be re-
commended for simple FS. The indication for rectal diazepam to pre-
vent recurrence should be reconsidered under conditions where the
benefit outweighs the risk, especially for children with parents showing
strong anxiety or under conditions of vulnerable local health infra-
structure.
Funding
This research did not receive any specific grant from funding
M. Inoue, et al. Seizure: European Journal of Epilepsy 75 (2020) 70–74

agencies in the public, commercial, or not-for-profit sectors. S0022-3476(05)82816-1.

[12] Berg AT, Shinnar S, Hauser WA, Alemany M, Shapiro ED, Salmon ME, et al. A
prospective study of recurrent febrile seizures. N Engl J Med 1992;327:1122–7.
Declaration of Competing Interest https://doi.org/10.1056/NEJM199210153271603.
[13] Thoman JE, Duffner PK, Shucard JL. Do serum sodium levels predict febrile seizure
None. recurrence within 24 hours? Pediatr Neurol 2004;31:342–4. https://doi.org/10.
1016/j.pediatrneurol.2004.05.013.
[14] Maksikharin A, Prommalikit O. Serum sodium levels do not predict recurrence of
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