Seizure 59 (2018) 5–10

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Seizure
journal homepage: www.elsevier.com/locate/yseiz

Cytokine levels in febrile seizure patients: A systematic review and

meta-analysis
Aram Kwona,1, Byung Ok Kwakb,1, Kyungmin Kima , Jongseok Haa , Soo-Jin Kimc,
Sun Hwan Baec, Jae Sung Sonc , Soo-Nyung Kimd, Ran Leec,*
a
Department of Pediatrics, Konkuk University Medical Center, Seoul, Republic of Korea
b
Biopharmaceuticals & Herbal Medicine Evaluation Department, Biologics Division, National Institute of Food and Drug Safety Evaluation, Chungcheongbuk-
do, Republic of Korea
c
Department of Pediatrics, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea
d
Department of Obstetrics and Gynecology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea

A R T I C L E I N F O A B S T R A C T

Article history: Purpose: Febrile seizures (FSs) are the most common form of childhood seizures. During infection, both
Received 29 November 2017 pro-inflammatory and anti-inflammatory cytokines are produced. Complex interactions among
Received in revised form 24 April 2018 immune-inflammatory process, cytokine activation, and genetic factors are involved in the pathogenesis
Accepted 26 April 2018
of FSs. The association between cytokines and FSs during childhood is inconclusive due to inconsistent
results reported in different studies. We performed a systematic review and meta-analysis to determine
Keywords: an association between cytokines and FS in children.
Pro-inflammatory cytokines
Methods: We searched PubMed, EMBASE, and Cochrane databases for studies published up to January
Anti-inflammatory cytokines
Cytokine
2017 using the following key words: [“cytokine” OR “interleukin” OR “tumor necrosis factor alpha” OR
Febrile seizures “interferon-gamma” OR “single nucleotide polymorphism”] AND [“febrile seizure” OR “febrile
Child convulsion”] AND [“pediatric” OR “infant” OR “child”]. Standardized mead difference (SMD) and 95%
Meta-analysis confidence intervals (CI) were calculated using standard meta-analysis techniques.
Results: A total of 6 studies enrolling 243 children with FS and 234 controls were included in the meta-
analysis. A total of 4 different inflammatory mediators were. The results indicated that CSF IL-1b level
and serum IL-6 level were significantly associated with FS (CSF IL-1b: SMD, 1.064; 95% CI, 0.217–1.611;
P < 0.01, serum IL-6 SMD, 2.654; 95% CI, 2.332–2.975; P < 0.01).
Conclusion: The results of this meta-analysis suggest that CSF IL-1b level and serum IL-6 level are
associated with an increased risk of FSs in children. Based on these results, it is expected that a
therapeutic agent for specific cytokines could be developed in the future to prevent FS.
© 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

1. Introduction meeting the criteria for other acute symptomatic seizures in

Febrile seizures (FSs) are the most common form of childhood
seizures, occurring in 2–5% of children younger than 6 years of age
[1]. FSs are defined by the International League Against Epilepsy as
an elevated or rapidly rising fever of short duration associated with
uncomplicated seizure that does not predispose to epilepsy and is
not accompanied by any neurologic abnormality, no previous
neonatal seizures or a previous unprovoked seizure, and not
* Corresponding author at: Department of Pediatrics, Konkuk University Medical
Center, 120 1 Neungdong ro (Hwayang dong), Gwangjin gu, Seoul, 05030,
Republic of Korea.
E-mail address: leeran67@kuh.ac.kr (R. Lee).
1
These authors contributed equally to this study.
children between 6 months and 5 years of age [2].
FS can be divided into 2 categories. Simple FS is a seizure that
only occurs once in 24 h, is generalized, has a duration of less than
15 min, while complex FS is a seizure recurs within 24 h, is focal,
and has a duration of more than 15 min [3].
The threshold fever temperature for FS varies among individu-
als and by age and maturation [4]. Genetic susceptibility to
inflammation may influence the threshold temperature of FSs, and
17–30% of FS patients have a family history of FSs [5].
Pro-inflammatory and anti-inflammatory cytokines regulate
immune response. During infection, both pro-inflammatory and
anti-inflammatory cytokines are produced [6]. IL-1b, TNF- a and
IL-6 are pro-inflammatory cytokines that participate in the
induction of acute-phase inflammation reactions, including fever.
IL-1 receptor antagonist (IL-1RA) and IL-10 are anti-inflammatory

https://doi.org/10.1016/j.seizure.2018.04.023
1059-1311/© 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
6 A. Kwon et al. / Seizure 59 (2018) 5–10
cytokines and have a negative feedback effect during fever [6,7].
The balance between these two cytokine groups influences the
severity of the fever. Complex interactions among immune-
inflammatory process, cytokine activation, and genetic factors
are involved in the pathogenesis of FSs [8]. Experimental studies
demonstrate that inflammation and inflammatory mediators are
the main causes and propagators of both febrile and epileptic
seizures [9].
Several case-control studies have been performed to measure
the concentration of cytokines in the serum or cerebrospinal fluid
(CSF) of seizure patients compared with that of healthy controls
without seizures [10–26]. Additionally, case-control genetic
association studies have been conducted to establish a potential
correlation between genetic polymorphisms and susceptibility to
common diseases [27].
Meta-analyses are required to pool the existing inconsistent
data. A systematic literature review of case-control studies that
measured cytokine concentrations was also performed.
2. Materials and methods
We conducted a systematic review and meta-analysis in
accordance with the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) statement.
2.1. Method for searching and identifying studies
A systematic literature search was conducted in PubMed,
EMBASE, Cochrane Trial (CENTRAL) by using various synonyms for
epilepsy and cytokines, such as “febrile seizure”, “febrile convul-
sion”, “cytokine”, “interleukin”, “tumor necrosis factor alpha”,
“TNF-alpha”, “interferon-gamma”, and “single nucleotide poly-
morphism”, with “pediatric”, “infant”, or “child”. There were no
restrictions on language, population, or publication year. The last
search was performed on January 17, 2017.
We included studies of human epilepsy or FSs concerning
cytokine measurement in serum and cerebrospinal fluid (CSF).
Animal studies, articles that were not included studies, reviews,
comments, case reports, and studies with inadequate data were
excluded. All titles and abstracts were independently screened by
two investigators (A and BO). Both authors independently checked
the remaining articles for full-text eligibility.
2.2. Study selection and data extraction
The following inclusion criteria were applied: 1) the study was
designed as a case-control study, 2) it diagnosed patients with FS/
epilepsy without any other neurologic complications 3) it enrolled
healthy controls, 4) it measured plasma cytokine concentrations,
and 5) it provided adequate data, including genotype/allele
frequency in both the case and control groups to allow calculation
of the pooled odds ratio. Reviews, comments, animal studies, case
reports and studies with inadequate data were excluded from the
meta-analysis. Additionally, we excluded studies that used a
definition of FS other than that used in our study, those that
stimulated seizure by using lipopolysaccharide, and studies that
did not include a healthy comparison group (i.e., the control group
had epilepsy, encephalopathy or CNS disorder).
The titles and abstracts of the identified articles were checked
and independently reviewed by two of the authors (A and BO), and
discrepancies were resolved by discussion. The following data
were extracted: the first author, publication year, study design,
study location, ethnicity, study population, sample size, sample
material, investigated cytokine gene, and the cytokine levels of the
case and control groups. Any discrepancies in the interpretations of
the data were resolved via discussion with a third reviewer.
2.3. Quality assessment
The two authors separately assessed the quality of the included
studies. Any disagreement was resolved via discussion with a third
reviewer, after which the study was reevaluated. We evaluated
case control studies by using the Newcastle-Ottawa Scale. Nine
points were given to studies of the highest quality, which were
considered to have sufficiently “high quality” for inclusion in the
meta-analysis. A total score 3 was considered to represent “low
quality,” a score of 4 or 5 was considered to represent “moderate
quality,” and a score 6 was considered to represent “high quality.”
2.4. Data synthesis and analysis
The mean differences and 95% confidence intervals (CIs) were
calculated from the extracted data. We assessed interstudy
heterogeneity by using I2 statistics. The I2 value was expressed
as a percentage of the total variation across studies; when I2 > 50%,
the assumption of homogeneity was deemed invalid, and the
random effects model (DerSimonian-Laird method) was applied;
otherwise, the fixed model (Mantel-Haenszel method) was used
for the meta-analysis. A sensitivity analysis was performed by
removing each study sequentially to evaluate the robustness of the
combined estimates and to examine its contribution to the pooled
odds ratio (OR). Publication bias was evaluated by using funnel
plots, Egger’s test and the Begg-Mazumdar rank correlation test.
P < 0.05 was considered statistically significant. The meta-analysis
was performed using Comprehensive Meta-Analysis version 2.0
(Biostat, Englewood, NJ, USA).
3. Result
3.1. Literature search and selection
Fig. 1 shows how relevant studies were identified for this meta-
analysis and why studies were excluded. Among a total of 206
studies that were identified from the initial search, 3 additional
studies were added; 27 duplicates were then removed. After the
abstracts and titles of 182 studies were reviewed, 31 articles
remained. Through the full text review, 25 studies were excluded
(the reasons are described in Fig. 1), and finally, 6 reports were
included in this meta-analysis.
3.2. Characteristics of the included studies
A total of 6 studies were selected for this meta-analysis. All the
studies were prospective case-controlled. Quality was evaluated
with the Newcastle-Ottawa Scale, and all the studies were awarded
7 to 8 stars, indicating high quality (Table 1).
Overall, 243 FS patients and 234 controls were enrolled in all
the included studies. The characteristics of the included studies are
summarized in Table 2. A total of 4 different inflammatory
mediators were investigated in these studies. The studies reported
protein levels in serum or CSF and compared them with those of
controls. We conducted meta-analyses of serum IL-1b levels based
on five studies [10,19,23,25,28], CSF IL-1b based on two studies
[10,28], serum TNF-a based on two studies [23,28] and serum IL-6
based on two studies [23,29]. The cytokine levels of patients and
controls were expressed in pg/ml and significant difference was
shown in P-value. Consistent significant differences in certain
cytokines were not detected.
3.3. Meta-analysis of serum IL-1b levels
Serum IL-1b levels were investigated in five case-control
studies with 143 patients with FS and 134 healthy controls. There
 A. Kwon et al. / Seizure 59 (2018) 5–10 7

Fig. 1. Flow diagram of the literature search and study selection process. The values in parentheses indicate the number of documents corresponding to each category.

Table 1 healthy controls. Compared with the control group’s serum IL-1b
Assessment of the quality of the included studies by using the Newcastle-Ottawa levels, the Asian patient group’s standardized mean difference was
scale.
1.403, the 95% CI was from 0.086 to 2.892, and the P-value was
Author Year Criterion Scores Total score 0.065. There were two studies of participants with Caucasian
Selection Comparability Exposure ethnicity; they included 39 patients with FS and 25 healthy
controls. Compared with the control group’s IL-1b levels, the
Lahat 1997 $$$ $ $$ 6
Haspolat 2002 $$$ $$ $$ 7 Caucasian patient group’s standardized mean difference was
Tomoum 2007 $$$ $$ $$ 7 0.122, the 95% CI was from 1.657 to 1.414, and the P-value
Choi 2011 $$$ $$ $$ 7 was 0.877. One investigation examined Egyptian participants and
Behmanesh 2012 $$$ $$ $$ 7
included 33 patients with FS and 38 healthy controls. Compared
Azab 2016 $$$ $ $$ 6
with the controls, the Egyptian patients’ standardized mean
difference was 0.186, the 95% CI was from 2.275 to 1.902, and
the P-value was 0.861 (Fig. 3). No significant differences were
were two investigations in Asian populations, two in Caucasians detected according to ethnicity (Fig. 3).
and one in Egyptians. Publication bias was found using a funnel plot (Fig. 4). However,
Compared with the control group, the FS patients’ serum IL-1b the Begg-Mazumdar rank correlation test and Egger’s regression
level did not differ significantly (standardized mean differ- test did not show evidence of publication bias.
ence = 0.487; 95% CI = 0.480 to +1.455, P > 0.05). The included
studies were statistically heterogeneous (I2 = 92.7%); thus, the 3.4. Meta-analysis of serum TNF-a levels
random effects model was used for the meta-analysis (Fig. 2).
In the subgroup analysis, there were two studies of participants There were 70 patients with FS and 56 healthy controls
with Asian ethnicity; they included 71 patients with FS and 71 extracted from 2 studies. The serum TNF-a levels of the FS patients

Table 2
Characteristics of the studies included in the meta-analysis.

Author Year Study Country Ethnicity Number of Number of Material Cytokine Case Control P-value
design cases controls (pg/ml) (pg/ml)
Lahat 1997 Prospective case-control Israel Caucasian 10 10 Serum IL-1b 2.92 3.44 0.28
CSF IL-1b 4.15 3.2 0.2
Haspolat 2002 Prospective case-control Turkey Caucasian 29 15 Plasma TNF-a 71.8 41.5 >0.05
IL-1b 20.5 21.6 >0.05
CSF IL-1b 23.1 17.6 <0.05
Tomoum 2007 Prospective case-control Egypt Egyptian 33 38 Plasma IL-1b 7.321 8.087 0.06
Choi 2011 Prospective case-control Korea Asian 41 41 Serum TNF-a 5.0 5.6 >0.05
IL-1b 12 3.1 <0.05
IL-6 247.1 134 0.7
IL-10 23.6 8.3 0.05
IFN-g 73.5 84.2 >0.05
Behmanesh 2012 Prospective case-control Iran Asian 30 30 Serum IL-1b 8.08 5.68 0.08
Azab 2016 Prospective case-control Egypt Egyptian 100 100 Serum IL-6 43.7 21.9 NA
8 A. Kwon et al. / Seizure 59 (2018) 5–10

Fig. 2. Meta-analysis of serum IL-1b levels using the random effects model.

Fig. 3. Subgroup meta-analysis of serum IL-1b levels according to ethnicity.

3.5. Meta-analysis of serum IL-6 levels

Two studies were included in the serum IL-6 meta-analysis. The

studies included 141 patients with FS and 141 healthy controls. The
FS group’s serum IL-6 level was significantly higher than that of the
control group. The standardized mean difference was 2.654, the
95% CI was from 2.332 to 2.975, and the P-value was <0.01. The
included studies were statistically heterogeneous (I2 = 78.248%);
thus, the random effects model was used for the meta-analysis
(Fig. 6).

3.6. Meta-analysis of CSF IL-1b levels

Thirty-nine patients with FS and 25 healthy controls were

Fig. 4. Publication bias regarding serum IL-1b levels.
extracted from 2 studies. Regarding CSF IL-1b, the FS group’s levels
were significantly higher than those of the control group. The
standardized mean difference was 1.064, 95% CI was from 0.217 to
1.611, and the P-value was <0.01. The included studies were
statistically heterogeneous (I2 = 73.1%); thus, the random effects
model was used for the meta-analysis (Fig. 7).

and the healthy controls did not differ significantly (standardized
mean difference = 0.006; 95% CI = 0.565 to 0.554, P > 0.05). The
included studies were statistically heterogeneous (I2 = 54.653%);
thus, the random effects model was used for the meta-analysis
(Fig. 5).
4. Discussion
In the present study, we reviewed and comprehensively
summarized case–control studies and found potentially important
information. First, the IL-1b level differed according to whether it

Fig. 5. Meta-analysis of serum TNF-a levels.

 A. Kwon et al. / Seizure 59 (2018) 5–10
Fig. 6. Meta-analysis of serum IL-6 levels.
Fig. 7. Meta-analysis of CSF IL-1b levels.
originated from the serum or the CSF. The serum IL-1b level of the
patient group did not significantly differ from that of the control
group. However, the CSF IL- 1b level of the patient group was
significantly higher than that of the control group. Second, the
serum IL-6 level was significantly higher in the patient group.
Although numerous studies have investigated FS, the exact
pathophysiology remains unclear. Since FSs occur during a high
body temperature or a rapidly rising fever, several factors
associated with fever generation could be involved in the
mechanism of FS. Cytokines are among the factors that may be
involved in the pathogenesis of FS [30]. Cytokines are mediators of
the host response to infections and induce fever, leukocytosis, and
acute-phase protein synthesis [31].
IL-1b is a polypeptide pro-inflammatory cytokine that is
produced by peripheral blood monocytes and CNS astrocytes
and glial cells [32,33]. IL-1b has various activities, including
fibroblast proliferation, cartilage breakdown, and initiation of the
host response to infection. IL-1b is a pluripotent pro-inflammatory
cytokine that binds to IL-1R1, a Toll receptor family member; via an
NFkB-dependent mechanism, it induces the transcription of
various genes that encode several downstream mediators of
inflammation, including IL-6 and TNF-a. The time scale of these
effects is between 30 and 90 min [34].
In a previous study, Tütüncüog lu S. et al. reported increased
levels of plasma IL-1b in FS patients. The report suggested that in
comparison with the control group, the patients’ IL-1b level during
the acute phase were significantly increased, but the IL-1b levels
during the delayed phase were not significantly different. The
direct relationship between plasma IL-1b concentration and fever
level indicated that IL-1b has a more active role than other
cytokines in fever development [35].
Conflicting results regarding the IL-1b levels in FS patients have
been reported for plasma and CSF. Tütüncüog lu S. et al. reported
that IL-1b levels were significantly high in plasma but not in CSF
[35]. Haspolat et al. reported that IL-1b levels were significantly
high in CSF but not in plasma [28]. Lahat et al. reported that both
plasma and CSF IL-1b levels were not significantly higher
compared with the control group. These results imply difficulties
with obtaining clinical samples and measuring free IL-1b [10].
In this study, the IL-1b level was significantly higher among
patients than controls when measured in the CSF but not when
measured in the serum. The suspected reason for this inconsistent
9
finding compared with previous studies is that the sampling time
of the included studies differed. As mentioned above, IL-1b
increases significantly during the acute phase of fever. Therefore, if
samples are obtained within 30 to 90 min, IL-1b levels might
appear significantly high. However, under different circumstances,
we can assume that blood samples and CSF samples were obtained
during different phases of fever. Consequently, the IL-1b levels
varied among the studies, and this meta-analysis only found
significantly high levels in the CSF. To perform a more sophisticated
study, sampling times should be documented, and the sample
should be divided into acute and delayed phases before the IL-1b
level is assessed.
IL-6 is a pro-inflammatory cytokine that is pleiotropic and is
secreted by T-lymphocytes, macrophages, endothelial cells and
epithelial cells. It has a wide range of biological activities in
immune regulation, hematopoiesis, inflammation, and neoplasia.
IL-6 also has a strong correlation with fever [36]. IL-6 is regulated at
the expression level; thus, it has a short plasma half-life of between
20 and 60 min [37].
Several studies reported that plasma IL-6 levels were signifi-
cantly higher in FS patient groups compared with control groups.
Azab S. et al. showed significant positive associations between FSs
and the IL-6 level and reported the related genotype (G allele at the
174 position and the 174 GG or 597 GG). Their findings
revealed that the patient group was more susceptible to FS. In
addition, they reported a negative association between FSs and the
C allele at the 174 position, indicating that this association could
represent a protective effect against FSs [29].
Choi J. et al. (2011) reported that serum IL-6 was higher in
children with FS than in healthy controls who had only fever. In
addition, the serum IL-6 levels in FS patients were much higher
than those in patients who had undergone an afebrile seizure
attack. These findings suggest that IL-6 has a pro-convulsant action
in FSs [23].
In this meta study, as expected, we found that serum IL-6 levels
in patients with FS were significantly elevated compared with
those of the control group. This result was consistent with the
findings of previous studies. Based on these results, it is expected
that a therapeutic agent for specific cytokines could be developed
in the future to prevent FS. However, in this meta-analysis, we did
not include genotyping results; therefore, in future studies,
cytokines and genotypes should be studied after sampling, and
10 A. Kwon et al. / Seizure 59 (2018) 5–10
their correlation, whether positive or negative, should be
evaluated.
This study had some limitations. First, among these was its
small sample size. We suggest that multicenter approaches may be
necessary to attain larger sample sizes. Second, only 3 different
cytokines were included in this meta-analysis. For better
understanding of pathogenesis of FS, we need to evaluate more
cytokines. Additional high-quality studies are required for further
verification. In addition, the genotypes of cytokines were not
evaluated. There was also publication bias indicated by funnel plot.
This may affect the interpretation of our results.
5. Conclusion
In conclusion, this meta-analysis systematically revealed that
the FS patients had significantly higher CSF IL-1b and serum IL-6
levels compared with the control group. Further studies, specifi-
cally well-designed, large-scale, case-controlled trials, are needed
to evaluate the precise concentrations of certain cytokines in FS
patients and to determine the cytokines’ various activities during
FS. Based on these results, it is expected that a therapeutic agent for
specific cytokines could be developed in the future to prevent FS.
Conflicts of interest
Conflict of interest relevant to this article was not reported.
Funding
This research did not receive grant support from funding
agencies in the public, commercial, or not-for-profit sectors.
Author contributions
AK, BOK, KK, JH, JSS, SJK, SWB, SNK, and RL contributed to the
study design, data collection and analysis, manuscript preparation,
and manuscript approval.
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