Proinflammatory and anti-inflammatory cytokines in febrile seizures and epilepsy: systematic review and meta-analysis.

DOI 10.1515/revneuro-2013-0045 Rev. Neurosci. 2014; 25(2): 281–305

Amene Saghazadeh, Maryam Gharedaghi, Alipasha Meysamie, Sebastian Bauer and Nima Rezaei*

Proinflammatory and anti-inflammatory cytokines in febrile seizures and epilepsy: systematic review and meta-analysis Abstract: Activation of proinflammatory and anti-inflammatory cytokines network seems to have a role in febrile seizures (FS). The present meta-analysis was aimed to pool the inconsistent data provided with case-control studies on the relationship of proinflammatory and anti-inflammatory cytokines and FS/epilepsy risk. The genotype interleukin (IL)-1α-889 1/1 (recessive model) was significantly correlated with increased risk of epilepsy ( p = 0.008) and FS/epilepsy ( p = 0.004). Patients with IL-1β-511 T/T homozygote were more susceptible to develop FS ( p = 0.036) but not epilepsy. Furthermore, the T/T genotype was totally associated with increased risk of FS/epilepsy ( p = 0.043). Although the recessive model was also confirmed for the Asian subgroup (FS and FS/epilepsy), we found a protective effect of C/C genotype toward developing FS in the Caucasian race ( p = 0.020). The second meta-analysis on cytokine levels showed a statistically higher serum level of IL-6 in patients with epilepsy compared to control subjects without epilepsy. The present meta-analysis showed that two alleles of proinflammatory cytokines (IL-1α-889 and IL-1β-511) in addition to the serum concentration of IL-6 were significantly associated with FS and epilepsy or both in various subgroup analyses. Keywords: cytokines; epilepsy; febrile seizures.

*Corresponding author: Nima Rezaei, Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Dr. Qarib Street, Keshavarz Boulevard, Tehran 14194, Iran, e-mail: [email protected]; Molecular Immunology Research Center; and Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 14194, Iran; and Department of Infection and Immunity, School of Medicine and Biomedical Sciences, The University of Sheffield, Sheffield, S10 2TN, UK Amene Saghazadeh: Molecular Immunology Research Center; and Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Maryam Gharedaghi: School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Alipasha Meysamie: Department of Community and Preventive Medicine, Tehran University of Medical Sciences, Tehran, Iran Sebastian Bauer: Klinik für Neurologie, Epilepsiezentrum Hessen (EZH), Philipps-Universität Marburg, Marburg, Germany

Introduction Febrile seizure (FS) is defined as a seizure in association with a febrile illness in the absence of any central nervous system (CNS) infection or acute electrolyte imbalance in children older than 1 month of age without prior afebrile seizures, based on the Commission on Epidemiology and Prognosis, International League Against Epilepsy (1993). FS, the most common type of epileptic seizures in early life world wide (Nakayama and Arinami, 2006; Kundu et al., 2012; Salzmann et al., 2012), is a matter of concern to pediatricians with a total prevalence of 3%–7% in children up to 7 years (Cross, 2012) and a cumulative incidence of 2%–5% in the first 5 years of life (Verity et al., 1985; Visser et al., 2012). FS, occurring during rapid rising of fever (Özaydın et al., 2012) between 6 months and 5 years of age (Klein et al., 2012; Kumari et al., 2012; Martinos et al., 2012; Teran et al., 2012; Zareifar et al., 2012), can be divided into simple forms (only occuring once in 24 h, generalized, and duration 15 min) (Kira et al., 2005; Abdel Rasol et al., 2012; French, 2012; Offringa and Newton, 2013; Sasidaran et al., 2012; Scott et al., 2012; Yu et al., 2012). Epilepsy is considered to be the most common chronic neurological condition in childhood (Home and Kerirey, 1991) and the second most frequent cause of mental health disability (Wiebe et al., 2001). It has an age-adjusted prevalence of 2.7–17.6 per 1000 and an incidence of 16–51 per 100 000 (Banerjee et al., 2009). Children with a history of FS frequently develop epilepsy and epileptiform discharges on electroencephalograms (EEG) (Cross, 2012). Accordingly, there is an antecedent of FS in 10%–15% of all patients with epilepsy, particularly among patients with temporal lobe epilepsy (TLE) (Nelson and Ellenberg, 1978; Hamati-Haddad and Abou-Khalil, 1998; Dubé et al., 2010). Gene-environment interactions led to understanding febrile and epileptic seizures as multifactorial diseases (Hahn et al., 2003). Experimental studies demonstrate that inflammation and inflammatory mediators form the

Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 5/25/15 10:12 PM

282 A. Saghazadeh et al.: Cytokines in febrile seizures main causers and propagators of both febrile and epileptic seizures (Dubé et al., 2007; Vezzani et al., 2008, 2010). Accordingly, several case-control studies have investigated the concentration of cytokines in serum or cerebrospinal fluid (CSF) samples of seizure patients compared to controls without seizures (Lahat et al., 1997; Peltola et al., 1998, 2000; Kawakami et al., 1999a; Jain et al., 2000; Hulkkonen et al., 2004; Lehtimaki et al., 2004, 2011; Lehtimäki et al., 2007; Tomoum et al., 2007; Carmeli et al., 2009; Haginoya et al., 2009; Liimatainen et al., 2009; Choi et al., 2011; Nowak et al., 2011; Behmanesh et al., 2012; Pollard et al., 2012). The fact that genetics have a leading role in the pathogenesis of FS (Waruiru and Appleton, 2004; Dubé et al., 2007; Heida et al., 2009; Wendorff and Zeman, 2011) has been proven by conducting various genetic studies including twin studies (Tsuboi, 1987; Corey et al., 1991; Berkovic et al., 1998; Miller et al., 1998, 1999; Kjeldsen et al., 2002, 2005), familial studies (Nelson and Ellenberg, 1978; Knudsen, 1985; Annegers et al., 1987, 1990; el-Radhi and Banajeh, 1989; van Esch et al., 1998; Huang et al., 1999), genome-wide association studies (GWAS) (Wallace et al., 1996; Johnson et al., 1998; Baulac et al., 1999; Moulard et al., 1999; Peiffer et al., 1999; Nakayama et al., 2000, 2004; Nabbout et al., 2002, 2007; Mantegazza et al., 2005; Audenaert et al., 2006; Hedera et al., 2006; Dai et al., 2008; Salzmann et al., 2012), and populationbased association studies (Chou et al., 2002, 2003a,b,c, 2004, 2010; Nakayama et al., 2002, 2003a,b; Tilgen et al., 2002; Tsai et al. 2002a,b; Virta et al., 2002a; Ma et al., 2004; Mulley et al., 2004; Yinan et al., 2004, 2006; Cho et al., 2005; Haspolat et al., 2005; Kira et al., 2005, 2010; Chung et al., 2006; Kinirons et al., 2006; Matsuo et al., 2006; Shu-hua et al., 2006; Blair et al., 2007; Gao et al., 2007; Lin et al., 2007; Wang et al., 2007b; Giray et al., 2008; Kim et al., 2008; Li et al., 2008; Yoon et al., 2008; Ishizaki et al., 2009; Schlachter et al., 2009; Serdaroğlu et al., 2009; Dibbens et al., 2010; Jamali et al., 2010; Zhao et al., 2010; Le Gal et al., 2011; Khoshdel et al., 2012; Nur et al., 2012a,b; Ponnala et al., 2012; Salam et al., 2012). Casecontrol genetic association studies have been performed to establish a potential correlation between genetic polymorphisms and susceptibility to common diseases. Meta-analyses are required to pool all the present inconsistent data. A subset of such studies were carried out to prove whether there is an association between common variants of the genes encoding cytokines, including interleukin (IL)-1, tumor necrosis factor (TNF)-α, and IL-6 and common disorders, for example, gastric cancer (Camargo et al., 2006; Kamangar et al., 2006; Wang et al., 2007a; Xue et al., 2010), breast cancer (Liu et al., 2010), schizophrenia (Sacchetti et al., 2007), Alzheimer’s

disease (Rainero et al., 2004), or type 2 diabetes (Qi et al., 2006). Another subset of meta-analyses was sought for whether there is a significant difference in concentrations of cytokines between patients with depression (Howren et al., 2009; Dowlati et al., 2010), Alzheimer’s disease (Swardfager et al., 2010), or schizophrenia (Miller et al., 2011) and control subjects. In the attempt to explain ‘what similarities and differences exist between febrile seizures and epilepsy on the genetics-related and environmental factors-related algorithms’, we conducted the present study including two meta-analyses for concentrations and genetic polymorphisms of proinflammatory and anti-inflammatory cytokines. However, initial hypothesizing about any similarity in the algorithms, either genetic or environmental, which govern febrile and epileptic seizures is impossible due to discrepant data, the present study eventually reveals a series of valuable similarities and differences, which both aid the design of our therapeutic approaches for patients with FS or epilepsy as well as the preventive approaches to avoid developing epileptic seizures in patients with FS, as far as possible. The first meta-analysis aims to assess whether the most frequently investigated genetic polymorphisms of cytokine genes [including IL-1α-889, IL-1β-511, IL-1 receptor antagonist (IL-1Ra), IL-6 -572, and TNF-α-308] are associated with development of FS/epilepsy. A systematically literature review on casecontrol studies that measured concentrations of cytokines was also performed. The second study was designed for serum concentrations of IL-1β, IL-1Ra, IL-6, and TNF-α in patients with febrile or epileptic seizures.

Study 1 Materials and methods Search strategy Our search strategy has been well summarized in Figure 1.

Inclusion criteria In the present meta-analysis, the original a ssociation studies were included if they met all of the following inclusion criteria: (a) it was designed as a case-control association study, (b) it diagnosed patients with FS/epilepsy without any other neurologic complications, (c) it enrolled healthy controls, (d) it assessed the association of genetic


A. Saghazadeh et al.: Cytokines in febrile seizures 283

((Febrile seizures) or FS or epilepsy) and (cytokine) and (association) and (polymorphism or SNP) PubMed

Web of Science

SCOPUS

25

13

11

Review Meta-analysis

3

Review 8 Related papers

15 Related papers 7 Duplicated papers

15 Included papers

2 1

3 E

1 1 1 1 2 1 1

1 3

FS 4

6 Related papers 6 Duplicated papers

1 Included paper Hand searching

FS

5

0 Included paper Google scholar

3

-308 -1037

TNF-α

3

25 Included papers

-511 IL-1β Exon 5

-850

FS 19 2

E FS

-251 IL-8

6

IL-1Ra

-2767

E

11 11

5 1

-1082 -592 -627 -889

E

IL-4

IL-10 Meta-analysis IL-1α

IL-1β -511 IL-1α -889 IL-1Ra IL-6 -572 TNF-α -308

IL-6

1 -572

3

-174

2

-597

1

FS E

1 1

Figure 1 Search strategy 1. We searched PubMed, Web of Science, and SCOPUS databases up to April 2013. Eventually, data extraction was performed for 25 studies. E, epilepsy.

variants of the genes encoding proinflammatory and antiinflammatory cytokines with susceptibility to FS/epilepsy, and (e) it provided adequate data including genotype/allele frequency in both case and control groups to calculate the pooled odds ratio (OR).

Data extraction The following data were extracted from each included publication: (a) first author, (b) year of publication, (c) country of origin, (d) ethnicity, (e) investigated cytokine gene and variant, (f) number of genotyped cases and controls, (g) genotype/allele frequency in cases and controls, (h) genetic methodology, and (i) syndrome type.

Statistical analyses The Hardy-Weinberg equilibrium (HWE) was assessed by using the exact test for goodness-of-fit. The Q statistic test

was used to calculate the heterogeneity across the included studies. We used the logistic regression test to evaluate the overall gene effect. If no heterogeneity is detected, the random-effect logistic regression should be used. To compare the pairwise differences, the OR1 (AA vs. aa), OR2 (Aa vs. aa), and OR3 (AA vs. Aa) were defined. Eventually, to pool the data, if there was a significant overall gene effect, we hypothesized the best genetic model as explained by Thakkinstian et al. (2005). In some analyses, we could not assume the best inheritance mode consistent with estimated ORs. Therefore, the data should then be pooled in three ways with regard to the three genetic models (dominant, recessive, and complete overdominant) to propose the best genetic model. If the overall gene effect was not significant, no further analyses to determine the best genetic model should be made. The Begg and Egger tests were used to assess the publication bias of included studies. p 0.69 and complete overdominant model: p > 0.36).

Meta-analysis of IL-1α-889 in patients with FS/epilepsy (HWE) Analysis of heterogeneity was replicated for three studies after excluding one study because of the Hardy-Weinberg disequilibrium (Peltola et al., 2001) (OR1: χ2 = 4.70, p = 0.915, OR2: χ2 = 4.74, p = 0.093, and OR3: χ2 = 0.18, p = 0.915). Logistic

Haspolat (2005)

Ozkara (2006)

Kanemoto (2000)

Peltola (2001)

1

1.39 (0.79, 2.43)

33.16

1.61 (0.80, 3.24)

19.42

1.12 (0.58, 2.16)

27.14

2.46 (1.31, 4.61)

20.28

1.58 (1.15, 2.15)

100.00

4.61

Figure 2 IL-1α-889 variant in patients with FS/epilepsy. Fixed-effect pooled OR for the recessive model.

Haspolat (2005) 0.62 (0.34, 1.11)

29.99

0.87 (0.43, 1.74)

17.75

0.74 (0.37, 1.45)

20.52

0.38 (0.19, 0.74)

31.74

0.61 (0.44, 0.84)

100.00

Ozkara (2006)

Kanemoto (2000)

Peltola (2001)

0.194

1

5.15

Figure 3 IL-1α-889 variant in patients with FS/epilepsy. Fixed-effect pooled OR for the complete overdominant model.

regression analysis did not indicate a significant overall gene effect (fixed-effect LR = 3.13, p = 0.2091). OR1, OR2, and OR3 were estimated as 1.083 (95% CI, 0.525–2.236), 0.746 (95% CI, 0.354–1.573), and 1.442 (95% CI, 0.983–2.114), respectively. Accordingly, none of the assumed genetic models indicated significantly increased risk of FS/epilepsy for a given genotype (OR1: 1.079, p = 0.833; OR2: 1.350, p = 0.106; and OR3: 0.717, p = 0.081). Publication bias was not found ( p > 0.43).

Meta-analysis of IL-1α-889 in patients with epilepsy There were 197 patients with epilepsy (FE, TLE, and MTLEHS) and 611 healthy controls extracted from three studies. The results of the Q statistic test did not indicate hetero geneity across the studies of IL-1α in the epilepsy subgroup (OR1: χ2 = 4.25, p = 0.119; OR2: χ2 = 4.79, p = 0.091; and OR3: χ2 = 2.83, p = 0.243). The overall gene effect was significant (fixed-effect LR = 7.59, p = 0.0225). The ORs including OR1 (1/1 vs. 2/2), OR2 (1/2 vs. 2/2), and OR3 (1/1 vs. 1/2) were estimated as 1.476 (95% CI, 0.655–3.325), 0.798 (95% CI, 0.340–1.870), and 1.750 (95% CI, 1.180–2.596), respectively. Similar to the confirmed genetic models for patients with FS/epilepsy, data of both recessive (Figure 4) and complete overdominant (Figure 5) models could be pooled (OR2: 1.669, p = 0.008, and OR3: 0.607, p = 0.011). Altogether, the 1/1 genotype has been associated with increased risk of developing epilepsy, while those with 1/2 genotype have a protective effect toward epilepsy. There was no evidence of publication bias for both genetic models (recessive model: p > 0.95 and the complete overdominant model: p > 0.81).



Ozkara (2006) 1.61 (0.80, 3.24)

29.06

1.12 (0.58, 2.16)

40.60

2.46 (1.31, 4.61)

30.34

Kanemoto (2000)

Peltola (2001)

1.67 (1.14, 2.44) 100.00

1

4.61

Meta-analysis of IL-1 β-511 in patients with FS/epilepsy (HWE)

Figure 4 IL-1α-889 variant in patients with epilepsy. Fixed-effect pooled OR for the recessive model.

Ozkara (2006)

0.87 (0.43, 1.74)

25.35

0.74 (0.37, 1.45)

29.31

0.38 (0.19, 0.74)

45.34

0.61 (0.41, 0.89)

100.00

Kanemoto (2000)

Peltola (2001)

0.194

population). The results of the Q statistic test showed heterogeneity for studies of IL-1β-511 polymorphism (OR1: χ2 = 2 8.58, p = 0.073; OR2: χ2 = 21.59, p = 0.305; and OR3: χ2 = 32.95, p = 0.024). Results of the logistic regression test did not indicate a significant overall gene effect (randomeffect logistic regression Wald = 5.72, p = 0.0574). The OR1 (T/T vs. C/C), OR2 (C/T vs. C/C), and OR3 (T/T vs. C/T) were estimated as 0.790 (95% CI, 0.664–0.940), 0.938 (95% CI, 0.824–1.067), and 0.878 (95% CI, 0.749–1.030), respectively. Of the three assumed genetic models, there was a significantly increased risk of FS/epilepsy for the T/T genotype (random-effect pooled OR: 1.193, 95% CI, 1.006–1.415, p = 0.043) (Figure 6). There was no evidence of publication bias ( p > 0.75).

1

5.15

Figure 5 IL-1α-889 variant in patients with epilepsy. Fixed-effect model for the complete overdominant model.

Meta-analysis of IL-1 β-511 in patients with FS/epilepsy The gene encoding IL-1β was investigated in 20 casecontrol association studies with a total of 2448 patients with FS, TLE ± HS, symptomatic localization-related epilepsy (SLE), and other unmentioned epileptic syndromes and 2701 healthy controls. The number of articles related to Asian and Caucasian races was the same (10 studies for an Asian population and 10 studies for a Caucasian

Heterogeneity was rechecked after excluding two papers (Haspolat et al., 2005; Shu-hua et al., 2006) because of deviation from the HWE (OR1: χ2 = 2 6.32, p = 0.069; OR2: χ2 = 12.23, p = 0.768; and OR3: χ2 = 2 8.37, p = 0.041). We reanalyzed the OR1, OR2, and OR3, which were 0.789 (95% CI, 0.659–0.944), 0.959 (95% CI, 0.839–1.095), and 0.857 (95% CI, 0.726–1.011), respectively. Although there was no overall significant gene effect across 18 included studies in this subgroup (random-effect LR Wald = 5.77, p = 0.0560), the recessive mode of inheritance (T/T homozygote) was associated with increased risk of FS/ epilepsy development, similar to the previous analysis (random-effect pooled OR: 1.211, 95% CI, 1.035–1.417, p = 0.017) (Figure 7). There was no evidence of publication bias ( p > 0.85).

Meta-analysis of IL-1 β-511 in Asian patients with FS/epilepsy The initial Q statistic test indicated homogeneity among 10 studies including 1038 patients with epilepsy and 1117 healthy controls (OR1: χ2 = 9.59, p = 0.385; OR2: χ2 = 6.01, p = 0.739; and OR3: χ2 = 7.41, p = 0.595). The OR1, OR2, and OR3 were estimated as 0.784 (95% CI, 0.613–1.002), 1.023 (95% CI, 0.837–1.250), and 0.774 (95% CI, 0.619–0.968), respectively. Although the results of the logic regression did not prove a significant overall gene effect (fixed-effect LR = 5.42, p = 0.0666), the recessive mode of inheritance was the best genetic model to represent that Asian patients with T/T genotype have an increased risk of developing FS/epilepsy (fixed-effect pooled OR: 1.281, 95% CI,


288 A. Saghazadeh et al.: Cytokines in febrile seizures

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Heils Peltola Buono Virta Tilgen Kanemoto Chou Jin Haspolat Cavalleri Ozkara Matsou Li Yoon Serdaroglu Chou Kira Nur Tiwari Chung

2000 2001 2001 2002 2002 2003 2003 2003 2005 2005 2006 2006 2006 2008 2009 2010 2010 2012 2012 2006

Overall (I-squared=15.2%, p =0.265)

0.93 (0.41, 2.12) 1.52 (0.75, 3.06)

3.84 5.05

1.75 (0.56, 5.44)

2.11

1.82 (0.84, 3.96)

4.24

1.14 (0.55, 2.36)

4.78

1.47 (0.92, 2.34) 0.52 (0.20, 1.35)

9.62 2.99

1.09 (0.59, 1.99) 0.63 (0.31, 1.27)

6.42 5.05

0.95 (0.63, 1.42)

11.70

1.30 (0.54, 3.12) 0.74 (0.19, 2.93)

3.44 1.48

3.97 (1.02, 15.37)

1.52

1.31 (0.41, 4.15) 2.63 (1.19, 5.81)

2.05 4.08

1.17 (0.65, 2.12) 1.43 (0.92, 2.22) 0.58 (0.28, 1.22)

6.66 10.51 4.61

1.32 (0.56, 3.11)

3.56

1.31 (0.71, 2.43)

6.29

1.19 (1.01, 1.42)

100.00

Note: Weights are from random effects analysis 0.0651

1

15.4

Figure 6 IL-1β-511 variant in patients with FS/epilepsy. Random-effect pooled OR for the recessive model.

1 Kanemoto

2003

1.47 (0.92, 2.34)

2 Chou

2003

0.52 (0.20, 1.35)

8.28

3 Jin

2003

1.09 (0.59, 1.99)

12.90

4 Matsou

2006

0.74 (0.19, 2.93)

3.01

5 Li

2006

3.97 (1.02, 15.37)

1.55

6 Yoon

2008

1.31 (0.41, 4.15)

3.29

7 Chou

2010

1.17 (0.65, 2.12)

12.93

8 Kira

2010

1.43 (0.92, 2.22)

21.79

9 Tiwari

2012

1.32 (0.56, 3.11)

5.95

10 Chung

2006

1.31 (0.71, 2.43)

11.15

1.28 (1.04, 1.58)

100.00


0.0651

1

19.14

15.4

Figure 7 IL-1β-511 variant in patients with FS/epilepsy (HWE). Random-effect pooled OR for the recessive model.

1.039–1.579, p = 0.021) (Figure 8). There was no evidence of publication bias ( p > 0.65).

Meta-analysis of IL-1 β-511 in Asian patients with FS/epilepsy (HWE) After excluding one (Shu-hua et al., 2006) out of 10 included studies because of deviation from the HWE in the control group, the homogeneity was rechecked (OR1: χ2 = 7.99, p = 0.435; OR2: χ2 = 3.04, p = 0.932; and OR3: χ2 = 7.17, p = 0.518). The OR1, OR2, and OR3 were estimated as 0.807 (95% CI, 0.629–1.036), 1.012 (95% CI, 0.823–1.243), and 0.804 (95%

CI, 0.640–1.010), respectively. However, there was a significantly increased risk of FS/epilepsy for T/T homozygotes compared with C/C and C/T combined (OR: 1.238, 95% CI, 1.001–1.532, p = 0.049) (Figure 9). The overall gene effect was not significant (fixed-effect LR = 3.88, p = 0.1440). There was no evidence of publication bias ( p > 0.06).

Meta-analysis of IL-1 β-511 in Caucasian patients with FS/epilepsy For the 10 included studies with 1410 patients with epilepsy and 1984 healthy controls in this category, the



1

Heils

2000

0.93 (0.41, 2.12)

3.67

2

Peltola

2001

1.52 (0.75, 3.06)

5.02

3

Buono

2001

1.75 (0.56, 5.44)

1.91

4

Virta

2002

1.82 (0.84, 3.96)

4.10

5

Tilgen

2002

1.14 (0.55, 2.36)

4.72

6

Kanemoto

2003

1.47 (0.92, 2.34)

11.36

7

Chou

2003

0.52 (0.20, 1.35)

2.78

8

Jin

2003

1.09 (0.59, 1.99)

6.70

9

Cavalleri

2005

0.95 (0.63, 1.42)

15.09

10 Ozkara

2006

1.30 (0.54, 3.12)

3.25

11 Matsou

2006

0.74 (0.19, 2.93)

1.31

12 Yoon

2008

1.31 (0.41, 4.15)

1.85

13 Serdaroglu 2009

2.63 (1.19, 5.81)

3.93

14 Chou

2010

1.17 (0.65, 2.12)

7.02

15 Kira

2010

1.43 (0.92, 2.22)

12.87

16 Nur

2012

0.58 (0.28, 1.22)

4.52

17 Tiwari

2012

1.32 (0.56, 3.11)

3.37

18 Chung

2006

1.31 (0.71, 2.43)

6.53

1.21 (1.03, 1.42) 100.00

Overall (I-squared=0.0%, p =0.515) Note: Weights are from random effects analysis 0.172

1

5.81

Figure 8 IL-1β-511 variant in Asian patients with FS/epilepsy. Fixed-effect pooled OR for the recessive mode of inheritance.

heterogeneity was calculated by the Q statistic test (OR1: χ2 = 18.97, p = 0.025; OR2: χ2 = 13.37, p = 0.147; and OR3: χ2 = 24.73, p = 0.003). There was no significant overall gene effect (random-effect LR Wald = 2.69, p = 0.2602) and pairwise OR difference (OR1: 0.796, 95% CI, 0.623–1.018, p = 0.069; OR2: 0.882, 95% CI, 0.745–1.044, p = 0.145; and OR3: 1.002, 95% CI, 0.798–1.259, p = 0.985). None of three assumed inheritance modes could be associated with increased risk of FS/epilepsy in Caucasian patients (random-effect pooled OR1: 0.805, p = 0.158; OR2: 1.141, p = 0.365; and OR3: 1.122, p = 0.368). There was no evidence of publication bias ( p > 0.13).

Meta-analysis of IL-1 β-511 in Caucasian patients with FS/epilepsy (HWE) The heterogeneity still remained after excluding one study (Haspolat et al., 2005) because the control group deviated from the HWE (OR1: χ2 = 18.31, p = 0.019; OR2: χ2 = 8.60, p = 0.377; and OR3: χ2 = 21.02, p = 0.007). Results of random-effect logistic regression did not reveal a significant overall gene effect among the rest of studies (random-effect LR Wald = 2.50, p = 0.2869). Pairwise comparisons were estimated as OR1: 0.770, 95% CI, 0.594–0.997, p = 0.047; OR2: 0.922, 95% CI, 0.774–1.099, p = 0.364; and OR3: 0.920, 95% CI, 0.723–1.170, p = 0.496, respectively. Similarly to the above analysis, no genetic model correlated with susceptibility to FS/epilepsy in Caucasian patients (random-effect pooled OR1: 0.821, p = 0.239; OR2: 1.217, p = 0.178; and OR3: 1.046, p = 0.711). There was no evidence of publication bias ( p > 0.14).

Meta-analysis of IL-1 β-511 in patients with FS There is a set of 11 studies, which have been conducted to assess the potential correlation of the IL-1β-511 polymorphism with FS risk. The information on IL-1β was extracted from 932 patients with FS diagnosis and 1562 healthy controls. There was not heterogeneity across the studies of IL-1β-511 polymorphism in patients with FS (OR1: χ2 = 13.32, p = 0.206; OR2: χ2 = 16.32, p = 0.091; and OR3: χ2 = 10.07, p = 0.434). The overall gene effect was significant (fixed-effect LR = 8.68, p = 0.0119). The OR1 of 0.677 (95% CI, 0.528–0.869), OR2 of 0.790 (95% CI, 0.647–0.966), and OR3 of 0.872 (95% CI, 0.696–1.093) proposed the recessive mode of inheritance to compare combined TT versus CC+CT genotypes. The TT genotype (recessive model) was associated with increased risk of FS (fixed-effect pooled OR: 1.256, 95% CI, 1.016–1.554, p = 0.036) (Figure 10). Further, we suggest that those with CC genotype have a protective effect toward FS development (Figure 11) (fixedeffect pooled OR: 0.760, 95% CI, 0.629–0.917, p = 0.004). There was no evidence of publication bias for both genetic models (dominant model: p > 0.85 and recessive model: p > 0.80).

Meta-analysis of IL-1 β-511 in patients with FS (HWE) The homogeneity was stable by retest after excluding two studies (Haspolat et al., 2005; Shu-hua et al., 2006) because of Hardy-Weinberg disequilibrium in the control groups (OR1: χ2 = 10.72, p = 0.218; OR2: χ2 = 6.79, p = 0.559; and



1 Kanemoto

2003

1.47 (0.92, 2.34)

2 Chou

2003

0.52 (0.20, 1.35)

8.41

3 Jin

2003

1.09 (0.59, 1.99)

13.11

4 Matsou

2006

0.74 (0.19, 2.93)

3.06

5 Yoon

2008

1.31 (0.41, 4.15)

3.34

6 Chou

2010

1.17 (0.65, 2.12)

13.14

7 Kira

2010

1.43 (0.92, 2.22)

22.13

8 Tiwari

2012

1.32 (0.56, 3.11)

6.05

9 Chung

2006

1.31 (0.71, 2.43)

11.33

1.24 (1.00, 1.53)

100.00


0.188

1

19.44

5.32

Figure 9 IL-1β-511 variant in Asian patients with FS/epilepsy (HWE). Fixed-effect pooled OR for the recessive mode of inheritance.

2002

1.82 (0.84, 3.96)

5.51

2 Tilgen

2002

1.32 (0.61, 2.85)

7.45

3 Haspolat

2005

0.63 (0.31, 1.27)

13.84

4 Matsou

2006

0.74 (0.19, 2.93)

3.11

5 Li

2006

3.97 (1.02, 15.37)

1.60

6 Serdaroglu

2009

2.63 (1.19, 5.81)

5.15

7 Chou

2010

1.17 (0.65, 2.12)

13.33

8 Kira

2010

1.43 (0.92, 2.22)

22.46

9 Nur

2012

0.58 (0.28, 1.22)

12.84

10 Yoon

2008

1.31 (0.41, 4.15)

3.39

11 Chung

2006

1.34 (0.72, 2.48)

11.31

1.26 (1.02, 1.55)

100.00

1 Virta


0.0651

1

15.4

Figure 10 IL-1β-511 variant in patients with FS. Fixed-effect pooled OR for the recessive model.

1 Virta

2002

0.43 (0.19, 1.02)

7.49

2 Tilgen

2002

1.01 (0.59, 1.72)

10.69

3 Haspolat

2005

0.65 (0.36, 1.17)

11.17

4 Matsou

2006

2.41 (0.67, 8.67)

1.24

5 Li

2006

1.03 (0.42, 2.49)

3.85

6 Serdaroglu

2009

0.51 (0.28, 0.95)

11.34

7 Chou

2010

0.81 (0.47, 1.41)

11.36

8 Kira

2010

0.77 (0.52, 1.13)

22.89

9 Nur

2012

0.88 (0.45, 1.73)

7.21

10 Yoon

2008

0.44 (0.15, 1.25)

4.20

11 Chung

2006

0.81 (0.43, 1.53)

8.56

0.76 (0.63, 0.92) 100.00


0.115

1

8.67

Figure 11 IL-1β-511 variant in patients with FS. Fixed-effect pooled OR for the dominant model.



OR3: χ2 = 6.85, p = 0.553). Reanalyzing nine studies with the HWE, the OR1, OR2, and OR3 were estimated as 0.659 (95% CI, 0.504–0.862), 0.812 (95% CI, 0.654–1.010), and 0.826 (95% CI, 0.647–1.053), respectively. The overall gene effect was significant (fixed-effect LR = 9.11, p = 0.0105). Similar to the above subgroup analysis, there was an increased risk of FS in patients with TT genotype (Figure 12), in contrast to the protective effect of CC genotype (Figure 13) (fixedeffect pooled OR1: 0.762, 95% CI, 0.621–0.935, p = 0.009 and OR2: 1.308, 95% CI, 1.040–1.644, p = 0.022). There was no evidence of publication bias for both genetic models (dominant model: p > 0.97 and recessive model: p > 0.70). Meta-analysis of IL-1 β-511 in Asian patients with FS Homogeneity was proven for six included studies among 543 patients with epilepsy and 646 healthy controls (OR1:

χ2 = 3.81, p = 0.577; OR2: χ2 = 3.37, p = 0.643; and OR3: χ2 = 4.50, p = 0.480). The OR1, OR2, and OR3 were estimated as 0.668 (95% CI, 0.481–0.928), 0.883 (95% CI, 0.672–1.160), and 0.756 (95% CI, 0.560–1.021), respectively. Eventually, although there was an increased risk of FS in patients with TT genotype (fixed-effect pooled OR: 1.377, 95% CI, 0.549–0.962, p = 0.026) (Figure 14), the overall gene effect was not significant (fixed-effect LR = 5.67, p = 0.0588). There was no evidence of publication bias for recessive genetic model ( p > 0.78). Meta-analysis of IL-1 β-511 in Asian patients with FS (HWE) After excluding one (Shu-hua et al., 2006) out of six studies because of deviation from HWE, the homogeneity remained constant (OR1: χ2 = 2.65, p = 0.617; OR2: χ2 = 0.41, p = 0.981; and OR3: χ2 = 3.80, p = 0.434). OR1, OR2, and OR3 were estimated as 0.699 (95% CI, 0.498–0.980), 0.851 (95%

1 Virta

2002

1.82 (0.84, 3.96)

6.51

2 Tilgen

2002

1.32 (0.61, 2.85)

8.82

3 Matsou

2006

0.74 (0.19, 2.93)

3.67

4 Serdaroglu

2009

2.63 (1.19, 5.81)

6.10

5 Chou

2010

1.17 (0.65, 2.12)

15.77

6 Kira

2010

1.43 (0.92, 2.22)

26.56

7 Nur

2012

0.58 (0.28, 1.22)

15.18

8 Yoon

2008

1.31 (0.41, 4.15)

4.01

9 Chung

2006

1.34 (0.72, 2.48)

13.38

1.31 (1.04, 1.64)

100.00


0.172

1

5.81

Figure 12 IL-1β-511 variant in patients with FS (HWE). Fixed-effect pooled OR for the recessive model. 1 Virta

2002

0.43 (0.19, 1.02)

8.82

2 Tilgen

2002

1.01 (0.59, 1.72)

12.58

3 Matsou

2006

2.41 (0.67, 8.67)

1.46

4 Serdaroglu

2009

0.51 (0.28, 0.95)

13.35

5 Chou

2010

0.81 (0.47, 1.41)

13.37

6 Kira

2010

0.77 (0.52, 1.13)

26.93

7 Nur

2012

0.88 (0.45, 1.73)

8.48

8 Yoon

2008

0.44 (0.15, 1.25)

4.94

9 Chung

2006

0.81 (0.43, 1.53)

10.07


0.115

0.76 (0.62, 0.93) 100.00

1

8.67

Figure 13 IL-1β-511 variant in patients with FS (HWE). Fixed-effect pooled OR for the dominant model.



Matsou 2006

0.74 (0.19, 2.93)

5.63

Li

3.97 (1.02, 15.37)

2.89

Chou

2006 2010

Kira

2010

Yoon

2008

1.17 (0.65, 2.12)

Chung 2006

24.15

1.43 (0.92, 2.22)

40.69

1.31 (0.41, 4.15)

6.14

1.34 (0.72, 2.48)

20.50

1.38 (1.04, 1.82)

100.00

Virta

2002

Tilgen

2002

Haspolat

2005

Serdaroglu

2009

Nur

2012

185

1

15.4

Figure 14 IL-1β-511 variant in Asian patients with FS. Fixed-effect pooled OR for the recessive model.

CI, 0.639–1.134), and 0.811 (95% CI, 0.595–1.107), respectively. There was no significant overall gene effect (fixedeffect LR = 4.31, p = 0.1157). Accordingly, none of three assumed genetic models was associated with increased risk of FS. No publication bias was found ( p > 0.29).

Meta-analysis of IL-1 β-511 in Caucasian patients with FS There was heterogeneity across this subgroup, which comprises five studies with 1539 patients with epilepsy and 1839 healthy controls (OR1: χ2 = 9.50, p = 0.050; OR2: χ2 = 11.30, p = 0.023; and OR3: χ2 = 4.29, p = 0.368). Results of the random effect revealed a significant overall gene effect (random-effect LR Wald = 6.43, p = 0.0402). OR1, OR2, and OR3 were estimated as 0.691 (95% CI, 0.472–1.011), 0.695 (95% CI, 0.517–0.934), and 1.052 (95% CI, 0.745–1.485), respectively. Considering three assumed genetic models, the CC genotype (dominant model) was associated with a lower risk of FS (random-effect pooled OR: 0.702, 95% CI, 1.057–1.922, p = 0.020) (Figure 15). No publication bias was found ( p > 0.24).

11.57

1.01 (0.59, 1.72)

27.02

0.65 (0.36, 1.17)

22.74

0.51 (0.28, 0.95)

20.84

0.88 (0.45, 1.73)

17.84

0.70 (0.52, 0.95)

100.00

5.39

Figure 15 IL-1β-511 variant in Caucasian patients with FS. Random-effect pooled OR for the dominant model.

genotype was correlated with a decreased risk of FS developing in Caucasians (fixed-effect pooled OR: 0.713, 95% CI, 1.021–1.927, p = 0.037) (Figure 16). However, there was no significant overall gene effect (fixed-effect LR = 5.18, p = 0.0751). No publication bias was found across the studies according to the dominant genetic model ( p > 0.31).

Meta-analysis of IL-1 β-511 in patients with epilepsy The data for IL-1β-511 were derived from 11 studies with 1539 epilepsy patients and 1839 healthy controls. Heterogeneity of the studies was not revealed by the Q statistic test (OR1: χ2 = 13.77, p = 0.184; OR2: χ2 = 6.37, p = 0.783; and OR3: χ2 = 17.93, p = 0.056). The OR1, OR2, and OR3 were estimated as 0.903 (95% CI, 0.715–1.140), 1.069 (95% CI, 0.907–1.260), and 0.865 (95% CI, 0.696–1.076), respectively. The overall gene effect was not significant (fixed-effect LR = 3.96, p = 0.1383). None of three assumed genetic models was a suitable inheritance mode for IL-1β-511 in patients with epilepsy (fixed-effect pooled OR1: 1.033, p = 0.687, OR2: 1.141,

Meta-analysis of IL-1 β-511 in Caucasian patients with FS (HWE) The Q statistic test revealed homogeneity across four studies after excluding one study (Haspolat et al., 2005) from the previous subgroup, which deviated from the HWE (OR1: χ2 = 7.75, p = 0.051; OR2: χ2 = 6.36, p = 0.095; and OR3: χ2 = 2.85, p = 0.416). The OR1, OR2, and OR3 were estimated as 0.596 (95% CI, 0.384–0.926), 0.763 (95% CI, 0.547–1.066), and 0.849 (95% CI, 0.573–1.256), respectively. Similar to the previous subgroup analysis, the CC

1

0.43 (0.19, 1.02)

0.185

Virta

2002

Tilgen

2002

Serdaroglu

2009

Nur

2012

1

0.43 (0.19, 1.02)

20.40

1.01 (0.59, 1.72)

29.10

0.51 (0.28, 0.95)

30.88

0.88 (0.45, 1.73)

19.62

0.71 (0.52, 0.98)

100.00

5.39

Figure 16 IL-1β-511 variant in Caucasian patients with FS (HWE). Fixed-effect pooled OR for the dominant model.



p = 0.209, and OR3: 0.906, p = 0.195). There was no evidence of publication bias ( p > 0.64).

Meta-analysis of IL-1 β-511 in Asian patients with epilepsy The Q statistic test indicated homogeneity across the five included studies with 518 epilepsy patients and 645 healthy controls (OR1: χ2 = 4.38, p = 0.357; OR2: χ2 = 3.08, p = 0.544; and OR3: χ2 = 0.52, p = 0.971). The OR1, OR2, and OR3 were estimated as 0.890 (95% CI, 0.653–1.214), 1.213 (95% CI, 0.911–1.615), and 0.962 (95% CI, 0.714–1.297), respectively. The overall gene effect was not significant (fixed-effect LR = 3.48, p = 0.1752). Accordingly, there was no association between the IL-1β polymorphism and risk of developing epilepsy in patients from Asia. There was no evidence of publication bias ( p > 0.42).

Meta-analysis of IL-1 β-511 in Caucasian patients with epilepsy Heterogeneity was indicated among six studies included in this subgroup analyses (OR1: χ2 = 9.39, p = 0.094; OR2: χ2 = 2.22, p = 0.817; and OR3: χ2 = 16.72, p = 0.005) involving 1021 epilepsy patients and 1194 healthy controls. The OR1, OR2, and OR3 were estimated as 0.691 (95% CI, 0.472–1.011), 1.004 (95% CI, 0.821–1.228), and 1.052 (95% CI, 0.745–1.485), respectively. Similar to the previous analyses in the epilepsy subgroups, none of the hypothesized inheritance modes could be confirmed and the overall gene effect was not significant (random-effect LR Wald = 0.24, p = 0.8867). There was no evidence of publication bias ( p > 0.24).

Meta-analysis of IL-1Ra in patients with FS/epilepsy The gene encoding IL-1Ra was investigated in six casecontrol association studies with a total of 422 patients with FS and TLE and 592 healthy controls. The number of investigations on Asian populations was twice that of Caucasian populations (four studies for Asian populations and two studies for Caucasian populations). After excluding four studies because of no observations for OR1 and OR2, the results of the Q statistic test showed heterogeneity across the studies of IL-1Ra (OR1: 0.839, 95% CI, 0.373–1.889, χ2 = 5.90, p = 0.015; OR2: 1.556, 95% CI, 0.632–3.831, χ2 = 4.01, p = 0.045; and OR3: 1.099, 95% CI, 0.771–1.567, χ2 = 13.51, p = 0.019). The overall gene effect was

not significant (random-effect LR Wald = 0.68, p = 0.7115). None of three assumed genetic models have been confirmed (random-effect pooled OR1: 0.730, 95%, p = 0.824; OR2: 1.305, p = 0.470; and OR3: 0.779, p = 0.476). One study deviated from the HWE (Serdaroğlu et al., 2009). There was no evidence of publication bias ( p > 0.23).

Meta-analysis of IL-1Ra in patients with FS The information on IL-1Ra was extracted from five studies with 320 patients with FS and 484 healthy controls. After excluding three studies because of no observations for OR1 and OR2, a Q statistic test could indicate the heterogeneity among studies of IL-1Ra in FS (OR1: 0.839, 95% CI, 0.373–1.889, χ2 = 5.90, p = 0.015; OR2: 1.556, 95% CI, 0.632– 3.831, χ2 = 54.01, p = 0.045; and OR3: 1.075, 95% CI, 0.743– 1.554, χ2 = 13.24, p = 0.010). The overall gene effect was not significant (random-effect LR Wald = 0.39, p = 0.8244). None of three assumed genetic models have been confirmed (random-effect pooled OR1: 0.730, 95%, p = 0.824; OR2: 1.310, p = 0.529; and OR3: 0.776, p = 0.536). One study deviated from HWE (Serdaroğlu et al., 2009). No publication bias was found ( p > 0.32).

Meta-analysis of IL-6-572 in patients with FS The gene encoding IL-6 was investigated in three casecontrol genetic association studies including 428 patients with FS diagnosis and 452 healthy controls. Of those, the control group of one study deviated from the HWE (Nur et al., 2012b). Further, the results of the Q statistic test revealed heterogeneity for studies of IL-6-572 in FS (OR1: 1.006, 95% CI, 0.517–1.957, χ2 = 0.20, p = 0.903; OR2: 0.629, 95% CI, 0.390–1.013, χ2 = 6.52, p = 0.038; and OR3: 0.789, 95% CI, 0.582–1.070, χ2 = 5.38, p = 0.068). The overall gene effect was not significant (random-effect LR Wald = 4.28, p = 0.1176). Eventually, none of three assumed models could be suggested as the best genetic model for IL-6-572 in patients with FS (random-effect pooled OR1: 1.441, 95% CI, 0.338–1.426, p = 0.320; OR2: 0.855, 95% CI, 0.743–1.841, p = 0.497; and OR3: 0.837, 95% CI, 0.526–2.713, p = 0.671). No publication bias was found ( p > 0.24).

Meta-analysis of TNF-α-308 in patients with FS/epilepsy The gene encoding TNF-α position -308 polymorphism was investigated in three case-control association studies. The extracted information was compiled from 324 patients


294 A. Saghazadeh et al.: Cytokines in febrile seizures with FS/epilepsy and 382 healthy controls, who were all Asian (Taiwan, Iran, and India). There was no heterogeneity for studies of TNF-α in FS/epilepsy (OR1: 1.561, 95% CI, 0.832–2.928, χ2 = 1.69, p = 0.429; OR2: 1.120, 95% CI, 0.770–1.628, χ2 = 1.88, p = 0.391; and OR3: 0.880, 95% CI, 0.340–2.280, χ2 = 1.49, p = 0.475). Following the insignificant overall gene effect (fixed-effect LR = 1.50, p = 0.4723), there was no association between the three analyzed genetic models and vulnerability to FS/epilepsy. Because of the lack of adequate studies for this gene, we could not reanalyze the information of studies without that deviated from the HWE (Khoshdel et al., 2012; Tiwari et al., 2012). A publication bias was not found ( p > 0.26).

Results

Study 2 Materials and methods The search strategy is summarized in Figure 17. The original studies were included if they met the following inclusion

33 Results

29 Results

14 Related results

5 Included articles

149 Results

110 Results

52 Related results Meta-analyses

4 Articles: without specific values (mean±SD) 2 Articles: lack of a control group without neurological complications 1 Article: specific condition of epileptic cases (surgery) 1 Article: no access to fulltext 1 Article: replicated data

162 Results Filter: english

31 Results

IL-1β concentration in sera of patients with FS: 4 studies IL-1β concentration in sera of patients with epilepsy: 5 studies IL-1Ra concentration in sera of patients with epilepsy: 4 studies IL-6 concentration in sera of patients with epilepsy: 10 studies TNF-α concentration in sera of patients with epilepsy: 5 studies

Scopus

Filter: article

1 Review 1 metaanalysis

We reviewed 189 papers (Figure 17). Some related articles were excluded because of unvalued data (Dias De Sousa et al., 2012), lack of specific values (mean ± SD) (Masuyama et al., 2002; Virta et al., 2002b; Ichiyama et al., 2004, 2008, 2009; Stoeck et al., 2006; Yamanaka et al., 2006, 2010; Fukumoto et al., 2007; Sinha et al., 2008; Takahashi

‘Cytokine’ or ‘interleukin’ or ‘interferon’ and ‘concentration’ or ‘level’ or ‘profile’ and ‘febrile seizures’or ‘epilepsy’ and ‘serum’ or ‘plasma’ or ‘CSF’ or ‘cerebrospinal fluid’

PubMed

Filter: english

criteria: (a) they were designed as a case-control study, (b) they measured plasma cytokine concentrations in patients with febrile or epileptic seizures diagnosis and in controls without any neurological complications, and (c) they provided sufficient data including mean ± SD for both case and control groups of each study. In this study, we used STATA version 12.0 for all the statistical analyses comprised of calculating standardized mean difference (SMD) and 95% confidence interval by using the random-effect model, testing heterogeneity by the Q statistic test and the I2 index for its impact, and assessing the publication bias by means of funnel plots and rank correlation tests.

14 extracted articles 17 Included articles Hand searching 3 Duplicated articles

16 Articles: without specific values (mean±SD) 5 Articles: lack of a control group without neurological complications 11 Article: no access to fulltext 5 Article: concomitant disorders in case or control group 1 Article: replicated data 1 Article: unvalued data 14 Included articles

Figure 17 Search strategy 2. We searched PubMed, and SCOPUS databases up to August 2013. Eventually, data extraction was performed for 14 studies.



et al., 2009, 2013; Asano et al., 2010; Blyth et al., 2011; Mathieu et al., 2011; Haberlandt et al., 2013), lack of a control group without any neurological complications interfered with immunological response or using baseline references (Billiau et al., 2007; Alapirtti et al., 2009; Bauer et al., 2009; Li et al., 2013; Uludag et al., 2013), concomitant disorders in epileptic cases [e.g., depression (Lehtimäki et al., 2008) and neurocysticercosis (Evans et al., 1998)], concomitant disorders in the control group (e.g., encephalitis) (Ichiyama et al., 1998; Hu et al., 2014), and replicated data (Peltola et al., 2002). Some abstracts seemed to be related, but full-text was not available to make sure if they met the inclusion criteria or not (Ling et al., 1993; Kawakami et al., 1999b; Haspolat et al., 2002; Ganor et al., 2005; Makis et al., 2005; Lehtimäki et al., 2010; Lukaszewicz et al., 2010; Majoie et al., 2010; Mine et al., 2013). Further hand searching of references was performed and 17 related articles met the inclusion criteria and involved TNF-α, interferon (IFN)-γ, IL-1β, IL-1Ra, IL-2, IL-6, IL-8, and IL-10 (Lahat et al., 1997; Peltola et al., 1998, 2000; Kawakami et al., 1999a; Jain et al., 2000; Hulkkonen et al., 2004; Lehtimaki et al., 2004, 2011; Lehtimäki et al., 2007; Tomoum et al., 2007; Carmeli et al., 2009; Haginoya et al., 2009; Liimatainen et al., 2009; Choi et al., 2011; Nowak et al., 2011; Behmanesh et al., 2012; Pollard et al., 2012). Eventually, with regard to the number of studies (a minimum of three studies for each cytokine), we performed meta-analyses for 14 studies: IL-1β in patients with FS versus patients with febrile illness without seizure (FWS): four studies (Lahat et al., 1997; Tomoum et al., 2007; Choi et al., 2011; B ehmanesh et al., 2012), IL-1β in epileptic patients versus controls: five studies (Peltola et al., 2000; Hulkkonen et al., 2004; Lehtimäki et al., 2007; Nowak et al., 2011; Pollard et al., 2012), IL-1Ra in epileptic patients versus controls: four studies (Peltola et al., 2000; Hulkkonen et al., 2004; Lehtimäki et al., 2007; Liimatainen et al., 2009), IL-6 in epileptic patients vs. controls: 10 studies (Peltola et al., 1998, 2000; Hulkkonen et al., 2004; Lehtimaki et al., 2004, 2011; Lehtimäki et al., 2007; Liimatainen et al., 2009; Choi et al., 2011; Nowak et al., 2011; Pollard et al., 2012), and TNF-α in epileptic patients vs. controls: three studies (Peltola et al., 2000; Nowak et al., 2011; Pollard et al., 2012) (Table 4).

Meta-analysis of IL-1β concentration in patients with FS Concentrations of IL-1β were extracted from four studies for 114 patients with FS and 119 subjects with FWS as a control group. There was no significant difference in serum concentrations of IL-1β in seizure patients

compared to controls (random Cohen: SMD = 0.624, 95% CI, -0.561–1.809, p = 0.302). There was heterogeneity across four included studies in the analysis ( p = 0.000, I2 = 94.1%). Publication bias was not found ( p > 0.958).

Meta-analysis of IL-1β concentration in patients with epilepsy Data were extracted from five studies including 155 epilepsy patients and 488 controls. However, one study was excluded because of SD = 0 in the control group. The overall SMD for IL-1β was not significant between patients with epilepsy and the control group (fixed Cohen: SMD = -0.041, 95% CI, -0.317–0.234, p = 0.768). There was no heterogeneity across included studies ( p = 0.553). Publication bias was not found ( p > 0.614).

Meta-analysis of IL-1Ra concentration in patients with epilepsy Concentrations of IL-1Ra were extracted from four studies including 134 patients with epilepsy and 289 controls without neurological complications. There was no significant difference in concentrations of IL-1Ra between epileptic patients and controls. The overall SMD for IL-1Ra was 0.082 (random Cohen: 95% CI, -0.456–0.621, p = 0.765). Heterogeneity was determined by Q test and I2 index ( p = 0.019, I2 = 69.9%). Publication bias was not found ( p > 0.736).

Meta-analysis of IL-6 concentration in patients with epilepsy Measurements of IL-6 were extracted from 10 studies including 386 epileptic patients and 463 controls without neurological complications, except for one control group, which had intellectual disability without epilepsy (Carmeli et al., 2009). Meanwhile, the case group of one study had concomitant developmental disorder (Lehtimaki et al., 2011). Concentrations of IL-6 were statistically higher in epileptic cases than in nonepileptic controls (Figure 18). The overall SMD was 1.084 (random Cohen: 95% CI, 0.646–1.523, p = 0.000). There was heterogeneity across the included studies ( p = 0.000, I2 = 85.3%). Publication bias was found ( p > 0.012) (Figure 19). After excluding two studies due to the presence of comorbid disorders in the case or control group, the meta-analysis was repeated for eight studies including 293 patients with epilepsy and



IL-1β IL-1β IL-1β IL-1β IL-1β IL-1β IL-1β IL-1β IL-1β IL-1Ra IL-1Ra IL-1Ra IL-1Ra IL-6 IL-6 IL-6 IL-6 IL-6 IL-6 IL-6 IL-6 IL-6 IL-6 TNF-α TNF-α TNF-α

SD Trait

n Mean

SD Trait

Finland 10 6.6 5.7 TLE: 6, TLE-HS: 2, FLE: 2 400 5.8 3.9 Healthy USA 10 0.2 0.1 Drug-resistant epilepsy 26 0.1 0 Normal Finland 12 0.25 0.15 TLE: 9, FLE: 2, MFE: 1 8 0.21 0.11 Healthy Finland 22 0.4 0.6 Tonic-clonic or partial secondarily generalized seizures 18 1.8 5.9 Controls without neurological complications Germany 101 15.7 19.3 GE: 26, FE: 75 36 17.2 19.9 Healthy Iran 30 8.08 6.59 FS 30 5.68 2.98 FWS Korea 41 12 5.3 FS 41 3.1 0.8 FWS Egypt 33 7.321 3.123 FS 38 8.087 4.8 FWS Israel 10 2.92 2.6 FS 10 3.44 3.16 FWS Finland 10 223 135 TLE: 6, TLE-HS: 2, FLE: 2 200 587 480 Healthy Finland 11 150 100 TLE: 9, FLE: 2, MFE: 1 8 120 100 Healthy Finland 22 680.1 1037.7 Tonic-clonic or partial secondarily generalized seizures 18 274.8 171 Controls without neurological complications Finland 91 382.38 457 TLE and XTLE 63 283 152 Healthy Finland 10 2.1 0.39 TLE: 6, TLE-HS: 2, FLE: 2 200 1.2 0.67 Healthy Finland 74 4.1 4.5 Developmental disorder with epilepsy 63 2.1 1 Healthy Germany 101 3.3 3.1 GE: 26, FE: 75 36 1.5 1.4 Healthy Israel 19 213 66 Epilepsy with ID 10 19.8 13 ID without epilepsy 26 1.1 0.2 Normal USA 10 3.1 1.3 Drug-resistant epilepsy Finland 11 2.9 1.57 TLE: 9, FLE: 2, MFE: 1 8 1.2 0.3 Healthy Finland 33 8.8 15 Single GTCS: 16, recurrent GTCS: 10, PFS: 7 17 3.65 2 Healthy Finland 15 4.23 6.57 Epilepsy 22 1.34 3.5 Controls without neurological complications Finland 22 3.8 3.7 Tonic-clonic or partial secondarily generalized seizures 18 1.3 1.1 Controls without neurological complications Finland 91 2.5 1.73 TLE and XTLE 63 2.1 1 Healthy USA 10 7.7 2.5 Epilepsy 25 5.5 0.4 Normal Finland 22 0.3 0.5 Tonic-clonic or partial secondarily generalized seizures 18 1.7 6 Controls without neurological complications Germany 101 7.5 8.9 Generalized: 26, focal: 75 36 7.9 7.9 Healthy

Mean

Controls

Measured unit, pg/ml. HS, hippocampal sclerosis; FLE, frontal lobe epilepsy; MFE, multifocal epilepsy; GE, generalized epilepsy; XTLE, extra-TLE; ID, intellectual disability; GTCS, generalized tonic clonic seizure; PFS, prolonged FS.

Hulkkonen (2004) Pollard (2012) Lehtimäki (2007) Peltola (2000) Nowak (2011) Behmanesh (2012) Choi (2011) Tomoum (2007) Lahat (1997) Hulkkonen (2004) Lehtimäki (2007) Peltola (2000) Liimatainen (2009) Hulkkonen (2004) Lehtimaki (2011) Nowak (2011) Carmeli (2009) Pollard (2012) Lehtimäki (2007) Lehtimaki (2004) Peltola (1998) Peltola (2000) Liimatainen (2009) Pollard (2012) Peltola (2000) Nowak (2011)

n

First author (year) Cytokine Country Cases

Table 4 Studies of meta-analysis on cytokine concentrations.



Study

%

ID

SMD (95% CI)

Weight

1

Hulkkonen

2004

1.36 (0.71, 2.01)

10.27

2

Lehtimäki

2011

0.59 (0.25, 0.94)

12.25

3

Nowak

2011

0.65 (0.26, 1.04)

12.00

4

Carmeli

2008

3.55 (2.33, 4.77)

6.55

5

Pollard

2013

2.90 (1.89, 3.90)

7.83

6

Lehtimäki

2007

1.39 (0.37, 2.42)

7.69

7

Lehtimäki

2004

0.42 (-0.17, 1.01)

10.68

8

Peltola

1998

0.58 (-0.09, 1.25)

10.12

9

Peltola

2000

0.88 (0.22, 1.53)

10.24

Liimatainen

2009

0.27 (-0.05, 0.59)

12.36

1.08 (0.65, 1.52)

100.00

10

Overall (I-squared=83.3%, p =0.000) Note: weights are from random effects analysis -4.77

0

4.77

Figure 18 Meta-analyses of IL-6 concentrations. Meta-analysis of IL-6 concentrations in patients with epilepsy (10 studies).

390 controls (Carmeli et al., 2009; Lehtimaki et al., 2011). Measurements of IL-6 were significantly higher in epileptic cases than in controls without neurological complications (random Cohen: SMD = 0.943, 95% CI, 0.499–1.386, p = 0.000) (Figure 20). The Q test and I2 index indicated heterogeneity across eight included studies ( p = 0.000, I2 = 78.3%). Publication bias was found ( p > 0.02) (Figure 21).

Meta-analysis of TNF-α concentration in patients with epilepsy Concentrations of TNF-α were extracted from three studies for 133 patients with epilepsy and 79 subjects as a control group. The overall SMD of 0.357 was not significant (random Cohen: 95% CI, -0.600–1.315, p = 0.465). Heterogeneity was observed as calculated by the Q test and I2 index ( p = 0.000, I2 = 87.1%).

General discussion Familial and sporadic cases of FS indicate the role of both genetic and environmental factors in FS development (Kira et al., 2005; Dubé et al., 2009). Although responsible genes for FS could not be discovered in many populations, experimental and human studies revealed the activation of the cytokine network during seizures (Virta et al., 2002b). Since FS occur in the course of high body temperature or rapid rising of fever in susceptible individuals,

genes associated with fever generation could be involved in possible causative mechanism of FS (Tilgen et al., 2002). Lipopolysaccharide (LPS) was used to provoke fever and induce seizures in experimental studies (Fabricio et al., 1998; Matsumura et al., 1998; Dinarello, 2004). By administrating of LPS, fever is generated over a cascade including (1) synthesis of TNF-α, IL-1β, IL-6, and IL-1Ra; (2) transport from peripheral to CNS via the triple signaling pathways; (3) stimulation of the enzyme cyclooxygenase-2 (COX-2); (4) conversion of arachidonic acid in prostaglandin E2 (PGE2); and (5) generation of fever (Heida et al., 2009). Fever generation involves many cytokines and endogenous mediators including IL-1 (both α and β), IL-6, TNF, IL-1Ra, and IL-10 in response to exogenous pyrogens (Kluger, 1991; Netea et al., 2000; Conti et al., 2004). The first step of fever generation deals with a positive feedback loop between IL-1 and TNF, which both unidirectionally lead to elevation of the serum concentration of IL-6. The IL-1 family is known as the major mediator of the inflammatory cascade in inflammation and development of fever and as the major generator of PGE2 synthesis (Akira et al., 1990; Vigers et al., 1997; Pascual et al., 2005). On the lines of inhibitory mechanisms and synaptic inhibition, γ-aminobutyric acid (GABA) neurotransmitter and its two receptors, GABAA and GABAB, play a principal role in maintaining the equilibrium between neuronal inhibition and excitation (Treiman, 2001; Ben-Ari, 2002). Although N-methyl-d-aspartate (NMDA) receptors, as one of receptors in hippocampal pyramidal cells that bind excitatory transmitters, can normally contribute to synaptic


298 A. Saghazadeh et al.: Cytokines in febrile seizures Study

%

ID

SMD (95% CI)

Weight

1 Hulkkonen

2004

1.36 (0.71, 2.01)

12.61

2 Nowak

2011

0.65 (0.26, 1.04)

15.25

3 Pollard

2013

2.90 (1.89, 3.90)

9.17

4 Lehtimäki

2007

1.39 (0.37, 2.42)

8.99

5 Lehtimäki

2004

0.42 (-0.17, 1.01)

13.21

6 Peltola

1998

0.58 (-0.09, 1.25)

12.38

7 Peltola

2000

0.88 (0.22, 1.53)

12.56

8 Liimatainen

2009

0.27 (-0.05, 0.59)

15.82

0.94 (0.50, 1.39)

100.00


Note: weights are from random effects analysis -3.9

0

3.9

Figure 19 Meta-analysis of IL-6 concentrations in patients with epilepsy (eight studies).

Funnel plot with pseudo 95% confidence limits 0

SE

0.2

0.4

0.6 -1

0

1

SMD

2

3

4

Figure 20 Funnel plot of publication bias for studies of IL-6 concentrations in patients with epilepsy compared to patients without epilepsy. Funnel plot with pseudo 95% confidence limits 0 0.1

SE

0.2 0.3 0.4 0.5 -1

0

1 SMD

2

3

Figure 21 Funnel plot of publication bias for studies of IL-6 concentrations in patients with epilepsy compared to control subjects.

excitation, it can counterbalance through close temporary coupling of glutamatergic excitation and GABAergic inhibition (Dingledine et al., 1990; Represa and Ben-Ari, 2005). Under abnormal conditions, voltage-dependent blockage of NMDA receptors can be disturbed by intense activation of GABAA receptors, which terminated in excitation in the exchange of inhibition (Staley et al., 1995). Based on this circuit, IL-1β can predispose to seizures via blockage of GABAA receptors and increasing activity of NMDA receptors in hippocampal neurons, which both could pathophysiologically provide hyperexcitability and hyperthermia conditions contributing to the seizures (Wang et al., 2000; Viviani et al., 2003; Dubé et al., 2005). The role of IL-1Ra, a third ligand in the IL-1 family, is to attenuate IL-1 activity by blocking the IL-1 receptors, thus reducing IL-6 elevation in serum (McIntyre et al., 1991). IL-6 is identified as the strong inducer of antibody production including IgA, IgM, and IgG (Akira et al., 1990). Autoantibodies might play a part in the epileptogenesis occasionally (Vezzani et al., 2010). Although TNF-α is biologically dependent on its two receptors: TNF-R1 (p55) and TNF-R2 (p75), seizure activity seems be mainly regulated by p75 (Balosso et al., 2005). Numerous case-control genetic association studies have been conducted to evaluate the potential correlation of the common variants of proinflammatory and anti-inflammatory cytokines with susceptibility to FS and epilepsy. However, the results provided are inconclusive. To become partially one-sided, meta-analysis seemed be the best approach, as there are two meta-analysis studies, which have been performed on the association of the IL-1β position -511 polymorphism with FS risk (see Kauffman et al., 2008; Wu et al., 2012). However, both



analyses reported a significant association of the IL-1β511 C/T variant with susceptibility to FS in Asian but not in European patients. Yu et al. (2012) recently published a meta-analysis to pool the literature through July 2010 on the measurements of IL-1β, IL-1Ra, and IL-6 in sera of epileptic patients and indicated that IL-6 concentrations are significantly higher in epilepsy patients (n = 261) than control subjects (n = 564) (Yu et al., 2012). The present study found that variant of IL-1α-889 1/1 is correlated with an increased risk of developing epilepsy as well as a generally increased risk of febrile and epileptic seizures. Further, those with variant IL-1α-889 1/2 have a lower risk of developing epilepsy and FS. The analysis was not performed for patients with FS due to a limited number of studies. Our findings provide support for a correlation between the variant IL-1β-511 T/T and an increase in the susceptibility to FS as well as in the overall risk of developing febrile and epileptic seizures. While the T/T genotype was confirmed as the risky genotype in Asian proportion of both populations (FS and FS/epilepsy), the C/C genotype has been demonstrated to provide a protective effect against FS in Caucasian population. Polymorphisms of IL-6, IL-1Ra, and TNF-α were not associated with the risk of FS/epilepsy (the overall gene effects were not significant).

The second meta-analysis did not find any contribution of two IL-1 family members including IL-β and IL-1Ra. Serum concentration of IL-6, on the contrary, was statistically elevated in patients with epilepsy. There was publication bias across included studies. The provided results are not sufficient to address our hypothetical question, ‘what similarities and differences exist between FS and epilepsy on the genetics-related and environmental factors-related algorithms’ for all the investigated cytokines, which was due to lack of adequate published data. IL-1β was the only cytokine well documented for both FS and epilepsy. Although serum concentrations of IL-β were not correlated with seizure activity in patients with febrile and epileptic seizures, the IL-1β-511 T/T genotype could be associated with an increased risk of developing FS but not epilepsy. The same pattern or mechanism might manage the serum concentration of IL-1β during FS and epilepsy. More original and subsequent meta-analysis studies should be depicted to challenge the finding and to achieve validated algorithms.

Received October 20, 2013; accepted December 26, 2013; previously published online February 7, 2014

References Abdel Rasol, H.A., Issac, M.S.M., Abdel Ghaffar, H., and El-Mously, S. (2012). Interleukin-1 receptor antagonist and interleukin-1β -511 gene polymorphisms among Egyptian children with febrile seizures. Comp. Clin. Pathol. 1–7. Available at http://link. springer.com/journal/580/onlineFirst/page/11. Akira, S., Hirano, T., Taga, T., and Kishimoto, T. (1990). Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). FASEB J. 4, 2860–2867. Alapirtti, T., Rinta, S., Hulkkonen, J., Mäkinen, R., Keränen, T., and Peltola, J. (2009). Interleukin-6, interleukin-1 receptor antagonist and interleukin-1beta production in patients with focal epilepsy: a video-EEG study. J. Neurol. Sci. 280, 94–97. Annegers, J.F., Hauser, W.A., Shirts, S.B., and Kurland, L.T. (1987). Factors prognostic of unprovoked seizures after febrile convulsions. N. Engl. J. Med. 316, 493–498. Annegers, J.F., Blakley, S.A., Allen Hauser, W., and Kurland, L.T. (1990). Recurrence of febrile convulsions in a population-based cohort. Epilepsy Res. 5, 209–216. Asano, T., Ichiki, K., Koizumi, S., Kaizu, K., Hatori, T., Fujino, O., Mashiko, K., Sakamoto, Y., Miyasho, T., and Fukunaga, Y. (2010). IL-8 in cerebrospinal fluid from children with acute encephalopathy is higher than in that from children with febrile seizure. Scand. J. Immunol. 71, 447–451. Audenaert, D., Schwartz, E., Claeys, K.G., Claes, L., Deprez, L., Suls, A., Van Dyck, T., Lagae, L., Van Broeckhoven, C., Macdonald, R.L., et al. (2006). A novel GABRG2 mutation associated with febrile seizures. Neurology 67, 687–690.

Balosso, S., Ravizza, T., Perego, C., Peschon, J., Campbell, I.L., De Simoni, M.G., and Vezzani, A. (2005). Tumor necrosis factor-α inhibits seizures in mice via p75 receptors. Ann. Neurol. 57, 804–812. Banerjee, P.N., Filippi, D., and Hauser, W.A. (2009). The descriptive epidemiology of epilepsy – a review. Epilepsy Res. 85, 31–45. Bauer, S., Cepok, S., Todorova-Rudolph, A., Nowak, M., Köller, M., Lorenz, R., Oertel, W.H., Rosenow, F., Hemmer, B., and Hamer, H.M. (2009). Etiology and site of temporal lobe epilepsy influence postictal cytokine release. Epilepsy Res. 86, 82–88. Baulac, S., Gourfinkel-An, I., Picard, F., Rosenberg-Bourgin, M., Prud’homme, J.-F., Baulac, M., Brice, A., and LeGuern, E. (1999). A second locus for familial generalized epilepsy with febrile seizures plus maps to chromosome 2q21-q33. Am. J. Hum. Genet. 65, 1078–1085. Behmanesh, F., Ashrafzadeh, F., Varasteh, A., Shakeri, A., and Shahsavand, S. (2012). Evaluation of interleukin 1beta in febrile convulsion. Iran J. Allergy Asthma Immunol. 11, 336–339. Ben-Ari, Y. (2002). Excitatory actions of GABA during development: the nature of the nurture. Nat. Rev. Neurosci. 3, 728–739. Berkovic, S.F., Howell, R.A., Hay, D.A., and Hopper, J.L. (1998). Epilepsies in twins: genetics of the major epilepsy syndromes. Ann. Neurol. 43, 435–445. Billiau, A.D., Witters, P., Ceulemans, B., Kasran, A., Wouters, C., and Lagae, L. (2007). Intravenous immunoglobulins in refractory


300 A. Saghazadeh et al.: Cytokines in febrile seizures childhood-onset epilepsy: effects on seizure frequency, EEG activity, and cerebrospinal fluid cytokine profile. Epilepsia 48, 1739–1749. Blair, M.A., Ma, S., Abou-Khalil, B., and Hedera, P. (2007). Genetic variants in the IMPA2 gene do not confer increased risk of febrile seizures in Caucasian patients. Eur. J. Neurol. 14, 424–427. Blyth, C.C., Currie, A.J., Wiertsema, S.P., Conway, N., Kirkham, L.A.S., Fuery, A., Mascaro, F., Geelhoed, G.C., and Richmond, P.C. (2011). Trivalent influenza vaccine and febrile adverse events in Australia, 2010: clinical features and potential mechanisms. Vaccine 29, 5107–5113. Buono, R.J., Ferraro, T.N., O’Connor, M.J., Sperling, M.R., Ryan, S.G., Scattergood, T., Mulholland, N., Gilmore, J., Lohoff, F.W., and Berrettini, W.H. (2001). Lack of association between an interleukin 1beta (IL-1β) gene variation and refractory temporal lobe epilepsy. Epilepsia 42, 782–784. Camargo, M.C., Mera, R., Correa, P., Peek, R.M., Fontham, E.T.H., Goodman, K.J., Piazuelo, M.B., Sicinschi, L., Zabaleta, J., and Schneider, B.G. (2006). Interleukin-1β and interleukin-1 receptor antagonist gene polymorphisms and gastric cancer: a meta-analysis. Cancer Epidemiol. Biomarkers Prev. 15, 1674–1687. Carmeli, E., Beiker, R., and Morad, M. (2009). Nitric oxide and interlukin-6 levels in intellectual disability adults with epilepsy. Res. Dev. Disabil. 30, 567–571. Cavalleri, G.L., Lynch, J.M., Depondt, C., Burley, M.-W., Wood, N.W., Sisodiya, S.M., and Goldstein, D.B. (2005). Failure to replicate previously reported genetic associations with sporadic temporal lobe epilepsy: where to from here? Brain 128, 1832–1840. Cho, S.M., Kim, Y.H., Chung, S.Y., Lee, I.G., Whang, K.T., Lee, B.C., and Lee, K.H. (2005). Single nucleotide polymorphisms of GABRG2 in febrile seizures and GEFS+. J. Kor. Child Neurol. Soc. 13, 144–151. Choi, J., Min, H.J., and Shin, J.-S. (2011). Increased levels of HMGB1 and pro-inflammatory cytokines in children with febrile seizures. J. Neuroinflamm. 8, 135. Chou, I.-C., Tsai, F.-J., Huang, C.-C., Lin, C.-C., and Tsai, C.-H. (2002). The voltage-gated potassium channel KCNQ2 in Taiwanese children with febrile convulsions. NeuroReport 13, 1971–1973. Chou, I.C., Lee, C.-C., Huang, C.-C., Wu, J.-Y., Tsai, J.J.P., Tsai, C.-H., and Tsai, F.-J. (2003a). Association of the neuronal nicotinic acetylcholine receptor subunit α4 polymorphisms with febrile convulsions. Epilepsia 44, 1089–1093. Chou, I.C., Peng, C.-T., Huang, C.-C., Tsai, J.J.P., Tsai, F.-J., and Tsai, C.-H. (2003b). Association analysis of γ2 subunit of γ-aminobutyric acid type a receptor polymorphisms with febrile seizures. Pediatr. Res. 54, 26–29. Chou, I.C., Tsai, C.H., Hsieh, Y.Y., Peng, C.T., and Tsai, F.J. (2003c). Association between polymorphism of interleukin-1β -511 promoter and susceptibility to febrile convulsions in Taiwanese children. Acta Pediatr. 92, 1356. Chou, I.C., Tsai, C.H., Lee, C.C., Lin, S.S., and Tsai, F.J. (2004). Brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms in febrile seizures. Epilepsy Res. 60, 27–29. Chou, I.C., Lin, W.-D., Wang, C.-H., Tsai, C.-H., Li, T.-C., and Tsai, F.-J. (2010). Interleukin (IL)-1β, IL-1 receptor antagonist, IL-6, IL-8, IL-10, and tumor necrosis factor α gene polymorphisms in patients with febrile seizures. J. Clin. Lab. Anal. 24, 154–159.

Chung, S.Y., Park, Y.J., Kim, Y.H., Lee, I.G., Whang, K.T., Lee, J.S., Kim, H.S., Lee, K.H., and Yim, S.V. (2006). Interleukin-1beta promoter polymorphisms in febrile seizures and GEFS+. J. Kor. Child Neurol. Soc. 14, 113–120. Conti, B., Tabarean, I., Andrei, C., and Bartfai, T. (2004). Cytokines and fever. Front. Biosci. 9, 1433–1449. Corey, L.A., Berg, K., Pellock, J.M., Solaas, M.H., Nance, W.E., and DeLorenzo, R.J. (1991). The occurrence of epilepsy and febrile seizures in Virginian and Norwegian twins. Neurology 41, 1433–1436. Cross, J.H. (2012). Fever and fever-related epilepsies. Epilepsia 53, 3–8. Dai, X.-H., Chen, W.-W., Wang, X., Zhu, Q.-H., Li, C., Li, L., Liu, M.-G., Wang, Q.-K., and Liu, J.-Y. (2008). A novel genetic locus for familial febrile seizures and epilepsy on chromosome 3q26.2q26.33. Hum. Genet. 124, 423–429. Dias De Sousa, M.A., Bonatti, R.C.F., Rodrigues V. Jr., Azevedo, D.S., Santos, M.H.A., Pereira, R.O.L., and Leboreiro-Fernandez, A. (2012). Cytokines in cerebrospinal fluid of children with West syndrome. J. Epilepsy Clin. Neurophysiol. 18, 63–66. Dibbens, L.M., Reid, C.A., Hodgson, B., Thomas, E.A., Phillips, A.M., Gazina, E., Cromer, B.A., Clarke, A.L., Baram, T.Z., Scheffer, I.E., et al. (2010). Augmented currents of an HCN2 variant in patients with febrile seizure syndromes. Ann. Neurol. 67, 542–546. Dinarello, C.A. (2004). Review: Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed. J. Endotoxin Res. 10, 201–222. Dingledine, R., McBain, C.J., and McNamara, J.O. (1990). Excitatory amino acid receptors in epilepsy. Trends. Pharmacol. Sci. 11, 334–338. Dowlati, Y., Herrmann, N., Swardfager, W., Liu, H., Sham, L., Reim, E.K., and Lanctôt, K.L. (2010). A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446–457. Dubé, C., Vezzani, A., Behrens, M., Bartfai, T., and Baram, T.Z. (2005). Interleukin-1β contributes to the generation of experimental febrile seizures. Ann. Neurol. 57, 152–155. Dubé, C.M., Brewster, A.L., Richichi, C., Zha, Q., and Baram, T.Z. (2007). Fever, febrile seizures and epilepsy. Trends Neurosci. 30, 490–496. Dubé, C.M., Brewster, A.L., and Baram, T.Z. (2009). Febrile seizures: mechanisms and relationship to epilepsy. Brain Dev. 31, 366–371. Dubé, C.M., McClelland, S., Choy, M.K., Brewster, A.L., Noam, Y., and Baram, T.Z. (2010). Fever, febrile seizures, and epileptogenesis. Epilepsia 51, 33. el-Radhi, A.S. and Banajeh, S. (1989). Effect of fever on recurrence rate of febrile convulsions. Arch. Dis. Child 64, 869–870. Evans, C.A.W., Garcia, H.H., Hartnell, A., Gilman, R.H., Jose, P.J., Martinez, M., Remick, D.G., Williams, T.J., and Friedland, J.S. (1998). Elevated concentrations of eotaxin and interleukin-5 in human neurocysticercosis. Infect. Immun. 66, 4522–4525. Fabricio, A.S.C., Silva, C.A.A., Rae, G.A., D’Orléans-Juste, P., and Souza, G.E.P. (1998). Essential role for endothelin ETB receptors in fever induced by LPS (E. coli) in rats. Br. J. Pharmacol. 125, 542–548. French, J.A. (2012). Febrile seizures: possible outcomes. Neurology 79, e80–e82. Fukumoto, Y., Okumura, A., Hayakawa, F., Suzuki, M., Kato, T., Watanabe, K., and Morishima, T. (2007). Serum levels of


A. Saghazadeh et al.: Cytokines in febrile seizures 301 cytokines and EEG findings in children with influenza associated with mild neurological complications. Brain Dev. 29, 425–430. Ganor, Y., Freilinger, M., Dulac, O., and Levite, M. (2005). Monozygotic twins discordant for epilepsy differ in the levels of potentially pathogenic autoantibodies and cytokines. Autoimmunity 38, 139–150. Gao, B., Hu M.-S., and Zhang, L. (2007). A study on the association of polymorphism of IL-10 with febrile convulsion. Chin. J. Birth Health Hered. 3. Giray, Ö., Ülgenalp, A., Bora, E., Uran, N., Yılmaz, E., Ünalp, A., and Erçal, D. (2008). Role of apolipoprotein E in febrile convulsion. Pediatr. Neurol. 39, 241–244. Guidelines for epidemiologic studies on epilepsy. Commission on Epidemiology and Prognosis, International League Against Epilepsy (1993). Epilepsia 34, 592–596. Haberlandt, E., Rauchenzauner, M., Morass, M., Wondrak, P., Burgi, S.S., Rostasy, K., and Karall, D. (2013). Matrixmetalloproteinases and proinflammatory cytokines in children with febrile convulsions and epilepsy-cause or consequence? Epilepsy Res. 105, 225–228. Haginoya, K., Noguchi, R., Zhao, Y., Munakata, M., Yokoyama, H., Tanaka, S., Hino-Fukuyo, N., Uematsu, M., Yamamoto, K., Takayanagi, M., et al. (2009). Reduced levels of interleukin-1 receptor antagonist in the cerebrospinal fluid in patients with West syndrome. Epilepsy Res. 85, 314–317. Hahn, L.W., Ritchie, M.D., and Moore, J.H. (2003). Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions. Bioinformatics 19, 376–382. Hamati-Haddad, A. and Abou-Khalil, B. (1998). Epilepsy diagnosis and localization in patients with antecedent childhood febrile convulsions. Neurology 50, 917–922. Haspolat, Ş., Mihçi, E., Coşkun, M., Gümüslü, S., Özbenm, T., and Yeğin, O. (2002). Interleukin-1β, tumor necrosis factor-α, and nitrite levels in febrile seizures. J. Child Neurol. 17, 749–751. Haspolat, Ş., Baysal, Y., Duman, Ö., Coşkun, M., Tosun, Ö., and Yein, O. (2005). Interleukin-1α, interleukin-1β, and interleukin-1Ra polymorphisms in febrile seizures. J. Child Neurol. 20, 565–568. Hedera, P., Ma, S., Blair, M.A., Taylor, K.A., Hamati, A., Bradford, Y., Abou-Khalil, B., and Haines, J.L. (2006). Identification of a novel locus for febrile seizures and epilepsy on chromosome 21q22. Epilepsia 47, 1622–1628. Heida, J.G., Moshé, S.L., and Pittman, Q.J. (2009). The role of interleukin-1β in febrile seizures. Brain Dev. 31, 388–393. Heils, A., Haug, K., Kunz, W.S., Fernandez, G., Horvath, S., Rebstock, J., Propping, P., and Elger, C.E. (2000). Interleukin-1beta gene polymorphism and susceptibility to temporal lobe epilepsy with hippocampal sclerosis. Ann. Neurol. 48, 948–950. Home, P. and Kerirey, S. (1991). Psychosocial adjustment of children with chronic epilepsy and their families. Dev. Med. Child Neurol. 33, 201–215. Howren, M.B., Lamkin, D.M., and Suls, J. (2009). Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom. Med. 71, 171–186. Hu, M.-H., Huang, G.-S., Wu, C.-T., Lin, J.-J., Hsia, S.-H., Wang, H.-S., and Lin, K.-L. (2014). Analysis of plasma multiplex cytokines for children with febrile seizures and severe acute encephalitis. J. Child Neurol. 29, 182–186 Huang, C.C., Wang, S.T., Chang, Y.C., Huang, M.C., Chi, Y.C., and Tsai, J.J. (1999). Risk factors for a first febrile convulsion in

children: a population study in southern Taiwan. Epilepsia 40, 719–725. Hulkkonen, J., Koskikallio, E., Rainesalo, S., Keränen, T., Hurme, M., and Peltola, J. (2004). The balance of inhibitory and excitatory cytokines is differently regulated in vivo and in vitro among therapy resistant epilepsy patients. Epilepsy Res. 59, 199–205. Ichiyama, T., Nishikawa, M., Yoshitomi, T., Hayashi, T., and Furukawa, S. (1998). Tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 in cerebrospinal fluid from children with prolonged febrile seizures. Comparison with acute encephalitis/encephalopathy. Neurology 50, 407–411. Ichiyama, T., Morishima, T., Isumi, H., Matsufuji, H., Matsubara, T., and Furukawa, S. (2004). Analysis of cytokine levels and NF-κB activation in peripheral blood mononuclear cells in influenza virus-associated encephalopathy. Cytokine 27, 31–37. Ichiyama, T., Suenaga, N., Kajimoto, M., Tohyama, J., Isumi, H., Kubota, M., Mori, M., and Furukawa, S. (2008). Serum and CSF levels of cytokines in acute encephalopathy following prolonged febrile seizures. Brain Dev. 30, 47–52. Ichiyama, T., Ito, Y., Kubota, M., Yamazaki, T., Nakamura, K., and Furukawa, S. (2009). Serum and cerebrospinal fluid levels of cytokines in acute encephalopathy associated with human herpesvirus-6 infection. Brain Dev. 31, 731–738. Ishizaki, Y., Kira, R., Fukuda, M., Torisu, H., Sakai, Y., Sanefuji, M., Yukaya, N., and Hara, T. (2009). Interleukin-10 is associated with resistance to febrile seizures: genetic association and experimental animal studies. Epilepsia 50, 761–767. Jain, M., Aneja, S., Mehta, G., Ray, G.N., Batra, S., and Randhava, V.S. (2000). CSF interleukin-1β, tumor necrosis factor-α and free radicals production in relation to clinical outcome in acute bacterial meningitis. Indian Pediatr. 37, 608–614. Jamali, S., Salzmann, A., Perroud, N., Ponsole-Lenfant, M., Cillario, J., Roll, P., Roeckel-Trevisiol, N., Crespel, A., Balzar, J., Schlachter, K., et al. (2010). Functional variant in complement C3 gene promoter and genetic susceptibility to temporal lobe epilepsy and febrile seizures. PLoS One 5, e12740. Jin, L., Jia, Y., Zhang, B., Xu, Q., Fan, Y., Wu, L., and Shen, Y. (2003). Association analysis of a polymorphism of interleukin 1β (IL-1β) gene with temporal lobe epilepsy in a Chinese population. Epilepsia 44, 1306–1309. Johnson, E.W., Dubovsky, J., Rich, S.S., O’Donovan, C.A., Orr, H.T., Anderson, V.E., Gil-Nagel, A., Ahmann, P., Dokken, C.G., Schneider, D.T., et al. (1998). Evidence for a novel gene for familial febrile convulsions, FEB2, linked to chromosome 19p in an extended family from the Midwest. Hum. Mol. Genet. 7, 63–67. Kamangar, F., Cheng, C., Abnet, C.C., and Rabkin, C.S. (2006). Interleukin-1B polymorphisms and gastric cancer risk – a meta-analysis. Cancer Epidemiol. Biomarkers Prev. 15, 1920–1928. Kanemoto, K., Kawasaki, J., Miyamoto, T., Obayashi, H., and Nishimura, M. (2000). Interleukin (IL)1beta, IL-1alpha, and IL-1 receptor antagonist gene polymorphisms in patients with temporal lobe epilepsy. Ann. Neurol. 47, 571–574. Kanemoto, K., Kawasaki, J., Yuasa, S., Kumaki, T., Tomohiro, O., Kaji, R., and Nishimura, M. (2003). Increased frequency of interleukin-1β -511T allele in patients with temporal lobe epilepsy, hippocampal sclerosis, and prolonged febrile convulsion. Epilepsia 44, 796–799.


302 A. Saghazadeh et al.: Cytokines in febrile seizures Kauffman, M.A., Moron, D.G., Consalvo, D., Bello, R., and Kochen, S. (2008). Association study between interleukin 1β gene and epileptic disorders: a HuGe review and meta-analysis. Genet. Med. 10, 83–88. Kawakami, Y., Fukunaga, Y., Kuwabara, K., Fujita, T., Fujino, O., and Hashimoto, K. (1999a). Clinical and immunological significance of neopterin measurement in cerebrospinal fluid in patients with febrile convulsions. Brain Dev. 21, 458–460. Kawakami, Y., Fukunaga, Y., Kuwabara, K., Fujita, T., Fujino, O., and Hashimoto, K. (1999b). Cerebrospinal fluid levels of neopterin in child patients with neurological diseases-in correlation with IFN-γ or TNF-α. Pteridines 10, 27–31. Khoshdel, A., Kheiri, S., Habibian, R., Nozari, A., and Baradaran, A. (2012). Lack of association between TNF-α gene polymorphisms at position -308A, -850T and risk of simple febrile convulsion in pediatric patients. Adv. Biomed. Res. 1, 85. Kim, S.E., Kim, H.G., Kim, Y.H., Choi, B.J., Hwang, H.S., Bin, J.H., Chung, S.Y., and Lee, I.G. (2008). Brain-derived neurotrophic factor (BDNF) SNP 6265 polymorphisms in febrile seizure and GEFS+. J. Kor. Child Neurol. Soc. 16, 114–120. Kinirons, P., Cavalleri, G.L., Shahwan, A., Wood, N.W., Goldstein, D.B., Sisodiya, S.M., Delanty, N., and Doherty, C.P. (2006). Examining the role of common genetic variation in the γ2 subunit of the GABAA receptor in epilepsy using tagging SNPs. Epilepsy Res. 70, 229–238. Kira, R., Torisu, H., Takemoto, M., Nomura, A., Sakai, Y., Sanefuji, M., Sakamoto, K., Matsumoto, S., Gondo, K., and Hara, T. (2005). Genetic susceptibility to simple febrile seizures: interleukin-1β promoter polymorphisms are associated with sporadic cases. Neurosci. Lett. 384, 239–244. Kira, R., Ishizaki, Y., Torisu, H., Sanefuji, M., Takemoto, M., Sakamoto, K., Matsumoto, S., Yamaguchi, Y., Yukaya, N., Sakai, Y., et al. (2010). Genetic susceptibility to febrile seizures: case-control association studies. Brain Dev. 32, 57–63. Kjeldsen, M.J., Kyvik, K.O., Friis, M.L., and Christensen, K. (2002). Genetic and environmental factors in febrile seizures: a Danish population-based twin study. Epilepsy Res. 51, 167–177. Kjeldsen, M.J., Corey, L.A., Solaas, M.H., Friis, M.L., Harris, J.R., Kyvik, K.O., Christensen, K., and Pellock, J.M. (2005). Genetic factors in seizures: a population-based study of 47,626 US, Norwegian and Danish twin pairs. Twin Res. Hum. Genet. 8, 138–147. Klein, N.P., Lewis, E., Baxter, R., Weintraub, E., Glanz, J., Naleway, A., Jackson, L.A., Nordin, J., Lieu, T., and Belongia, E.A. (2012). Measles-containing vaccines and febrile seizures in children age 4 to 6 years. Pediatrics 129, 809–814. Kluger, M.J. (1991). Fever: role of pyrogens and cryogens. Physiol. Rev. 71, 93–127. Knudsen, F.U. (1985). Recurrence risk after first febrile seizure and effect of short term diazepam prophylaxis. Arch. Dis. Child 60, 1045–1049. Kumari, P.L., Nair, M.K.C., Nair, S.M., Kailas, L., and Geetha, S. (2012). Iron deficiency as a risk factor for simple febrile seizures-a case control study. Indian Pediatr. 49, 17–19. Kundu, G.K., Rabin, F., Nandi, E.R., Sheikh, N., and Akhter, S. (2012). Etiology and risk factors of febrile seizure – an update. Bangladesh J. Child Health 34, 103–112. Lahat, E., Livne, M., Barr, J., and Katz, Y. (1997). Interleukin-1β levels in serum and cerebrospinal fluid of children with febrile seizures. Pediatr. Neurol. 17, 34–36.

Le Gal, F., Salzmann, A., Crespel, A., and Malafosse, A. (2011). Replication of association between a SCN1A splice variant and febrile seizures. Epilepsia 52, e135–e138. Lehtimaki, K.A., Keranen, T., Huhtala, H., Hurme, M., Ollikainen, J., Honkaniemi, J., Palmio, J., and Peltola, J. (2004). Regulation of IL-6 system in cerebrospinal fluid and serum compartments by seizures: the effect of seizure type and duration. J. Neuroimmunol. 152, 121–125. Lehtimaki, K.A., Liimatainen, S., Peltola, J., and Arvio, M. (2011). The serum level of interleukin-6 in patients with intellectual disability and refractory epilepsy. Epilepsy Res. 95, 184–187. Lehtimäki, K.A., Keränen, T., Palmio, J., Mäkinen, R., Hurme, M., Honkaniemi, J., and Peltola, J. (2007). Increased plasma levels of cytokines after seizures in localization-related epilepsy. Acta Neurol. Scand. 116, 226–230. Lehtimäki, K., Keränen, T., Huuhka, M., Palmio, J., Hurme, M., Leinonen, E., and Peltola, J. (2008). Increase in plasma proinflammatory cytokines after electroconvulsive therapy in patients with depressive disorder. J. ECT 24, 88–91. Lehtimäki, K.A., Keränen, T., Palmio, J., and Peltola, J. (2010). Levels of IL-1β and IL-1ra in cerebrospinal fluid of human patients after single and prolonged seizures. Neuroimmunomodulation 17, 19–22. Li, Y., Ma, Y., Chen, Z., Tian, G., Zou, L., Fang, F., and Qi, Y. (2008). Association study on simple febrile seizures and casein kinase 1, gamma 1 gene. J. Appl. Clin. Pediatr. 4. Li, X., Wang, R., Wang, X., Xue, X., Ran, D., and Wang, S. (2013). Relevance of IL-6 and MMP-9 to cerebral arteriovenous malformation and hemorrhage. Mol. Med. Rep. 7, 1261–1266. Liimatainen, S., Fallah, M., Kharazmi, E., Peltola, M., and Peltola, J. (2009). Interleukin-6 levels are increased in temporal lobe epilepsy but not in extra-temporal lobe epilepsy. J. Neurol. 256, 796–802. Lin, L.-C., Lin, H.-S., and Yang, R.-C. (2007). Neuropeptide Y gene polymorphism and plasma neuropeptide Y level in febrile seizure patients in Taiwan. Kaohsiung J. Med. Sci. 23, 560–565. Ling, Z.D., Yeoh, E., Webb, B.T., Farrell, K., Doucette, J., and Matheson, D.S. (1993). Intravenous immunoglobulin induces interferon-γ and interleukin-6 in vivo. J. Clin. Immunol. 13, 302–309. Liu, X., Wang, Z., Yu, J., Lei, G., and Wang, S. (2010). Three polymorphisms in interleukin-1β gene and risk for breast cancer: a meta-analysis. Breast Cancer Res. Treat. 124, 821–825. Lukaszewicz, A.C., Faivre, V., Villa, F., and Payen, D. (2010). Anti-inflammatory profile of circulating immune cells after surgery for seizure. Min. Anestesiol. 76, 477–484. Ma, Y.N., Hao, L., Niu, S.L., Xu, Y.F., Zhang, Y., Pei, P., Bu, D.F., and Qi, Y. (2004). Five single nucleotide polymorphisms of casein kinase I gamma 2 gene in children with familial febrile convulsions. Chin. J. Med. Genet. 21, 347–350. Majoie, H.J.M., Rijkers, K., Berfelo, M.W., Hulsman, J., Myint, A., Schwarz, M., and Vles, J.S.H. (2010). Vagus nerve stimulation in refractory epilepsy: effects on pro-and anti-inflammatory cytokines in peripheral blood. Neuroimmunomodulation 18, 52–56. Makis, A.C., Tzoufi, M., Kateri, M.D., Bourantas, K.I., and Papadopoulou, Z.L. (2005). Valproate-induced eosinophilia in children with epilepsy: role of interleukin-5. J. Child Neurol. 20, 150–152.


A. Saghazadeh et al.: Cytokines in febrile seizures 303 Mantegazza, M., Gambardella, A., Rusconi, R., Schiavon, E., Annesi, F., Cassulini, R.R., Labate, A., Carrideo, S., Chifari, R., Canevini, M.P., et al. (2005). Identification of an Nav1.1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures. Proc. Natl. Acad. Sci. USA. 102, 18177–18182. Martinos, M.M., Yoong, M., Patil, S., Chin, R.F.M., Neville, B.G., Scott, R.C., and de Haan, M. (2012). Recognition memory is impaired in children after prolonged febrile seizures. Brain 135, 3153–3164. Masuyama, T., Matsuo, M., Ichimaru, T., Ishii, K., Tsuchiya, K., and Hamasaki, Y. (2002). Possible contribution of interferon-α to febrile seizures in influenza. Pediatr. Neurol. 27, 289–292. Mathieu, O., Picot, M.-C., Gelisse, P., Breton, H., Demoly, P., and Hillaire-Buys, D. (2011). Effects of carbamazepine and metabolites on IL-2, IL-5, IL-6, IL-10 and IFN-g secretion in epileptic patients: the influence of co-medication. Pharmacol. Rep. 63, 86–94. Matsumura, K., Cao, C., Ozaki, M., Morii, H., Nakadate, K., and Watanabe, Y. (1998). Brain endothelial cells express cyclooxygenase-2 during lipopolysaccharide-induced fever: light and electron microscopic immunocytochemical studies. J. Neurosci. 18, 6279–6289. Matsuo, M., Sasaki, K., Ichimaru, T., Nakazato, S., and Hamasaki, Y. (2006). Increased IL-1β production from dsRNA-stimulated leukocytes in febrile seizures. Pediatr. Neurol. 35, 102–106. McIntyre, K.W., Stepan, G.J., Kolinsky, K.D., Benjamin, W.R., Plocinski, J.M., Kaffka, K.L., Campen, C.A., Chizzonite, R.A., and Kilian, P.L. (1991). Inhibition of interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody. J. Exp. Med. 173, 931–939. Miller, L.L., Pellock, J.M., DeLorenzo, R.J., Meyer, J.M., and Corey, L.A. (1998). Univariate genetic analyses of epilepsy and seizures in a population-based twin study: the Virginia Twin Registry. Genet. Epidemiol. 15, 33–49. Miller, L.L., Pellock, J.M., Boggs, J.G., DeLorenzo, R.J., Meyer, J.M., and Corey, L.A. (1999). Epilepsy and seizure occurrence in a population-based sample of Virginian twins and their families. Epilepsy Res. 34, 135–143. Miller, B.J., Buckley, P., Seabolt, W., Mellor, A., and Kirkpatrick, B. (2011). Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol. Psychiatry 70, 663–671. Mine, J., Takahashi, Y., Mogami, Y., Ikeda, H., Kubota, Y., and Imai, K. (2013). Characteristics of epilepsy and immunological markers in epileptic patients after influenza associated encephalopathy. Neurol. Asia 18, 35–45. Moulard, B., Guipponi, M., Chaigne, D., Mouthon, D., Buresi, C., and Malafosse, A. (1999). Identification of a new locus for generalized epilepsy with febrile seizures plus (GEFS+) on chromosome 2q24-q33. Am. J. Hum. Genet. 65, 1396–1400. Mulley, J., Heron, S., Scheffer, I., and Berkovic, S. (2004). Febrile convulsions and genetic susceptibility: role of the neuronal nicotinic acetylcholine receptor α4 subunit. Epilepsia 45, 561–562. Nabbout, R., Prud’homme, J.F., Herman, A., Feingold, J., Brice, A., Dulac, O., and LeGuern, E. (2002). A locus for simple pure febrile seizures maps to chromosome 6q22-q24. Brain 125, 2668–2680.

Nabbout, R., Baulac, S., Desguerre, I., Bahi-Buisson, N., Chiron, C., Ruberg, M., Dulac, O., and LeGuern, E. (2007). New locus for febrile seizures with absence epilepsy on 3p and a possible modifier gene on 18p. Neurology 68, 1374–1381. Nakayama, J. and Arinami, T. (2006). Molecular genetics of febrile seizures. Epilepsy Res. 70, 190–198. Nakayama, J., Hamano, K., Iwasaki, N., Nakahara, S., Horigome, Y., Saitoh, H., Aoki, T., Maki, T., Kikuchi, M., Migita, T., et al. (2000). Significant evidence for linkage of febrile seizures to chromosome 5q14-q15. Hum. Mol. Genet. 9, 87–91. Nakayama, J., Yamamoto, N., Hamano, K., Iwasaki, N., Ohta, M., Nakahara, S., Horigome, Y., Nakahara, C., Noguchi, E., and Shiono, J. (2002). Failure to find evidence for association between voltage-gated sodium channel gene SCN2A variants and febrile seizures in humans. Neurosci. Lett. 329, 249–251. Nakayama, J., Hamano, K., Iwasaki, N., Ohta, M., Nakahara, S., Matsui, A., and Arinami, T. (2003a). Mutation analysis of the leucine-rich, glioma inactivated 1 gene (LGI1) in Japanese febrile seizure patients. Neuropediatrics 34, 234–236. Nakayama, J., Hamano, K., Noguchi, E., Horiuchi Y, Iwasaki, N., Ohta, M., Nakahara, S., Naoi, T., Matsui, A., and Arinami, T. (2003b). Failure to find causal mutations in the GABAA-receptor γ2 subunit (GABRG2) gene in Japanese febrile seizure patients. Neurosci. Lett. 343, 117–120. Nakayama, J., Yamamoto, N., Hamano, K., Iwasaki, N., Ohta, M., Nakahara, S., Matsui, A., Noguchi, E., and Arinami, T. (2004). Linkage and association of febrile seizures to the IMPA2 gene on human chromosome 18. Neurology 63, 1803–1807. Nelson, K.B. and Ellenberg, J.H. (1978). Prognosis in children with febrile seizures. Pediatrics 61, 720–727. Netea, M.G., Kullberg, B.J., and Van der Meer, J.W.M. (2000). Circulating cytokines as mediators of fever. Clin. Infect. Dis. 31, S178–S184. Nowak, M., Bauer, S., Haag, A., Cepok, S., Todorova-Rudolph, A., Tackenberg, B., Norwood, B., Oertel, W.H., Rosenow, F., Hemmer, B., et al. (2011). Interictal alterations of cytokines and leukocytes in patients with active epilepsy. Brain Behav. Immun. 25, 423–428. Nur, B., Sahinturk, D., Coskun, M., Duman, O., Yavuzer, U., and Haspolat, S. (2012a). Single nucleotide polymorphism and production of IL-1β and IL-10 cytokines in febrile seizures. Neuropediatrics 43, 194–200. Nur, B.G., Kahramaner, Z., Duman, O., Dundar, N.O., Sallakcı, N., Yavuzer, U., and Haspolat, S. (2012b). Interleukin-6 gene polymorphism in febrile seizures. Pediatr. Neurol. 46, 36–38. Offringa, M. and Newton, R. (2013). Prophylactic drug management for febrile seizures in children (Review). (Evid. Base. Child Health) Cochrane Rev. J. 8, 1376–1485. Özaydın, E., Arhan, E., Cetinkaya, B., Özdel, S., Değerliyurt, A., Güven, A., and Köse, G. (2012). Differences in iron deficiency anemia and mean platelet volume between children with simple and complex febrile seizures. Seizure 21, 211–214. Ozkara, C., Uzan, M., Tanriverdi, T., Baykara, O., Ekinci, B., Yeni, N., Kafadar, A., and Buyru, N. (2006). Lack of association between IL-1β/α gene polymorphisms and temporal lobe epilepsy with hippocampal sclerosis. Seizure 15, 288–291. Pascual, V., Allantaz, F., Arce, E., Punaro, M., and Banchereau, J. (2005). Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J. Exp. Med. 201, 1479–1486.


304 A. Saghazadeh et al.: Cytokines in febrile seizures Peiffer, A., Thompson, J., Charlier, C., Otterud, B., Varvil, T., Pappas, C., Barnitz, C., Gruenthal, K., Kuhn, R., and Leppert, M. (1999). A locus for febrile seizures (FEB3) maps to chromosome 2q23-24. Ann. Neurol. 46, 671–678. Peltola, J., Hurme, M., Miettinen, A., and Keränen, T. (1998). Elevated levels of interleukin-6 may occur in cerebrospinal fluid from patients with recent epileptic seizures. Epilepsy Res. 31, 129–133. Peltola, J., Palmio, J., Korhonen, L., Suhonen, J., Miettinen, A., Hurme, M., Lindholm, D., and Keränen, T. (2000). Interleukin-6 and interleukin-1 receptor antagonist in cerebrospinal fluid from patients with recent tonic-clonic seizures. Epilepsy Res. 41, 205–211. Peltola, J., Keränen, T., Rainesalo, S., and Hurme, M. (2001). Polymorphism of the interleukin-1 gene complex in localization-related epilepsy. Ann. Neurol. 50, 275–276. Peltola, J., Laaksonen, J., Haapala, A.M., Hurme, M., Rainesalo, S., and Keranen, T. (2002). Indicators of inflammation after recent tonic-clonic epileptic seizures correlate with plasma interleukin-6 levels. Seizure 11, 44–46. Pollard, J.R., Eidelman, O., Mueller, G.P., Dalgard, C.L., Crino, P.B., Anderson, C.T., Brand, E.J., Burakgazi, E., Ivaturi, S.K., and Pollard, H.B. (2012). The TARC/sICAM5 ratio in patient plasma is a candidate biomarker for drug resistant epilepsy. Front. Neurol. 3, 181. Ponnala, S., Chaudhari, J.R., Jaleel, M.A., Bhiladvala, D., Kaipa, P.R., Das, U.N., and Hasan, Q. (2012). Role of MDR1 C3435T and GABRG2 C588T gene polymorphisms in seizure occurrence and MDR1 effect on anti-epileptic drug (phenytoin) absorption. Genet. Test. Mol. Biomarkers 16, 550–557. Qi, L., van Dam, R.M., Meigs, J.B., Manson, J.E., Hunter, D., and Hu, F.B. (2006). Genetic variation in IL6 gene and type 2 diabetes: tagging-SNP haplotype analysis in large-scale case-control study and meta-analysis. Hum. Mol. Genet. 15, 1914–1920. Rainero, I., Bo, M., Ferrero, M., Valfrè, W., Vaula, G., and Pinessi, L. (2004). Association between the interleukin-1α gene and Alzheimer’s disease: a meta-analysis. Neurobiol. Aging 25, 1293–1298. Represa, A. and Ben-Ari, Y. (2005). Trophic actions of GABA on neuronal development. Trends Neurosci. 28, 278–283. Sacchetti, E., Bocchio-Chiavetto, L., Valsecchi, P., Scassellati, C., Pasqualetti, P., Bonvicini, C., Corsini, P., Rossi, G., Cesana, B.M., and Barlati, S. (2007). -G308A tumor necrosis factor alpha functional polymorphism and schizophrenia risk: meta-analysis plus association study. Brain Behav. Immun. 21, 450–457. Salam, S.A., Rahman, H.A., and Karam, R. (2012). GABRG2 gene polymorphisms in Egyptian children with simple febrile seizures. Indian J. Pediatr. 79, 1514–1516. Salzmann, A., Guipponi, M., Lyons, P.J., Fricker, L.D., Sapio, M., Lambercy, C., Buresi, C., Ouled Amar Bencheikh, B., Lahjouji, F., Ouazzani, R., et al. (2012). Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy. Hum. Mutat. 33, 124–135. Sasidaran, K., Singhi, S., and Singhi, P. (2012). Management of acute seizure and status epilepticus in pediatric emergency. Indian J. Pediatr. 79, 510–517. Schlachter, K., Gruber-Sedlmayr, U., Stogmann, E., Lausecker, M., Hotzy, C., Balzar, J., Schuh, E., Baumgartner, C., Mueller, J.C., Illig, T., et al. (2009). A splice site variant in the sodium

channel gene SCN1A confers risk of febrile seizures. Neurology 72, 974–978. Scott, J.A.G., Wonodi, C., Moïsi, J.C., Deloria-Knoll, M., DeLuca, A.N., Karron, R.A., Bhat, N., Murdoch, D.R., Crawley, J., and Levine, O.S. (2012). The definition of pneumonia, the assessment of severity, and clinical standardization in the Pneumonia Etiology Research for Child Health Study. Clin. Infect. Dis. 54, S109–S116. Serdaroğlu, G., Alpman, A., Tosun, A., Pehlıvan, S., Özkınay, F., Tekgül, H., and Gökben, S. (2009). Febrile seizures: interleukin 1β and interleukin-1 receptor antagonist polymorphisms. Pediatr. Neurol. 40, 113–116. Shu-hua, L., Chao-feng, H., and Te-chang, L. (2006). Relationship between the children interleukin 1β(-511) gene polymorphisms and susceptibility to febrile seizures. Chin. J. Pathophysiol. 22, 1168–1170. Sinha, S., Patil, S.A., Jayalekshmy, V., and Satishchandra, P. (2008). Do cytokines have any role in epilepsy? Epilepsy Res. 82, 171–176. Staley, K.J., Soldo, B.L., and Proctor, W.R. (1995). Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. Science (New York NY) 269, 977–981. Stoeck, K., Bodemer, M., and Zerr, I. (2006). Pro- and anti-inflammatory cytokines in the CSF of patients with Creutzfeldt-Jakob disease. J. Neuroimmunol. 172, 175–181. Swardfager, W., Lanctôt, K., Rothenburg, L., Wong, A., Cappell, J., and Herrmann, N. (2010). A meta-analysis of cytokines in Alzheimer’s disease. Biol. Psychiatry 68, 930–941. Takahashi, Y., Mine, J., Kubota, Y., Yamazaki, E., and Fujiwara, T. (2009). A substantial number of Rasmussen syndrome patients have increased IgG, CD4+ T cells, TNFα, and granzyme B in CSF. Epilepsia 50, 1419–1431. Takahashi, Y., Imai, K., Ikeda, H., Kubota, Y., Yamazaki, E., and Susa, F. (2013). Open study of pranlukast add-on therapy in intractable partial epilepsy. Brain Dev. 35, 236–244. Teran, C.G., Medows, M., Wong, S.H., Rodriguez, L., and Varghese, R. (2012). Febrile seizures: current role of the laboratory investigation and source of the fever in the diagnostic approach. Pediatr. Emerg. Care 28, 493–497. Thakkinstian, A., McElduff, P., D’Este, C., Duffy, D., and Attia, J. (2005). A method for meta-analysis of molecular association studies. Stat. Med. 24, 1291–1306. Tilgen, N., Pfeiffer, H., Cobilanschi, J., Rau, B., Horvath, S., Elger, C.E., Propping, P., and Heils, A. (2002). Association analysis between the human interleukin 1β (-511) gene polymorphism and susceptibility to febrile convulsions. Neurosci. Lett. 334, 68–70. Tiwari, P., Dwivedi, R., Mansoori, N., Alam, R., Chauhan, U.K., Tripathi, M., and Mukhopadhyay, A.K. (2012). Do gene polymorphism in IL-1β, TNF-α and IL-6 influence therapeutic response in patients with drug refractory epilepsy? Epilepsy Res. 101, 261–267. Tomoum, H.Y., Badawy, N.M., Mostafa, A.A., and Harb, M.Y. (2007). Plasma interleukin-1β levels in children with febrile seizures. J. Child Neurol. 22, 689–692. Treiman, D.M. (2001). GABAergic mechanisms in epilepsy. Epilepsia 42, 8–12. Tsai, F.-J., Hsieh, Y.-Y., Chang, C.-C., Lin C.-C., and Tsai, C.-H. (2002a). Polymorphisms for interleukin 1β exon 5 and interleukin 1 receptor antagonist in Taiwanese children with febrile convulsions. Arch. Pediatr. Adolesc. Med. 156, 545–548.


A. Saghazadeh et al.: Cytokines in febrile seizures 305 Tsai, F.-J., Chou, I.C., Hsieh, Y.-Y., Lee, C.-C., Lin, C.-C., and Tsai, C.-H. (2002b). Interleukin-4 intron 3 polymorphism is not related to susceptibility to febrile seizures. Pediatr. Neurol. 27, 271–274. Tsuboi, T. (1987). Genetic analysis of febrile convulsions: twin and family studies. Hum. Genet. 75, 7–14. Uludag, I.F., Bilgin, S., Zorlu, Y., Tuna, G., and Kirkali, G. (2013). Interleukin-6, interleukin-1beta and interleukin-1 receptor antagonist levels in epileptic seizures. Seizure 22, 457–461. van Esch, A., Steyerberg, E.W., van Duijn, C.M., Offringa, M., Derksen-Lubsen, G., van Steensel-Moll, H.A., and van Esch, A. (1998). Prediction of febrile seizures in siblings: a practical approach. Eur. J. Pediatr. 157, 340–344. Verity, C.M., Butler, N.R., and Golding, J. (1985). Febrile convulsions in a national cohort followed up from birth. I. Prevalence and recurrence in the first five years of life. Br. Med. J. 290, 1307–1310. Vezzani, A., Balosso, S., and Ravizza, T. (2008). The role of cytokines in the pathophysiology of epilepsy. Brain Behav. Immun. 22, 797–803. Vezzani, A., French, J., Bartfai, T., and Baram, T.Z. (2010). The role of inflammation in epilepsy. Nat. Rev. Neurol. 7, 31–40. Vigers, G.P.A., Anderson, L.J., Caffes, P., and Brandhuber, B.J. (1997). Crystal structure of the type-I interleukin-1 receptor complexed with interleukin-1β. Nature 386, 190–194. Virta, M., Hurme, M., and Helminen, M. (2002a). Increased frequency of interleukin-1β (-511) allele 2 in febrile seizures. Pediatr. Neurol. 26, 192–195. Virta, M., Hurme, M., and Helminen, M. (2002b). Increased plasma levels of pro- and anti-inflammatory cytokines in patients with febrile seizures. Epilepsia 43, 920–923. Visser, A.M., Jaddoe, V.W., Ghassabian, A., Schenk, J.J., Verhulst, F.C., Hofman, A., Tiemeier, H., Moll, H.A., and Arts, W.F.M. (2012). Febrile seizures and behavioural and cognitive outcomes in preschool children: the Generation R Study. Dev. Med. Child Neurol. 54, 1006–1011. Viviani, B., Bartesaghi, S., Gardoni, F., Vezzani, A., Behrens, M.M., Bartfai, T., Binaglia, M., Corsini, E., Di Luca, M., and Galli, C.L. (2003). Interleukin-1β enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J. Neurosci. 23, 8692–8700. Wallace, R.H., Berkovic, S.F., Howell, R.A., Sutherland, G.R., and Mulley, J.C. (1996). Suggestion of a major gene for familial febrile convulsions mapping to 8q13-21. J. Med. Genet. 33, 308–312. Wang, S., Cheng, Q., Malik, S., and Yang, J. (2000). Interleukin-1β inhibits γ-aminobutyric acid type A (GABAA) receptor current in cultured hippocampal neurons. J. Pharmacol. Exp. Ther. 292, 497–504. Wang, P., Xia, H.H.-X., Zhang, J.-Y., Dai, L.-P., Xu, X.-Q., and Wang, K.-J. (2007a). Association of interleukin-1 gene polymorphisms with gastric cancer: a meta-analysis. Int. J. Cancer 120, 552–562.

Wang, X., Xu, M., and Du, L. (2007b). Association analysis of γ2 subunit of γ-aminobutyric acid (GABA) type A receptor and voltage-gated sodium channel type II α-polypeptide gene mutation in southern Chinese children with febrile seizures. J. Child Neurol. 22, 714–719. Waruiru, C. and Appleton, R. (2004). Febrile seizures: an update. Arch. Dis. Child 89, 751–756. Wendorff, J. and Zeman, K. (2011). Immunology of febrile seizures. Neurol. Dziec. 20, 41–46. Wiebe, S., Blume, W.T., Girvin, J.P., and Eliasziw, M. (2001). A randomized, controlled trial of surgery for temporal-lobe epilepsy. N. Engl. J. Med. 345, 311–318. Wu, Z.Q., Sun, L., Sun, Y.H., Ren, C., Jiang, Y.H., and Lv, X.L. (2012). Interleukin 1beta -511 C/T gene polymorphism and susceptibility to febrile seizures: a meta-analysis. Mol. Biol. Rep. 39, 5401–5407. Xue, H., Lin, B., Ni, P., Xu, H., and Huang, G. (2010). Interleukin-1B and interleukin-1 RN polymorphisms and gastric carcinoma risk: a meta-analysis. J. Gastroenterol. Hepatol. 25, 1604–1617. Yamanaka, G., Kawashima, H., Suganami, Y., Watanabe, C., Watanabe, Y., Miyajima, T., Takekuma, K., Oguchi, S., and Hoshika, A. (2006). Diagnostic and predictive value of CSF d-ROM level in influenza virus-associated encephalopathy. J. Neurol. Sci. 243, 71–75. Yamanaka, G., Kawashima, H., Oana, S., Ishida, Y., Miyajima, T., Kashiwagi, Y., and Hoshika, A. (2010). Increased level of serum interleukin-1 receptor antagonist subsequent to resolution of clinical symptoms in patients with West syndrome. J. Neurol. Sci. 298, 106–109. Yinan, M., Yu, Q., Zhiyue, C., Jianjun, L., Lie, H., Liping, Z., Jianhui, Z., Fang, S., Dingfang, B., Qing, L., et al. (2004). Polymorphisms of casein kinase I gamma 2 gene associated with simple febrile seizures in Chinese Han population. Neurosci. Lett. 368, 2–6. Yinan, M., Yu, Q., Zhiyue, C., Liping, Z., Fang, F., Liwen, W., Fuying, S., Jianhui, Z., Dingfang, B., and Tianjun, W. (2006). HCN2, NRTN, CAPS and GPX4 genes are not associated with simple febrile seizures in Chinese Han population. J. Pediatr. Neurol. 4, 83–87. Yoon, J.W., Choen, E.J., and Lee, Y.H. (2008). Polymorphisms of interleukin-1β promoter in simple febrile seizures. Kor. J. Pediatr. 51, 1007–1011. Yu, N., Di, Q., Hu, Y., Zhang, Y.-F., Su, L.-Y., Liu, X.-H., and Li, L.-C. (2012). A meta-analysis of pro-inflammatory cytokines in the plasma of epileptic patients with recent seizure. Neurosci. Lett. 514, 110–115. Zareifar, S., Hosseinzadeh, H.R., and Cohan, N. (2012). Association between iron status and febrile seizures in children. Seizure 21, 603–605. Zhao, F., Liu, X.-M., Ke, X.-Y., Ming, M., Gui, W.-X., Zhao, D.-C., and Wang, D.-B. (2010). Association of febrile seizures and human myo-inositol monophosphatase 2 gene. J. Appl. Clin. Pediatr. 12.


Febrile seizures and genetic epilepsy with febrile seizures plus (GEFS+).

Melatonin's Effect in Febrile Seizures and Epilepsy.

Proinflammatory and antiinflammatory cytokines in multiple sclerosis and central nervous system acquired immunodeficiency syndrome.

Familial history and recurrence of febrile seizures; a systematic review and meta-analysis.

Origins of temporal lobe epilepsy: febrile seizures and febrile status epilepticus.

Prognostic factors for subsequent epilepsy in children with febrile seizures.

Predictors of epilepsy in children who have experienced febrile seizures.

Diagnostic markers for hyperemesis gravidarum: a systematic review and metaanalysis.

Epilepsy After Febrile Seizures: Twins Suggest Genetic Influence.

Recent Research on Febrile Seizures: A Review.

Increased CPA6 promoter methylation in focal epilepsy and in febrile seizures.

Possible role of trace elements in epilepsy and febrile seizures: a meta-analysis.

Vagus nerve stimulation for genetic epilepsy with febrile seizures plus (GEFS+) accompanying seizures with impaired consciousness.

Febrile seizures.

Febrile seizures.

Febrile seizures.

Febrile seizures in children.

Association between hypocapnia and febrile seizures.

Vaccines and Febrile Seizures: Quantifying the Risk.

Diurnal and seasonal occurrence of febrile seizures.

Generation of Febrile Seizures and Subsequent Epileptogenesis.

Prenatal and perinatal antecedents of febrile seizures.

Febrile seizures: etiology, prevalence, and geographical variation.

Male sexual dysfunction and ankylosing spondylitis: a systematic review and metaanalysis.