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ORIGINAL ARTICLE
Year : 2018  |  Volume : 31  |  Issue : 3  |  Page : 1005-1010

High-mobility group box 1 protein serum level in children with febrile seizures


1 Department of Pediatrics, Faculty of Medicine, Menoufia University, Giza, Egypt
2 Department of Pediatrics, El Sheikh Zayed Specialized Hospital, 6thof October, Giza, Egypt

Date of Submission08-Mar-2017
Date of Acceptance07-May-2017
Date of Web Publication31-Dec-2018

Correspondence Address:
Mohamed M Debdeb
Department of Pediatrics, El Sheikh Zayed Specialized Hospital, 6th of October, Giza
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_156_17

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  Abstract 


Objective
The aim of the work was to assess the level of high-mobility group box 1 (HMGB1) protein in the serum of children with febrile seizures (FS) versus other groups of children suffering from afebrile seizures or febrile children without seizures in order to detect the relationship between HMGB1 and FSs.
Background
FS is considered as one of the most common seizure types during childhood. Fever is induced by increased HMGB1 level during infection and this may induce the development of FSs. HMGB1 is a highly conserved protein found in the nuclei and cytoplasm of nearly all cell types. HMGB1 is considered to be a key mediator of inflammatory diseases.
Patients and methods
This case–control study was held at Menoufia University Hospital on 80 children from January 2016 to July 2016. Our population was classified into four groups: the FS group (n = 20), febrile children without seizures (n = 20), afebrile seizure patients (n = 20), and healthy controls (n = 20). All groups were subjected to history taking, complete neurological examination, and laboratory investigations [serum blood (sodium, potassium, calcium, blood urea nitrogen, and creatinine), C-reactive protein, complete blood count, and serum HMGB1].
Results
Serum HMGB1 was significantly higher in the FS group of children than in other groups.
Conclusion
From this study we conclude that serum HMGB1 was significantly higher in patients with FSs. Our data suggest that HMGB1 may contribute to the generation of FSs.

Keywords: febrile seizures, high-mobility group box 1 protein, serum HMGB1


How to cite this article:
Mahmoud AT, Abd Alnabya SA, Debdeb MM. High-mobility group box 1 protein serum level in children with febrile seizures. Menoufia Med J 2018;31:1005-10

How to cite this URL:
Mahmoud AT, Abd Alnabya SA, Debdeb MM. High-mobility group box 1 protein serum level in children with febrile seizures. Menoufia Med J [serial online] 2018 [cited 2019 Mar 20];31:1005-10. Available from: http://www.mmj.eg.net/text.asp?2018/31/3/1005/248724




  Introduction Top


Febrile seizures (FSs) are considered among the most common reasons of pediatric emergencies. These seizures are associated with high fever in children during their early lives. FS was thought to be a benign condition, requiring nothing apart from reassurance. Over time, we had explored that the benign nature of FS should be carefully rethought, as there are a number of atypical presentations with different outcomes[1]. Pathophysiology of FS is not unknown. However, several features may interact with the development of FS, such as immature brain development, fever, and genetic predisposition. Moreover, there are several risk factors for the development of first FS, includingthe degree of fever height, presence of history of FS in a first-degree relative, pre-existing developmental delays, stay in the neonatal nursery for long times, and associations with some mineral deficiencies, such as zinc and iron[2].

High-mobility group box 1 (HMGB1) protein is a small protein (215 amino acids) identified as a 30-kDa protein associated with nuclear chromatin. It consists of two consecutive L-shaped domains (called HMG boxes) and a 30 amino acid-long acidic ‘tail’, linked by short linkers. HMGB1 has two close relatives, HMGB2 and HMGB3, with an 80% amino acid identity among the three forms. HMGB1 is highly conserved and has 99% identity among all mammals[3]. HMGB1 functions had been well characterized. It was thought that HMGB1 functions only as a nuclear factor that enhances transcription; however, it was discovered to be an important cytokine that mediates the response to infection, inflammation, and injury. These observations had led to the emergence of a new field in immunology that was interested in understanding the mechanisms of HMGB1 release, its biological activities, and its pathological effects in sepsis, arthritis, cancer, seizures, and other diseases[4]. HMGB1 was found to act as a proinflammatory cytokine peripherally and evidence suggested that HMGB1 had the same action in the brain, but the role of HMGB1 in the central nervous system needs further examinations. Although many proinflammatory cytokines exhibit pyrogenic activity and increase interleukin-1 (IL-1) levels when injected directly into the brain, the effect of HMGB1 on core body temperature and hypothalamic IL-1 levels still need further workup[5]. HMGB1 is secreted by activated macrophages and monocytes and it is considered to be associated with epilepsy and FS as it can bind to lipopolysaccharide and IL-1 and synergize the inflammatory response and is actively released after proinflammatory stimuli, such as lipopolysaccharide, tumor necrotic factor-α, IL-1, IL-6, and IL-8, and the modification of HMGB1 by phosphorylation and acetylation. These data show that HMGB1 may play a role as an endogenous pyrogen and support that HMGB1 has a proinflammatory effect within the central nervous system[6].

The aim of this study was to assess the level of HMGB1 in the serum of children with FSs versus other groups of children suffering from afebrile seizures or febrile children without seizures in order to detect the relationship between HMGB1 and FSs.


  Patients and Methods Top


This case–control study was conducted on 80 children from January 2016 to July 2016 in Pediatric Emergency Room, Pediatric Department, and Outpatient Clinic, Menoufia University Hospital. Informed consent was obtained from the guardians of each child and this study was approved by Ethical Committee of Menoufia Faculty of Medicine.

All children in this study were subjected to the following.

First, they were classified into four groups, each including 20 children with different presentations: group A included those with FS; group B included febrile children without seizures; group C included afebrile seizure patients; and group D included normal healthy controls. All children were subjected to full clinical assessment and laboratory investigation.

Full clinical assessment including history and physical examination was carried out. Laboratory investigations included complete blood count, serum electrolytes (sodium, potassium, calcium levels), kidney and liver function tests, quantitative C-reactive protein, and serum HMGB1 protein level. HMGB1 was measured using commercially available, enzyme-linked immunosorbent assay kits according to the manufacturer's instructions (Wkea Med Supplies Corp., Changchun, China).

Statistical analysis

All data were collected, tabulated, and statistically analyzed using SPSS 19.0 for Windows (SPSS Inc., Chicago, Illinois, USA).

Two types of statistics were performed:

  1. Descriptive statistics (e.g., percentage, mean, and SD)
  2. Analytic statistics included the following tests:


    1. χ2: It was used to study the association between two qualitative variables
    2. t-Test: It is a test of significance used for comparison between two groups normally distributed having quantitative variables
    3. Mann–Whitney U test: It is a nonparametric test of significance used for comparison between two groups not normally distributed having quantitative variables.


A P value of 0.05 was considered statistically significant.


  Results Top


On comparing the total number of children included in the four groups of this study, it was found that there were no significant differences between the four groups as regards the age and sex of children [Table 1]. Generalized tonic–clonic seizures represented about 85% of seizure types in children with FS (group A) and 75% in afebrile seizures (group C). Myoclonic convulsions represented 10% among both seizures groups; focal type represented only 5% of the FS group and 15% of the afebrile seizure group [Table 2]. The mean total leukocytic count of children with FS was significantly higher than that in healthy control children (group D) and those with afebrile seizure (group C) (P ≤ 0.001), but not significantly higher in comparison with children with fever only (group B). There were no significant differences between four groups as regards hemoglobin level and platelet counts [Table 3]. Asregardsserum electrolytes, random blood glucose, and both liver and renal function tests, there were no significant differences between children with FS and other control children in this study as all children's levels were within normal [Table 4] and [Table 5]. The mean C-reactive protein of children with FS was significantly higher than that in healthy control children (group D), afebrile seizure children (group C) (P < 0.001), and those with fever only (group B) (P 0.025) [Table 6]. The mean serum HMGB1 in children with FS (group A) was significantly higher than that in healthy control children (group D) (P ≤ 0.001), children with afebrile seizure (group C) (P = 0.018), and those with fever only (group B) (P = 0.017). Moreover, the mean HMGB1 in children with afebrile seizures (group C) was significantly higher than that in healthy controls (group D) (P = 0.034) [Table 7] and [Figure 1]. HMGB1 on a cutoff more than 54.8 ng/ml had a sensitivity of 90% and specificity of 63.3% in the prediction of cases of FSs with positive predictive value is equal to 48.65% and negative predictive value is equal to 95.3%. Therefore, we can consider HMGB1 as a good negative test for FSs [Table 8] and [Figure 2].
Table 1: Demographic data among studied groups (n=80)

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Table 2: Character of seizures among children with seizures

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Table 3: Complete blood count finding among four studied groups

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Table 4: Serum electrolytes and random glucose among four studied groups (n=80)

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Table 5: Liver and kidney function tests among four studied groups (n=80)

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Table 6: Serum C-reactive protein finding among four studied groups (n=80)

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Table 7: Serum high-mobility group box 1 level among four studied groups (ng/ml) (n=80)

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Figure 1: Serum high-mobility group box 1 (HMGB1) level among four studied groups (ng/ml).

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Table 8: Agreement (sensitivity, specificity, and accuracy) for predict febrile seizure cases (vs. others)

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Figure 2: Receiver operating characteristic curve for high-mobility group box 1 to predict febrile seizure cases (vs. others).

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  Discussion Top


This study is a trial to detect the role of inflammation and inflammatory mediators such as HMGB1 protein in the development of seizures, especially FSs, and was carried out in children at Menoufia University Hospital during the period from January 2016 to July 2016.

Our study showed that there was no significant difference between the four groups as regards sex and age. The sex distribution among children with FSs showed that boys were slightly more prevalent than girls, with a male percentage of 55%. This is in agreement with the findings of Dalben et al.[7], whoreported that there was no difference in sex between children with FS. As regards features and duration of FS, the present study showed that the most common type of seizures in children with FS is generalized tonic–clonic (85%), the incidence of myoclonic type was 10%, and that of focal type was 5%. Moreover, about 80% of children with FS have a duration of seizures less than 10 min. These findings are concordant with those ofSadlier and Scheffer[8], who reported that generalized tonic–clonic seizures are the most common type, and that 4–16% have focal features and febrile myoclonic seizures had been perceived. Moreover, they reported that the duration of the FS is less than 10 min in 87% of children, whereas seizures last more than 15 min in 9% of children.

This study showed no significant difference as regards total leukocytic count between the FS group and children with fever only as both groups showed mild leukocytosis as a sign of infection found in them. Shah et al.[9] said that children 2–40 months of age with FS are at the same risk for occult bacteremia as those with fever alone. He added that increasing the usage of the pneumococcal conjugate vaccine may further eliminate the incidence of bacteremia in this population. As regards renal and liver function tests, this study showed that there were no significant differences between children with FS and other control groups of children as all children results were within normal values, which is in agreement with a cross-sectional study conducted on 291 children with FSs from 2008 to 2013 by Afsharkhas and Tavasoi[10]. They reported that there were no significant abnormalities in serum urea, creatinine, aspartate aminotransferase, and alanine aminotransferase in children with FS. As regards serum HMGB1, the present study showed that the median HMGB1 level in the serum of healthy controls (group D) was 23 ng/ml, that in febrile children without seizures (group B) was 34.2 ng/ml, and that in afebrile seizures patients (group C) was 44.6 ng/ml, whereas in FS patients (group A) it was 73.3 ng/ml. On comparing the HMGB1 levels between healthy controls, febrile children, and the two seizure groups, there were significant trends of higher HMGB1 levels in both FS and afebrile seizure patients than in the febrile children and healthy controls. Moreover, the mean HMGB1 level in the serum of FS patients was found to be significantly higher than that in afebrile seizures groups (P = 0.018). These outcomes are in accordance with the study by Choi et al.[11], which was the primary review showing a significant height of HMGB1 in the serum of FS patients. Moreover, they announced that it was unrealistic to infer causality from distinct human reviews; however, their information recommended that HMGB1 may add to the era of FS in children.


  Conclusion Top


From this study we can conclude that HMGB1 is significantly elevated in children with FS in comparison with afebrile seizures patients, febrile children without seizures, and healthy controls. Therefore, HMGB1 may be attributed to the generation of FS in children and may be used as good negative test for FSs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Shinnar S. Febrile seizures and mesial temporal sclerosis. Epilepsy Curr 2003; 3:115–118.  Back to cited text no. 1
    
2.
Hampers LC, Spina LA. Evaluation and management of pediatric febrile seizures in the emergency department. Emerg Med Clin North Am 2011; 29:83–93.  Back to cited text no. 2
    
3.
Khair AM, Elmagrabi D. Febrile seizures and febrile seizures syndromes: an updated overview of old and current knowledge. Neurol Res Int 2015; 2015:849341.  Back to cited text no. 3
    
4.
Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 2005; 5:331–342.  Back to cited text no. 4
    
5.
Agnello D, Wang H, Yang H, Tracey KJ, Ghezzi P. HMGB-1, a DNA-binding protein with cytokine activity induces brain TNF and IL-6 production and mediates anorexia and taste aversion. Cytokine 2002; 18:231–239.  Back to cited text no. 5
    
6.
Agalave NM, Svensson C. Extracellular HMGB1 as a mediator of persistent pain. Mol Med 2014; 20:569–578.  Back to cited text no. 6
    
7.
Dalben J, Siqueira H, Espinosa M, Alvarenga R. Febrile seizures: a population-based study. J Pediatr (Rio J) 2015; 91:529–534.  Back to cited text no. 7
    
8.
Sadlier LG, Scheffer IE. Febrile seizures. BMJ 2007; 334:407.  Back to cited text no. 8
    
9.
Shah S, Alprn E, Zwerling L, Reid JR, McGowan KL, Bell LM. Low risk of bacteremia in children with febrile seizures. Arch Pediatr Adolesc Med 2002; 156:469–472.  Back to cited text no. 9
    
10.
Afsharkhas L, Tavasoi, A. Renal function in children with febrile convulsions. Iran J Child Neurol 2014; 8:57–61.  Back to cited text no. 10
    
11.
Choi J, Min HJ, Shin JS. Increased levels of HMGB1 and pro-inflammatory cytokines in children with febrile seizures. J Neuroinflammation 2011; 8:135.  Back to cited text no. 11
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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