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Meta-analysis of HMGB1 levels in the cerebrospinal fluid and serum of patients with epilepsy

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Abstract

Background

Epilepsy pathogenesis and progression are strongly influenced by inflammation. High-mobility group box-1 (HMGB1) is a key proinflammatory factor. The purpose of this study was to quantify and assess the relationship between HMGB1 level and epilepsy.

Methods

We searched Embase, Web of Science, PubMed, and the Cochrane Library for studies examining the relationship between HMGB1 and epilepsy. Two independent researchers extracted data and assessed quality using the Cochrane Collaboration tool. Data extracted were analyzed using Stata 15 and Review Manager 5.3. The study protocol was registered prospectively at INPLASY, ID: INPLASY2021120029.

Results

A total of 12 studies were eligible for inclusion. After exclusion of one study with reduced robustness, 11 studies were included, with a total of 443 patients and 333 matched controls. Two of the articles included cerebrospinal fluid and serum HMGB1 data, which were distinguished by “a” and “b,” respectively. The meta-analysis indicated that in comparison with the control group, the HMGB1 level was higher in epilepsy patients (SMD = 0.56, 95% CI = 0.27–0.85, P = 0.0002). Subgroup analysis of specimen types indicated that both serum HMGB1 and cerebrospinal fluid HMGB1 were higher in epilepsy patients than in the control group, with the increase in cerebrospinal fluid HMGB1 being more obvious. Subgroup analysis of disease types demonstrated that the serum HMGB1 level of epileptic seizure patients (including febrile and nonfebrile seizures) was significantly higher than that of matched controls. However, serum HMGB1 levels did not differ significantly between mild epilepsy patients and severe epilepsy patients. Patient age subgroup analysis showed higher HMGB1 in adolescents with epilepsy. Begg’s test did not indicate publication bias.

Conclusions

This is the first meta-analysis to summarize the association between HMGB1 level and epilepsy. The results of this meta-analysis indicate that epilepsy patients have elevated HMGB1. Large-scale studies with a high level of evidence are needed to reveal the exact relationship between HMGB1 level and epilepsy.

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References

  1. Fisher RS, Acevedo C, Arzimanoglou A et al (2014) ILAE official report: a practical clinical definition of epilepsy[J]. Epilepsia 55(4):475–482

    Article  PubMed  Google Scholar 

  2. Ngugi AK, Bottomley C, Kleinschmidt I et al (2010) Estimation of the burden of active and life-time epilepsy: a meta-analytic approach[J]. Epilepsia 51(5):883–890

    Article  PubMed  PubMed Central  Google Scholar 

  3. Thijs RD, Surges R, O’Brien TJ et al (2019) Epilepsy in adults[J]. Lancet 393(10172):689–701

    Article  PubMed  Google Scholar 

  4. Sanz P, Garcia-Gimeno MA (2020) Reactive glia inflammatory signaling pathways and epilepsy [J]. Int J Mol Sci 21(11):4096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rana A, Musto AE (2018) The role of inflammation in the development of epilepsy[J]. J Neuroinflammation 15(1):144

    Article  PubMed  PubMed Central  Google Scholar 

  6. Alyu F, Dikmen M (2017) Inflammatory aspects of epileptogenesis: contribution of molecular inflammatory mechanisms[J]. Acta Neuropsychiatr 29(1):1–16

    Article  PubMed  Google Scholar 

  7. Eyo UB, Murugan M, Wu LJ (2017) Microglia-neuron communication in epilepsy[J]. Glia 65(1):5–18

    Article  PubMed  Google Scholar 

  8. Mo M, Eyo UB, Xie M et al (2019) Microglial P2Y12 receptor regulates seizure-induced neurogenesis and immature neuronal projections[J]. J Neurosci 39(47):9453–9464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hemmer B, Kerschensteiner M, Korn T (2015) Role of the innate and adaptive immune responses in the course of multiple sclerosis[J]. Lancet Neurol 14(4):406–419

    Article  CAS  PubMed  Google Scholar 

  10. Corps KN, Roth TL, Mcgavern DB (2015) Inflammation and neuroprotection in traumatic brain injury[J]. JAMA Neurol 72(3):355–362

    Article  PubMed  PubMed Central  Google Scholar 

  11. Vezzani B, Carinci M, Patergnani S et al (2020) The dichotomous role of inflammation in the CNS: a mitochondrial point of view [J]. Biomolecules 10(10):1437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Vezzani A, Balosso S, Ravizza T (2019) Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy[J]. Nat Rev Neurol 15(8):459–472

    Article  CAS  PubMed  Google Scholar 

  13. Zhang Z, Liu Q, Liu M et al (2018) Upregulation of HMGB1-TLR4 inflammatory pathway in focal cortical dysplasia type II[J]. J Neuroinflammation 15(1):27

    Article  PubMed  PubMed Central  Google Scholar 

  14. Iori V, Maroso M, Rizzi M et al (2013) Receptor for advanced glycation endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures[J]. Neurobiol Dis 58:102–114

    Article  CAS  PubMed  Google Scholar 

  15. Maroso M, Balosso S, Ravizza T et al (2010) Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures[J]. Nat Med 16(4):413–419

    Article  CAS  PubMed  Google Scholar 

  16. Shi Y, Zhang L, Teng J et al (2018) HMGB1 mediates microglia activation via the TLR4/NF-kappaB pathway in coriaria lactone induced epilepsy[J]. Mol Med Rep 17(4):5125–5131

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Iori V, Frigerio F, Vezzani A (2016) Modulation of neuronal excitability by immune mediators in epilepsy[J]. Curr Opin Pharmacol 26:118–123

    Article  CAS  PubMed  Google Scholar 

  18. Zhao J, Zheng Y, Liu K et al (2020) HMGB1 is a therapeutic target and biomarker in diazepam-refractory status epilepticus with wide time window[J]. Neurotherapeutics 17(2):710–721

    Article  CAS  PubMed  Google Scholar 

  19. Ravizza T, Terrone G, Salamone A et al (2018) High mobility group box 1 is a novel pathogenic factor and a mechanistic biomarker for epilepsy[J]. Brain Behav Immun 72:14–21

    Article  CAS  PubMed  Google Scholar 

  20. Wykes RC, Heeroma JH, Mantoan L et al (2012) Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy[J]. Sci Transl Med 4(161):152r–161r

    Article  Google Scholar 

  21. Fu L, Liu K, Wake H et al (2017) Therapeutic effects of anti-HMGB1 monoclonal antibody on pilocarpine-induced status epilepticus in mice[J]. Sci Rep 7(1):1179

    Article  PubMed  PubMed Central  Google Scholar 

  22. Paudel YN, Shaikh MF, Chakraborti A et al (2018) HMGB1: a common biomarker and potential target for TBI, neuroinflammation, epilepsy, and cognitive dysfunction[J]. Front Neurosci 12:628

    Article  PubMed  PubMed Central  Google Scholar 

  23. Choi J, Min HJ, Shin J (2011) Increased levels of HMGB1 and pro-inflammatory cytokines in children with febrile seizures [J]. J Neuroinflammation 8:135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Asano T, Ichiki K, Koizumi S et al (2011) High mobility group box 1 in cerebrospinal fluid from several neurological diseases at early time points[J]. Int J Neurosci 121(8):480–484

    Article  PubMed  Google Scholar 

  25. Issac MSM, Girgis M, Haroun M et al (2015) Association of genetic polymorphism of pre-MicroRNA-146a rs2910164 and serum high-mobility group box 1 with febrile seizures in Egyptian children[J]. J Child Neurol 30(4):437–444

    Article  PubMed  Google Scholar 

  26. Mahmoud A, Alnabya SA, Debdeb M (2018) High-mobility group box 1 protein serum level in children with febrile seizures [J]. Menoufia Med J 31:1005–1010

    Google Scholar 

  27. Salih KS, Hamdan FB, Al-Mayah QS (2020) Diagnostic value of matrix metalloproteinase-2 and high mobility group box 1 in patients with refractory epilepsy [J]. Egyptian J Neurol Psychiatry Neurosurg 56:102

    Article  Google Scholar 

  28. Kamaşak T, Dilber B, Yaman SÖ et al (2020) HMGB-1, TLR4, IL-1R1, TNF-α, and IL-1β: novel epilepsy markers?[J]. Epileptic Disord 22(2):183–193

    Article  PubMed  Google Scholar 

  29. Kaya M A, Erin N, Bozkurt O et al (2021) Changes of HMGB-1 and sTLR4 levels in cerebrospinal fluid of patients with febrile seizures [J]. Epilepsy Res 169:106516

  30. Morichi S, Yamanaka G, Watanabe Y et al (2021) High mobility group box 1 and angiogenetic growth factor levels in children with central nerve system infections [J]. J Infect Chemother 27:840–844

    Article  CAS  PubMed  Google Scholar 

  31. Wang N, Liu H, Ma B et al (2021) CSF high-mobility group box 1 is associated with drug-resistance and symptomatic etiology in adult patients with epilepsy[J]. Epilepsy Res 177:106767

    Article  CAS  PubMed  Google Scholar 

  32. Walker LE, Sills GJ, Jorgensen A et al (2022) High-mobility group box 1 as a predictive biomarker for drug-resistant epilepsy: a proof-of-concept study[J]. Epilepsia 63(1):e1–e6

    Article  CAS  PubMed  Google Scholar 

  33. Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses[J]. Eur J Epidemiol 25(9):603–605

    Article  PubMed  Google Scholar 

  34. Kwan P, Brodie MJ (2000) Early identification of refractory epilepsy[J]. N Engl J Med 342(5):314–319

    Article  CAS  PubMed  Google Scholar 

  35. Pitkanen A, Loscher W, Vezzani A et al (2016) Advances in the development of biomarkers for epilepsy[J]. Lancet Neurol 15(8):843–856

    Article  CAS  PubMed  Google Scholar 

  36. Vezzani A, Balosso S, Ravizza T (2008) The role of cytokines in the pathophysiology of epilepsy[J]. Brain Behav Immun 22(6):797–803

    Article  CAS  PubMed  Google Scholar 

  37. Ravizza T, Gagliardi B, Noe F et al (2008) Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy[J]. Neurobiol Dis 29(1):142–160

    Article  CAS  PubMed  Google Scholar 

  38. Zhen C, Wang Y, Li D et al (2019) Relationship of high-mobility group box 1 levels and multiple sclerosis: a systematic review and meta-analysis[J]. Mult Scler Relat Disord 31:87–92

    Article  PubMed  Google Scholar 

  39. Le K, Mo S, Lu X et al (2018) Association of circulating blood HMGB1 levels with ischemic stroke: a systematic review and meta-analysis[J]. Neurol Res 40(11):907–916

    Article  CAS  PubMed  Google Scholar 

  40. Xia Q, Tao P, Xu J (2021) Association of polymorphism rs1045411 in the HMGB1 gene with cancer risk: evidence from a meta-analysis[J]. Int J Med Sci 18(6):1348–1355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Walker LE, Griffiths MJ, Mcgill F et al (2017) A comparison of HMGB1 concentrations between cerebrospinal fluid and blood in patients with neurological disease[J]. Biomarkers 22(7):635–642

    CAS  PubMed  Google Scholar 

  42. Berger RP, Beers SR, Papa L et al (2012) Common data elements for pediatric traumatic brain injury: recommendations from the biospecimens and biomarkers workgroup[J]. J Neurotrauma 29(4):672–677

    Article  PubMed  PubMed Central  Google Scholar 

  43. Pedersen BK, Steensberg A, Fischer C et al (2001) Exercise and cytokines with particular focus on muscle-derived IL-6[J]. Exerc Immunol Rev 7:18–31

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Laboratory, General Hospital of the Yangtze River Shipping, Wuhan, 430005, China

    Yue Chen, Xilu Chen & Ying Liang

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  1. Yue Chen
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  2. Xilu Chen
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Correspondence to Yue Chen.

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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The authors declare that all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

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Highlights

• This is the first meta-analysis to investigate the association between HMGB1 level and epilepsy.

• HMGB1 levels are elevated in epileptic patients, particularly children.

• HMGB1 has the potential to serve as a biomarker for epilepsy.

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Chen, Y., Chen, X. & Liang, Y. Meta-analysis of HMGB1 levels in the cerebrospinal fluid and serum of patients with epilepsy. Neurol Sci 44, 2329–2337 (2023). https://doi.org/10.1007/s10072-023-06720-0

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  • DOI: https://doi.org/10.1007/s10072-023-06720-0

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