An overview of risk factors in children with febrile seizures


Imane Abbari
Widad Gueddari
Ahmed Aziz Bousfiha


Introduction: Febrile seizures (FS) are the most common neurologic disorder seen in children. Caused mainly by fever without any damage to the central nervous system (CNS). The associations of several factors, which we can find in the inflammatory response and genetic predisposition, are involved in the occurrence of FS.

Aim: This review provides insight into risk factors, particularly the involvement of the inflammatory response and genetic susceptibility in the occurrence of FS.

Methods: A PubMed search was performed using the keywords « febrile seizures », « inflammatory response », « Pro-inflammatory cytokines », «And anti-inflammatory cytokines ». The search strategy included meta-analyses, prospective case-control studies, clinical trials, observational studies, and reviews.

Results: Febrile seizures with a peak incidence of 18 months usually occur between 6 months and 5 years. A variety of genetic, inflammatory, and environmental factors, including viruses and vaccines, trigger FS. A positive family history of febrile seizures increases the risk for FS occurrence with (20%) in siblings and (33%) in one parent. The involvement of inflammatory response genes, including the cytokine genes IL1B, IL1R, IL6, and IL4. According to these findings, FS is associated with the activation of a cascade of pro- and anti-inflammatory cytokines and the unbalance between these cytokines in the inflammation regulation plays a role in the development of FS.

Conclusion: Current knowledge suggests that genetic susceptibility and inflammatory response dysregulation contribute to FS's genesis.


Febrile seizures , inflammatory response, Cytokines, Genetics



  1. Leung AK, Hon KL, Leung TN. Febrile seizures: an overview. Drugs Context. 2018 Jul 16; 7:212536.
  2. Freeman, John M. Febrile seizures: a consensus of their significance, evaluation, and treatment. National Institute of Health. Pediatrics1980; 66:1009–12.
  3. Guidelines for epidemiologic studies on epilepsy. Commission on Epidemiology and Prognosis, International League Against Epilepsy. Epilepsia. 1993; 34:592–596.
  4. Steering Committee on Quality Improvement and Management. Febrile seizures: clinical practice guideline for the long-term management of the child with simple febrile seizures. Pediatrics. 2008; 121:1281–1286.
  5. Waruiru, C., and R. Appleton. "Febrile seizures: an update." Archives of Disease in Childhood 2004; 751-756.
  6. Forsgren L, Sidenvall R, Blomquist HK, Heijbel J. A prospective incidence study of febrile convulsions. Acta Paediatr Scand. 1990; 79:550–557.
  7. Sawires R, Buttery J, Fahey M. A Review of Febrile Seizures: Recent Advances in Understanding of Febrile Seizure Pathophysiology and Commonly Implicated Viral Triggers. Front Pediatr. 2022 Jan 13; 9:801321.
  8. Tsuboi, Takayuki, and Shigeko Okada. Seasonal variation of febrile convulsion in Japan. Acta Neurol Scand. 1984; 69:285–292.
  9. Mikkonen, Kirsi, Matti Uhari, Tytti Pokka, and Heikki Rantala. Diurnal and seasonal occurrence of febrile seizures. Pediatr Neurol. 2015 Apr; 52(4):424-7.
  10. Manfredini R, Vergine G, Boari B, Faggioli R, Borgna-Pignatti C. Circadian and seasonal variation of first febrile seizures. J Pediatr. 2004 Dec; 145(6):838-9.
  11. Van Zeijl JH, Mullaart RA, Borm GF, Galama JM. Recurrence of febrile seizures in the respiratory season is associated with influenza A. J Pediatr. 2004 Dec;145(6):800-5.
  12. Carman KB, Calik M, Karal Y, Isikay S, Kocak O, Ozcelik A, Yazar AS, Nuhoglu C, Sag C, Kilic O, Dinleyici M, Lacinel Gurlevik S, Yimenicioglu S, Ekici A, Perk P, Tosun A, Isik I, Yarar C, Arslantas D, Dinleyici EC. Viral etiological causes of febrile seizures for respiratory pathogens (EFES Study). Hum Vaccin Immunother. 2019;15(2):496-502
  13. Francis JR, Richmond P, Robins C, Lindsay K, Levy A, Effler PV, Borland M, Blyth CC. An observational study of febrile seizures: the importance of viral infection and immunization. BMC Pediatr. 2016 Dec 3;16(1):202
  14. Sawires R, Buttery J, Fahey M. A Review of Febrile Seizures: Recent Advances in Understanding of Febrile Seizure Pathophysiology and Commonly Implicated Viral Triggers. Front Pediatr. 2022 Jan 13;9:801321.
  15. Kamoun Feki F, Fendri Kriaa N, Kolsi D, Rabai A, Fakhfakh F, Charfi Triki C. Clinical and genetic aspect of 30 Tunisian families with febrile seizures. Tunis Med. 2019 Apr;97(4):525-532.
  16. Mosili P, Maikoo S, Mabandla MV, Qulu L. The Pathogenesis of Fever-Induced Febrile Seizures and Its Current State. Neurosci Insights. 2020 Nov 2; 15:2633105520956973.
  17. Zare-shahabadi A, Soltani S, Ashrafi MR, et al. Association of IL4 Single-Nucleotide Polymorphisms With Febrile Seizures. Journal of Child Neurology. 2015;30(4):423-428.
  18. Chen Q, Li M, Zhang X, Zhang X, Zhong R, Lin W. Association between interleukin-6 gene polymorphisms and febrile seizure risk: A meta-analysis. Medicine (Baltimore). 2019 Sep;98(39):e17167.
  19. Al Morshedy S, Elsaadany HF, Ibrahim HE, Sherif AM, Farghaly MAA, Allah MAN, Abouzeid H, Elashkar SSA, Hamed ME, Fathy MM, Khalil AM, Noah MA, Hegab MS, Ahmed AR, Hashem MIA, Emam AA, Anany HG, Ibrahim BR, Gawish HH, Nabil RM, Fattah LA, Alsayed SF. Interleukin-1β and interleukin-1 receptor antagonist polymorphisms in Egyptian children with febrile seizures: A case-control study. Medicine (Baltimore). 2017 Mar;96(11):e6370.
  20. Mewasingh, Leena D, Chin, Richard FM, Scott, Rod C. Current understanding of febrile seizures and their outcomes. Developmental Medicine & Child Neurology, (2020) dmcn.14642–.
  21. Auvin S, Vallée L. Connaissances actuelles sur les mécanismes physiopathologiques des convulsions fébriles. 2009 ;16(5), 0–456.
  22. Youn Y, Sung IK, Lee IG. The role of cytokines in seizures: interleukin (IL)-1β, IL-1Ra, IL-8, and IL-10. Korean J Pediatr. 2013 Jul;56(7):271-4. Epub 2013 Jul 19.
  23. Hashimoto, Risa; Suto, Maiko; Tsuji, Mariko; Sasaki, Hatoko; Takehara, Kenji; Ishiguro, Akira; Kubota, Masaya. Use of antipyretics for preventing febrile seizure recurrence in children: a systematic review and meta-analysis. European Journal of Pediatrics, (2020).
  24. Camfield PR, Camfield CS, Shapiro SH, et al. The first febrile seizure antipyretic instruction plus either phenobarbital or placebo to prevent a recurrence. J Pediatr1980; 97:16–
  25. Elwood E, Lim Z, Naveed H, Galea I. The effect of systemic inflammation on human brain barrier function. Brain Behav Immun. 2017 May;62:35-40.
  26. Candelario-Jalil, E.; Taheri, S.; Yang, Y.; Sood, R.; Grossetete, M.; Estrada, E. Y.; Fiebich, B. L.; Rosenberg, G. A. (2007). Cyclooxygenase Inhibition Limits Blood-Brain Barrier Disruption Following Intracerebral Injection of Tumor Necrosis Factor- in the Rat. Journal of Pharmacology and Experimental Therapeutics. (2007), 323(2), 488–498.
  27. Dubé C, Vezzani A, Behrens M, Bartfai T, Baram TZ. Interleukin-1β contributes to the generation of experimental febrile seizures. Ann Neurol. 2005;57:152-155.
  28. Galic MA, Riazi K, Pittman QJ. Cytokines and brain excitability. Front Neuroendocrinol. 2012;33:116-125.
  29. HAida JG, Pittman QJ. Causal links between brain cytokines and experimental febrile convulsions in the rat. Epilepsia. 2005;46:1906-1913.
  30. Annamaria Vezzani; Silvia Balosso; Teresa Ravizza (2008). The role of cytokines in the pathophysiology of epilepsy. (2008) , 22(6), 0–803.
  31. Barker-Haliski M, White HS. Glutamatergic mechanisms associated with seizures and epilepsy. Cold Spring Harb Perspect Med. 2015;5:a022863.
  32. Schäfers M, Sorkin L. Effect of cytokines on neuronal excitability. Neurosci Lett. 2008;437:188-193.
  33. Waruiru C, Appleton R. Febrile seizures: an update. Arch Dis Child. 2004; 89:751-756.
  34. Chung S. Febrile seizures. Korean J Pediatr. 2014 Sep;57(9):384-95.
  35. Saghazadeh, Amene; Gharedaghi, Maryam; Meysamie, Alipasha; Bauer, Sebastian; Rezaei, Nima . Proinflammatory and anti-inflammatory cytokines in febrile seizures and epilepsy: systematic review and meta-analysis. Reviews in the Neurosciences, (2014), 25(2).
  36. Vezzani A, Moneta D, Conti M, Richichi C, Ravizza T, De Luigi A, De Simoni MG, Sperk G, Andell-Jonsson S, Lundkvist J, Iverfeldt K, Bartfai T. Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proc Natl Acad Sci U S A. 2000 Oct 10; 97(21):11534-9.
  37. Choi J, Min HJ, Shin JS. Increased levels of HMGB1 and pro-inflammatory cytokines in children with febrile seizures. J Neuroinflammation. 2011 Oct 11;8:135.
  38. Virta, M., Hurme, M., & Helminen, M. Increased Plasma Levels of Pro- and Anti-inflammatory Cytokines in Patients with Febrile Seizures. Epilepsia 2002; 43(8), 920–923.
  39. Heida, J. G., Moshé, S. L., & Pittman, Q. J. The role of interleukin-1β in febrile seizures. Brain and Development 2009; 31(5), 388–393.
  40. Hu MH, Huang GS, Wu CT, Lin JJ, Hsia SH, Wang HS, Lin KL; CHEESE Study Group. Analysis of plasma multiplex cytokines for children with febrile seizures and severe acute encephalitis. J Child Neurol. 2014 Feb;29(2):182-6.
  41. Talebian A, Hassani F, Nikoueinejad H, Akbari H. Investigating the Relationship between Serum Levels of Interleukin-22 and Interleukin-1 Beta with Febrile Seizure. Iran J Allergy Asthma Immunol. 2020 Aug 25;19(4):409-415.
  42. Lehtimäki KA, Keränen T, Palmio J, Peltola J. Levels of IL-1beta and IL-1ra in cerebrospinal fluid of human patients after single and prolonged seizures. Neuroimmunomodulation. 2010;17(1):19-22.
  43. Mahyar A, Ayazi P, Orangpour R, Daneshi-Kohan MM, Sarokhani MR, Javadi A, Habibi M, Talebi-Bakhshayesh M. Serum interleukin-1beta and tumor necrosis factor-alpha in febrile seizures: is there a link? Korean J Pediatr. 2014 Oct;57(10):440-4.
  44. Behmanesh F, Ashrafzadeh F, Varasteh A, Shakeri A, Shahsavand S. Evaluation of interleukin 1β in febrile convulsion. Iran J Allergy Asthma Immunol. 2012 Dec;11(4):336-9. PMID: 23264411.
  45. Kim K, Kwak BO, Kwon A, Ha J, Kim SJ, Bae SW, Son JS, Kim SN, Lee R. Analysis of plasma multiplex cytokines and increased level of IL-10 and IL-1Ra cytokines in febrile seizures. J Neuroinflammation. 2017 Oct 10;14(1):200.
  46. Şahin S, Uysal S, Yentür SP, Kaçar A. Reduced cerebrospinal fluid levels of interleukin-10 in children with febrile seizures. Seizure. 2019 Feb;65:94-97.
  47. Ha J, Choi J, Kwon A, Kim K, Kim SJ, Bae SH, Son JS, Kim SN, Kwak BO, Lee R. Interleukin-4 and tumor necrosis factor-alpha levels in children with febrile seizures. Seizure. 2018 May;58:156-162.
  48. Gupta S, Aggarwal A, Faridi MM, Rai G, Das S, Kotru M. Serum Interleukin-6 Levels in Children with Febrile Seizures. Indian Pediatr. 2018 May 15;55(5):411-413. Epub 2018 Feb 9. PMID: 29428914.
  49. Gallentine WB, Shinnar S, Hesdorffer DC, Epstein L, Nordli DR Jr, Lewis DV, Frank LM, Seinfeld S, Shinnar RC, Cornett K, Liu B, Moshé SL, Sun S; FEBSTAT Investigator Team. Plasma cytokines associated with febrile status epilepticus in children: A potential biomarker for acute hippocampal injury. Epilepsia. 2017 Jun;58(6):1102-1111.