Plasma cytokines associated with febrile status epilepticus in children: A potential biomarker for acute hippocampal injury

FEBSTAT Investigator Team

doi:10.1111/epi.13750

Plasma cytokines associated with febrile status epilepticus in children: A potential biomarker for acute hippocampal injury

FEBSTAT Investigator Team

Research output: Contribution to journal › Article › peer-review

68 Scopus citations

Abstract

Objective: Our aim was to explore the association between plasma cytokines and febrile status epilepticus (FSE) in children, as well as their potential as biomarkers of acute hippocampal injury. Methods: Analysis was performed on residual samples of children with FSE (n = 33) as part of the Consequences of Prolonged Febrile Seizures in Childhood study (FEBSTAT) and compared to children with fever (n = 17). Magnetic resonance imaging (MRI) was obtained as part of FEBSTAT within 72 h of FSE. Cytokine levels and ratios of antiinflammatory versus proinflammatory cytokines in children with and without hippocampal T2 hyperintensity were assessed as biomarkers of acute hippocampal injury after FSE. Results: Levels of interleukin (IL)-8 and epidermal growth factor (EGF) were significantly elevated after FSE in comparison to controls. IL-1β levels trended higher and IL-1RA trended lower following FSE, but did not reach statistical significance. Children with FSE were found to have significantly lower ratios of IL-1RA/IL-1β and IL-1RA/IL-8. Specific levels of any one individual cytokine were not associated with FSE. However, lower ratios of IL-1RA/IL-1β, IL-1RA/1L-6, and IL-1RA/ IL-8 were all associated with FSE. IL-6 and IL-8 levels were significantly higher and ratios of IL-1RA/IL-6 and IL-1RA/IL-8 were significantly lower in children with T2 hippocampal hyperintensity on MRI after FSE in comparison to those without hippocampal signal abnormalities. Neither individual cytokine levels nor ratios of IL-1RA/IL-1β or IL-1RA/IL-8 were predictive of MRI changes. However, a lower ratio of IL-1RA/IL-6 was strongly predictive (odds ratio [OR] 21.5, 95% confidence interval [CI] 1.17–393) of hippocampal T2 hyperintensity after FSE. Significance: Our data support involvement of the IL-1 cytokine system, IL-6, and IL-8 in FSE in children. The identification of the IL-1RA/IL-6 ratio as a potential biomarker of acute hippocampal injury following FSE is the most significant finding. If replicated in another study, the IL-1RA/IL-6 ratio could represent a serologic biomarker that offers rapid identification of patients at risk for ultimately developing mesial temporal lobe epilepsy (MTLE).

Original language	English (US)
Pages (from-to)	1102-1111
Number of pages	10
Journal	Epilepsia
Volume	58
Issue number	6
DOIs	https://doi.org/10.1111/epi.13750
State	Published - Jun 1 2017

Keywords

Cytokine
Febrile status epilepticus
Hippocampal injury
Interleukin
Mesial temporal lobe epilepsy

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1111/epi.13750

Cite this

@article{3566b51ea33e4a7db3b6e3727e1e254c,

title = "Plasma cytokines associated with febrile status epilepticus in children: A potential biomarker for acute hippocampal injury",

abstract = "Objective: Our aim was to explore the association between plasma cytokines and febrile status epilepticus (FSE) in children, as well as their potential as biomarkers of acute hippocampal injury. Methods: Analysis was performed on residual samples of children with FSE (n = 33) as part of the Consequences of Prolonged Febrile Seizures in Childhood study (FEBSTAT) and compared to children with fever (n = 17). Magnetic resonance imaging (MRI) was obtained as part of FEBSTAT within 72 h of FSE. Cytokine levels and ratios of antiinflammatory versus proinflammatory cytokines in children with and without hippocampal T2 hyperintensity were assessed as biomarkers of acute hippocampal injury after FSE. Results: Levels of interleukin (IL)-8 and epidermal growth factor (EGF) were significantly elevated after FSE in comparison to controls. IL-1β levels trended higher and IL-1RA trended lower following FSE, but did not reach statistical significance. Children with FSE were found to have significantly lower ratios of IL-1RA/IL-1β and IL-1RA/IL-8. Specific levels of any one individual cytokine were not associated with FSE. However, lower ratios of IL-1RA/IL-1β, IL-1RA/1L-6, and IL-1RA/ IL-8 were all associated with FSE. IL-6 and IL-8 levels were significantly higher and ratios of IL-1RA/IL-6 and IL-1RA/IL-8 were significantly lower in children with T2 hippocampal hyperintensity on MRI after FSE in comparison to those without hippocampal signal abnormalities. Neither individual cytokine levels nor ratios of IL-1RA/IL-1β or IL-1RA/IL-8 were predictive of MRI changes. However, a lower ratio of IL-1RA/IL-6 was strongly predictive (odds ratio [OR] 21.5, 95% confidence interval [CI] 1.17–393) of hippocampal T2 hyperintensity after FSE. Significance: Our data support involvement of the IL-1 cytokine system, IL-6, and IL-8 in FSE in children. The identification of the IL-1RA/IL-6 ratio as a potential biomarker of acute hippocampal injury following FSE is the most significant finding. If replicated in another study, the IL-1RA/IL-6 ratio could represent a serologic biomarker that offers rapid identification of patients at risk for ultimately developing mesial temporal lobe epilepsy (MTLE).",

keywords = "Cytokine, Febrile status epilepticus, Hippocampal injury, Interleukin, Mesial temporal lobe epilepsy",

author = "{FEBSTAT Investigator Team} and Gallentine, {William B.} and Shlomo Shinnar and Hesdorffer, {Dale C.} and Leon Epstein and Nordli, {Douglas R.} and Lewis, {Darrell V.} and Frank, {L. Matthew} and Syndi Seinfeld and Shinnar, {Ruth C.} and Karen Cornett and Binyi Liu and Mosh{\'e}, {Solomon L.} and Shumei Sun and Jacqueline Bello and William Gomes and James Hannigan and Sharyn Katz and Ann Mancini and David Masur and Erica Weiss and Stephen Chan and Melanie Bonner and James MacFall and James Provenzale and Allen Song and James Voyvodic and Yuan Xu and Joanne Andy and Terrie Conklin and Susan Grasso and Powers, {Connie S.} and David Kushner and Susan Landers and {Van de Water}, Virginia and Bush, {Brian J.} and Davis, {Lori L.} and Xiaoyan Deng and Christiane Rogers and Sabo, {Cynthia Shier} and John Curran and Andrew Kim and Julie Rinaldi and Emilia Bagiella and Tanya Brazemore and James Culbert and Kathryn O{\textquoteright}Hara and Jean Snow",

note = "Publisher Copyright: Wiley Periodicals, Inc. {\textcopyright} 2017 International League Against Epilepsy",

year = "2017",

month = jun,

day = "1",

doi = "10.1111/epi.13750",

language = "English (US)",

volume = "58",

pages = "1102--1111",

journal = "Epilepsia",

issn = "0013-9580",

publisher = "Wiley-Blackwell",

number = "6",

}

TY - JOUR

T1 - Plasma cytokines associated with febrile status epilepticus in children

T2 - A potential biomarker for acute hippocampal injury

AU - FEBSTAT Investigator Team

AU - Gallentine, William B.

AU - Shinnar, Shlomo

AU - Hesdorffer, Dale C.

AU - Epstein, Leon

AU - Nordli, Douglas R.

AU - Lewis, Darrell V.

AU - Frank, L. Matthew

AU - Seinfeld, Syndi

AU - Shinnar, Ruth C.

AU - Cornett, Karen

AU - Liu, Binyi

AU - Moshé, Solomon L.

AU - Sun, Shumei

AU - Bello, Jacqueline

AU - Gomes, William

AU - Hannigan, James

AU - Katz, Sharyn

AU - Mancini, Ann

AU - Masur, David

AU - Weiss, Erica

AU - Chan, Stephen

AU - Bonner, Melanie

AU - MacFall, James

AU - Provenzale, James

AU - Song, Allen

AU - Voyvodic, James

AU - Xu, Yuan

AU - Andy, Joanne

AU - Conklin, Terrie

AU - Grasso, Susan

AU - Powers, Connie S.

AU - Kushner, David

AU - Landers, Susan

AU - Van de Water, Virginia

AU - Bush, Brian J.

AU - Davis, Lori L.

AU - Deng, Xiaoyan

AU - Rogers, Christiane

AU - Sabo, Cynthia Shier

AU - Curran, John

AU - Kim, Andrew

AU - Rinaldi, Julie

AU - Bagiella, Emilia

AU - Brazemore, Tanya

AU - Culbert, James

AU - O’Hara, Kathryn

AU - Snow, Jean

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Objective: Our aim was to explore the association between plasma cytokines and febrile status epilepticus (FSE) in children, as well as their potential as biomarkers of acute hippocampal injury. Methods: Analysis was performed on residual samples of children with FSE (n = 33) as part of the Consequences of Prolonged Febrile Seizures in Childhood study (FEBSTAT) and compared to children with fever (n = 17). Magnetic resonance imaging (MRI) was obtained as part of FEBSTAT within 72 h of FSE. Cytokine levels and ratios of antiinflammatory versus proinflammatory cytokines in children with and without hippocampal T2 hyperintensity were assessed as biomarkers of acute hippocampal injury after FSE. Results: Levels of interleukin (IL)-8 and epidermal growth factor (EGF) were significantly elevated after FSE in comparison to controls. IL-1β levels trended higher and IL-1RA trended lower following FSE, but did not reach statistical significance. Children with FSE were found to have significantly lower ratios of IL-1RA/IL-1β and IL-1RA/IL-8. Specific levels of any one individual cytokine were not associated with FSE. However, lower ratios of IL-1RA/IL-1β, IL-1RA/1L-6, and IL-1RA/ IL-8 were all associated with FSE. IL-6 and IL-8 levels were significantly higher and ratios of IL-1RA/IL-6 and IL-1RA/IL-8 were significantly lower in children with T2 hippocampal hyperintensity on MRI after FSE in comparison to those without hippocampal signal abnormalities. Neither individual cytokine levels nor ratios of IL-1RA/IL-1β or IL-1RA/IL-8 were predictive of MRI changes. However, a lower ratio of IL-1RA/IL-6 was strongly predictive (odds ratio [OR] 21.5, 95% confidence interval [CI] 1.17–393) of hippocampal T2 hyperintensity after FSE. Significance: Our data support involvement of the IL-1 cytokine system, IL-6, and IL-8 in FSE in children. The identification of the IL-1RA/IL-6 ratio as a potential biomarker of acute hippocampal injury following FSE is the most significant finding. If replicated in another study, the IL-1RA/IL-6 ratio could represent a serologic biomarker that offers rapid identification of patients at risk for ultimately developing mesial temporal lobe epilepsy (MTLE).

AB - Objective: Our aim was to explore the association between plasma cytokines and febrile status epilepticus (FSE) in children, as well as their potential as biomarkers of acute hippocampal injury. Methods: Analysis was performed on residual samples of children with FSE (n = 33) as part of the Consequences of Prolonged Febrile Seizures in Childhood study (FEBSTAT) and compared to children with fever (n = 17). Magnetic resonance imaging (MRI) was obtained as part of FEBSTAT within 72 h of FSE. Cytokine levels and ratios of antiinflammatory versus proinflammatory cytokines in children with and without hippocampal T2 hyperintensity were assessed as biomarkers of acute hippocampal injury after FSE. Results: Levels of interleukin (IL)-8 and epidermal growth factor (EGF) were significantly elevated after FSE in comparison to controls. IL-1β levels trended higher and IL-1RA trended lower following FSE, but did not reach statistical significance. Children with FSE were found to have significantly lower ratios of IL-1RA/IL-1β and IL-1RA/IL-8. Specific levels of any one individual cytokine were not associated with FSE. However, lower ratios of IL-1RA/IL-1β, IL-1RA/1L-6, and IL-1RA/ IL-8 were all associated with FSE. IL-6 and IL-8 levels were significantly higher and ratios of IL-1RA/IL-6 and IL-1RA/IL-8 were significantly lower in children with T2 hippocampal hyperintensity on MRI after FSE in comparison to those without hippocampal signal abnormalities. Neither individual cytokine levels nor ratios of IL-1RA/IL-1β or IL-1RA/IL-8 were predictive of MRI changes. However, a lower ratio of IL-1RA/IL-6 was strongly predictive (odds ratio [OR] 21.5, 95% confidence interval [CI] 1.17–393) of hippocampal T2 hyperintensity after FSE. Significance: Our data support involvement of the IL-1 cytokine system, IL-6, and IL-8 in FSE in children. The identification of the IL-1RA/IL-6 ratio as a potential biomarker of acute hippocampal injury following FSE is the most significant finding. If replicated in another study, the IL-1RA/IL-6 ratio could represent a serologic biomarker that offers rapid identification of patients at risk for ultimately developing mesial temporal lobe epilepsy (MTLE).

KW - Cytokine

KW - Febrile status epilepticus

KW - Hippocampal injury

KW - Interleukin

KW - Mesial temporal lobe epilepsy

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U2 - 10.1111/epi.13750

DO - 10.1111/epi.13750

M3 - Article

C2 - 28448686

AN - SCOPUS:85018999417

SN - 0013-9580

VL - 58

SP - 1102

EP - 1111

JO - Epilepsia

JF - Epilepsia

IS - 6

ER -

Plasma cytokines associated with febrile status epilepticus in children: A potential biomarker for acute hippocampal injury

Abstract

Keywords

ASJC Scopus subject areas

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