William B Gallentine1, Shlomo Shinnar2, Dale C Hesdorffer3, Leon Epstein4, Douglas R Nordli5, Darrell V Lewis1, L Matthew Frank6, Syndi Seinfeld7, Ruth C Shinnar2, Karen Cornett1, Binyi Liu3, Solomon L Moshé2, Shumei Sun8. 1. Department of Pediatrics (Neurology), Duke Children's Hospital, Durham, North Carolina, U.S.A. 2. Departments of Neurology and Pediatrics, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, U.S.A. 3. Department of Epidemiology and GH Sergievsky Center, Columbia University, New York, New York, U.S.A. 4. Department of Neurology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, U.S.A. 5. Department of Pediatrics (Neurology), Children's Hospital Los Angeles, Los Angeles, California, U.S.A. 6. Department of Neurology, Children's Hospital of The King's Daughters and Eastern Virginia Medical School, Norfolk, Virginia, U.S.A. 7. Department of Neurology, Virginia Commonwealth University, Richmond, Virginia, U.S.A. 8. Department of Biostatistics and International Epilepsy Consortium, Virginia Commonwealth University, Richmond, Virginia, U.S.A.
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). Wiley Periodicals, Inc.
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). Wiley Periodicals, Inc.
Authors: Dale C Hesdorffer; Shlomo Shinnar; Darrell V Lewis; Solomon L Moshé; Douglas R Nordli; John M Pellock; James MacFall; Ruth C Shinnar; David Masur; L Matthew Frank; Leon G Epstein; Claire Litherland; Syndi Seinfeld; Jacqueline A Bello; Stephen Chan; Emilia Bagiella; Shumei Sun Journal: Epilepsia Date: 2012-06-28 Impact factor: 5.864
Authors: J A French; P D Williamson; V M Thadani; T M Darcey; R H Mattson; S S Spencer; D D Spencer Journal: Ann Neurol Date: 1993-12 Impact factor: 10.422
Authors: Barbara C Jobst; Elinor Ben-Menachem; Kevin E Chapman; Aradia Fu; Alica Goldman; Lawrence J Hirsch; Lara E Jehi; Eric H Kossoff; Madona Plueger; Jong M Rho; Catherine A Schevon; Shlomo Shinnar; Michael R Sperling; Timothy A Simeone; Janelle L Wagner; Fred Lado Journal: Epilepsy Curr Date: 2019-05-03 Impact factor: 7.500
Authors: Kevin D Chen; Alicia M Hall; Megan M Garcia-Curran; Gissell A Sanchez; Jennifer Daglian; Renhao Luo; Tallie Z Baram Journal: Epilepsia Date: 2021-01-21 Impact factor: 5.864
Authors: Luca Bartolini; Eleonora Piras; Kathryn Sullivan; Sean Gillen; Adrian Bumbut; Cheng-Te Major Lin; Emily C Leibovitch; Jennifer S Graves; Emmanuelle L Waubant; James M Chamberlain; William D Gaillard; Steven Jacobson Journal: Front Neurol Date: 2018-10-05 Impact factor: 4.003