Neonatal seizures are associated with adverse neurologic sequelae including epilepsy in childhood. Here we aim to determine whether levels of cytokines in neonates with brain injury are associated with acute symptomatic seizures or remote epilepsy.
This is a cohort study of term newborns with encephalopathy at UCSF between 10/1993 and 1/2000 who had dried blood spots. Maternal, perinatal/postnatal, neuroimaging, and epilepsy variables were abstracted by chart review. Logistic regression was used to compare levels of cytokines with acute seizures and the development of epilepsy.
In a cohort of 26 newborns with neonatal encephalopathy at risk for hypoxic ischemic encephalopathy with blood spots for analysis, diffuse alterations in both pro- and anti-inflammatory cytokine levels were observed between those with (11/28, 39%) and without acute symptomatic seizures. Seventeen of the 26 (63%) patients had >2 years of follow-up and 4/17 (24%) developed epilepsy. Higher levels of pro-inflammatory cytokines IL-6 and TNF-α within the IL-1β pathway were significantly associated with epilepsy.
Elevations in pro-inflammatory cytokines in the IL-1β pathway were associated with later onset of epilepsy. Larger cohort studies are needed to confirm the predictive value of these circulating biomarkers.
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Ronen, G. M., Penney, S. & Andrews, W. The epidemiology of clinical neonatal seizures in Newfoundland: a population-based study. J. Pediatr. 134, 71–75 (1999).
Lanska, M. J., Lanska, D. J., Baumann, R. J. & Kryscio, R. J. A population-based study of neonatal seizures in Fayette County, Kentucky. Neurology 45, 724–732 (1995).
Fox, C. K., Glass, H. C., Sidney, S., Smith, S. E. & Fullerton, H. J. Neonatal seizures triple the risk of a remote seizure after perinatal ischemic stroke. Neurology 86, 2179–2186 (2016).
Glass, H. C. et al. Risk factors for epilepsy in children with neonatal encephalopathy. Pediatr. Res. 70, 535–540 (2011).
Glass, H. C., Numis, A. L., Gano, D., Bali, V. & Rogers, E. E. Outcomes after acute symptomatic seizures in children admitted to a neonatal neurocritical care service. Pediatr. Neurol. 84, 39–45 (2018).
Sillanpaa, M., Camfield, P. & Camfield, C. Predicting long-term outcome of childhood epilepsy in Nova Scotia, Canada, and Turku, Finland. Validation of a simple scoring system. Arch. Neurol. 52, 589–592 (1995).
Ronen, G. M., Buckley, D., Penney, S. & Streiner, D. L. Long-term prognosis in children with neonatal seizures: a population-based study. Neurology 69, 1816–1822 (2007).
Vezzani, A., Friedman, A. & Dingledine, R. J. The role of inflammation in epileptogenesis. Neuropharmacology 69, 16–24 (2013).
De Simoni, M. G. et al. Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus. Eur. J. Neurosci. 12, 2623–2633 (2000).
Rooker, S. et al. Spatiotemporal pattern of neuroinflammation after impact-acceleration closed head injury in the rat. Mediat. Inflamm. 2006, 90123 (2006).
Wang, S., Cheng, Q., Malik, S. & Yang, J. Interleukin-1beta inhibits gamma-aminobutyric acid type A (GABA(A)) receptor current in cultured hippocampal neurons. J. Pharm. Exp. Ther. 292, 497–504 (2000).
Lai, A. Y., Swayze, R. D., El-Husseini, A. & Song, C. Interleukin-1 beta modulates AMPA receptor expression and phosphorylation in hippocampal neurons. J. Neuroimmunol. 175, 97–106 (2006).
Roseti, C. et al. GABAA currents are decreased by IL-1beta in epileptogenic tissue of patients with temporal lobe epilepsy: implications for ictogenesis. Neurobiol. Dis. 82, 311–320 (2015).
Pugazhenthi, S., Zhang, Y., Bouchard, R. & Mahaffey, G. Induction of an inflammatory loop by interleukin-1beta and tumor necrosis factor-alpha involves NF-kB and STAT-1 in differentiated human neuroprogenitor cells. PLoS ONE 8, e69585 (2013).
Ross, F. M., Allan, S. M., Rothwell, N. J. & Verkhratsky, A. A dual role for interleukin-1 in LTP in mouse hippocampal slices. J. Neuroimmunol. 144, 61–67 (2003).
del Rey, A., Balschun, D., Wetzel, W., Randolf, A. & Besedovsky, H. O. A cytokine network involving brain-borne IL-1beta, IL-1ra, IL-18, IL-6, and TNFalpha operates during long-term potentiation and learning. Brain Behav. Immun. 33, 15–23 (2013).
Yin, P. et al. Neonatal immune challenge exacerbates seizure-induced hippocampus-dependent memory impairment in adult rats. Epilepsy Behav. 27, 9–17 (2013).
Balosso, S. et al. A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1beta. Brain 131, 3256–3265 (2008).
Qin, L. J., Gu, Y. T., Zhang, H. & Xue, Y. X. Bradykinin-induced blood-tumor barrier opening is mediated by tumor necrosis factor-alpha. Neurosci. Lett. 450, 172–175 (2009).
Didier, N. et al. Secretion of interleukin-1beta by astrocytes mediates endothelin-1 and tumour necrosis factor-alpha effects on human brain microvascular endothelial cell permeability. J. Neurochem. 86, 246–254 (2003).
Bartha, A. I. et al. Neonatal encephalopathy: association of cytokines with MR spectroscopy and outcome. Pediatr. Res. 56, 960–966 (2004).
Foster-Barber, A. & Ferriero, D. M. Neonatal encephalopathy in the term infant: neuroimaging and inflammatory cytokines. Ment. Retard. Dev. Disabil. Res. Rev. 8, 20–24 (2002).
Bonifacio, S. L. et al. Perinatal events and early magnetic resonance imaging in therapeutic hypothermia. J. Pediatr. 158, 360–365 (2011).
Youn, Y. A. et al. Serial examination of serum IL-8, IL-10 and IL-1Ra levels is significant in neonatal seizures induced by hypoxic-ischaemic encephalopathy. Scand. J. Immunol. 76, 286–293 (2012).
O’Shea, T. M. et al. Elevated concentrations of inflammation-related proteins in postnatal blood predict severe developmental delay at 2 years of age in extremely preterm infants. J. Pediatr. 160, 395.e4–401.e4 (2012).
Phillips, T. M. & Krum, J. M. Recycling immunoaffinity chromatography for multiple analyte analysis in biological samples. J. Chromatogr. B Biomed. Sci. Appl. 715, 55–63 (1998).
Barkovich, A. J. et al. Prediction of neuromotor outcome in perinatal asphyxia: evaluation of MR scoring systems. AJNR Am. J. Neuroradiol. 19, 143–149 (1998).
Hajnal, B. L., Sahebkar-Moghaddam, F., Barnwell, A. J., Barkovich, A. J. & Ferriero, D. M. Early prediction of neurologic outcome after perinatal depression. Pediatr. Neurol. 21, 788–793 (1999).
Leviton, A. et al. Systemic inflammation, intraventricular hemorrhage, and white matter injury. J. Child Neurol. 28, 1637–1645 (2013).
Diamond, M. L. et al. IL-1beta associations with posttraumatic epilepsy development: a genetics and biomarker cohort study. Epilepsia 55, 1109–1119 (2014).
Gallentine, W. B. et al. Plasma cytokines associated with febrile status epilepticus in children: a potential biomarker for acute hippocampal injury. Epilepsia 58, 1102–1111 (2017).
Vezzani, A., Aronica, E., Mazarati, A. & Pittman, Q. J. Epilepsy and brain inflammation. Exp. Neurol. 244, 11–21 (2013).
Chiavegato, A., Zurolo, E., Losi, G., Aronica, E. & Carmignoto, G. The inflammatory molecules IL-1beta and HMGB1 can rapidly enhance focal seizure generation in a brain slice model of temporal lobe epilepsy. Front. Cell. Neurosci. 8, 155 (2014).
Tao, A. F. et al. The pro-inflammatory cytokine interleukin-1beta is a key regulatory factor for the postictal suppression in mice. CNS Neurosci. Ther. 21, 642–650 (2015).
Ding, X. et al. IL-9 signaling affects central nervous system resident cells during inflammatory stimuli. Exp. Mol. Pathol. 99, 570–574 (2015).
Orbach, S. A., Bonifacio, S. L., Kuzniewicz, M. W. & Glass, H. C. Lower incidence of seizure among neonates treated with therapeutic hypothermia. J. Child Neurol. 29, 1502–1507 (2014).
Pisani, F., Facini, C., Pavlidis, E., Spagnoli, C. & Boylan, G. Epilepsy after neonatal seizures: literature review. Eur. J. Paediatr. Neurol. 19, 6–14 (2015).
Skogstrand, K. et al. Effects of blood sample handling procedures on measurable inflammatory markers in plasma, serum and dried blood spot samples. J. Immunol. Methods 336, 78–84 (2008).
Schiffer, J. M. et al. Quantitative assessment of anthrax vaccine immunogenicity using the dried blood spot matrix. Biologicals 41, 98–103 (2013).
Feldmeyer, L., Werner, S., French, L. E. & Beer, H. D. Interleukin-1, inflammasomes and the skin. Eur. J. Cell Biol. 89, 638–644 (2010).
The authors thank Dr. Agnes Bartha for providing the groundwork for this dataset This work was supported by the National Institutes of Health Grants RR 01271, NS 35902, NS 40117, L40 NS094060, and the American Academy of Neurology Clinical Research Training Fellowship in Epilepsy.
The authors declare no competing interests.
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