Early changes in pro-inflammatory cytokine levels in neonates with encephalopathy are associated with remote epilepsy

Adam L Numis, Audrey Foster-Barber, Xutao Deng, Elizabeth E Rogers, A James Barkovich, Donna M Ferriero, Hannah C Glass, Adam L Numis, Audrey Foster-Barber, Xutao Deng, Elizabeth E Rogers, A James Barkovich, Donna M Ferriero, Hannah C Glass

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Conflict of interest statement

Disclosures statement: The authors declare no conflicts of interest.

Disclosures

Dr. Adam Numis: The author declares no conflicts of interest.

Dr. Xutao Deng: The author declares no conflicts of interest.

Dr. Audrey Foster-Barber: The author declares no conflicts of interest.

Dr. Elizabeth E Rogers: The author declares no conflicts of interest.

Dr. A James Barkovich: The author declares no conflicts of interest.

Dr. Donna M Ferriero: The author declares no conflicts of interest.

Dr. Hannah C Glass: The author declares no conflicts of interest.

Figures

Figure 1:
Figure 1:
Neonatal cytokine levels in children with acute symptomatic/early seizures (n=151) compared to those without seizures (n=11). Levels are plotted from 0–200 pg/mL, except for IL-12 and IL-13, which are plotted from 0–60 pg/mL. * p

Figure 2:

Neonatal cytokine levels in children…

Figure 2:

Neonatal cytokine levels in children with epilepsy (n=4) compared to those without epilepsy…

Figure 2:
Neonatal cytokine levels in children with epilepsy (n=4) compared to those without epilepsy (n=13). Levels are plotted from 0–200 pg/mL, except for IL-12 and IL-13, which are plotted from 0–60 pg/mL. * p

Figure 3:

Dendrogram and heatmap of neonatal…

Figure 3:

Dendrogram and heatmap of neonatal cytokines levels in 26 neonates with neonatal encephalopathy…

Figure 3:
Dendrogram and heatmap of neonatal cytokines levels in 26 neonates with neonatal encephalopathy using hierarchical agglomerative clustering. Children with epilepsy are denoted with “1” and children without epilepsy are denoted with “0”. Dark blue colors represent low cytokine values, white colors represent average values, and red represent high values.

Figure 4:

Correlations among cytokine levels in…

Figure 4:

Correlations among cytokine levels in 26 neonates with neonatal encephalopathy. Larger bubbles and…

Figure 4:
Correlations among cytokine levels in 26 neonates with neonatal encephalopathy. Larger bubbles and darker red coloring indicates a higher correlation coefficient whereas smaller bubbles and dark blue coloring indicate lower correlation coefficients.
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References
    1. Ronen GM, Penney S, Andrews W 1999. The epidemiology of clinical neonatal seizures in Newfoundland: a population-based study. J Pediatr 134:71–75. - PubMed
    1. Lanska MJ, Lanska DJ, Baumann RJ, Kryscio RJ 1995. A population-based study of neonatal seizures in Fayette County, Kentucky. Neurology 45:724–732. - PubMed
    1. Fox CK, Glass HC, Sidney S, Smith SE, Fullerton HJ 2016. Neonatal seizures triple the risk of a remote seizure after perinatal ischemic stroke. Neurology 86:2179–2186. - PMC - PubMed
    1. Glass HC, Hong KJ, Rogers EE, et al. 2011. Risk factors for epilepsy in children with neonatal encephalopathy. Pediatr Res 70:535–540. - PMC - PubMed
    1. Glass HC, Numis AL, Gano D, Bali V, Rogers EE 2018. Outcomes After Acute Symptomatic Seizures in Children Admitted to a Neonatal Neurocritical Care Service. Pediatr Neurol 84:39–45. - PubMed
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Figure 2:
Figure 2:
Neonatal cytokine levels in children with epilepsy (n=4) compared to those without epilepsy (n=13). Levels are plotted from 0–200 pg/mL, except for IL-12 and IL-13, which are plotted from 0–60 pg/mL. * p

Figure 3:

Dendrogram and heatmap of neonatal…

Figure 3:

Dendrogram and heatmap of neonatal cytokines levels in 26 neonates with neonatal encephalopathy…

Figure 3:
Dendrogram and heatmap of neonatal cytokines levels in 26 neonates with neonatal encephalopathy using hierarchical agglomerative clustering. Children with epilepsy are denoted with “1” and children without epilepsy are denoted with “0”. Dark blue colors represent low cytokine values, white colors represent average values, and red represent high values.

Figure 4:

Correlations among cytokine levels in…

Figure 4:

Correlations among cytokine levels in 26 neonates with neonatal encephalopathy. Larger bubbles and…

Figure 4:
Correlations among cytokine levels in 26 neonates with neonatal encephalopathy. Larger bubbles and darker red coloring indicates a higher correlation coefficient whereas smaller bubbles and dark blue coloring indicate lower correlation coefficients.
Figure 3:
Figure 3:
Dendrogram and heatmap of neonatal cytokines levels in 26 neonates with neonatal encephalopathy using hierarchical agglomerative clustering. Children with epilepsy are denoted with “1” and children without epilepsy are denoted with “0”. Dark blue colors represent low cytokine values, white colors represent average values, and red represent high values.
Figure 4:
Figure 4:
Correlations among cytokine levels in 26 neonates with neonatal encephalopathy. Larger bubbles and darker red coloring indicates a higher correlation coefficient whereas smaller bubbles and dark blue coloring indicate lower correlation coefficients.

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