Fas-ligand and interleukin-6 in the cerebrospinal fluid are early predictors of hypoxic-ischemic encephalopathy and long-term outcomes after birth asphyxia in term infants

Abstract

BackgroundCerebral ischemia generates neuroinflammation that can induce neural cell death. This cohort study assessed whether Fas-ligand (FasL) and interleukin (IL)-6 levels in the cerebrospinal fluid (CSF) after hypoxic-ischemic encephalopathy (HIE) can serve as biomarkers of hypoxic brain injury in neonates.MethodsTerm infants (> 37-week gestational age) who were admitted to the neonatal intensive care unit of Karolinska University Hospital in years 2002 to 2004 with perinatal asphyxia were enrolled prospectively. Control infants without brain pathology underwent lumbar puncture for suspected infection. FasL and IL-6 levels were measured in the CSF, by enzyme-linked immunosorbent assays. All patients underwent neurological assessment at 18 months. HIE was classified as mild, moderate, or severe (HIE I–III). Adverse neurological outcome at 18 months was defined as a mental developmental index < 85, deafness, blindness, cerebral palsy, or seizure disorder.ResultsOf the 44 HIE patients, 14, 16, and 14 had HIE-I, HIE-II, and HIE-III, respectively. HIE-II and HIE-III patients had higher FasL and IL-6 levels than HIE-I patients and the 20 controls (all p < 0.0001). Patients with adverse outcomes had higher FasL and IL-6 levels than patients with normal outcomes and controls (both p < 0.0001). On receiver-operator curve analyses, FasL and IL-6 (alone and together) were highly predictive of HIE grade and outcome (areas under the curve range 0.86–0.94) and showed high sensitivity (66.7–100%). These biomarkers performed better than cord blood pH (areas under the curve: HIE grade = 0.80, adverse outcomes = 0.86).ConclusionCSF biomarkers FasL and IL-6 predicted severity of encephalopathy and long-term outcomes in post-asphyxiated infants better than a standard biomarker.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1253-y) contains supplementary material, which is available to authorized users.

Temporal Characterization of Microglia-Associated Pro- and Anti-Inflammatory Genes in a Neonatal Inflammation-Sensitized Hypoxic-Ischemic Brain Injury Model

“…It has been demonstrated that neuronal self-injury after exposure to LPS could be alleviated by using specific cytokine blockers, as it was already shown for IL-1beta [78]. On the other side, some cytokines like IL-6 has a dual function, where high levels early after HI insults are associated with adverse HIE outcomes; a secondary peak later after HIE was associated with better outcomes by regulating expression levels of IL-1beta and TNF-alpha [56,[82][83][84][85] and by its ability to promote neuronal differentiation of neural stem progenitor cells (NSPCs) and promote angiogenesis [86].…”

Proteomic profiles in cerebrospinal fluid predicted death and disability in term infants with perinatal asphyxia: A pilot study

“…Information was gathered from outpatient paediatric care centres on the outcomes of the control group when they were 18 months of age. Some of the clinical characteristics of a subgroup of the recruited infants have previously been published 12 …”

Cerebral palsy biomarker

“…Поскольку концентрации IL-6 и FasL в спинномозговой жидкости положительно коррелируют с плохими 18-месячными клиническими исходами (p <0,0001), они могут быть полезны в качестве биомаркеров тяжести гипоксического по-вреждения головного мозга и для прогнозирования отдаленного исхода, в том числе риска ДЦП после перинатальной асфиксии. Комбинация этих маркеров повышает их прогностическую ценность [25].…”