Abstract
BackgroundIn human neonatal high pressure hydrocephalus (HPHC), diffuse white matter injury and gliosis predispose to poor neuro-developmental outcome. The underlying mechanism for diffuse white matter damage in neonatal HPHC is still unclear. Analogous to inflammatory white matter damage after neonatal hypoxemia/ischemia, we hypothesized that pro-inflammatory cytokines could be involved in neonatal HPHC. If so, early anti-inflammatory therapy could ameliorate white matter damage in HPHC, before irreversible apoptosis has occurred. In HPHC and control neonates, we therefore aimed to compare cerebrospinal fluid (CSF) concentrations of IL18, IFNγ and sFasL (interleukin 18, interferon gamma and apoptosis marker soluble-Fas ligand, respectively).MethodsIn neonatal HPHC (n = 30) and controls (n = 15), we compared CSF concentrations of IL18, IFNγ and sFasL using sandwich ELISA. HPHC was grouped according to etiology: spina bifida aperta (n = 20), aqueduct stenosis (n = 4), and fetal intra-cerebral haemorrhage (n = 6). Neonatal control CSF was derived from otherwise healthy neonates (n = 15), who underwent lumbar puncture for exclusion of meningitis.ResultsIn all three HPHC groups, CSF IL18 concentrations were significantly higher than control values, and the fetal intracranial haemorrhage group was significantly higher than SBA group. Similarly, in all HPHC groups CSF-IFNγ concentrations significantly exceeded the control group. In both HPHC and control neonates, CSF FasL concentrations remained within the range of reference values.ConclusionIndependent of the pathogenesis, neonatal HPHC is associated with the activation of the pro-inflammatory cytokines (IL-18 and IFNγ) in the CSF, whereas CSF apoptosis biomarkers (sFasL) were unchanged. This suggests that anti-inflammatory treatment (in addition to shunting) could be helpful to preserve cerebral white matter.
Highlights
In human neonatal high pressure hydrocephalus (HPHC), diffuse white matter injury and gliosis predispose to poor neuro-developmental outcome
Independent of the pathogenesis, neonatal HPHC is associated with the activation of the pro-inflammatory cytokines (IL-18 and IFNγ ) in the cerebrospinal fluid (CSF), whereas CSF apoptosis biomarkers were unchanged
In neonates with post-hemorrhagic hydrocephalus and cystic white matter damage, we have subsequently shown that enhanced growth factor concentrations (i.e. vascular endothelial growth factor (VEGF) and transforming growth factor β1 (TGF-β1)) will reflect tissue repair [21,22]
Summary
In human neonatal high pressure hydrocephalus (HPHC), diffuse white matter injury and gliosis predispose to poor neuro-developmental outcome. Analogous to inflammatory white matter damage after neonatal hypoxemia/ischemia, we hypothesized that pro-inflammatory cytokines could be involved in neonatal HPHC. After hypoxemia/ischemia, white matter damage consists of a diffuse, inflammatory pattern involving pro-inflammatory cytokines, oligodendrocytic injury, gliosis and myelin loss [5,6,7]. In contrast to elevated CSF IL18 concentrations which last for months, IL-1β and TNFα concentrations are only elevated for hours [14,15] This may explain our previously reported negative association between CSF IL-1β concentration and cystic white matter damage [6]. Cytokine IFNγ is involved in the regulation of the inflammatory response by activation of cytotoxic T-cells and macrophages [16] Upon activation, this may result in apoptosis, myelin loss and gliosis [5,12,17,18,19,20]. In neonates with post-hemorrhagic hydrocephalus and cystic white matter damage, we have subsequently shown that enhanced growth factor concentrations (i.e. vascular endothelial growth factor (VEGF) and transforming growth factor β1 (TGF-β1)) will reflect tissue repair [21,22]
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