Histologic Appearance of Iatrogenic Obstructive Hydrocephalus in the Fetal Lamb Model

Introduction: Documentation of histologic findings associated with congenital hydrocephalus in the fetal lamb model is a critical step in evaluating the efficacy of ventriculoamniotic shunting in the human fetus. Methods: Four fetal sheep had hydrocephalus induced at approximately 95 days’ gestation. Two co-twins remained as controls. The ewes were euthanized at term. The lamb brains were fixed in formalin, paraffin-embedded, stained, and analyzed for markers of neuropathology. Astrocytosis, microgliosis, and axonal loss were assessed with immunocytochemistry for glial fibrillary acidic protein, ionized calcium-binding adapter, and neurofilament/amyloid precursor protein, respectively. Cortical gray matter extracellular matrix was assessed with staining for the lectin Wisteria Floribunda agglutinin. Results: Hydrocephalic lamb brains demonstrated deep white matter damage with loss of projecting axonal tracts in regions physically distorted by hydrocephalus, similar to that seen in hydrocephalic humans. There was no evidence of abnormal neocortical neuronal migration; however, there was evidence for delayed maturation of the neocortical gray matter, possibly from increased intracerebral pressure and subsequent ischemia. Control lamb brains demonstrated none of the above findings. Conclusion: This histological approach can be used to further define the mechanism of brain damage associated with hydrocephalus and interpret the efficacy of ventriculoamniotic shunting on fetal lamb brain neuroanatomy.