Histological Findings in the Kernicterus-Associated Vulnerable Brain Regions are Linked to Neurodegeneration, Alterations in Astrocyte and Pericyte Distribution, and Vascular Modifications

Inês Palmela

doi:10.23937/2469-5807/1510003

Abstract

Kernicterus is a severe manifestation of neonatal unconjugated hyperbilirubinemia. We investigated the neuro-glia-vascular alterations in autopsy material from three infants with kernicterus. Histological and immunohistochemical studies were performed in the cerebellum, hippocampus and basal ganglia, the most vulnerable brain regions to bilirubin-induced neurotoxicity. The data obtained were compared with the relatively spared temporal cortex, as well as with three aged-matched controls with no hyperbilirubinaemia. Our data showed a reduction of the external germinal layer thickness e kernicterus cases cerebellum, indicating that bilirubin compromises the neural progenitor cells. Results also showed that neuronal dysfunction, including neuronal death and reduced neuronal bodies, was prevalent in the cerebellum, hippocampus and basal ganglia. The hippocampus was the region presenting the greatest neuronal loss and vacuolation, also showing astrogliosis and loss of pericyte vascular coverage. A marked decrease in the basement membrane collagen IV immunoreactivity was observed in the cerebellum, a region presenting increased vessel density, particularly in the cerebellar cortex. Moreover, based on the enhanced caveolin-1 expression observed in the cerebellum and hippocampus we hypothesize that a transcellular hyperpermeability may have been involved in cases of kernicterus. The temporal cortex did not show signs of endothelial dysfunction and was the one with the lowest microvessel density and the highest basement membrane thickness, features that may account to the limited bilirubin passage across the blood-brain barrier into the brain and to the low propensity of the temporal cortex to kernicterus. Conclusion: The results obtained in three post-mortem brain samples of children with kernicterus and comorbid factors indicate that neuronal impairment and astrocytosis occur in parallel with microvascular alterations commonly associated with blood-brain barrier impairment.

Highlights

Neonatal jaundice is extremely common in the first week of life, affecting 60 to 85% of neonates [1]
The results obtained in three post-mortem brain samples of children with kernicterus and comorbid factors indicate that neuronal impairment and astrocytosis occur in parallel with microvascular alterations commonly associated with blood-brain barrier impairment
In the present study we investigated the histopathological alterations in the cerebellum, hippocampus and basal ganglia in postmortem samples from kernicterus cases, and evaluated the associated neuronal-glial-vascular changes by comparing data with that from non-icteric controls

Summary

Introduction

Neonatal jaundice is extremely common in the first week of life, affecting 60 to 85% of neonates [1]. The condition is usually benign and resolved with no treatment requirement. Under circumstances such as prematurity and glucose-6-phosphate dehydrogenase deficiency [2,3] unconjugated bilirubin (UCB) levels may increase dramatically or extend beyond the first week of life and lead to acute bilirubin encephalopathy, or kernicterus, a potentially lethal disease [1,4,5]. Ex vivo studies of a kernicterus case revealed angiogenic sprouting and the presence of blood-borne components in the brain parenchyma, together with neuronal impairment [8,9]. In vitro studies in conditions mimicking a moderate and severe neonatal jaundice (UCB/albumin molar ratios of 0.5 and 1.0, respectively), revealed that UCB induces the disruption of tight junctions and increases caveolae formation, reflecting an enhanced paracellular and transcellular hyperpermeability, respectively [10,11]. It was recently demonstrated that UCB compromises pericytes [12], which are known to play a key role in the maintenance of BBB properties [13]

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Conclusion