Cumulative Damage: Cell Death in Posthemorrhagic Hydrocephalus of Prematurity

Abstract

Globally, approximately 11% of all infants are born preterm, prior to 37 weeks’ gestation. In these high-risk neonates, encephalopathy of prematurity (EoP) is a major cause of both morbidity and mortality, especially for neonates who are born very preterm (<32 weeks gestation). EoP encompasses numerous types of preterm birth-related brain abnormalities and injuries, and can culminate in a diverse array of neurodevelopmental impairments. Of note, posthemorrhagic hydrocephalus of prematurity (PHHP) can be conceptualized as a severe manifestation of EoP. PHHP impacts the immature neonatal brain at a crucial timepoint during neurodevelopment, and can result in permanent, detrimental consequences to not only cerebrospinal fluid (CSF) dynamics, but also to white and gray matter development. In this review, the relevant literature related to the diverse mechanisms of cell death in the setting of PHHP will be thoroughly discussed. Loss of the epithelial cells of the choroid plexus, ependymal cells and their motile cilia, and cellular structures within the glymphatic system are of particular interest. Greater insights into the injuries, initiating targets, and downstream signaling pathways involved in excess cell death shed light on promising areas for therapeutic intervention. This will bolster current efforts to prevent, mitigate, and reverse the consequential brain remodeling that occurs as a result of hydrocephalus and other components of EoP.

Hydrocephalus: historical analysis and considerations for treatment

“…In the context of hydrocephalus, the pathophysiology of the choroid plexus is poorly explored. However, it is known that choroid plexus cell death and corresponding junctional breakdown can occur as a result of oxidative stress and inflammation, leading to dysfunction of CSF production and movement, secretion of signaling molecules, and maintenance of CSF volume [ 67 , 68 ] as visualized in Figs. 1 and 2 .…”

“…Several studies have identified that impaired neurogenesis, gliogenesis, and an upregulation of inflammatory pathways contribute to the development of hydrocephalus [5,14,26,29,[67][68][69]. Furthermore, it has been shown that damage to the ependymal lining of the ventricles due to blood, inflammation, fibrosis, or trauma, can cause hydrocephalus [67][68][69]. Recent studies have identified several agents which may protect against this damage and/or restore already damaged tissue.…”

A scoring system categorizing risk factors to evaluate the need for ventriculoperitoneal shunt in pediatric patients after brain tumor resection

“…Intraoperative hemorrhage can induce an inflammatory reaction and local tissue adhesion in the surgical area. Consequently, this can disrupt the connections between choroid plexus cells and corresponding cells, leading to impaired CSF flow and decreased ventricular volume maintenance function ( 28 ). Karimy et al.…”

Design of a stem cell-based therapy for ependymal repair in hydrocephalus associated with germinal matrix hemorrhages

“…Disruption of multiciliated ependyma development 12,[14][15][16] is a relevant and key event associated with GMH/IVH and PHH. The ependyma constitutes a cell barrier between the brain parenchyma and the ventricle (which was not certified by peer review) is the author/funder.…”

“…Microglial and astrocytic activation following GMH/IVH and subsequent inflammation are primary determinants of white matter brain damage in preterm infants 61 . A third group could be constituted by proteins implicated in cell death and axonal injury in the periventricular cerebral parenchyma 15,62,63 . The presence of blood components has been proven to be directly related to the disruption of ependymal development by affecting cell junctions and activating the periventricular astroglial reaction 16,64 .…”