Secondary Brain Injury Following Neonatal Intraventricular Hemorrhage: The Role of the Ciliated Ependyma

Abstract

Intraventricular hemorrhage is recognized as a leading cause of hydrocephalus in the developed world and a key determinant of neurodevelopmental outcome following premature birth. Even in the absence of haemorrhagic infarction or posthaemorrhagic hydrocephalus, there is increasing evidence of neuropsychiatric and neurodevelopmental sequelae. The pathophysiology underlying this injury is thought to be due to a primary destructive and secondary developmental insult, but the exact mechanisms remain elusive and this has resulted in a paucity of therapeutic interventions. The presence of blood within the cerebrospinal fluid results in the loss of the delicate neurohumoral gradient within the developing brain, adversely impacting on the tightly regulated temporal and spatial control of cell proliferation and migration of the neural stem progenitor cells within the subventricular zone. In addition, haemolysis of the erythrocytes, associated with the release of clotting factors and leucocytes into the cerebrospinal (CSF), results in a toxic and inflammatory CSF microenvironment which is harmful to the periventricular tissues, resulting in damage and denudation of the multiciliated ependymal cells which line the choroid plexus and ventricular system. The ependyma plays a critical role in the developing brain and beyond, acting as both a protector and gatekeeper to the underlying parenchyma, controlling influx and efflux across the CSF to brain interstitial fluid interface. In this review I explore the hypothesis that damage and denudation of the ependymal layer at this critical juncture in the developing brain, seen following IVH, may adversely impact on the brain microenvironment, exposing the underlying periventricular tissues to toxic and inflammatory CSF, further exacerbating disordered activity within the subventricular zone (SVZ). By understanding the impact that intraventricular hemorrhage has on the microenvironment within the CSF, and the consequences that this has on the multiciliated ependymal cells which line the neuraxis, we can begin to develop and test novel therapeutic interventions to mitigate damage and reduce the associated morbidity.

Cranial Point‐of‐Care Ultrasound for Neonatal Providers

“…31,39 Additionally, with the advent of promising therapeutic measures such as endoscopic washout of blood from the ventricular space (eg, the DRIFT study), 40,41 determining the timing of initial bleed and whether rebleeding or progression is occurring in real-time would be beneficial. 42 The strengths of this study include the involvement of both radiology and neonatology subspecialties for the development of educational protocols to ensure the training met both radiologic quality assurance metrics as well as neonatal goals of patient safety and diagnosis. We also demonstrated successful learning of cranial POCUS by providers of varying roles and experience.…”

“…A further implication of serial early cranial POCUS exams is the potential to establish a clear timeline for bleeding to allow for more granular identification of risk factors and probable mitigating factors that may help direct clinical management and prevention 31,39 . Additionally, with the advent of promising therapeutic measures such as endoscopic washout of blood from the ventricular space (eg, the DRIFT study), 40,41 determining the timing of initial bleed and whether rebleeding or progression is occurring in real‐time would be beneficial 42 …”

Therapeutic strategies to recover ependymal barrier after inflammatory damage: relevance for recovering neurogenesis during development

“…The presence of blood and the presence of inflammatory molecules and cells during and after the GMH/IVH ( Holste et al, 2022 ) constitute a serious threat to ependymal integrity. The components and by-products contained in the blood may hinder ependymal cells function and survival ( Dawes, 2022 ).…”

“…Perinatal intraventricular hemorrhages correlate with ependymal damage ( McAllister et al, 2017 ). Studies show how the severity of the inflammatory response associated to GMH/IVH also correlates with the severity of the ependymal damage ( Dawes, 2022 ). Following GMH/IVH, erythrocytes are released into the ventricular system, they lyse, and their potentially neurotoxic components are released into the CSF ( Klebe et al, 2015 ; Tsuji et al, 2020 ).…”