Cerebellar hemorrhagic injury in premature infants occurs during a vulnerable developmental period and is associated with wider neuropathology

Abstract

BackgroundCerebellar hemorrhagic injury (CHI) is being recognized more frequently in premature infants. However, much of what we know about CHI neuropathology is from autopsy studies that date back to a prior era of neonatal intensive care. To update and expand our knowledge of CHI we reviewed autopsy materials and medical records of all live-born preterm infants (<37 weeks gestation) autopsied at our institution from 1999–2010 who had destructive hemorrhagic injury to cerebellar parenchyma (n = 19) and compared them to matched non-CHI controls (n = 26).ResultsCHI occurred at a mean gestational age of 25 weeks and involved the ventral aspect of the posterior lobe in almost all cases. CHI arose as a large hemorrhage or as multiple smaller hemorrhages in the emerging internal granule cell layer of the developing cortex or in the nearby white matter. Supratentorial germinal matrix hemorrhage occurred in 95% (18/19) of CHI cases compared to 54% (14/26) of control cases (p = 0.003). The cerebellar cortex frequently showed focal neuronal loss and gliosis (both 15/19, 79%) in CHI cases compared to control cases (both 1/26, 4% p < 0.0001). The cerebellar dentate had more neuronal loss (8/15, 53%) and gliosis (9/15, 60%) in CHI cases than controls (both 0/23, 0%; p < 0.0001). The inferior olivary nuclei showed significantly more neuronal loss in CHI (10/17, 59%) than in control cases (5/26, 19%) (p = 0.0077). All other gray matter sites examined showed no significant difference in the incidence of neuronal loss or gliosis between CHI and controls.ConclusionsWe favor the possibility that CHI represents a primary hemorrhage arising due to the effects of impaired autoregulation in a delicate vascular bed. The incidences of neuronal loss and gliosis in the inferior olivary and dentate nuclei, critical cerebellar input and output structures, respectively were higher in CHI compared to control cases and may represent a transsynpatic degenerative process. CHI occurs during a critical developmental period and may render the cerebellum vulnerable to additional deficits if cerebellar growth and neuronal connectivity are not established as expected. Therefore, CHI has the potential to significantly impact neurodevelopmental outcome in survivors.

Brain Injury in Preterm Infants: Pathogenesis and Nursing Implications

“…15 The incidence of CH is unknown but has received increased attention in recent years due to improved imaging techniques. 25 Data suggest that CH is more common than previously thought especially in infants <750 grams. 25,27 Studies based solely on neuroimaging (i.e.…”

“…1,7,16,26 Cerebellar growth and development is primarily due to an increase in external granule cell numbers, granule cell migration and initial establishment of cerebellar neuronal circuitry. 17,25 The cerebellar germinal matrix reaches its maximum around 25 weeks, then decreases rapidly. 7 This secondary germinal matrix in the cerebellum is vulnerable to bleeding.…”

“…13,18 Injury to the cerebellum during this time can impair growth and development and alter the developmental trajectory. 25 Three mechanisms have been proposed for the alterations seen in the cerebellum in VLBW infants: (1) direct injury (usually due to cerebral hemorrhage) leading to atrophy and growth failure; (2) indirect cerebellar injury or underdevelopment associated with cerebral injury; and (3) underdevelopment without any evidence of direct or indirect injury (e.g., prematurity itself may be associated with impaired cerebellar development due to unknown causes). 23,27 Indirect injury involves cerebellar injury in areas contralateral to the cerebral injury that leads to decreased blood flow and metabolism in the contralateral cerebellum resulting in decreased growth and cerebellar hypoplasia.…”

“…6,15,23,24 The cerebellum acts as a node in distribution of neural networks with interconnections with thalamus and parietal and prefrontal cortex, integrates sensory information and is important in socialization skills. 1,18,25 The cerebellum is one of the later areas of the brain to mature, During late second trimester and third trimester, when preterm infants are in the neonatal intensive care unit, the cerebellum undergoes rapid growth and complex, critical developmental processes. 6,25 From 24 to 40 weeks gestation, cerebellar volume increases 5-fold and surface area increases more than 30-fold.…”

“…1,18,25 The cerebellum is one of the later areas of the brain to mature, During late second trimester and third trimester, when preterm infants are in the neonatal intensive care unit, the cerebellum undergoes rapid growth and complex, critical developmental processes. 6,25 From 24 to 40 weeks gestation, cerebellar volume increases 5-fold and surface area increases more than 30-fold. 1,7,16,26 Cerebellar growth and development is primarily due to an increase in external granule cell numbers, granule cell migration and initial establishment of cerebellar neuronal circuitry.…”