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

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      Abstract

      Background

      Cerebellar 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).

      Results

      CHI 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.

      Conclusions

      We 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.

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      Most cited references 55

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      Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm.

      We have performed brain scanning by computed tomography on 46 consecutive live-born infants whose birth weights were less than 1,500 gm; 20 of them had evidence of cerebral intraventricular hemorrhage. Nine of the 29 infants who survived had IVH. Four grades of IVH were identified. Grade I and II lesions resolved spontaneously, but there was prominence of the interhemispheric fissue on CT of the infants at six months of age. Hydrocephalus developed in infants with Grade III and IV lesions. Seven of the surviving infants with IVH did not have clinical evidence of hemorrhage. There were no significant differences between the infants with and without IVH in birth weight, gestational age, one- and five-minute Apgar scores, or the need for resuscitation at birth or for subsequent respiratory assistance.
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        Regional brain volume abnormalities and long-term cognitive outcome in preterm infants.

        Preterm infants have a high prevalence of long-term cognitive and behavioral disturbances. However, it is not known whether the stresses associated with premature birth disrupt regionally specific brain maturation or whether abnormalities in brain structure contribute to cognitive deficits. To determine whether regional brain volumes differ between term and preterm children and to examine the association of regional brain volumes in prematurely born children with long-term cognitive outcomes. Case-control study conducted in 1998 and 1999 at 2 US university medical schools. A consecutive sample of 25 eight-year-old preterm children recruited from a longitudinal follow-up study of preterm infants and 39 term control children who were recruited from the community and who were comparable with the preterm children in age, sex, maternal education, and minority status. Volumes of cortical subdivisions, ventricular system, cerebellum, basal ganglia, corpus callosum, amygdala, and hippocampus, derived from structural magnetic resonance imaging scans and compared between preterm and term children; correlations of regional brain volumes with cognitive measures (at age 8 years) and perinatal variables among preterm children. Regional cortical volumes were significantly smaller in the preterm children, most prominently in sensorimotor regions (difference: left, 14.6%; right, 14.3% [P<.001 for both]) but also in premotor (left, 11.2%; right, 12.6% [P<.001 for both]), midtemporal (left, 7.4% [P =.01]; right, 10.2% [P<.001]), parieto-occipital (left, 7.9% [P =.01]; right, 7.4% [P =.005]), and subgenual (left, 8.9% [P =.03]; right, 11.7% [P =.01]) cortices. Preterm children's brain volumes were significantly larger (by 105. 7%-271.6%) in the occipital and temporal horns of the ventricles (P<. 001 for all) and smaller in the cerebellum (6.7%; P =.02), basal ganglia (11.4%-13.8%; P
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          Does cerebellar injury in premature infants contribute to the high prevalence of long-term cognitive, learning, and behavioral disability in survivors?

          Although cerebellar hemorrhagic injury is increasingly diagnosed in infants who survive premature birth, its long-term neurodevelopmental impact is poorly defined. We sought to delineate the potential role of cerebellar hemorrhagic injury in the long-term disabilities of survivors of prematurity. We compared neurodevelopmental outcome in 3 groups of premature infants (N = 86; 35 isolated cerebellar hemorrhagic injury, 35 age-matched controls, 16 cerebellar hemorrhagic injury plus supratentorial parenchymal injury). Subjects underwent formal neurologic examinations and a battery of standardized developmental, functional, and behavioral evaluations (mean age: 32.1 +/- 11.1 months). Autism-screening questionnaires were completed. Neurologic abnormalities were present in 66% of the isolated cerebellar hemorrhagic injury cases compared with 5% of the infants in the control group. Infants with isolated cerebellar hemorrhagic injury versus controls had significantly lower mean scores on all tested measures, including severe motor disabilities (48% vs 0%), expressive language (42% vs 0%), delayed receptive language (37% vs 0%), and cognitive deficits (40% vs 0%). Isolated cerebellar hemorrhagic injury was significantly associated with severe functional limitations in day-to-day activities. Significant differences were noted between cases of cerebellar hemorrhagic injury versus controls on autism screeners (37% vs 0%) and internalizing behavioral problems (34% vs 9%). Global developmental, functional, and social-behavioral deficits were more common and profound in preterm infants with injury to the vermis. Preterm infants with cerebellar hemorrhagic injury and supratentorial parenchymal injury were not at overall greater risk for neurodevelopmental disabilities, although neuromotor impairment was more severe. Cerebellar hemorrhagic injury in preterm infants is associated with a high prevalence of long-term pervasive neurodevelopment disabilities and may play an important and underrecognized role in the cognitive, learning, and behavioral dysfunction known to affect survivors.
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            Author and article information

            Affiliations
            [1 ]Department of Pediatrics, Nationwide Children’s Hospital, Columbus, USA
            [2 ]The Biostatistics Core, Nationwide Children’s Hospital, Columbus, USA
            [3 ]Department of Pathology & Laboratory Medicine, J0359 Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA
            [4 ]The Ohio State University College of Medicine, Columbus, USA
            Contributors
            Journal
            Acta Neuropathol Commun
            Acta Neuropathol Commun
            Acta Neuropathologica Communications
            BioMed Central
            2051-5960
            2013
            21 October 2013
            : 1
            : 69
            24252570
            3893422
            2051-5960-1-69
            10.1186/2051-5960-1-69
            Copyright © 2013 Haines et al.; licensee BioMed Central Ltd.

            This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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