Cerebral White and Gray Matter Injury in Newborns: New Insights into Pathophysiology and Management

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Key points

  • Contemporary cohorts of preterm infants commonly show less severe injury, which does not seem to involve pronounced neuronal or glial loss. These milder forms of injury are still associated with reduced cerebral growth.

  • Myelination disturbances are one of the hallmarks of chronic white matter injury arising from hypoxia-ischemia.

  • Although immature neurons seem to be more resistant to cell death from hypoxia-ischemia than glia, they show widespread disturbances in maturation of their dendritic

Preterm survivors show an evolving spectrum of brain injury

Although major advances in the care of premature infants have resulted in striking improvements in the survival of very low birth weight (VLBW) infants (<1.5 kg), enhanced survival has been accompanied by a significant increase in the number of preterm survivors with long-term neurodevelopmental morbidity.1, 2 In the United States, the rate of preterm birth continues to increase, with prematurity complicating 1 in 8 deliveries, and VLBW infants comprise about 1.5% of the 4 million live births

What defines an insult to the developing brain and why does this matter?

Although the full impact of preterm cerebral insults is often not fully defined until a childhood neurodevelopmental assessment occurs, there is a critical need for improved means to identify insults closer to the time of occurrence in order to implement potential therapies to prevent early injury38 or promote regeneration and repair of chronic lesions.39 However, the critical windows for interventions remain poorly defined, because of our limited tools to define primary or secondary insults in

A maturation-dependent role for H-I in the pathogenesis of cerebral injury

Multiple lines of evidence support that cerebral ischemia is often the major factor that initiates cerebral injury in VLBW infants.55, 56, 57 Given the limitations of human studies to directly link blood flow disturbances with injury, experimental studies in fetal sheep and other animal models have greatly strengthened our understanding of the contribution of cerebral H-I to gray matter injury and WMI. The timing of CBF disturbances during development is a critical factor that contributes to

Do disturbances in cerebral autoregulation play a role in the pathogenesis of cerebral injury from H-I?

A complex interplay of factors related to cerebrovascular immaturity predispose preterm cerebral white matter to injury from H-I. Central among these factors is a disturbance in cerebral autoregulation. Cerebral autoregulation refers to the maintenance of constant CBF over a range of changes in arterial blood pressure or cerebral perfusion pressure.55, 71, 72 This autoregulatory range has both upper and lower limits; higher or lower than these limits, CBF does not remain constant but instead

Do vascular end and border zones play a role in the pathogenesis of cerebral injury from H-I?

Cerebral vascular development, particularly in the periventricular region, is clinically relevant, because of the propensity of the premature infant to both cerebral WMI and hemorrhage in the germinal matrix and ventricles.83, 84 The role of cerebral vascular immaturity in the pathogenesis of preterm WMI has been difficult to define in preterm infants. Analysis of the vascular supply to the periventricular white matter has yielded conflicting results. The periventricular white matter has 2

Relative contributions of H-I and oligodendrocyte lineage immaturity to WMI

The preterm fetal sheep (0.65 gestation) shows heterogeneous maturation of the oligodendrocyte (OL) lineage in periventricular white matter, which allowed us to define the relative contributions of OL maturation and vascular factors to acute WMI.59 OL lineage maturation in medial cerebral white matter was similar to human (∼23–28 weeks’ gestation), in that preOLs were the major OL stage present. By contrast, lateral cerebral white matter was more differentiated and contained predominantly

The changing spectrum of human WMI

Cerebral WMI is the major form of brain injury recognized in survivors of premature birth.98 The period of highest risk for WMI is ∼23 to 32 weeks postconceptional age. Perinatal WMI, including periventricular leukomalacia (PVL), was the most common finding, seen in almost half (42.5%) of affected children.99 MRI-defined WMI but not gray matter injury manifests in the first months of life as abnormal movements that are predictive of CP.100, 101, 102

The spectrum of white matter disease includes

Current limitations for neuroimaging of WMI

Although cranial ultrasonography is the preferred bedside imaging technique for diagnosing cystic necrotic WMI, it has limited sensitivity for diagnosing diffuse WMI.112, 115, 116 MRI provides a noninvasive means for diagnosis of injury in the developing brain by conventional T1-weighted, T2-weighted, and diffusion-weighted images.41, 121 Nevertheless, there remains unexplained variability in the nature of lesions detected at different centers, which may reflect differences in clinical

Dysmaturation of glial progenitors in chronic WMI and myelination failure

The propensity for myelination failure is a central feature of chronic diffuse WMI, the primary white matter lesion in preterm neonates.118 The major cellular elements that contribute to myelination failure are the axon and the preOL. Recently, it was shown that axons also show maturation-dependent vulnerability to oxidative stress and H-I.122 Larger caliber axons, in preparation for myelination, are particularly susceptible to injury, in contrast to smaller caliber unmyelinated axons, which

Clinical implications of potential arrested white matter development

As shown in Fig. 3C, the severity of an ischemic insult defines whether myelination failure arises primarily from necrotic WMI (upper pathway) or preOL maturation arrest (lower pathway). As discussed earlier, contemporary preterm survivors show less severe WMI, which coincides with preOL arrest. The potential for therapeutic interventions seems more promising for this form of injury than for WMI dominated by necrosis, in which essentially all cell types degenerate.

Chronic WMI thus coincides

An emerging spectrum of gray matter injury and neuronal dysmaturation

As proposed by Volpe146 with the concept of an encephalopathy of prematurity, the cerebral gray matter of preterm survivors may involve both destructive and developmental disturbances.

Although several large human neuroimaging studies have identified significant reductions in the growth of cortical and subcortical gray matter structures, including the basal ganglia, thalamus, hippocampus, and cerebellum,51, 147, 148, 149, 150 the relative contributions of destructive and developmental processes

Susceptibility of preterm cerebral gray matter to H-I

The susceptibility of the preterm gray matter to injury from H-I seems to be fundamentally different from that at term. Studies that used biomarkers of oxidative damage provide indirect support for preterm cerebral injury from H-I.107, 120 The magnitude of oxidative stress in preterm white matter was similar to that sustained by gray matter from H-I at term. Under these conditions of oxidative stress, we analyzed human autopsy cases with diffuse WMI and preOL degeneration and found that neither

Impaired cerebral growth from preterm cerebral H-I can occur without neuronal loss

H-I to the preterm brain also causes disturbances in growth of gray matter structures. This reduced growth of the cerebral cortex and the basal ganglia can also occur in response to conditions that disrupt neuronal maturation without neuronal or axonal loss. In response to cerebral ischemia, preterm fetal sheep acquired diffuse WMI, as well as a progressive reduction in cortical growth, which was not explained by neuronal loss.163 The basis for this unexpected result was explained by detailed

Summary

Our understanding of the pathogenesis of brain injury in the premature infant has recently undergone significant redefinition, which coincides with advances in neonatal care that have markedly reduced the overall severity and extent of the destructive processes associated with cerebral injury. Significant improvement in the care of premature neonates has also coincided with the emergence and application of improved brain imaging, which has provided better resolution of some of the key features

Acknowledgments

We are grateful to Dr Steven Miller and Dr Evelyn McClendon for their many helpful suggestions in the preparation of the article.

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  • Cited by (0)

    This work was supported by the NIH (National Institutes of Neurologic Diseases and Stroke: 1R01NS054044, and R37NS045737-06S1/06S2, the National Institute of Aging: 1R01AG03189, the American Heart Association and the March of Dimes Birth Defects Foundation [S.A. Back]). The Neuroscience Imaging Center at Oregon Health & Science University is supported by NINDS grant P30NS061800.

    Potential Conflicts of Interest: Nothing to report.

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