The Encephalopathy of Prematurity—Brain Injury and Impaired Brain Development Inextricably Intertwined

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The field of neonatal neurology, and specifically its focus on the premature infant, had its inception in neuropathologic studies. Since then, the development of advanced imaging techniques has guided our developing understanding of the etiology and nature of neonatal brain injury. This review promotes the concept that neonatal brain injury has serious and diverse effects on subsequent brain development, and that these effects likely are more important than simple tissue loss in determining neurologic outcome. Brain injury in the premature infant is best illustrative of this concept. This “encephalopathy of prematurity” is reviewed in the context of the remarkable array of developmental events actively proceeding during the last 16-20 weeks of human gestation. Recent insights into the brain abnormalities in survivors of preterm birth obtained by both advanced magnetic resonance imaging and neuropathologic techniques suggest that this encephalopathy is a complex amalgam of destructive and developmental disturbances. The interrelations between destructive and developmental mechanisms in the genesis of the encephalopathy are emphasized. In the future, advances in neonatal neurology will likely reiterate the dependence of this field on neuropathologic studies, including new cellular and molecular approaches in developmental neurobiology.

Section snippets

Personal Perspective

This presentation will focus on the brain of the premature infant. My interest in premature infants began in the early 1970s when neonatal intensive care began its ascendancy to the highly accomplished medical discipline of today. I was inspired by the seminal neuropathologic studies of Betty Banker, Jeanne-Claudie Larroche, E. Pierson Richardson, Gilles Lyon, Dawna Armstrong, Lucy Rorke, Floyd Gilles, Jonathan Wigglesworth, and my colleague of the past 20 years, Hannah Kinney. My review of the

Neuropathology—Encephalopathy of Prematurity

The neuropathology of encephalopathy of prematurity consists of PVL and the often-associated neuronal/axonal disease. These 2 aspects are discussed briefly next.

Major Developmental Events in Human Brain During the Premature Period

The encephalopathy of prematurity, that is, both PVL and the associated neuronal/axonal disease, occurs during a period of extraordinarily rapid and complex events in human brain development.1, 10 The developmental events between 24 and 40 weeks involve, particularly (1) in cerebral white matter—pre-OLs, axons, microglia, and neurons (subplate and late migrating GABAergic neurons); (2) two proliferative zones—the dorsal cerebral subventricular zone (SVZ) and the ventral germinative epithelium

Encephalopathy of Prematurity—Combination of Destructive and Developmental Disturbances

As noted in the Introduction, the hypothesis of this review is that the encephalopathy of prematurity, that is, the combination of PVL and neuronal/axonal disease described under Neuropathology, is a complex amalgam of primary destructive and secondary developmental disturbances.1 The developmental disturbances include impaired cell–cell interactions, involving intercellular trophic support, retrograde effects (“dying back”), and anterograde effects (eg, Wallerian degeneration, trans-synaptic

Conclusions

It is unclear which of the 5 potential scenarios depicted in Figure 3 is most important in the encephalopathy of prematurity. Pre-OL injury may be the most common starting point. However, it seems likely that more than one and perhaps all the scenarios shown in Figure 3 operate to a varying extent.1 Determinants of the relative importance of each scenario could relate to factors such as the gestational age of the infant, the timing and nature of the insult(s), critical associated factors such

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    This work was supported by the NINDS, Grant Number P01-NS038475.

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