myelination, perfusion, and glucose uptake at the time of injury.35

Finally, a transient layer of deep subplate neurons may be selectively vulnerable to injury in PVL. These subplate neurons act as a way-station for axons that will ultimately connect with permanent cortical layers.191,523 Subplate neurons also appear transiently during brain development and play a critical role in the formation of connections between the thalamus and the visual cortex.306 In the term neonate with ischemic brain injury, however, certain neurons in the deep gray nuclei and perirolandic cortex are most likely to be injured, whereas other cells, such as neurons expressing nitric oxide synthase, seem resistant to ischemic injury.161 Neurons expressing nitric oxide synthase participate in processes of oxidative stress and excitotoxicity that lead to the death of neighboring cells.26,163,228 If an ischemic injury occurs early in gestation and the baby is born prematurely, some developing oligodendrocytes and subplate neurons are lost.26,399 Shatz and colleagues have shown that these subplate neurons, which lie below the cortical plate during development, are involved in cortical organization and are necessary for secondary guidance of axon collaterals from the cortex toward subcortical targets (e.g., other cortical sites, thalamus, corpus callosum).190,394 These subplate cells are generated in the subependymal germinative zones and migrate to the primitive subpial marginal zones before generation and migration of neurons in the cortical plate.600 The peak time for the development of subplate neurons corresponds to the times for PVL and IVH.600 Volpe600 has proposed that preterm injury to these subplate neurons, by secondarily affecting cortical organization and projections, could account for the complex cognitive and attentional deficits that are often seen in the preterm child.

The periventricular white matter is particularly sensitive to inflammatory chorioamnionitis during a specific period of brain development, and maternal infection is now implicated in the pathogenesis of PVL.8,107,195,356,357,630 Our concept of injury has therefore changed from a monophasic ischemic birth injury to a more multifactorial mechanism in which similar factors may give rise to preterm labor and perinatal damage. Adverse perinatal events that correlate with the development of PVL include perinatal asphyxia, recurrent apnea, septicemia, hypocarbia, and prolonged mechanical ventilation.32,76,280 A range of pathogenetic factors, including free radicals, glutamate, and proinflammatory cytokines, have been shown to induce the death of immature oligodendroglial cell lines. In addition, the presence of free iron following germinal matrix or IVH may exacerbate the sensitivity of oligodendroglial cells to free radical injury. The result of these pathological processes is cystic tissue necrosis within the periventricular white matter regions and the development of PVL.32 The complex molecular mechanisms governing cell death in periventricular leukomalacia and involving inflammatory cells and associated cytokine upregulation,

apoptosis and, ultimately, white matter damage, continue to be elucidated.161,303

In summary, it is inadvisable to attribute PVL to perinatal perturbations that may lead to hypoxia because there is an abundant evidence for the role in a variety of contributory factors, and it is usually difficult to assess their relative roles.108 Maturational, circulatory, and inflammatory risk factors are all being studied as potential cocontributors to PVL.108 Moreover, multiple experimental studies support the claim that hypoxia without ischemia does not cause brain damage.355,358,478 While the evidence that hypoxia-ischemia can indeed cause brain lesions is indisputable,590 the legalistic inference that brain damage in human newborns must therefore be hypoxic-ischemic in origin is not well supported by solid observational evidence.216

Intraventricular Hemorrhage

Periventricular and Intraventricular

Hemorrhage

Although the incidence of severe IVH has fallen with improvements in management and increased antenatal steroid use, it remains a major cause of brain injury, with consequent abnormal neurodevelopment.143 Most IVHs in preterm infants occur within the first few days of life. They arise from poorly supported small vessels in the subependymal germinal matrix (the metabolically active area within the ventricular wall in which the cells that compose the brain are produced), either spontaneously or as a result of hypoxia or hypertensive crisis.

When ischemic brain tissue is reperfused, the weakened blood vessels frequently rupture, resulting in parenchymal hemorrhage. The hemorrhage extends into the ventricles and may eventually result in hydrocephalus and dissect into the brain parenchyma, causing direct damage to neural structures, including the posterior visual pathways. Because the germinal matrix diminishes in activity and begins to involute during the third trimester, germinal matrix hemorrhages are unusual after 34 weeks of gestation. Choroid plexus hemorrhages are common in premature infants, often accompanying hemorrhages of the germinal matrix. It should therefore be evident that the consequences of hypoxia-ischemia in premature­ infants result in injury represented largely by periventricular hemorrhages and leukomalacia.32

Periventricular and IVH in the premature infant has been divided into four grades related to its severity.455 Grade 1 refers to germinal matrix hemorrhage with little or no IVH. Grade II bleeds extend from the subependymal germinal zone into the ventricles (which remain normal in size). In grade III bleeds, IVH is associated with ventricular enlargement, which can result from either IVH or ex vacuo enlargement (Fig. 1.21).