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White Matter Damage and Encephalopathy of Prematurity
Brain injury in the premature infant is composed of multiple lesions, traditionally described as germinal matrix intraventricular hemorrhage (IVH) with or without parenchymal involvement, posthemorrhagic hydrocephalus (PHH), and periventricular leukomalacia (PVL). These mostly focal lesions mainly affecting white matter have, in recent years, been recognized to be associated with various other brain alterations, such as cortical and subcortical neuronal loss and distant alteration of white matter integrity.
Periventricular leukomalacia has classically been described as a disorder characterized by multifocal areas of necrosis, with formation of cysts in the deep periventricular cerebral white matter, which are often symmetrical and occur adjacent to the lateral ventricles. These focal necrotic lesions correlate well with the development of spastic cerebral palsy in very low birth weight (VLBW) infants. With the advances in neonatal care and the survival at increasingly low gestational ages, a large number of VLBW infants are now seen with mild motor impairment and often considerable cognitive and behavioral deficits, which may relate to a more diffuse injury to the developing brain.
This chapter presents the current concepts of injury to the immature brain, which has been termed encephalopathy of prematurity , summarizing the old and new neuropathologic findings, mechanisms of pathogenesis through animal models, and the characteristics of this type of lesions in modern neuroimaging.
Neuropathology of White Matter Injury
Historical View
Congenital encephalomyelitis was the term first used by Virchow in 1867 to describe a disease in newborns who demonstrated pale softened zones of degeneration within the periventricular white matter at autopsy. Microscopically, these lesions were characterized by glial hyperplasia, with the presence of foamy macrophages and signs of tissue destruction with necrosis. Interestingly, Virchow related the disease to acute infection, as many of the cases were seen in infants of infected mothers. Clinically, he suggested that these lesions might be related to a disease described earlier by Little, in which the patients suffered from spasmodic limb contractures, diplegia, and mental retardation, occasionally with an additional epileptic condition. Parrot, in 1873, first linked the pathologic entity to premature birth and proposed that the lesions were caused by a particular vulnerability of the immature white matter, as a result of nutritional and circulatory disturbances resulting in infarction. Much later, Rydberg again proposed a hemodynamic etiology with a reduction of cerebral blood flow to the vulnerable regions of the immature white matter. Banker and Larroche, in 1962, first introduced the term periventricular leukomalacia to define this characteristic lesion that they found in 20% of autopsies of infants deceased prior to 1 month of age and described the macroscopic and microscopic neuropathology in more detail.
Periventricular Leukomalacia
Macroscopic Neuropathology
The topography of the lesions is uniform, primarily affecting the white matter in a zone within the subcallosal, superior fronto-occipital, and superior longitudinal fasciculi; the external and internal border zones of the temporal and occipital horns of the lateral ventricles; and some parts of the corona radiata. These areas appear pale, usually bilateral, but without definite symmetry ( Fig. 52.1 ). Although not unanimously accepted, it has been noted that the anatomic distribution of PVL correlates with the development of perforating medullary arteries and areas that represent the arterial borders or end zones, that arise between ventriculopetal and ventriculofugal arteries within the deep white matter ( Fig. 52.2 ). Immunohistochemical studies further confirm low vessel density in the deep white matter between 28-36 weeks’ gestation, whereas in the subcortical white matter, the vessel density is low between 16 and 24 weeks and thereafter increases ( Fig. 52.3 ).
Microscopic Neuropathology
The earliest recorded changes are of coagulation necrosis of all cellular elements, with loss of cytoarchitecture and tissue vacuolation. Axonal swelling and intense activated microglial reactivity and proliferation have been observed as early as 3 hours after an insult. In addition, in the periphery of these focal lesions, a marked astrocytic and vascular endothelial hyperplasia characterize the brain tissue reaction at the end of the first week. After 1-2 weeks, macrophage activity, with characteristic lipid-laden macrophages, is predominant over the astrocytic reactivity, with progressive cavitation of the tissue and cyst formation thereafter. During subacute and chronic stages of PVL, swollen axons calcify, accumulate iron, and degenerate particularly at the periphery of the injured zone. Additional minor changes are also found within gray matter, with some diffuse neuronal loss especially in the lower cortical layers, the hippocampus, and the cerebellar Purkinje cell layer. Many conventional neuropathology studies subsequently have noted widespread diffuse central cerebral white matter astrocytosis, often with abnormal glial cells, which were termed perinatal telencephalic leukoencephalopathy . On the basis of these studies, Leviton and Gilles described, for the first time, a differentiation between focal and diffuse white matter damage.
New Neuropathologic Insights
This diffuse white matter damage is macroscopically characterized by a paucity of white matter; thinning of the corpus callosum; ventriculomegaly and delayed myelination in the later stages; and, as shown in recent studies, reduction of thalamic, striatal, and hippocampal size and cortical gray matter. With the use of immunocytochemical techniques, the assessment of autopsy tissue has allowed for further localization of cell-specific injury in white matter damage. The deep periventricular white matter is prone to showing focal necrosis regionally, consistent with the presumed vascular end zones/border zones, whereas in the peripheral white matter, diffuse injury could be characterized by preferential death or injury of late oligodendrocyte progenitors and immature oligodendrocytes (preoligodendrocytes [pre-OLs]; see Chapter 51 ). This leads to a proliferative response of early pre-OLs, but their differentiation into mature cells remains partly arrested. Postmortem data support the hypothesis that in very preterm infants, blockade of maturation of oligodendrocytes, rather than their death, is the key neuropathologic hallmark in diffuse white matter damage. In addition, more recent neuropathologic studies on human preterm material have shown the extensive involvement of axonal damage, especially thalamocortical fibers and damage to white matter neuronal populations (GABAergic interneurons), and damage to the cerebellar white matter.
These new neuropathologic features lead to the well-discussed hypothesis that the encephalopathy of the preterm infant is an amalgam of damage and disrupting development.
Vulnerability of Oligodendroglia Cell Line
Several lines of evidence implicate damage to immature oligodendrocytes during a specific window of vulnerability as a significant underlying factor in the pathogenesis of PVL (see section on Models of Encephalopathy of Prematurity below). Oligodendrocyte progenitor cells proliferate and die by apoptosis (programmed cell death) (see Chapter 51 ), regulated by trophic factors, such as platelet-derived growth factor and insulin-like growth factor. The activation of cytokine receptors on the surface of oligodendrocytes can lead to the death or maturation blockade of these cells. Studies in vitro have shown that the inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN- gamma) are toxic to cultured oligodendrocyte progenitor cells. Selective injury to oligodendrocytes is mediated by induction of “death” receptors, such as Fas on the surface of oligodendrocytes. Direct axonal contact appears to be another important factor for the survival and maturation of oligodendrocytes. Oligodendrocytes are further susceptible to oxidative damage mediated by free radicals, such as reactive oxygen and nitrogen species, and as a consequence of the depletion of the main antioxidant, glutathione are subject to epigenetic alterations. Injury-induced swelling and disruption to axons within white matter leads to locally elevated glutamate, which also induces oligodendrocyte cell death and/or injury. Glutamate toxicity depends on the maturational stage of the oligodendrocyte and is mediated via the alpha-3-amino-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor and potentially through N-methyl-D-aspartate (NMDA) receptors.
Experimental data show, however, an important increase in NG2 (high-molecular-weight, integral membrane chondroitin sulfate proteoglycan)–positive oligodendrocyte progenitor cells within the area of the injury. The role of this increase in NG2 cells is currently unknown, but this population is distinct from neurons, oligodendrocytes, astrocytes, and microglia. This cell population could comprise multipotent cells capable of differentiating into any other type of cells and playing a role in axonal growth and myelination and in regeneration after injury with functional integration in neural circuitry.
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