CHAPTER THREE
PERINATAL ISCHEMIA AND STROKE

PERIVENTRICULAR LEUKOMALACIA

Periventricular leukomalacia (PVL) is a form of ischemic white matter damage, which affects premature infants especially ones who have cardiorespiratory abnormalities and sepsis. It develops usually in the neonatal period but may also occur in utero and is frequent in mature infants with congenital heat disease.

PVL-classic early pathology	PVL-Calcified lesions	PVL-Severe advanced lesions

Bilateral, roughly symmetric foci of white matter necrosis develop around the lateral ventricles, especially in the frontal and occipital lobes. The evolution of these lesions is similar to infarcts, i.e. liquefaction, phagocytosis, cavitation (cystic PVL), and gliosis. An added feature of PVL and other necrotic brain lesions in fetuses and neonates is calcification. In the acute phase, the necrotic lesions can be detected by ultrasound because of their echogenicity. Cysts appear in 2-4 weeks. Later, the cysts collapse and the lateral ventricles enlarge. At the calcified stage, the lesions appear as whitish spots in the periventricular white matter. Cortical ischemic lesions are also present in some cases.

The key element in the pathogenesis of PVL is ischemia and its consequences, i. e., excitotoxins and free radicals (see also Asphyxia and HIE in Mature Infants). During development, blood vessels from the meninges penetrate the cerebral cortex and then extend into the white matter. In the premature infant, the deep white matter, where the lesions of PVL are located, is vulnerable to ischemia because it is not fully vascularized. Additionally, the white matter in the premature infant is populated by immature oligodendrocytes, which are vulnerable to ischemia. Inflammatory cytokines that are generated during maternal, placental, and fetal infection probably also damage the white matter directly and by activating microglial cells (which appear in the white matter in large numbers around mid-gestation). Activated microglial cells kill oligodendrocytes and neurons.

Diffuse PVL

Ischemia may damage developing oligodendrocytes and axons diffusely without causing focal necrotic lesions. This results in white matter loss, atrophy of the corpus callosum, and dilatation of the lateral ventricles (diffuse PVL). A component of diffuse damage is also present around the focal cystic lesions.

The effects of ischemia are not selective for oligodendrocytes and axons. White matter damage, especially during the second trimester, may also affect the subplate (a thick ephemeral neuronal layer under the permanent cortex) and late migrating neurons that traverse the white matter on their way to the deep cortical layers. The subplate is important for the development of connections between the thalamus and cortex. Its premature loss disconnects the cortex from the thalamus. Damage of migrating neurons results in decreased cortical volume. Neuronal loss in PVL adds to the devastating effects of myelin and axonal damage.

The clinical manifestations of PVL are spastic diplegia or tetraplegia due to damage of corticospinal tract axons, visual impairment due to damage of the optic radiations, cognitive deficits, and seizures. The clinical deficits of PVL are not apparent initially. They are only fully appreciated months or years after the injury occurs.

Diffuse PVL

The cortex and deep nuclei are not always spared by HIE in premature infants. As the picture on the left illustrates, the full range of gray matter HIE pathology that occurs at term may also develop in premature infants, usually along with white matter damage.

Further reading:
Woodward LJ, Andeson PJ, Austin NC et al. Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N Engl J Med 2006;355:685-94. PubMed

Leviton a, Gressens P. Neuronal damage accompanies white matter damage. Trends in Neurosciences 2007;30:473-8. PubMed

Miller S P, McQuillen PS, Hamrick S et al. Abnormal brain development in newborns with congenital heart disease. N Engl J Med 2007;357:1928-38. (PubMed)

Updated: January, 2008