Chapter 3



Periventricular leukomalacia (PVL) is a form of ischemic white matter damage, which affects premature infants especially ones with 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 heart disease.

Acute PVL

Acute PVL. Coagulative white matter necrosis adjacent to the lateral ventricle. The clusters of small cells are residual germinal matrix.

PVL-Axonal swellings

PVL. Axonal swellings at the edge of necrosis.

Cystic PVL

Classic PVL. Bilateral cavitated white matter lesions in a constant distribution, involving frontal and occipital lobes.

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, and gliosis. Axonal damage is evident by the presence of axonal swellings, which may be obvious on H&E stains or detected with immunostains for Beta Amyloid Precursor Protein. An added feature of PVL and other necrotic brain lesions in fetuses and neonates is calcification, which makes lesions appear as whitish spots in the periventricular white matter. Large necrotic lesions cavitate in 2-4 weeks and remain cystic (cystic PVL). Small necrotic lesions do not cavitate at all or form small cysts that collapse into glial scars (non-cystic PVL).

PVL-Calcified lesions

PVL. Calcification of the necrotic areas gives them a blue color on H&E.


Old PVL. Severe loss of white matter, atrophy of the corpus callosum, and dilatation of the lateral ventricles. Notice angulated contour of the ventricles.

Diffuse white matter gliosis

Diffuse white matter gliosis, GFAP immunostain. The 2 week old patient had congenital heart disease.

The cysts and scars are they epicenter of the pathology. They are surrounded by wide zone of cellular injury leading to gliosis. Cystic PVL is now infrequent, thanks to improved neonatal intensive care. A more common pattern is focal noncystic white matter injury (WMI) or diffuse white matter gliosis. This diffuse form of PVL is characteriized by hypomyelination, decreased white matter mass, dilatation of the lateral ventricles, and atrophy of the corpus callosum becomes. Cortical ischemic lesions and diffuse loss of cortical and thalamic neurons are present in some cases.

PVL-cranial ultrasound

PVL. PVL. Ultrasound of early lesions. Echodensity in the left hemisphere; echolucency (early cvitation) in the right.

Cystic PVL-MRI

Cystic PVL-MRI of early lesions.

The method of choice for the diagnosis of PVL is cranial ultrasound (US) but it is not suitable for imaging of WMI. The recommendation for infants less than 30 weeks gestation is a screening ultrasound at 7-14 days and a repeat ultrasound at 30-40 weeks. Echodensities correlate with the acute phase of necrosis. They transition into coalescent echolucencies (cavities) that give the affected white matter a “Swiss cheese” appearance. Ultrasound is best for the detection of cystic PVL. The MRI is more accurate than US for the detection of cystic and non-cystic PVL but is not practical for the diagnosis of acute PVL.

PVL-MRI of advanced lesion

PVL. MRI of advanced stage. Loss of white matter and dilatation of the lateral ventricles. Compare with pathology image above.

PVL-MRI of advanced lesion

PVL. MRI of advanced stage. Decreased white matter with abnormal signal.

PVL-MRI of advanced lesion

PVL. MRI of advanced stage. Atrophy of the corpus callosum.

More often, it is used for follow-up of acute lesions detected earlier by US. The burned out stage of PVL as detected by the MRI consists of: 1) loss of white matter with atrophy of the corpus callosum; 2) enlargement of the ventricles with an irregular angular (scalloped) appearance of their contours; and 3) abnormal or delayed myelination.

Today, based on US and MRI, approximately 3% of neonates weighing less than 1,500 gm have cystic PVL and 20-50% have non-cystic PVL. Congenital heart disease (CHD) is the most common congenital abnormality, affecting about 8 of every 1000 newborn infants. The fetal circulation is designed in a way that conveys a large proportion of oxygenated blood preferentially to the brain. In some forms of severe CHD, especially transposition of great vessels and hypoplastic left heart syndrome, the brain develops in a state of chronic ischemia and hypoxia. A large proportion of such patients have motor, cognitive, and behavioral abnormalities. The encephalopathy of CHD affects mature infants and has identical imaging and pathological features to WMI affecting preterm infants. In patients with CHD, WMI is caused by cerebral ischemia and hypoxia which occurs prenatally or after birth, preoperatively or postoperatively, especially following deep hypothermic circulatory arrest and cardiopulmonary bypass, procedures that are necessary for surgical correction of CHD.

The most important cause of PVL is ischemia. The lesions are located at the termination of major cerebral vessels in the border zones between the ACA, MCA, and PCA and involve the deeper parts of the white matter, where the developing vascular tree has not yet advanced. Hypoxia causes activation of microglia, the tissue histiocyte in the CNS, leading to secretion of toxic oxygen and nitrogen radicals and the release of glutamate. Free radicals and glutamate are the key agents of cellular injury in PVL and other forms of HIE (see also Asphyxia and HIE in Mature Infants). Inflammatory cytokines and activated monocytes that are generated during maternal, placental, and fetal infection enter the brain by crossing the immature blood-brain barrier and activate microglial cells setting in motion the same toxic cascade that damages the white matter in ischemia. Clinical studies show a high association of PVL and CP with chorioamnionitis, funisitis and premature rupture of membranes.

The principal target of oxygen and nitrogen radicals and of glutamate is the immature premyelinating oligodendrocyte (pre-OL). In the premature brain, there is no myelin. The white matter is populated by pre-OLs which are vulnerable to hypoxia because they are deficient in Superoxide Dismutase, the key antioxidant enzyme. Additionally, the premature white matter is rich in iron, the most important source of free radicals. So, the key event in PVL is loss of pre-OLs and the main outcome is deficient myelination. Advanced imaging methods and pathology show also loss and disarray of axons, which is especially obvious in cystic PVL.

White matter damage, especially during the second trimester, may also affect the subplate (an 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.

HPeV3 meningoencephalitis

PVL-like lesions caused by HPeV3.

Necrotic white matter lesions identical to PVL are caused by Human Parechovirus 3 (HPeV3) which is the most common cause of viral meningoencephalitis in young infants. HPeV3 causes cyclic outbreaks and nosocomial infections every 2-3 years, characterized by high fever, irritability, and seizures. There is no CSF pleiocytosis, and PCR is required for diagnosis. White matter necrosis is due to the direct effects of the virus.

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 may not be apparent initially. They are only fully appreciated months or years after the injury occurs. PVL is the substrate of cerebral palsy (CP). The leading risk factor in 75% of CP is prematurity and the underlying pathology in most of CP is PVL.

Our concept of PVL has evolved over the past 50 years. Initially, it was conceived of as an acute ischemic lesion with cavitated white matter infarcts. Now, it is a spectrum of pathology some of which is caused by chronic hypoxia-ischemia or infection and results in diffuse white matter injury and neuronal loss.

HIE-thalamic and hippocampal lesions

HIE in a 30 week gestation infant, with involvement of the deep nuclei and hippocampus. Note the lighter color of these structures. The pathology is identical to HIE lesions seen in term infants.

A distinction is often made between HIE in premature infants, which is PVL, and HIE in mature infants, which affects predominantly the cortex and deep nuclei. This is an oversimplification. Pathological and volumetric MRI studies show that, in PVL, there is loss of neurons (and reduction in mass) in the cortex and deep nuclei, especially the thalamus. Moreover, 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

Updated: July, 2017

Top of Page