PERIVENTRICULAR LEUKOMALACIA

Periventricular leukomalacia (PVL) is a form of ischemic white matter lesion which affects premature infants especially ones with cardiorespiratory abnormalities and sepsis. Very low birth weight (VLBW) infants between 24-32 weeks gestation are most vulnerable but mature infants, especially those with congenital heart disease, may be affected. In VLBW infants, PVL usually develops in the neonatal period but may also occur in utero. There are 3 "grades" of PVL: focal cystic necrosis (cystic PVL) , focal microscopic necrosis, and diffuse, nonnecrotic, diffuse white matter injury (WMI) . Today, thanks to improved neonatal intensive care, cystic PVL is infrequent. The most common pattern is diffuse WMI.


Acute PVL

PVL-Axonal swellings

Cystic PVL

PVL-Calcified lesions

In cystic PVL, the most severe form, bilateral, roughly symmetric foci of white matter necrosis, involving all cellular elements, 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 and can be detected also 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).


Diffuse white matter gliosis

Diffuse white matter injury

In focal microscopic necrosis, small necrotic lesions form microcysts or do not cavitate at all but collapse into glial scars. Diffuse noncystic WMI is characterized by hypomyelination, gliosis, decreased white matter mass, dilatation of the lateral ventricles, and atrophy of the corpus callosum. Cortical ischemic lesions and diffuse loss of cortical and thalamic neurons are present in some cases.


PVL-cranial ultrasound

Cystic PVL-MRI

The method of choice for the diagnosis of cystic PVL is cranial ultrasound (US). 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.


PVL-MRI of advanced lesion

PVL-MRI of advanced lesion

PVL-MRI of advanced lesion

The MRI/is more accurate than US for the detection of focal microscopic necrosis and diffuse WMI and for following-up of acute lesions detected earlier by US. The MRI findings in diffuse WMI are 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.

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 diffuse WMI affecting preterm infants. In patients with CHD, WMI is caused by cerebral ischemia and hypoxia which occur 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.

PVL is caused by hypoxia/ischemia and by infection. In cystic PVL, ischemia, causes white matter necrosis (infarction) that affects all tissue elements, including axons and oligodendrocytes. 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.

Diffuse WMI is caused by selective damage of premyelinating oligodendrocytes (pre-OL). In the premature brain, there is no myelin. The white matter is populated by oligodendrocyte (OL) precursors that evolve in 3 stages: OL progenitors, pre-OLs, and immature OLs. The principal targets of oxygen and nitrogen radicals and of glutamate are 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 diffuse WMI is loss of pre-OLs and the main outcome is deficient myelination.

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.

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.


HPeV3 meningoencephalitis
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.


HIE-thalamic and hippocampal lesions

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: October, 2020

Back to top of page