Pathology of Periventricular Leukomalacia

Periventricular leukomalacia (PVL) is a term used to describe cerebral white matter injury with both focal and diffuse components. ^{[1, 2]} In relatively recent years, this terminology has been somewhat controversial, as PVL reflects a categorization by neuropathologic findings. There have been suggestions that "white matter injury" be used instead, of which PVL would be a subcategory. ^[3]

The focal component of PVL consists of localized necrosis with loss of all cellular elements deep within the periventricular white matter, usually around the upper and outer angles of the lateral ventricles (see the images below). Older lesions may become cystic. The diffuse component of PVL more widely affects the cerebral white matter and is characterized by marked astrogliosis and microgliosis, and, initially, by a decrease in premyelinating oligodendrocytes and subplate neurons. ^{[1, 4, 5]}

Pathology of Periventricular Leukomalacia. Gross appearance of acute periventricular leukomalacia (PVL). A white dot (arrow) is seen at the upper, outer angle of the lateral ventricle in this coronal brain section.

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Pathology of Periventricular Leukomalacia. Gross appearance of older periventricular leukomalacia (PVL) lesion. Cystic cavities (arrow) are seen at the upper, outer angle of the lateral ventricle.

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PVL is the most common type of brain injury affecting survivors of premature birth (< 32 weeks' gestation, very low birth weight [VLBW] [< 1500 g] infants). ^[6] Imaging studies report 50% or more of VLBW infants show findings consistent with this condition. ^[1] Clinical sequelae of cognitive, behavioral, attentional, or socialization deficits are found in 25-50% of VLBW infants, whereas major motor deficits (eg, cerebral palsy) are seen in 5-10%. ^[1]

The differential diagnosis of PVL includes diffuse white matter gliosis and periventricular venous infarction.

See Periventricular Leukomalacia for more details.

Epidemiologic studies demonstrate that periventricular leukomalacia (PVL) is highly associated with prematurity and less so with chorioamnionitis. ^[7] A study by Herzog et al found that maternal obesity and chorioamnionitis increase the risk of PVL beyond that expected solely from prematurity. ^[8]

The pathogenesis of PVL is thought to relate to a confluence of factors that make the premature white matter vulnerable to injury and include two broad upstream mechanisms: ischemia and inflammation. ^{[9, 10, 11]}

The propensity of premature infants to cerebral ischemia is thought to be due to: (1) intrinsic vascular anatomic factors—susceptible areas of the cerebral white matter lie in the distribution of end zones of deep penetrating arteries and are thus highly vulnerable to even minor decreases in cerebral perfusion; and (2) impaired regulation of cerebral blood flow due to immaturity of intrinsic vasoregulatory mechanisms. Inflammation (often due to maternal and/or fetal infection) contributes through upregulation of cytokines and diffuse microglial activation with generation of free-radicals. Furthermore, oligodendroglial precursors, which are abundant in the white matter during this period of development, are particularly vulnerable to free-radical damage as well as to excitotoxicity. ^[12]

Molecular/genetic factors

Investigation of possible genetic factors underlying susceptibility to perinatal brain injury suggests polymorphisms in cytokine and coagulation pathway genes may be risk modifiers for PVL. ^[13]

Periventricular leukomalacia (PVL) most commonly arises in the setting of a sick premature infant. Clinical signs secondary to PVL are often undetected in the newborn period, with the injury instead documented using neuroimaging techniques. However, with improved survival of very low birth weight infants, clinical sequelae including cognitive, behavioral, attentional, or socialization deficits are found in 25-50%, whereas major motor deficits/cerebral palsy are seen in 5-10% of these children. ^[1]

Cranial ultrasonography, computed tomography (CT) scanning, and magnetic resonance imaging (MRI) can all be used to detect injury to the premature brain—each has its relative strengths as well as weaknesses. (See Periventricular Leukomalacia Imaging.)

Cranial ultrasonography

This imaging modality is commonly used for detection of cystic PVL, and a characteristic progression of imaging features has been well documented. ^[14] During the first week following injury, there are echogenic foci in the periventricular white matter due to local necrosis with congestion and/or hemorrhage. This is followed, during weeks 1-3, by the appearance of echolucent cysts, which correlates with cyst formation due to tissue dissolution. By 2-3 months, ventriculomegaly appears, often with disappearance of the cysts.

Ultrasonography is, however, relatively insensitive for the detection of diffuse noncystic white matter injury and, thus, for predicting cognitive disabilities. For this, MRI is much more sensitive. ^{[15, 16]}

Magnetic resonance imaging

MRI is much more sensitive than ultrasonography in detecting diffuse noncystic PVL and predicting cognitive disabilities; however, studies correlating these findings with long-term clinical sequelae are lacking. Instead, most studies with long-term clinical follow-up have focused on the use of MRI for investigation of patients diagnosed with PVL by ultrasonography during the perinatal period. Studies of adolescents who were born very premature show reductions in overall brain volume, including white and gray matter, with an increase in size of the lateral ventricles. ^[17] These alterations in cerebral volumes are associated with cognitive and motor deficits. ^{[18, 19]}

Only a small minority of periventricular leukomalacia (PVL) lesions is readily apparent macroscopically during the perinatal period, namely those lesions that fall into the category of cystic PVL. The most acute lesions are not seen grossly but become visible as white spots, approximately 2-6 mm in size, several days after the insult due to infiltration of macrophages (see the image below).

Pathology of Periventricular Leukomalacia. Gross appearance of acute periventricular leukomalacia (PVL). A white dot (arrow) is seen at the upper, outer angle of the lateral ventricle in this coronal brain section.

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These lesions are usually found at the upper, outer angles of the lateral ventricles at the level of the foramen of Monroe, the lateral regions of the trigone and occipital horns, and anterior to the frontal horns. After several weeks, these lesions cavitate, leaving cystic spaces, which may eventually collapse to form glial scars in the same regions. See the image below.

Pathology of Periventricular Leukomalacia. Gross appearance of older periventricular leukomalacia (PVL) lesion. Cystic cavities (arrow) are seen at the upper, outer angle of the lateral ventricle.

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With severe damage, ventriculomegaly will be apparent, and there may be an overall reduction in cerebral volume and thinning of the corpus callosum.

Focal lesions of periventricular leukomalacia (PVL) represent areas of coagulative necrosis that are apparent within 24 hours of the insult (see the image below). These areas are characterized by hypereosinophilia and nuclear pyknosis.

Pathology of Periventricular Leukomalacia. Acute microscopic appearance of periventricular leukomalacia (PVL). Within 24 hours, PVL lesions can be recognized microscopically as hypereosinophilic areas within the periventricular white matter.

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Axonal spheroids can usually be found around the lesion. Within 3-5 days, macrophages begin to infiltrate and, by approximately 1 week, reactive astrogliosis can be seen at the margins. See the following images.

Pathology of Periventricular Leukomalacia. Microscopic appearance of subacute periventricular leukomalacia (PVL). At this stage (about 3-5 days) there is macrophage infiltration.

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Pathology of Periventricular Leukomalacia. Microscopic appearance of subacute periventricular leukomalacia (PVL). This higher power view of the previous image shows the macrophage infiltration and early reactive gliosis at the margin of the lesion.

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After several weeks, there is cavitation with cyst formation. Some cysts may collapse to form a glial scar which may be associated with mineralized axons. Foamy macrophages may be found in the region for months after the insult. The diffuse component of PVL consists of widespread astrogliosis and microgliosis and, initially, by a decrease in premyelinating oligodendrocytes. ^[1] Perivascular amphophilic globules and/or mineralizations may be present. Reduced premyelinating oligodendrocytes results in a deficit of mature, myelin-producing oligodendrocytes and, as a consequence, cerebral hypomyelination with white matter pallor. ^[20]

Pathology of Periventricular Leukomalacia. Microscopic appearance of periventricular leukomalacia (PVL). The diffuse component of PVL is characterized by marked astrogliosis with reactive-appearing astrocytes.

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PVL is also frequently associated with neuronal loss and/or gliosis in gray matter structures, including the thalamus, basal ganglia, and cerebral cortex. These changes may result from direct injury, secondary maturational/trophic disturbances, or both. ^[1]

Infiltrating macrophages and activated microglia can be identified with immunohistochemical staining for CD68. Glial fibrillary acidic protein (GFAP) highlights the diffuse astrogliosis component of periventricular leukomalacia (PVL) (see the image below). Human beta-amyloid precursor protein immunostaining can be used as a marker of damaged axons and may be helpful in highlighting more subtle focal lesions of PVL. More experimentally, markers for various cytokines and reactive oxygen species have been used to investigate the underlying pathogenesis.

Pathology of Periventricular Leukomalacia. Microscopic appearance of periventricular leukomalacia (PVL). Immunohistochemical stain for glial fibrillary acidic protein (GFAP) highlights the diffuse white matter astrogliosis component of PVL.

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The clinical sequelae of periventricular leukomalacia (PVL) include major motor deficits/cerebral palsy, which are most highly correlated with cystic PVL. The diffuse component of PVL is thought to correlate with subsequent cognitive, behavioral, attentional, and socialization deficits. ^{[1, 21]}

Most studies have looked at the ability of imaging modalities including ultrasonography and magnetic resonance imaging (MRI) to predict clinical outcome. Head ultrasonograms before 32 weeks' gestation are able to predict subsequent cerebral palsy with a positive predictive value of, at best, about 50%. ^[14] This modality is very poor at predicting subsequent cognitive disabilities. However, the presence of parenchymal lesions by conventional MRI studies obtained at corrected term age have a sensitivity of 100% and specificity of 79% for motor abnormality. ^[22] Early studies suggest that MRI may be a more sensitive predictor of cognitive outcome as well. ^[23]