AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Differentials
• CT SCAN
• MRI
• Ultrasound
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Differentials
• CT SCAN
• MRI
• Ultrasound
• Acknowledgments
• Multimedia
• References

Background

Periventricular leukomalacia (PVL) is the second most common CNS complication in preterm infants, after periventricular hemorrhage. PVL is caused by ischemia in the watershed territory of the preterm infant.

Pathophysiology

PVL is pathologically characterized by the softening of periventricular white matter as a result of vascular ischemia between 26 and 34 weeks of gestation. The watershed area between different vascular territories is in the periventricular region in preterm infants, unlike full-term infants, in whom it is located in the cortical and subcortical region. This area is the watershed between penetrating arterial vessels from the cortex and vessels arising from deep ventricular margins

Any vascular insult to the brain during this critical period, especially in the perinatal period when metabolic demand is high, results in ischemia of periventricular region, which is supplied by medullary arteries from the cortical surface. The regions in the periventricular white matter most commonly affected are the optic radiation, the trigone of the corpus callosum, and the frontal periventricular region. PVL specifically affects the corticospinal tract, the sensory association fibers, the visual tract, and the auditory tract, producing debilitating cerebral palsy and visual and auditory symptoms. Ischemia is most severe in the oligodendroglia that forms myelin; hence, myelination is impaired. Cytokines are also released and aggravate the injury.

Acute and chronic stages

In the acute stage, coagulation necrosis affects the periventricular white matter. Macrophages migrate to the lesion, and vascular dilation occurs. Microscopic calcifications develop are occasionally seen on MRI.

The infarcted tissue subsequently liquefies (2-3 wk), producing microcystic changes, which usually disappear but occasionally persist. Cavitation and cyst formation are characteristic findings.

Further changes depend on the age of the injury. If the injury occurs before 26 weeks, no scar tissue forms, and the damaged tissue is reabsorbed. However, if the injury occurs after 26 weeks, gliosis ensues.

Hemorrhage is seen in a subtype of PVL (25%). A subacute stage is identified.

Predisposing factors

Factors predisposing individuals to PVL include the following: preterm birth, steroid treatment in preterm infants, premature rupture of the membranes, chorioamniotis, and high bilirubin level.

Frequency

United States

PVL has incidence rates of 10-83% at 23 weeks' gestation, 10-22% at 25 weeks' gestation, and an estimated 1.1% in neonates born after 29 weeks' gestation.

International

The prevalence of PVL varies with the series: Pierrat et al reported 2.8%, Bass et al reported 3.6% in neonates weighing less than 1500 g, and Perlman et al noted a 2.3% prevalence of cystic PVL in those weighing less than 1750 g. Zupan et al found a prevalence of 9.2%.

Mortality/Morbidity

PVL is a debilitating condition that results in developmental delay and delayed myelination.

Clinical Details

Clinical features

The periventricular location of the lesion affects mainly the corticospinal tracts and optic radiations. Cognitive function substantially declines in bilateral PVL. Involvement of motor functions may result in spastic monoplegia, diplegia, or hemiplegia.

Patients may have decreased visual acuity, insufficient holding of the upgaze, a decreased visual field, abnormal eye movements, opticokinetic nystagmus, and abnormal visual evoked potentials. These visual effects are mainly due to abnormalities in the retrochiasmatic optic pathway, particularly the optic radiation. Visual symptoms can be the cause of the motor and cognitive abnormalities. Weakness of the lower extremity and abnormal visual evoked potentials are the earliest problems. Because the brain is not fully functional at the time of insult, the sequelae become obvious only with time. Spastic diplegia is common in lower limb. The upper limbs are involved and intellectual deficits are common in severe cases. Visual deficits due to involvement of the occipital radiation.

Other problems to be considered

Other problems to be considered in the diagnosis of PVL are frontal horn cysts, isolated subependymal cysts, and pseudocysts.

Frontal-horn cysts are well-defined, smooth-walled cysts occasionally seen in term infants. The origin of these cysts is yet unclear, and different theories have been proposed. They may arise as diverticula from the frontal horn of the lateral ventricle and eventually disappear or might persist as cysts during a part of development. They may arise from necrosis or trapping or ependymal and/or choroidal cells in the germinal matrix. They could be hamartomatous lesions.

Ependymal cells line frontal-horn cysts. They grow as a result of the secretory activity of the ependymal cells, and the cysts eventually atrophy when the secretory activity of the ependymal cells stops. They have a prevalence of approximately 0.7% and no neurologic sequelae. These cysts are easily differentiated from cysts of PVL, which are small, irregular, and multiseptate and which occur in young individuals.

PVL can be seen in term infants, away from the ependyma. It is also seen after surgical repair of congenital heart disease because of hypothermia and bypass. It can be associated with hemorrhages of the germinal matrix.

Preferred Examination

Ultrasonography is the common and most easily available examination. Sonography is good for assessment in the early stages, and the results are good predictors in subacute and chronic changes. Ultrasonography can make differentiation of the normal periventricular halo and homogenous periventricular flares difficult, but MRIs do not show notable changes in the homogenous flares. Because PVL is a disease of premature infants, who are often assisted with ventilators, ultrasonography is the easiest modality, which also saves the problem of transporting the child to a CT or MRI.

MRI was originally thought to be superior to other investigations in only the subacute and chronic phases. However, recent studies showed that MRI is also good in identifying and characterizing acute changes. MRI shows extensive, large lesions and hemorrhages. The findings are also good predictors of the eventual outcome in that patients with many changes in acute stage eventually develop cystic changes.

A single examination may not be enough to diagnose PVL in early infancy. A combination of sonography, MRI, and CT is useful for diagnosing PVL and for predicting the neurologic outcome. Ultrasonography is usually performed twice a week in the first week and once a week thereafter for diagnosis. Results of MRI performed between 12 and 18 months confirm the diagnosis, and the results are predictive of the ultimate neurologic outcome.

DIFFERENTIALS

Section 3 of 9  

• Authors and Editors
• Introduction
• Differentials
• CT SCAN
• MRI
• Ultrasound
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

Frontal horn cyst
Isolated subependymal cyst
Pseudocyst

CT SCAN

Section 4 of 9  

• Authors and Editors
• Introduction
• Differentials
• CT SCAN
• MRI
• Ultrasound
• Acknowledgments
• Multimedia
• References

Findings

CT scanning shows ill-defined hypoattenuating ischemic areas in the periventricular white matter. This finding is difficult to distinguish in the highly hydrated, low attenuation of the unmyelinated premature brain matter. Hence, CT is not used in the diagnosis is PVL. CT is most useful if hemorrhage is present. In severe injuries, extensive bilateral edema produces low attenuation, which produces ventricular compression. These findings are difficult to identify.

In the subacute stage, the ventricles have an irregular contour. The white matter is decreased in the periventricular region. Deep sulci are seen adjacent to the lateral ventricle due to a loss of white matter.

In the chronic stage, periventricular cysts are seen.

In the end stage, volume is lost along the lateral margins. Other findings are irregularly dilated ventricles and cortical gray matter extending deep towards ventricular walls. On gross inspection, an undulated ventricular wall is a typical feature. An elongated head due to loss of periventricular white matter is another feature. (A differential diagnosis is scaphocephaly.)

CT findings of end-stage PVL are irregular enlargement of the body and trigone of lateral ventricles; decreased white matter, which is conspicuous in the trigone but also in the centrum semiovale in severe cases; and deep sulci abutting the white matter due to loss of white matter.

Degree of Confidence

The neurologic outcome can be predicted on the basis of the size and location of the cysts. Cysts smaller than 1 cm have a normal neurologic outcome. The risk of cerebral palsy is high in cysts larger than 1 cm, especially in those larger than 2 cm. Cysts located in only the frontal region do not affect the outcome. Cysts located bilaterally and in the parieto-occipital region pose a high risk of cerebral palsy.

False Positives/Negatives

The differential diagnosis of irregular ventricular walls includes PVL ventriculitis, ventricular hemorrhage, and disseminated tumor.

MRI

Section 5 of 9  

• Authors and Editors
• Introduction
• Differentials
• CT SCAN
• MRI
• Ultrasound
• Acknowledgments
• Multimedia
• References

Findings

Detecting PVL in acute stages is difficult because of the similar intensities of infarct and unmyelinated brain matter. However, T1-weighted MRIs sometimes show low signal intensity in the early stages, and T2-weighted MRIs show high signal intensity in the periventricular region. These appearances are due to periventricular ischemic changes. Diffusion images are more sensitive than these and show abnormal high signal due to restricted motion of intracellular water. These areas are seen as low signal on images of the apparent diffusion coefficient (ADC). Magnetic resonance (MR) spectroscopy can show high levels of lactate.

Areas of hemorrhage are seen as high signal intensity on T1-weighted images and low signal intensity on T2-weighted images. Punctate areas of high signal on T1-weighted MRIs that are in large area of high signal intensity on T2-weighted MRIs are seen as early as 2-3 days after the injury. Low signal intensity on T2-weighted MRIs appears in 6-7 days.

In the subacute phase, high T1 signal can be due to transient calcification at site of ischemia. Contrast enhancement is also seen.

Cysts subsequently form because of necrosis of periventricular tissue. The cysts shrink in 3-4 weeks, and the abnormal signal areas approach the ventricular wall and eventually disappear.

Sequela of PVL includes atrophic changes in the cerebral parenchyma, loss of periventricular white matter, deep and prominent sulci that abut the ventricles with little or no white matter, irregularly dilated ventricles, cyst formation, and atrophy of the corpus callosum and thalamus. The volume of brainstem can be decreased. Thinning of corpus callosum is due to degeneration of transcallosal fibers and is most commonly seen in the splenium and posterior body.

Other patterns of injury in ischemic hypoxic damage can also occur. These can involve necrosis in basal ganglia, central cortical and subcortical damage, and multicystic encephalopathy.

Sie et al (2000) reported an MRI grading system for PVL, as follows: Grade I = normal MRI; grade II = altered periventricular intensity; grade III = fewer than 6 punctuate hemorrhages in the white matter; grade IV = multiple punctuate hemorrhages, a few large focal hemorrhages, and/or small periventricular cysts; grade V = extensive signal intensity changes within hemorrhagic and/or cystic lesions in the white matter with minimal focal extension into the subcortical region; and grade VI = diffuse signal intensity changes within hemorrhagic and/or cystic lesions in the white matter and subcortical region.

Murgo et al (1999) described a combined sonographic and MRI grading system, as follows: Grade I = periventricular hyperechogenicity > 1 week, with MRIs negative for PVL; grade 2 = periventricular hemorrhage and/or decreased white matter on MRIs; and grade 3 cysts.

Argyropoulou et al (2003) demonstrated the following findings, which are due to the loss of white matter:decrease in anteroposterior (AP) diameter of the pons, decrease in the volume of the cerebellum, decrease in the area of the corpus callosum, and decrease in the area of the vermis.

The correlation between these measurements and the severity of PVL is good. The measurements are lowest in patients who received prolonged mechanical ventilation.

In end-stage PVL, T2-weighted MRI shows abnormally high signal intensity in the bilateral peritrigonal regions and delayed myelination, which is most common in patients with a young gestational age. This appearance resembles normally unmyelinated areas of white matter. However, a thin band of myelinated white matter in the splenium and tapetum separated these normal areas from the wall of ventricles. The abnormal signal in PVL is in direct contact with the ventricular wall. These findings are best seen on coronal T2-weighted images and may not be seen on axial MRIs. The association with loss of volume of cerebral white matter and irregularly dilated ventricles are other helpful features. These changes are best seen on T2-weighted, proton density–weighted, or fluid attenuated inversion recovery (FLAIR) images. If injury occurs in second trimester, loss of white matter occurs without gliosis

Degree of Confidence

MRI is sensitive in the subacute and chronic phases of PVL. The severity of changes on MRI is well correlated with neurologic outcomes, such as cerebral palsy, visual impairment, and delayed motor development. MRI is the best modality for assessing delayed myelination of the white matter.

However, Sie et al (2000) reported that MRI is useful even in the early acute stages of hypoxic-ischemic injury. In their study, 64% of patients had hemorrhagic lesions ranging from punctuate to gross lesions on MRI.

MRI is also useful for characterizing the exact site and extent of the PVL in the early stages, and it is better than ultrasonography for differentiating early stages. MRI shows more cysts than sonography does. MRI shows changes in signal intensity, hemorrhages, and cysts, even when sonograms show only periventricular echogenicity. Findings on MRI are good predictors of the final sonographic score. Moreover, MRI is superior to sonography in predicting neurologic outcomes in patients with noncystic PVL because sonographic findings are nonspecific in these instances.

Interobserver and intraobserver correlation are better with MRI than with sonography in cases of cystic PVL. The neurologic defect in noncystic PVL and the paucity of white matter are milder than that of cystic PVL.

The presence of hemorrhage on MRI is a bad prognostic factor. However, in some studies, hemorrhage was found frequently, and its exact prognostic significance is not yet clear.

The correlation between MRI changes in the acute stage and the eventual sonographic grade is good. Patients with normal or minimal MRI changes do not develop severe cystic changes. However, those with severe MRI changes eventually have severe cystic changes.

False Positives/Negatives

Many conditions produce periventricular T2 high signal and volume loss, including ventriculitis, inborn errors of metabolism, hydrocephalus, and in utero damage.

ULTRASOUND

Section 6 of 9  

• Authors and Editors
• Introduction
• Differentials
• CT SCAN
• MRI
• Ultrasound
• Acknowledgments
• Multimedia
• References

Findings

In preterm infants, ultrasonography is done twice a week in the first week and once a week thereafter to detect periventricular hemorrhage and leukomalacia.

Findings in the acute, subacute, and chronic stages

In the acute stage, sonograms show ill-defined, hyperechoic areas in the periventricular region. In comparison to the normal periventricular halo, this hyperechogenicity is brighter than that of choroid plexus. This appearance manifests 24-48 hours after the ischemic injury. It is particularly bright if periventricular hemorrhage is present. In the subsequent 1-2 weeks, these areas become less hyperechoic than before.

Although DiPietro et al indicated that irregular, inhomogeneous flares indicate hemorrhagic PVL, hemorrhagic or nonhemorrhagic PVL are difficult to predict on the basis of its sonographic appearance. Sie et al (2000) found a direct correlation between irregular, inhomogeneous periventricular flares and the development of hemorrhagic and cystic changes on MRI. Hence, the presence of an irregular flare is an important prognostic indicator.

In the subacute stage, the ventricular margins are irregular because of atrophic changes. In the chronic stage, well-defined hypoechoic cysts are seen in the periventricular regions. The cysts are large if hemorrhage occurred. The ventricles are large and irregular because of atrophic and ischemic changes. The cysts eventually disappear as the ventricles enlarge and the damaged tissue is reabsorbed.

Grading of periventricular densities and PVL

Periventricular densities and PVL are graded as follows (de Vries, 1992): Grade I includes periventricular flares less than 1 week old. Grade II involves periventricular flares more than 1 week old (PVL grade I). Grade III indicates small periventricular cysts (PVL grade II).Grade IV is defined as extensive periventricular cysts (PVL grade III). Grade V is multicystic leukomalacia in the periventricular and subcortical region (PVL grade IV).

In grade II, the cysts often develop after the first month, but in grade III, the cysts develop in the first 2-3 weeks. About 54% of all grade II cysts are unilateral despite the early appearance of bilateral periventricular densities. However, all grade III cysts are bilateral. Grade II cysts are most common in the anterior frontal periventricular region and least common in the parietal and occipital regions. More than 85% of grade III cysts are seen in the parieto-occipital periventricular region.

Cerebral palsy is less common in grade II PVL than in disease of other grades. The location of the cysts is not correlated with neurologic outcome in grade II, unlike grade III.

A modified sonographic grading system is as follows (Sie, 2000): Grade IA includes transient flares involving periventricular densities less than 1 week old. Grade IB includes homogenous periventricular densities more than 1 week old. Grade II includes inhomogeneous periventricular densities more than 1 week old. Grade III includes periventricular densities evolving into small cysts. Grade IV is defined as periventricular densities evolving into extensive cysts. Grade V involves densities in the periventricular and subcortical regions with extensive and evolving periventricular and subcortical cysts.

Ventriculomegaly indicates white-matter disease and is predictive of a poor neurologic outcome. Ventriculomegaly can also be a sequela of periventricular hemorrhage, which has a good prognosis. Ventricular enlargement is irregular in PVL and smooth in periventricular hemorrhage.

Degree of Confidence

Ultrasonography is sensitive in the acute stage of PVL. Difficulties arise in small or bilaterally symmetrical cases. Affected areas also appear similar to normal areas of high echogenicity in the periventricular region. Sonography is not as sensitive as MRI in the subacute and chronic stages. Ultrasonography can depict 28-80% of all cases of pathologically detected PVL. It is superior to MRI in the detection of cysts, though the cysts can be transient and missed on sonograms.

Sonographic findings are well correlated with the neurologic outcome. The presence of cysts on sonograms indicates that the disease is severe and that the prognosis is poor, with adverse neurologic outcomes. The development of cysts, as shown on sonograms, is also correlated with volume loss on MRIs and a poor neurologic outcome.

Levine et al indicated that cranial ultrasonography performed at 40 weeks provides the best predictor of neurologic outcome. Almost all patients with bilateral frontal, occipital, and parietal white-matter lesions develop cerebral palsy: 35% of patients with small lesions, and 65% with medium lesions develop cerebral palsy. Irregular, inhomogeneous, periventricular echogenicities shown on sonograms and hemorrhage depicted on MRIs are well correlated with subsequent severe cystic PVL.

One of the difficulties is differentiating normal periventricular halos from periventricular flares of PVL. The periventricular flare of PVL is brighter than the choroid plexus, unlike the halo, which is not as bright.

The findings are operator dependent, and considerable intraobserver and interobserver variation can occur.

Sonography is not good for assessing the exact grade of the PVL. It cannot be used to assess the cortical region and the structures of the posterior fossa.

Studies have shown that ultrasonography is inferior to MRI in assessing the exact extent and severity of PVL. It may be useful in the premature infants younger than 29 weeks, in whom sonograms show only moderate homogenous periventricular flares. However, Carson et al indicated that these changes are normal findings in very premature infants; therefore, MRIs are normal.

False Positives/Negatives

Ultrasonography may not help in differentiating the normal periventricular halo from the homogenous periventricular flare in the early acute stage of the disease. However, this differentiation is not essential because a homogenous flare can be seen in healthy individuals in premature infants and because homogenous flares are not associated with clinically significant changes on MRI.

ACKNOWLEDGMENTS

Section 7 of 9  

• Authors and Editors
• Introduction
• Differentials
• CT SCAN
• MRI
• Ultrasound
• Acknowledgments
• Multimedia
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous coauthor Dr Biswaranjan Banerje to the development and writing of this article.

MULTIMEDIA

Section 8 of 9  

• Authors and Editors
• Introduction
• Differentials
• CT SCAN
• MRI
• Ultrasound
• Acknowledgments
• Multimedia
• References

Media file 1:  Acute stage of periventricular leukomalacia (PVL). Fluid-attenuated inversion recovery (FLAIR) MRI shows bilateral periventricular hyperintensity.
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Media file 2:  High signal on a T1-weighted image obtained adjacent to the frontal horn of the right lateral ventricle. This is hemorrhagic periventricular leukomalacia (PVL).
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Media file 3:  Cystic change in periventricular white matter adjacent to the right lateral ventricle.
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Media file 4:  Mildly high signal intensity in the trigonal region secondary to periventricular leukomalacia (PVL).
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Media file 5:  Bilateral symmetrical periventricular hyperintensities and an enlarged occipital horn, especially on the right side.
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Media file 6:  Another case of late-stage periventricular leukomalacia (PVL). Fluid-attenuated inversion recovery (FLAIR) image shows bilateral symmetrical periventricular hyperintensities.
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Media file 7:  Distorted occipital horns due to periventricular leukomalacia (PVL).
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Media file 8:  Late-stage periventricular leukomalacia (PVL). Asymmetrical loss white matter, more on the right side than on the left, with a distorted frontal horn of the right lateral ventricle.
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Media file 9:  Late-stage periventricular leukomalacia (PVL). Loss of periventricular white matter and dilated lateral ventricles.View Details
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Media file 10:  Severe late-stage periventricular leukomalacia (PVL). Extensive loss of white matter on the right side, with a grossly dilated frontal horn of the right lateral ventricle. Image shows atrophy of the brain parenchyma on both sides that is more marked on the right side than on the left. Note the sulci extending almost up to the ventricular margin; this is due to a loss of white-matter volume.
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Media file 11:  Axial image of late-stage periventricular leukomalacia (PVL) shows a dilated right occipital horn with irregular margins and periventricular high signal intensity.
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Media file 12:  Axial image shows a distorted right lateral ventricle and cortical atrophy with prominent and deep sulci.
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Media file 13:  T2-weighted image in another patient with Late-stage periventricular leukomalacia (PVL) shows a distorted occipital horn on the left side with atrophy and deep sulci that almost reach the ventricular margin.
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Media file 14:  Late-stage periventricular leukomalacia (PVL). Sagittal T1-weighted MRI shows an atrophied, irregular corpus callosum and atrophic brain parenchyma.
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Media file 15:  Sagittal T1-weighted MRI of late-stage periventricular leukomalacia (PVL) shows atrophy of the corpus callosum, cerebral parenchyma, and brainstem. Prominent sulci, many of which reach the ventricular margin, are depicted.
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REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Differentials
• CT SCAN
• MRI
• Ultrasound
• Acknowledgments
• Multimedia
• References

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Article Last Updated: Jul 14, 2006