Pediatric Periventricular Leukomalacia 

Updated: Jan 15, 2015
Author: Terence Zach, MD; Chief Editor: Ted Rosenkrantz, MD 

Overview

Background

Periventricular leukomalacia (PVL) is the most common ischemic brain injury in premature infants. The ischemia occurs in the border zone at the end of arterial vascular distributions. The ischemia of periventricular leukomalacia occurs in the white matter adjacent to the lateral ventricles. The traditional diagnostic hallmarks of periventricular leukomalacia are periventricular echodensities or cysts detected by cranial ultrasonography, as shown below. More recently MRI studies have demonstrated a relatively common diffuse non-cystic form of periventricular leukomalacia in premature infants. Diagnosing periventricular leukomalacia is important because a significant percentage of surviving premature infants develop cerebral palsy (CP), intellectual impairment, or visual disturbances.

Cranial ultrasound, coronal view, in a 3-week-old Cranial ultrasound, coronal view, in a 3-week-old premature infant. Multiple bilateral periventricular cysts are typical of this stage of periventricular leukomalacia (PVL). Courtesy of Matthew Omojola, MD.

Pathophysiology

The pathophysiology of periventricular leukomalacia is a complex process. Periventricular leukomalacia occurs because of ischemia induced injury to oligodendrocytes in the periventricular area of the developing brain. Cytokine-induced damage following maternal or fetal infection may play a role.

Periventricular leukomalacia is a white matter lesion in premature infants that results from hypotension, ischemia, and coagulation necrosis at the border or watershed zones of deep penetrating arteries of the middle cerebral artery.

Several factors related to vascular development make the periventricular region of the preterm brain uniquely sensitive to ischemic injury. First, early in development, the deep penetrating arteries that supply the watershed zone of the periventricular white matter lack the vascular anastomoses that help maintain perfusion during periods of hypotension. As the fetus matures, the number of anastomoses between the deep penetrating arteries increases, and the periventricular white matter becomes less susceptible to small decreases in blood pressure.

The second vascular developmental factor that plays a role in periventricular leukomalacia is related to cerebral autoregulation. Premature infants have impaired cerebrovascular blood flow autoregulation, increasing their susceptibility to periventricular leukomalacia and intracranial hemorrhage (ICH). Decreased blood flow affects the white matter at the superolateral borders of the lateral ventricles. The site of injury affects the descending corticospinal tracts, visual radiations, and acoustic radiations.

Maternal infection, placental inflammation, and vasculitis are also important in the pathogenesis of periventricular leukomalacia. A link between maternal infection, preterm birth, and CNS injury has been established by epidemiological studies.[1, 2] A role for infection and cytokine-induced injury in periventricular leukomalacia is strengthened by studies that demonstrate the presence of tumor necrosis factor in periventricular leukomalacia lesions[3] and in the cerebrospinal fluid (CSF) of infants with cerebral white matter injury.[4]

After the initial insult, either ischemia or inflammation, injury to the immature premyelinating oligodendrocytes occurs by either free radical attack or by excitotoxicity. The preterm infant is particularly sensitive to oxygen free radical attack because of delayed development of superoxide dismutase and catalase.[5]

In a 2014 report, Inomata et al suggested that combined elevations in serum levels of interleukin (IL) 6 and C-reactive protein (CRP) at birth are predictive of white matter injury in preterm infants with a fetal inflammatory response (FIR).[6]

Injury to the premyelinating oligodendrocytes results in astrogliosis and microgliosis. This results in a deficit of mature, myelin-producing oligodendrocytes, which leads to cerebral hypomyelination.[7]

Premature infants on mechanical ventilation may develop hypocarbia. Several studies have linked hypocarbia, particularly in the first few days of life, with the development of periventricular leukomalacia.[8, 9] Cumulative exposure during the first 7 days of life has been shown to independently increase the risk of periventricular leukomalacia in low birth weight infants.[10, 11]

Epidemiology

Frequency

United States

The incidence of periventricular leukomalacia ranges from 4-26% in premature infants in neonatal intensive care units (NICUs). The incidence of periventricular leukomalacia is much higher in reports from autopsy studies of premature infants. As many as 75% of premature infants have evidence of periventricular leukomalacia on postmortem examination.

Prognosis

Infants with periventricular leukomalacia are at risk for development of neurodevelopmental deficits. Mild periventricular leukomalacia is often associated with spastic diplegia. Severe periventricular leukomalacia is associated with quadriplegia. Severe periventricular leukomalacia is also associated with a higher incidence of intelligence deficiencies and visual disturbances.

Morbidity/mortality

Periventricular leukomalacia occurs most commonly in premature infants born at less than 32 weeks' gestation. Many infants with periventricular leukomalacia later develop signs of CP. Spastic diplegia is the most common form of CP following mild periventricular leukomalacia. Severe periventricular leukomalacia is frequently associated with quadriplegia.

Varying degrees of intellectual impairment, developmental impairment, or both have been reported in association with periventricular leukomalacia. Fixation difficulties, nystagmus, strabismus, and blindness have been associated with periventricular leukomalacia. Some cases of visual dysfunction in association with periventricular leukomalacia occur in the absence of retinopathy of prematurity, suggesting damage to optic radiations as causation.

 

Presentation

History

Periventricular leukomalacia (PVL) occurs most commonly in premature infants born at less than 32 weeks' gestation who have a birth weight of less than 1500 g. Many of these infants have a history of maternal chorioamnionitis. Most affected infants experience cardiorespiratory problems, such as respiratory distress syndrome or pneumonia, in association with hypotension or patent ductus arteriosus during their first days of life. Bacterial infection at birth also appears to be a risk factor.

Physical

Initially, most premature infants are asymptomatic. If symptoms occur, they are usually subtle. Symptoms may include the following:

  • Decreased tone in lower extremities

  • Increased tone in neck extensors

  • Apnea and bradycardia events

  • Irritability

  • Pseudobulbar palsy with poor feeding

  • Clinical seizures (may occur in 10-30% of infants)

Causes

Mechanically ventilated premature infants born at less than 32 weeks' gestation are at greatest risk for periventricular leukomalacia.

Hypotension, hypoxemia, and acidosis may result in ischemic brain injury and periventricular leukomalacia.

Marked hypocarbia in ventilated premature infants has been associated with increased risk of developing periventricular leukomalacia.

Other associated risk factors include the following:

  • Placental vascular anastomoses, twin gestation, antepartum hemorrhage

  • Chorioamnionitis and funisitis

  • Sepsis

  • Maternal cocaine abuse

 

DDx

Diagnostic Considerations

The timing of initial cranial ultrasonography can be useful in determining the timing of the insult. Cystic periventricular leukomalacia (PVL) has been identified on cranial sonograms on the first day of life, indicating that the event was prenatal rather than perinatal or postnatal.

Differential Diagnoses

 

Workup

Cranial Ultrasonography

Cranial ultrasonography is the modality of choice for the initial evaluation of hypoxic-ischemic damage of the CNS in premature infants. Ultrasonography may be performed in the NICU without the need to transport fragile infants.

The earliest ultrasonographic appearance of periventricular leukomalacia (PVL) is abnormal increased echotexture in the periventricular white matter. This is a nonspecific finding that must be differentiated from the normal periventricular halo and mild periventricular edema that may not result in permanent injury.

The abnormal periventricular echotexture of periventricular leukomalacia usually disappears at 2-3 weeks. Approximately 15% of infants experiencing periventricular leukomalacia demonstrate periventricular cysts first appearing at 2-3 weeks after the initial increased echodensities.

The severity of periventricular leukomalacia is related to the size and distribution of these cysts. Initial cranial ultrasonographic findings may be normal in patients who go on to develop clinical and delayed imaging findings of periventricular leukomalacia. Examples of cranial ultrasonography in periventricular leukomalacia are shown in the images below.

Cranial ultrasound, coronal view, in 1-week-old pr Cranial ultrasound, coronal view, in 1-week-old premature infant. The periventricular echotexture is abnormally increased (greater than or equal to that of the choroid plexus), which is consistent with the early changes of periventricular leukomalacia (PVL). Courtesy of Matthew Omojola, MD.
Cranial ultrasound, coronal view, in 1-week-old pr Cranial ultrasound, coronal view, in 1-week-old premature infant without periventricular leukomalacia (PVL). The periventricular echotexture is normal. Compare with the previous image. Courtesy of Matthew Omojola, MD.
Cranial ultrasound, coronal view, in a 3-week-old Cranial ultrasound, coronal view, in a 3-week-old premature infant. Multiple bilateral periventricular cysts are typical of this stage of periventricular leukomalacia (PVL). Courtesy of Matthew Omojola, MD.
Cranial ultrasound, sagittal view, in 3-week-old p Cranial ultrasound, sagittal view, in 3-week-old premature infant. Multiple periventricular cysts are typical of this stage of periventricular leukomalacia (PVL). Courtesy of Matthew Omojola, MD.

Computed Tomography Scanning

CT scanning is not a first-line modality in evaluating these fragile premature infants in the first weeks of life. CT scanning may be helpful to better evaluate the extent and severity of periventricular leukomalacia.

Findings include ventriculomegaly involving the lateral ventricles with irregular margins of the ventricles and loss of deep white matter. Examples of CT scanning in periventricular leukomalacia are shown in the images below.

Cranial CT scan, axial image, in a 5-week-old prem Cranial CT scan, axial image, in a 5-week-old premature infant with periventricular leukomalacia (PVL). The ventricular margins are irregular, which is consistent with incorporation of the periventricular cysts of PVL. Mild ventriculomegaly and loss of the periventricular white matter is observed. Courtesy of Matthew Omojola, MD.
Cranial CT scan, axial image, in 14-month-old with Cranial CT scan, axial image, in 14-month-old with periventricular leukomalacia (PVL). Ventriculomegaly is limited to the lateral ventricles secondary to diffuse loss of periventricular white matter. Courtesy of Matthew Omojola, MD.

Magnetic Resonance Imaging

As with CT scanning, MRI does not play a major role in the early evaluation of periventricular leukomalacia. MRI is most helpful in detecting infants with non-cystic periventricular leukomalacia or evaluating infants who develop clinical signs suggestive of periventricular leukomalacia.[12]

MRI demonstrates the loss of white matter, abnormal signal intensity of the deep white matter, and ventriculomegaly; it also reveals thinning of the posterior body and splenium of the corpus callosum in severe cases of periventricular leukomalacia.

In a study of MRIs at term-equivalent age from 3 cohorts of 325 very preterm infants, Kidokoro et al found 33% (n=107) had some grade of brain injury (eg, periventricular leukomalacia, intraventricular/cerebellar hemorrhage) and 10% (n=33) had severe brain injury.[13] The investigators noted severe brain injury and impaired growth patterns were independently associated with perinatal risk factors and delayed cognitive development.[13]

Volumetric MRI scanning is also helpful in determining the extent of injury to the descending corticospinal tracts.

A relationship between the degree of injury to the descending corticospinal tracts as assessed by MRI and the severity of diplegia has been reported.

Examples of MRI in periventricular leukomalacia are shown in the images below.

Cranial MRI, T1-weighted axial image, in an 18-mon Cranial MRI, T1-weighted axial image, in an 18-month-old with periventricular leukomalacia (PVL). The lateral ventricles are enlarged without hydrocephalus. The periventricular white matter is diminished. Courtesy of Matthew Omojola, MD.
Cranial MRI, T2-weighted axial image, in an 18-mon Cranial MRI, T2-weighted axial image, in an 18-month-old with periventricular leukomalacia (PVL). Again, enlarged ventricles and loss of white matter are demonstrated. Also noted is the abnormal increased signal in the periventricular regions on this T2-weighted image. Courtesy of Matthew Omojola, MD.
Cranial MRI, sagittal T1-weighted image in the mid Cranial MRI, sagittal T1-weighted image in the midline, in an 18-month-old with periventricular leukomalacia (PVL). Hypoplasia of the corpus callosum is present and is most evident, involving the body. Courtesy of Matthew Omojola, MD.

Other Studies

Obtain electroencephalography (EEG) studies in preterm infants for early detection of periventricular leukomalacia. Changes in hypoxic-ischemic encephalopathy and EEG wave patterns may change over time and indicate the severity of the brain injury.[14] EEG abnormalities may be apparent before anomalies seen on ultrasonography.

Spectral-domain optical coherence tomography (SD-OCT) shows promise in the evaluation of prematurity on early optic nerve development and of central nervous system development and anomalies.[15]

On histologic examination, periventricular leukomalacia lesions demonstrate widespread loss of oligodendrocytes and an increase in astrocytes.

 

Treatment

Medical Care

No medical treatment is currently available. Free radical scavengers are being investigated to determine if they have a role in preventing oligodendrocyte injury in periventricular leukomalacia (PVL).

Consultations

Infants with periventricular leukomalacia require close neurodevelopmental follow-up after discharge from the hospital. Potential consultants include pediatricians, developmental specialists, neurologists, and occupational and physical therapists.

 

Follow-up

Further Outpatient Care

Developmental follow-up: Premature infants with evidence of periventricular leukomalacia (PVL) require close developmental follow-up because of the high association with cerebral palsy (CP).

Early intervention strategies carried out by occupational therapists or physical therapists may decrease symptoms and may increase the infant's motor function.

Deterrence/Prevention

Prevention of premature birth is the most important means of preventing periventricular leukomalacia.

Prior to birth, diagnosing and managing chorioamnionitis may prevent periventricular leukomalacia. In 1999, Baud et al reported that betamethasone administered to mothers at 24-31 weeks' gestation, before delivery, significantly reduced the risk of periventricular leukomalacia, suggesting the possible effect of steroids on fetal inflammatory response.[16, 17]

Avoiding maternal cocaine abuse and avoiding maternal-fetal blood flow alterations has been suggested to minimize periventricular leukomalacia.

Following delivery of a premature infant, attempts to minimize blood pressure (BP) swings and hypotension may also be beneficial in preventing periventricular leukomalacia.

Avoidance of prolonged hypocarbia in the mechanically ventilated premature infant may be useful in the prevention of periventricular leukomalacia.