White matter injury in the premature infant

Case history

JD is a 30-week appropriate for gestational-age male infant born to a 26-year-old primigravida woman whose pregnancy was complicated by intermittent vaginal bleeding from 20 weeks’ gestation. Partial placental abruption was diagnosed and mom was placed on bedrest, given a course of steroids and treated with magnesium sulfate. At 30 weeks, she had spontaneous rupture of membranes. Within several hours, labor progressed, and the infant was delivered vaginally with delayed cord clamping. He initially cried vigorously, followed by a series of apneas in the delivery room necessitating continuous positive airway pressure (CPAP). Apgar scores were 7 and 7 at 1 and 5 minutes, respectively and he was brought to the neonatal intensive care unit on CPAP with 40% FiO ₂ . He was treated empirically with antibiotics until cultures came back sterile. He was weaned off respiratory support at 12 days of life. The clinical course was complicated by recurrent apneas, for which he was treated with caffeine. Cranial ultrasound (US) on the third day of life showed bilateral periventricular echogenicities ( Fig. 4.1 ). Follow-up US 1 week later showed white matter cysts ( Fig. 4.2 ) and magnetic resonance imaging (MRI) performed at 33 weeks postmenstrual age showed cystic periventricular leukomalacia (PVL) ( Fig. 4.3 ). Repeat MRI at term-equivalent age (TEA) demonstrated white matter volume loss and ventriculomegaly. Developmentally, at 9 months of age, he was a communicative and curious infant with significant motor delays. He was diagnosed with diplegic spastic cerebral palsy (CP) for which he received occupational and physical therapies. Follow-up at 2 years old revealed language delays requiring speech therapy and at 6 years old he has an individualized education plan including physical therapy and special education services at his school.

This case illustrates the classic evolution of severe white matter injury (WMI) in the preterm infant characterized by hyperechogenicity or “flaring,” the subsequent appearance of cystic changes, and eventually, enlarged lateral ventricles indicating progressive volume loss. While MRI is a more sensitive modality for visualizing WMI, cranial US is the most frequent bedside imaging modality used in the NICU. Recognition of the patterns of injury prior to discharge enables providers to refer to developmental follow-up and support for those at highest risk for neurodevelopmental impairments.

The scope and spectrum of white matter injury

WMI, the most common form of brain injury in preterm infants, occurs most often among infants born between 23 and 32 weeks’ gestation with a peak incidence at 28 weeks’ gestational age. The prevalence of WMI varies according to the gestational age of the cohort, as well as the timing and modality of imaging. A recent systematic review has described that up to 40% of preterm infants are born before 28 weeks’ gestational age. The spectrum of preterm WMI ranges from discrete lesions to diffuse volume loss and includes three pathologic forms: cystic necrosis, microscopic necrosis, and nonnecrotic lesions. The most severe injury consists of destructive lesions of all cellular elements with areas of cystic necrosis greater than 2 mm in diameter, known as cystic PVL. The incidence of these lesions has decreased substantially in the last few decades and occurs in current cohorts of very low birth weight infants at a rate of less than 5%. ^, More commonly, microscopic foci less than 1 mm in diameter occur and evolve into areas of gliosis, commonly referred to as noncystic PVL. Interestingly, the incidence of noncystic WMI is decreasing over time in some cohorts of preterm neonates, without a clear explanation. In contemporary cohorts of preterm newborns, the most common form of injury is diffuse WMI. Unlike necrotic injury, diffuse WMI is caused by selective degeneration of premyelinating oligodendrocytes (pre-OLs) that fail to mature into oligodendrocytes, leading to myelination failure and secondary axonal disturbances.

Notably, the patterns of WMI associated with very preterm infants, born before 32 weeks, are increasingly being recognized in other populations. Recent studies have demonstrated WMI in a substantial number of moderate to late preterm infants, though severe lesions are less common than at lower gestational ages. In a prospective study of neonates born between 32 and 36 weeks, WMI was the most frequent form of brain injury encountered, with MRI at TEA revealing diffuse injury in 23% and punctate lesions in 16%. Term-born infants with severe congenital heart disease demonstrate similar lesions, ^, postulated to be a result of destructive and dysmaturational disturbances that overlap with the mechanisms in preterm infants. Punctate lesions have also been reported among near-term and term-born infants associated with perinatal asphyxia and genetic diagnoses. Nevertheless, as the hallmark brain lesion among very preterm infants, the imaging characteristics, pathogenesis, and outcomes of WMI are currently best understood in the context of prematurity as illustrated below.

Diagnosis and imaging

The evolution of preterm WMI from the first few days of life until TEA has been extensively characterized by serial cranial US imaging. This method has been used to diagnose cystic WMI since the 1980s due to its availability, safety, and reliability. Typically, the initial presentation of WMI on US is enhanced periventricular echogenicity. This may persist or resolve within several days; after resolution, it may then evolve into gliotic or cystic changes or, alternatively, leave no abnormality. Cysts may only appear after 2 to 6 weeks and may subsequently disappear due to resorption of fluid within gliotic brain tissue and can therefore be missed without sequential imaging. At TEA, US may only demonstrate ex vacuo ventriculomegaly and enlarged extra-axial spaces. Thus the number and timing of US studies are critical to consider when evaluating the diagnostic performance of this imaging modality.

When cystic WMI persists, it is associated with significant developmental abnormalities that are primarily motor impairments, classically, spastic diplegic CP. A widely utilized grading classification for the severity of cystic PVL was developed by de Vries et al. and increasing severity of PVL according to this classification is associated with increased incidence and severity of CP. Prolonged duration of periventricular hyperechogenicities, even in the absence of cystic evolution, has also been associated with adverse motor outcomes. ^,

MRI is the preferred modality to diagnose diffuse WMI. At TEA and onward, diffuse WMI may appear on MRI as ventriculomegaly, irregularly shaped ventricles, white matter loss (enlarged cerebrospinal fluid spaces surrounding the sulci), white matter tract thinning (e.g., thin corpus callosum), diffuse signal intensity changes, and myelination disturbances. Scoring systems for these white matter abnormalities have been developed that are inversely associated with neurodevelopmental outcomes at preschool age.

Many centers also perform early MRIs, at approximately 32 weeks postmenstrual age, or as soon as infants are sufficiently stable to undergo the exam. Increased use of early MRI has demonstrated more subtle focal lesions that may not be appreciated on US imaging or follow-up TEA imaging. Visualized soon after the insult, WMI lesions may appear as clusters of punctate hyperintense T1 signal abnormalities often accompanied by diffusion restriction. ^{, ,} Linear punctate lesions with a hemorrhagic component, indicated by signal loss on susceptibility-weighted imaging, may also be seen. ^, Clinical factors associated with punctate lesions include higher gestational age and birth weight among very preterm neonates and the presence of intraventricular hemorrhage (IVH). ^, These multifocal WMI lesions are most readily visualized on early-life MRI. In a significant number of infants, these early lesions fade or become challenging to detect on MRI at TEA, though they are still associated with neurodevelopmental outcomes, even if harder to detect on these later age MRI scans. The change in imaging characteristics of these lesions over time supports the destructive/necrotic nature of these early lesions and not that they are transient imaging phenomena. ^, Importantly for clinicians, both the volume and location of lesions on early-life MRI are predictive of outcomes, with anterior lesions being most concerning for motor and cognitive deficits. ^, A summary of US and MRI findings can be found in Table 4.1 .

More sophisticated imaging modalities reveal microstructural disturbances and aberrant connectivity patterns among preterm infants with WMI. Diffusion tensor imaging (DTI) shows reduced fractional anisotropy in white matter tracts, indicating delayed maturation among preterm neonates with focal lesions, ^, including distal to the original site of injury and even in the absence of overt injury on conventional MRI. Diffuse white matter abnormalities are also associated with abnormal radial and axial diffusivities on DTI. ^, Functional resting state MRI has also demonstrated altered connectivity among neonates with WMI.

WMI does not typically have a clinical correlate in the immediate neonatal period and the diagnosis is usually made by routine imaging. Guidelines from the American Academy of Pediatrics and Canadian Paediatric Society recommend performing serial cranial US in very preterm infants in the first week of life, at 4 to 6 weeks, and again prior to discharge, with minor differences between the guidelines regarding the gestational age cutoff and timing of the first US. ^, The first US is primarily meant for the detection of IVH and the latter for WMI, although, as discussed earlier, US may miss the more prevalent diffuse WMI, better demonstrated on MRI. Some controversy exists surrounding the routine use of MRI as a screening tool at TEA given its limited overall predictive value for long-term outcomes, and in current guidelines, MRI is suggested for infants with abnormal imaging findings on US. Other experts offer evidence-based indications for using routine MRI in high-risk infants in conversation with the family concerning the performance of this imaging modality to predict long-term neurodevelopment. It is important to note that the absence of WMI carries a particularly high negative predictive value for significant adverse outcomes, allowing clinicians to be reassuring when WMI is not demonstrated. And, as noted above, multifocal WMI lesions are more readily detected on early-life MRI rather than at TEA.

Pathogenesis

The central mechanisms of WMI in preterm neonates are hypoxia-ischemia and infection-inflammation, leading to oxidative stress, glutamate-mediated excitotoxicity, and the production of proinflammatory cytokines and reactive oxygen species (ROS) that are toxic to the developing white matter. The primary cellular target of injury is oligodendrocyte precursors, called premyelinating oligodendrocytes (pre-OLs). Extensive human and experimental studies have demonstrated the vulnerability of pre-OLs, the predominant white matter cells in the preterm brain during the peak window of WMI. Oligodendrocytes, primarily derived from radial glial cells, mature in four principal stages that have distinct morphology, immune markers, and functional characteristics. The earliest form of oligodendrocyte progenitors can migrate and proliferate, whereas pre-OLs are proliferative but nonmigratory, and the more mature oligodendrocytes have myelinating properties. Pre-OLs are uniquely vulnerable to oxidative stress due to maturation-dependent features, including an immature antioxidant system that renders them vulnerable to ROS. ^, This intrinsic susceptibility is not seen in earlier and later oligodendrocyte lineage stages, or in cortical neurons, and it is potentiated by both hypoxia-ischemia and inflammation, which in turn, potentiate each other. The role of hypoxia-ischemia is postulated to be a result of disturbances in cerebral autoregulation, heart-rate-dependent cardiac output, and the immature vasculature precipitated by episodes of hypoxia, bradycardia, and hypotension. Infection-inflammation is mediated by microglial activation via Toll-like receptors (TLRs), as a result of common inflammatory disturbances in the preterm neonate, including sepsis and necrotizing enterocolitis (NEC). These mechanisms trigger a cascade of events, leading to the degeneration of pre-OLs and a subsequent increase in dysmature oligodendrocyte progenitors that are unable to fully differentiate into myelin-producing cells, causing diffuse injury characterized by impaired myelination and volume loss.