Noncystic White Matter Injury Research Articles

Progress in Neonatal Neurology with a Focus on Neuroimaging in the Preterm Infant.

There have been tremendous changes in the methods used to evaluate brain injury in the preterm infant in the past 30 years. In particular, major improvements have been made in how we use neuroimaging techniques and now magnetic resonance imaging (MRI) is used more often and considered complimentary to routine and sequential cranial ultrasound. The focus has shifted from severe lesions such as large intraventricular and parenchymal hemorrhages and cystic periventricular leukomalacia to assessing and understanding the etiology of more subtle noncystic white matter injury, punctate hemorrhage, and cerebellar lesions. The more severe lesions that dominated the early period of preterm neonatal brain imaging occur less frequently but are still associated with major disabilities, such as, cerebral palsy, while subtle white matter injury and cerebellar lesions are more often associated with cognitive and behavioral problems, which have become the most prevalent issues among the survivors of extremely preterm birth.

Developmental synergy between thalamic structure and interhemispheric connectivity in the visual system of preterm infants.

Thalamic structural co-variation with cortical regions has been demonstrated in preterm infants, but its relationship to cortical function and severity of non-cystic white matter injury (non-cystic WMI) is unclear. The relationship between thalamic morphology and both cortical network synchronization and cortical structural connectivity has not been established. We tested the hypothesis that in preterm neonates, thalamic volume would correlate with primary cortical visual function and microstructural integrity of cortico-cortical visual association pathways. A total of 80 term-equivalent preterm and 44 term-born infants underwent high-resolution structural imaging coupled with visual functional magnetic resonance imaging or diffusion tensor imaging. There was a strong correlation between thalamic volume and primary visual cortical activation in preterms with non-cystic WMI (r = 0.81, p-value = 0.001). Thalamic volume also correlated strongly with interhemispheric cortico-cortical connectivity (splenium) in preterm neonates with a relatively higher severity of non-cystic WMI (p-value < 0.001). In contrast, there was lower correlation between thalamic volume and intrahemispheric cortico-cortical connectivity, including the inferior longitudinal fasciculus and inferior frontal orbital fasciculus. This study shows distinct temporal overlap in the disruption of thalamo-cortical and interhemispheric cortico-cortical connectivity in preterm infants suggesting developmental synergy between thalamic morphology and the emergence of cortical networks in the last trimester.

Diminished White Matter Injury over Time in a Cohort of Premature Newborns

To determine the rate of magnetic resonance imaging (MRI)-detected noncystic white matter injury (WMI) in a prospective cohort of premature newborns, and to evaluate its associations with changes in clinical predictors of WMI over the study period. A prospective cohort of premature newborns (<33 weeks gestational age) was studied with MRI within 4 weeks of birth and near term-equivalent age. A pediatric neuroradiologist scored the severity of WMI on T1-weighted MRI according to published criteria. WMI was classified as none/mild or moderate/severe. Subjects with severe cystic WMI, periventricular hemorrhagic infarction, or motion artifact on MRI were excluded. Changes in clinical characteristics and predictors of WMI over the study period (1998-2011) were evaluated. Predictors of moderate/severe WMI, including birth year, were evaluated using multivariate logistic regression. Among 267 newborns, 45 (17%) had moderate/severe WMI. The rate of moderate/severe WMI decreased over the study period (P = .002, χ(2) test for trends). On multivariate logistic regression, the odds of moderate/severe WMI decreased by 11% for each birth year of the cohort (OR, 0.89; 95% CI, 0.81-0.98; P = .02). Prolonged exposure to indomethacin also was independently associated with reduced odds of moderate/severe WMI. The decreasing burden of MRI-detected moderate/severe noncystic WMI in our cohort of premature newborns is independent over time of changes in the known clinical predictors of WMI. Prolonged exposure to indomethacin is associated with reduced WMI.

Persistent Periventricular Echogenicities in Preterms Are Not Related to Smaller Brains at Term-Equivalent Age

Background: Periventricular white matter (PWM) is particularly vulnerable in very preterm infants. Non-cystic white matter injury, known as non-cystic periventricular leukomalacia (ncPVL), is the commonest ‘lesion' affecting the preterm brain. There is no consensus about whether ncPVL can be reliably identified from cerebral ultrasound (cUS) or whether there is any reliable correlate of ncPVL on cUS at term-equivalent age (TEA). Objective: To compare brain volumes and linear measures at TEA in infants with and without a diagnosis of ncPVL. Methods: Preterm infants of ≤32 weeks' gestation without major lesions were serially assessed using cUS. ncPVL was defined as PWM echogenicity comparable to the choroid plexus on two scans at least 2 weeks apart after the first postnatal week. At TEA, infants were scanned for the estimation of brain volume and ventricular and tissue dimensions. Head circumference was measured. The data were compared between those with/without ncPVL. Observer agreement was assessed using kappa statistic. Results: Of 63 eligible infants 29% had ncPVL. Significant differences were found between those with/without ncPVL for 5 min Apgar score, CRIB score, invasive ventilation rates and chronic lung disease but not for other relevant clinical data. No significant differences were found for estimated brain volume, ventricular size, corpus callosum length/thickness or central grey matter width. Intra-observer reliability was moderate (kappa = 0.51-0.56); inter-observer reliability was poor (kappa = 0.20-0.32). Conclusions: This study indicates that an ultrasound diagnosis of ncPVL should not be used as a sole predictor of lower brain growth detectable at TEA.

Isolated acute non-cystic white matter injury in term infants presenting with neonatal encephalopathy

We discuss possible aetiological factors, MRI evolution of injury and neuro-developmental outcomes of neonatal encephalopathy (NE). Thirty-six consecutive infants diagnosed with NE were included. In this cohort, four infants (11%)...

Effect of chorioamnionitis on brain development and injury in premature newborns

The association of chorioamnionitis and noncystic white matter injury, a common brain injury in premature newborns, remains controversial. Our objectives were to determine the association of chorioamnionitis and postnatal risk factors with white matter injury, and the effects of chorioamnionitis on early brain development, using advanced magnetic resonance imaging. Ninety-two preterm newborns (24-32 weeks gestation) were studied at a median age of 31.9 weeks and again at 40.3 weeks gestation. Histopathological chorioamnionitis and white matter injury were scored using validated systems. Measures of brain metabolism (N-acetylaspartate/choline and lactate/choline) on magnetic resonance spectroscopy, and microstructure (average diffusivity and fractional anisotropy) on diffusion tensor imaging were calculated from predefined brain regions. Thirty-one (34%) newborns were exposed to histopathological chorioamnionitis, and 26 (28%) had white matter injury. Histopathological chorioamnionitis was not associated with an increased risk of white matter injury (relative risk: 1.2; p = 0.6). Newborns with postnatal infections and hypotension requiring therapy were at higher risk of white matter injury (p < 0.03). Adjusting for gestational age at scan and regions of interest, histopathological chorioamnionitis did not significantly affect brain metabolic and microstructural development (p > 0.1). In contrast, white matter injury was associated with lower N-acetylaspartate/choline (-8.9%; p = 0.009) and lower white matter fractional anisotropy (-11.9%; p = 0.01). Histopathological chorioamnionitis does not appear to be associated with an increased risk of white matter injury on magnetic resonance imaging or with abnormalities of brain development. In contrast, postnatal infections and hypotension are associated with an increased risk of white matter injury in the premature newborn.

White Matter Injury in Term Newborns With Neonatal Encephalopathy

White matter injury (WMI) is the characteristic pattern of brain injury detected on magnetic resonance imaging in the premature newborn. Focal noncystic WMI is increasingly recognized in populations of term newborns. The aim of this study was to describe the occurrence of focal noncystic WMI in a cohort of 48 term newborns with encephalopathy studied with magnetic resonance imaging at 72 +/- 12 h of life, and to identify clinical risk factors for this pattern of injury. Eleven newborns (23%; 95% CI 11-35) were found to have WMI (four minimal, three moderate, and four severe). In 10 of the 11 newborns, the WMI was associated with restricted diffusion on apparent diffusion coefficient maps. An increasing severity of WMI was associated with lower gestational age at birth (p = 0.05), but not lower birth weight. Newborns with WMI had milder encephalopathy and fewer clinical seizures relative to other newborns in the cohort. Other brain injuries were seen in three of the 11 newborns: basal nuclei predominant pattern of injury in one and cortical strokes in two. These findings suggest that WMI in the term newborn is acquired near birth and that the state of brain maturation is an important determinant of this pattern of brain injury.

Encephalopathy of Prematurity Includes Neuronal Abnormalities

The dominant encephalopathy of premature infants is considered generally to involve principally white matter.1 Periventricular leukomalacia (PVL) is the major form of white matter injury and consists classically of focal necrotic lesions, with subsequent cyst formation, and a less severe but more diffuse injury to cerebral white mater, with prominent astrogliosis and microgliosis but without overt necrosis. Injury to premyelinating oligodendrocytes appears to be a feature of the diffuse lesions,2 although the nature and extent of this cellular injury require additional study. This diffuse, noncystic white matter injury without focal necrosis is much more common than classic PVL. Results of neonatal imaging studies indicate that classic PVL with focal necrotic/cystic lesions occurs in ∼3% to 5% of very low birth weight premature infants (<1500 g), whereas the more diffuse noncystic lesions are demonstrable, on average, in 20% to 50%, depending on the imaging modality and the definition of abnormality (see ref 1 for review). Despite the longstanding emphasis on cerebral white matter among premature infants, numerous recent MRI studies of such infants at term and later ages suggest strongly that cerebral neuronal structures are abnormal frequently (see below). These observations are of particular importance because of the high incidence (∼50%) among survivors of prematurity of subsequent cognitive deficits without prominent motor deficits, a combination classically attributed in neurology to neuronal abnormalities rather than white matter abnormalities. The report by Lodygensky et al3 published elsewhere in this issue is focused on abnormal gray matter development, defined with volumetric MRI, among premature infants studied at 8 years of age and is highly relevant to the issue of neuronal abnormalities among premature infants. In addition, this work addresses the effect of postnatal hydrocortisone administration on subsequent structural and functional brain development. The focus on hydrocortisone is presented briefly next, and … Reprint requests to (J.J.V.) Department of Neurology, Fegan 1103, Children’s Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail: joseph.volpe{at}childrens.harvard.edu