Brain Volumes at Term-Equivalent Age in Preterm Infants: Imaging Biomarkers for Neurodevelopmental Outcome through Early School Age.

OBJECTIVE: To evaluate the relationship between brain volumes at term and neurodevelopmental outcome through early school age in preterm infants. STUDY DESIGN: One hundred twelve preterm infants (born mean gestational age 28.6 ± 1.7 weeks) were studied prospectively with magnetic resonance imaging (imaged at mean 41.6 ± 1.0 weeks). T2- and T1-weighted images were automatically segmented, and volumes of 6 tissue types were related to neurodevelopmental outcome assessed using the Bayley Scales of Infant and Toddler Development, Third Edition (cognitive, fine, and gross motor scores) at 24 months corrected age (n = 112), Griffiths Mental Development Scales (developmental quotient) at age 3.5 years (n = 98), Movement Assessment Battery for Children, Second Edition (n = 85), and Wechsler Preschool and Primary Scale of Intelligence, Third Edition at age 5.5 years (n = 44). Corrections were made for intracranial volume, maternal education, and severe brain lesions. RESULTS: Ventricular volumes were negatively related to neurodevelopmental outcome at age 24 months and 3.5 years, as well as processing speed at age 5.5 years. Unmyelinated white matter (UWM) volume was positively associated with motor outcome at 24 months and with processing speed at age 5.5 years. Cortical gray matter (CGM) volume demonstrated a negative association with motor performance and cognition at 24 months and with developmental quotient at age 3.5 years. Cerebellar volume was positively related to cognition at these time points. Adjustment for brain lesions attenuated the relations between cerebellar and CGM volumes and cognition. CONCLUSIONS: Brain volumes of ventricles, UWM, CGM, and cerebellum may serve as biomarkers for neurodevelopmental outcome in preterm infants. The relationship between larger CGM volumes and adverse neurodevelopment may reflect disturbances in neuronal and/or axonal migration at the UWM-CGM boundary and warrants further investigation.

Hydrocortisone treatment for bronchopulmonary dysplasia and brain volumes in preterm infants.

OBJECTIVE: To assess whether there was an adverse effect on brain growth after hydrocortisone (HC) treatment for bronchopulmonary dysplasia (BPD) in a large cohort of infants without dexamethasone exposure. STUDY DESIGN: Infants who received HC for BPD between 2005 and 2011 and underwent magnetic resonance imaging at term-equivalent age were included. Control infants born in Geneva (2005-2006) and Utrecht (2007-2011) were matched to the infants treated with HC according to segmentation method, sex, and gestational age. Infants with overt parenchymal pathology were excluded. Multivariable analysis was used to determine if there was a difference in brain volumes between the 2 groups. RESULTS: Seventy-three infants treated with HC and 73 matched controls were included. Mean gestational age was 26.7 weeks, and mean birth weight was 906 g. After correction for gestational age, postmenstrual age at time of scanning, the presence of intraventricular hemorrhage, and birth weight z-score, no differences were found between infants treated with HC and controls in total brain tissue or cerebellar volumes. CONCLUSIONS: In the absence of associated parenchymal brain injury, no reduction in brain tissue or cerebellar volumes could be found at term-equivalent age between infants with or without treatment with HC for BPD.

Changes in carotid blood flow after unilateral perinatal arterial ischemic stroke.

INTRODUCTION: Little is known about changes in carotid blood flow after perinatal arterial ischemic stroke (PAIS). The aim of this study was to assess the blood flow in the internal carotid arteries (ICAs) after unilateral PAIS. METHODS: The carotid flow (ml/min) was measured noninvasively by means of two-dimensional phase-contrast magnetic resonance angiography (2D PC-MRA) in 25 full-term infants who had unilateral PAIS within 10 d after birth. In 17 infants a second 2D PC-MRA was carried out at the age of 3 mo. Asymmetry of carotid blood flow was calculated at both time points, and the circle of Willis (CoW) was assessed with a three-dimensional (3D) time-of-flight MRA. RESULTS: On the early magnetic resonance imaging (MRI), a significant increase in ipsilateral blood flow was observed (7.7%, 95% confidence interval (CI) 3.0-14.9%), which persisted after correcting for CoW configuration. At 3 mo, this asymmetry was no longer observed. No relationship was found between the asymmetry in blood flow and either stroke size or postnatal age at scan. DISCUSSION: A higher blood flow in the ipsilateral ICA was observed during the acute phase after unilateral PAIS, and this disappeared after 3 mo. Further research into the role of hyperperfusion after PAIS may suggest new approaches to neuroprotection.

Cerebellar volume and proton magnetic resonance spectroscopy at term, and neurodevelopment at 2 years of age in preterm infants.

AIM: To assess the relation between cerebellar volume and spectroscopy at term equivalent age, and neurodevelopment at 24 months corrected age in preterm infants. METHODS: Magnetic resonance imaging of the brain was performed around term equivalent age in 112 preterm infants (mean gestational age 28wks 3d [SD 1wk 5d]; birthweight 1129g [SD 324g]). Cerebellar volume (60 males, 52 females), and proton magnetic resonance spectroscopy ((1) H-MRS) of the cerebellum in a subgroup of 58 infants were assessed in relation to cognitive, fine motor, and gross motor scores on the Bayley Scales of Infant and Toddler Development-III. Different neonatal variables and maternal education were regarded possible confounders. RESULTS: Cerebellar volume was significantly associated with postmenstrual age at time of magnetic resonance imaging. Cerebellar volume corrected for postmenstrual age was significantly and positively associated with cognition. Cognitive scores related significantly with N-acetylaspartate/choline (NAA/Cho) ratio obtained from cerebellar (1) H-MRS in 53 infants. Correction for neonatal and maternal variables did not change these results. Cerebellar variables were not related to motor performance. INTERPRETATION: In preterm infants, both cerebellar volume and cerebellar NAA/Cho ratio at term equivalent age were positively associated with cognition; however, no relation was found with motor outcome at 2 years of age. These findings support the importance of the cerebellum in cognitive development in preterm infants.

Cerebral white matter and neurodevelopment of preterm infants after coagulase-negative staphylococcal sepsis.

OBJECTIVE: Coagulase-negative staphylococci are the most common pathogens causing late-onset sepsis in the neonatal intensive care unit. Neonatal sepsis can be associated with cerebral white matter damage in preterm infants. Neurodevelopment has been shown to be correlated with apparent diffusion coefficients, fractional anisotropy, and axial and radial diffusivities of the white matter. DESIGN: Prospective cohort study. SETTING: Twenty-eight-bed neonatal intensive care unit at a tertiary care children's hospital. PATIENTS: Seventy preterm infants (gestational age <32 wks), 28 with coagulase-negative staphylococcal sepsis (group 1) and 42 without sepsis (group 2). INTERVENTION: The values of apparent diffusion coefficients, fractional anisotropy, and axial and radial diffusivity of three white matter regions (parietal, frontal, and occipital), estimated with diffusion-tensor magnetic resonance imaging with a 3.0-T magnetic resonance imaging system, were obtained at term-equivalent age. Neurodevelopmental outcome assessments were performed at 15 months (Griffiths Mental Developmental Scales) and 24 months (Bayley Scales of Infant and Toddler Development, Third Edition) corrected age. MEASUREMENTS AND MAIN RESULTS: Values of apparent diffusion coefficients, fractional anisotropy, and axial and radial diffusivity of the left and right white matter regions were equal in all patients. There was no significant difference in apparent diffusion coefficient values (mean of total: 1.593 ± 0.090 × 10mm(-3)/sec(2) and 1.601 ± 0.117 × 10mm(-3)/sec(2), respectively, p = .684), fractional anisotropy values (mean of total: 0.19 ± 0.04 and 0.19 ± 0.03, respectively, p = .350), radial diffusivity (mean of total: 1.420 ± 0.09 × 10mm(-3)/sec(2)and 1.425 ± 0.12 × 10mm(-3)/sec(2), respectively, p = .719), and axial diffusivity (mean of total: 1.940 ± 0.12 × 10mm(-3)/sec(2) and 1.954 ± 0.13 × 10mm(-3)/sec(2), respectively, p = .590) in the three combined regions between the two groups. No significant differences were found in neurodevelopmental outcome at 24 months. CONCLUSIONS: No association was found between coagulase-negative staphylococcal sepsis in preterm infants and cerebral white matter damage as determined by values of apparent diffusion coefficients, fractional anisotropy, and radial and axial diffusivity at term-equivalent age, and no adverse effect was seen on early neurodevelopmental outcome.

Fiber tracking at term displays gender differences regarding cognitive and motor outcome at 2 years of age in preterm infants.

White matter microstructural changes can be detected with diffusion tensor imaging. It was hypothesized that diffusion parameters in the posterior limb of the internal capsule (PLIC) and corpus callosum (CC) bundles in preterm infants at term equivalent age (TEA) were associated with neurodevelopment at 2 y corrected age. In 67 preterm infants, fiber tracking was performed at TEA for the CC and both PLIC bundles. Volume, length, fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity were determined for the three bundles. These parameters were assessed in relation to outcome on the Bayley Scales of Infant and Toddler Development III. In girls, volume and length of the CC bundle and right PLIC bundle volume were associated with cognition. In boys, volume, FA, mean and radial diffusivity, and length of the left PLIC were associated with fine motor scores. Correction for GA, birth weight, intraventricular hemorrhage, white matter injury, and maternal education did not change the results. Fiber tracking parameters in the PLIC and CC bundles in preterm infants at TEA revealed different associations with neurodevelopment between boys and girls. This study suggested that fiber tracking is a useful method to predict neurodevelopment in preterm infants.

Serial MRI and neurodevelopmental outcome in 9- to 10-year-old children with neonatal encephalopathy.

OBJECTIVE: To assess the relation between patterns of brain injury on neonatal and childhood magnetic resonance imaging (MRI) and long-term neurodevelopmental outcome. STUDY DESIGN: Neonatal (n = 34) and childhood MRIs (n = 77) were analyzed for 80 children with neonatal encephalopathy and for 51 control subjects during childhood. MRIs were graded as normal, mildly abnormal (white matter lesions), or moderately/severely abnormal (watershed injury, lesions in basal ganglia/thalamus or focal infarction). Severity of brain injury was related to different aspects of neurologic outcome: Total impairment score of the Movement Assessment Battery for Children, intelligence quotient score, cerebral palsy, postneonatal epilepsy, and need for special education. Seven children with neonatal encephalopathy required extracorporeal membrane oxygenation treatment. RESULTS: Neonatal and childhood MRI were comparable in 25/33 children (75.8%, P < .001). Children with moderate/severe lesions on neonatal or childhood MRI more often had a total impairment score

Preterm brain injury on term-equivalent age MRI in relation to perinatal factors and neurodevelopmental outcome at two years.

OBJECTIVES: First, to apply a recently extended scoring system for preterm brain injury at term-equivalent age (TEA-)MRI in a regional extremely preterm cohort; second, to identify independent perinatal factors associated with this score; and third, to assess the prognostic value of this TEA-MRI score with respect to early neurodevelopmental outcome. STUDY DESIGN: 239 extremely preterm infants (median gestational age [range] in weeks: 26.6 [24.3-27.9]), admitted to the Wilhelmina Children's Hospital between 2006 and 2012 were included. Brain abnormalities in white matter, cortical and deep grey matter and cerebellum and brain growth were scored on T1- and T2-weighted TEA-MRI using the Kidokoro scoring system. Neurodevelopmental outcome was assessed at two years corrected age using the Bayley Scales of Infant and Toddler Development, third edition. The association between TEA-MRI and perinatal factors as well as neurodevelopmental outcome was evaluated using multivariable regression analysis. RESULTS: The distribution of brain abnormalities and brain metrics in the Utrecht cohort differed from the original St. Louis cohort (p < .05). Mechanical ventilation >7 days (ß [95% confidence interval, CI]: 1.3 [.5; 2.0]) and parenteral nutrition >21 days (2.2 [1.2; 3.2]) were independently associated with higher global brain abnormality scores (p < .001). Global brain abnormality scores were inversely associated with cognitive (ß in composite scores [95% CI]: -.7 [-1.2; -.2], p = .004), fine motor (ß in scaled scores [95% CI]: -.1 [-.3; -.0], p = .007) and gross motor outcome (ß in scaled scores [95% CI]: -.2 [-.3; -.1], p < .001) at two years corrected age, although the explained variances were low (R2 ≤.219). CONCLUSION: Patterns of brain injury differed between cohorts. Prolonged mechanical ventilation and parenteral nutrition were identified as independent perinatal risk factors. The prognostic value of the TEA-MRI score was rather limited in this well-performing cohort.

Sequential cranial ultrasound and cerebellar diffusion weighted imaging contribute to the early prognosis of neurodevelopmental outcome in preterm infants.

OBJECTIVE: To evaluate the contribution of sequential cranial ultrasound (cUS) and term-equivalent age magnetic resonance imaging (TEA-MRI) including diffusion weighted imaging (DWI) to the early prognosis of neurodevelopmental outcome in a cohort of very preterm infants (gestational age [GA] <31 weeks). STUDY DESIGN: In total, 93 preterm infants (median [range] GA in weeks: 28.3 [25.0-30.9]) were enrolled in this prospective cohort study and underwent early and term cUS as well as TEA-MRI including DWI. Early cUS abnormalities were classified as normal, mild, moderate or severe. Term cUS was evaluated for ex-vacuo ventriculomegaly (VM) and enlargement of the extracerebral cerebrospinal fluid (eCSF) space. Abnormalities on T1- and T2-weighted TEA-MRI were scored according to Kidokoro et al. Using DWI at TEA, apparent diffusion coefficients (ADCs) were measured in four white matter regions bilaterally and both cerebellar hemispheres. Neurodevelopmental outcome was assessed at two years' corrected age (CA) using the Bayley Scales of Infant and Toddler Development, third edition. Linear regression analysis was conducted to explore the correlation between the different neuroimaging modalities and outcome. RESULTS: Moderate/severe abnormalities on early cUS, ex-vacuo VM and enlargement of the eCSF space on term cUS and increased cerebellar ADC values on term DWI were independently associated with worse motor outcome (p<.05). Ex-vacuo VM on term cUS was also related to worse cognitive performance at two years' CA (p<.01). CONCLUSION: These data support the clinical value of sequential cUS and recommend repeating cUS at TEA. In particular, assessment of moderate/severe early cUS abnormalities and ex-vacuo VM on term cUS provides important prognostic information. Cerebellar ADC values may further aid in the prognostication of gross motor function.

Automatic segmentation of eight tissue classes in neonatal brain MRI.

PURPOSE: Volumetric measurements of neonatal brain tissues may be used as a biomarker for later neurodevelopmental outcome. We propose an automatic method for probabilistic brain segmentation in neonatal MRIs. MATERIALS AND METHODS: In an IRB-approved study axial T1- and T2-weighted MR images were acquired at term-equivalent age for a preterm cohort of 108 neonates. A method for automatic probabilistic segmentation of the images into eight cerebral tissue classes was developed: cortical and central grey matter, unmyelinated and myelinated white matter, cerebrospinal fluid in the ventricles and in the extra cerebral space, brainstem and cerebellum. Segmentation is based on supervised pixel classification using intensity values and spatial positions of the image voxels. The method was trained and evaluated using leave-one-out experiments on seven images, for which an expert had set a reference standard manually. Subsequently, the method was applied to the remaining 101 scans, and the resulting segmentations were evaluated visually by three experts. Finally, volumes of the eight segmented tissue classes were determined for each patient. RESULTS: The Dice similarity coefficients of the segmented tissue classes, except myelinated white matter, ranged from 0.75 to 0.92. Myelinated white matter was difficult to segment and the achieved Dice coefficient was 0.47. Visual analysis of the results demonstrated accurate segmentations of the eight tissue classes. The probabilistic segmentation method produced volumes that compared favorably with the reference standard. CONCLUSION: The proposed method provides accurate segmentation of neonatal brain MR images into all given tissue classes, except myelinated white matter. This is the one of the first methods that distinguishes cerebrospinal fluid in the ventricles from cerebrospinal fluid in the extracerebral space. This method might be helpful in predicting neurodevelopmental outcome and useful for evaluating neuroprotective clinical trials in neonates.

Corpus callosum size in relation to motor performance in 9- to 10-year-old children with neonatal encephalopathy.

Magnetic resonance imaging studies have contributed to recognize the patterns of cerebral injury related to neonatal encephalopathy (NE). We assessed whether a smaller corpus callosum (CC) explained the difference in motor performance between school-age children with NE and controls. Frontal, middle, and posterior areas of the CC were measured in 61 9-10-y-old children with NE and in 47 controls. Motor performance was determined using the Movement Assessment Battery for Children (M-ABC). Linear regression was used to assess whether differences in M-ABC between NE children and controls could be explained by CC size. The CC of 11/30 children with NE type I according to Sarnat (NE I) and 19/36 children with NE type II according to Sarnat (NE II) showed generalized or focal thinning, compared with 8/49 controls. Children with NE II had significantly smaller middle and posterior parts and total areas of the CC. Children with NE scored significantly worse on the M-ABC than controls. The reduction in size of the posterior part of the CC partly explained the mean differences on the M-ABC. Children with NE have poorer motor skills than controls, which is partly explained by a smaller size of the CC.