Anticoagulation therapy and the risk of perioperative brain injury in neonates with congenital heart disease.

OBJECTIVE: There is considerable variability in anticoagulation use in neonates with transposition of the great arteries (TGA) and single ventricle physiology (SVP) for secondary stroke prevention and primary cardiovascular indications. Leveraging cross-center differences in anticoagulation use, we compared the risk of new postoperative brain injury in neonates with TGA and SVP treated with anticoagulation relative to untreated neonates. METHODS: Two-center observational cohort study of 118 term-born neonates with TGA (n = 83) and SVP (n = 35), undergoing cardiopulmonary bypass surgery and pre- and postoperative brain magnetic resonance imaging. Anticoagulation and antiplatelet therapy details were obtained. Magnetic resonance images were scored for stroke, white matter injury, and hemorrhage. New postoperative injury was compared between neonates with and without anticoagulation for the 2-center cohort, and subsequently stratified by cardiac lesion type and anticoagulation indication. RESULTS: Thirty-six out of 118 neonates (29%) received anticoagulation: 11 (30%) for preoperative stroke, 20 (56%) for preoperative peripheral/intracardiac thrombus, and 5 (14%) for Blalock-Taussig shunt. Five out of 36 neonates (14%) treated with anticoagulation also received antiplatelet therapy. Although no differences were identified for the 2-center cohort or for neonates with TGA separately, significantly more new postoperative parenchymal brain injury (P = .04), particularly stroke, was found in SVP neonates with compared to without anticoagulation (31% vs 5%). In neonates who experienced preoperative stroke, new subdural hemorrhage (36% vs 0%) was more frequent in neonates treated with anticoagulation therapy compared with those without anticoagulation therapy. CONCLUSIONS: In our cohort of neonates with TGA and SVP, anticoagulation for preoperative stroke, preoperative thrombus, and/or Blalock-Taussig shunt did not have the anticipated benefit of preventing new perioperative brain injury. These findings indicate the critical need for rigorous randomized trials on the safety and effectiveness of anticoagulation therapy in this population.

Pattern of Brain Injury Predicts Long-Term Epilepsy Following Neonatal Encephalopathy.

OBJECTIVE: To determine if patterns of hypoxic-ischemic brain injury on magnetic resonance imaging (MRI) in term newborns predict subsequent childhood epilepsy. METHODS: This retrospective cohort study includes term newborns with encephalopathy (n = 181) born between 2004-2012 and admitted to British Columbia Children's Hospital. MRI was performed between 3 and 5 days of age. The predominant patterns of hypoxic-ischemic injury were classified as Normal, Watershed, Basal Nuclei, Total, and Focal-Multifocal. Lesions in hippocampus, motor and occipital cortex were noted. RESULTS: Of 181 newborns, 166 (92%) survived the neonatal period, and 132 (80%) had follow-up with a median duration of 61 months (IQR: 28-95). Twenty-three children (17%) developed epilepsy. A higher proportion with Watershed, Basal Nuclei, or Total patterns developed epilepsy (P < .001). Injury to motor cortex, hippocampus, and occipital lobe (P < .01) were independent risk factors for epilepsy. In the adjusting logistic model, Watershed (odds ratio = 16.0, 95% CI [1.3, 197.2], P = .03) and Basal Nuclei injury (odds ratio = 19.4, 95% CI [1.9, 196.3], P = .01) remained independent risk factors. Therapeutic hypothermia did not alter these associations. Severity of brain injury and recurrent neonatal seizures are other clinical risk factors. SIGNIFICANCE: In term newborns with hypoxic-ischemic encephalopathy, the predominant pattern of Watershed and Basal Nuclei injury are valuable predictors for development of epilepsy in later childhood.

Multiple Postnatal Infections in Newborns Born Preterm Predict Delayed Maturation of Motor Pathways at Term-Equivalent Age with Poorer Motor Outcomes at 3 Years.

OBJECTIVES: To evaluate whether the number of postnatal infections is associated with abnormal white matter maturation and poorer motor neurodevelopmental outcomes at 36 months of corrected age. STUDY DESIGN: A prospective longitudinal cohort study was undertaken of 219 newborns born preterm at 24-32 weeks of gestational age recruited between 2006 and 2013 with magnetic resonance imaging of the brain both early in life and at term-equivalent age. Postnatal infection was defined as any clinical infection or positive culture ≥72 hours after birth. White matter maturation was assessed by magnetic resonance spectroscopic imaging, magnetic resonance diffusion tensor imaging, and tract-based spatial statistics. Neurodevelopmental outcomes were assessed in 175 (82% of survivors) infants with Bayley Scales of Infant and Toddler Development-III composite scores and Peabody Developmental Motor Scales at 35 months of corrected age (IQR 34-37 months). Infection groups were compared via the Fisher exact test, Kruskal-Wallis test, and generalized estimating equations. RESULTS: Of 219 neonates born preterm (median gestational age 27.9 weeks), 109 (50%) had no postnatal infection, 83 (38%) had 1 or 2 infections, and 27 (12%) had ≥3 infections. Infants with postnatal infections had more cerebellar hemorrhage. Infants with ≥3 infections had lower N-acetylaspartate/choline in the white matter and basal ganglia regions, lower fractional anisotropy in the posterior limb of the internal capsule, and poorer maturation of the corpus callosum, optic radiations, and posterior limb of the internal capsule on tract-based spatial statistics analysis as well as poorer Bayley Scales of Infant and Toddler Development-III (P = .02) and Peabody Developmental Motor Scales, Second Edition, motor scores (P < .01). CONCLUSIONS: In newborns born preterm, ≥3 postnatal infections predict impaired development of the motor pathways and poorer motor outcomes in early childhood.

Severe retinopathy of prematurity predicts delayed white matter maturation and poorer neurodevelopment.

OBJECTIVE: To determine whether severe retinopathy of prematurity (ROP) is associated with (1) abnormal white matter maturation and (2) neurodevelopmental outcomes at 18 months' corrected age (CA) compared with neonates without severe ROP. DESIGN: We conducted a prospective longitudinal cohort of extremely preterm neonates born 24-28 weeks' gestational age recruited between 2006 and 2013 with brain MRIs obtained both early in life and at term-equivalent age. Severe ROP was defined as ROP treated with retinal laser photocoagulation. Using diffusion tensor imaging and tract-based spatial statistics (TBSS), white matter maturation was assessed by mean fractional anisotropy (FA) in seven predefined regions of interest. Neurodevelopmental outcomes were assessed with Bayley Scales of Infant and Toddler Development-III (Bayley-III) composite scores at 18 months' CA. Subjects were compared using Fisher's exact, Kruskal-Wallis and generalised estimating equations. SETTING: Families were recruited from the neonatal intensive care unit at BC Women's Hospital. PATIENTS: Of 98 extremely preterm neonates (median: 26.0 weeks) assessed locally for ROP, 19 (19%) had severe ROP and 83 (85%) were assessed at 18 months' CA. RESULTS: Severe ROP was associated with lower FA in the posterior white matter, and with decreased measures of brain maturation in the optic radiations, posterior limb of the internal capsule (PLIC) and external capsule on TBSS. Bayley-III cognitive and motor scores were lower in infants with severe ROP. CONCLUSIONS: Severe ROP is associated with maturational delay in the optic radiations, PLIC, external capsule and posterior white matter, housing the primary visual and motor pathways, and is associated with poorer cognitive and motor outcomes at 18 months' CA.

Quantitative assessment of white matter injury in preterm neonates: Association with outcomes.

OBJECTIVE: To quantitatively assess white matter injury (WMI) volume and location in very preterm neonates, and to examine the association of lesion volume and location with 18-month neurodevelopmental outcomes. METHODS: Volume and location of WMI was quantified on MRI in 216 neonates (median gestational age 27.9 weeks) who had motor, cognitive, and language assessments at 18 months corrected age (CA). Neonates were scanned at 32.1 postmenstrual weeks (median) and 68 (31.5%) had WMI; of 66 survivors, 58 (87.9%) had MRI and 18-month outcomes. WMI was manually segmented and transformed into a common image space, accounting for intersubject anatomical variability. Probability maps describing the likelihood of a lesion predicting adverse 18-month outcomes were developed. RESULTS: WMI occurs in a characteristic topology, with most lesions occurring in the periventricular central region, followed by posterior and frontal regions. Irrespective of lesion location, greater WMI volumes predicted poor motor outcomes (p = 0.001). Lobar regional analysis revealed that greater WMI volumes in frontal, parietal, and temporal lobes have adverse motor outcomes (all, p < 0.05), but only frontal WMI volumes predicted adverse cognitive outcomes (p = 0.002). To account for lesion location and volume, voxel-wise odds ratio (OR) maps demonstrate that frontal lobe lesions predict adverse cognitive and language development, with maximum odds ratios (ORs) of 78.9 and 17.5, respectively, while adverse motor outcomes are predicted by widespread injury, with maximum OR of 63.8. CONCLUSIONS: The predictive value of frontal lobe WMI volume highlights the importance of lesion location when considering the neurodevelopmental significance of WMI. Frontal lobe lesions are of particular concern.

Clinical Risk Factors for Punctate White Matter Lesions on Early Magnetic Resonance Imaging in Preterm Newborns.

OBJECTIVE: To identify clinical risk factors for punctate white matter lesions (PWML) on early magnetic resonance imaging (MRI) in 2 cohorts of newborns born extremely preterm in different neonatal centers. STUDY DESIGN: A total of 250 newborns born preterm at less than 28 weeks of gestation (mean 26.4 ± 1.1 weeks) with an early MRI were identified from 2 neonatal centers, in Vancouver, Canada (cohort A, n = 100) and Utrecht, the Netherlands (cohort B, n = 150). Cohort A was imaged as part of a prospective research study and cohort B was imaged as part of routine clinical care. PWML were defined as cluster type foci of hyperintensity on T1-weighted imaging and were identified at a mean postmenstrual age of 31.1 (±1.9) weeks. Multivariable analysis was used to identify clinical factors predictive of PWML. RESULTS: Cluster type PWML were found in 47 newborns born extremely preterm (18.8%) and were more common in cohort A (32%) than in cohort B (10%). Newborns in cohort A generally were sicker than those in cohort B. Multivariable analyses revealed that greater birth weight (B = 0.002; P < .02), grade II-III intraventricular hemorrhage (B = 0.83; P < .02), and cohort A (B = 1.34; P < .0001) were independent predictors of PWML. CONCLUSION: Several risk factors for PWML on early MRI were identified. The interaction among birth weight, intraventricular hemorrhage, and other aspects of postnatal illness as risk factors for PWML warrants further investigation in newborns born extremely preterm and may help to identify modifiable risk factors for PWML.

Association between corpus callosum development on magnetic resonance imaging and diffusion tensor imaging, and neurodevelopmental outcome in neonates born very preterm.

AIM: To characterize corpus callosum development in neonates born very preterm from early in life to term-equivalent age and its relationship with neurodevelopmental outcome at 18 months corrected age. METHOD: In a prospective cohort of 193 neonates born preterm, 24 to 32 weeks' gestation, we used magnetic resonance imaging and diffusion tensor imaging acquired early in life (n=193) and at term-equivalent age (n=159) to measure corpus callosum development: mid-sagittal area (including corpus callosum subdivisions) and length, and fractional anisotropy from the genu and splenium. We examined the association of (1) intraventricular haemorrhage (IVH) and white matter injury (WMI) severity, and (2) neurodevelopmental outcome at 18 months corrected age with corpus callosum development. RESULTS: Severe WMI and severe IVH were strongly associated with reduced corpus callosum area (both p<0.001) and WMI with lower fractional anisotropy (p=0.002). Mild WMI predicted smaller corpus callosum area only posteriorly; mild IVH predicted smaller area throughout. Adverse motor outcome was associated with smaller corpus callosum size in the posterior subdivision (p=0.003). Abnormal cognitive outcomes were associated with lower corpus callosum fractional anisotropy (p=0.008). INTERPRETATION: In newborn infants born very preterm, brain injury is associated with changes in simple metrics of corpus callosum development. In this population, the development of the corpus callosum, as reflected by size and microstructure, is associated with neurodevelopmental outcomes at 18 months corrected age.

Low plasma magnesium is associated with impaired brain metabolism in neonates with hypoxic-ischaemic encephalopathy.

AIM: To determine the association between lowest plasma magnesium concentration and brain metabolism, and whether magnetic resonance imaging brain injury patterns moderated the association in hypoxic-ischemic encephalopathy. METHODS: In 131 early (day-of-life 3) and 65 late (day-of-life 10) scans of term encephalopathic infants born between 2004 and 2012, we examined the association of lowest plasma magnesium (until day-of-life 3) on basal ganglia and white matter peak metabolite ratios on magnetic resonance spectroscopy independent of covariates, stratified by the predominant patterns of injury (normal, basal nuclei/total, watershed, multifocal) using multiple linear regression. RESULTS: Lowest plasma magnesium was associated with lower white matter N-acetyl-aspartate/choline in the multifocal pattern on early scan (regression-coefficient, ß: 0.13; 95% CI: 0.04, 0.22) and in the basal nuclei/total pattern on late scan (ß: 0.08; 95% CI: 0.02, 0.15), and was negatively associated with basal ganglia lactate/N-acetyl-aspartate (ß: -0.16; 95% CI: -0.05, -0.28) and lactate/choline (ß: -0.1; 95% CI: -0.03, -0.17) ratio in the basal nuclei/total pattern on late scan independent of hypomagnesaemia correction, cooling and postmenstrual age at scan. Lowest plasma magnesium was not associated with metabolite ratios in other brain injury patterns. CONCLUSION: In infants with hypoxic-ischaemic encephalopathy, predominant patterns of brain injury moderated the association between lowest plasma magnesium in the first three days of life and impaired brain metabolism.

Association of Prenatal Diagnosis of Critical Congenital Heart Disease With Postnatal Brain Development and the Risk of Brain Injury.

IMPORTANCE: The relationship of prenatal diagnosis of critical congenital heart disease (CHD) with brain injury and brain development is unknown. Given limited improvement of CHD outcomes with prenatal diagnosis, the effect of prenatal diagnosis on brain health may reveal additional benefits. OBJECTIVE: To compare the prevalence of preoperative and postoperative brain injury and the trajectory of brain development in neonates with prenatal vs postnatal diagnosis of CHD. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of term newborns with critical CHD recruited consecutively from 2001 to 2013 at the University of California, San Francisco and the University of British Columbia. Term newborns with critical CHD were studied with brain magnetic resonance imaging preoperatively and postoperatively to determine brain injury severity and microstructural brain development with diffusion tensor imaging by measuring fractional anisotropy and the apparent diffusion coefficient. Comparisons of magnetic resonance imaging findings and clinical variables were made between prenatal and postnatal diagnosis of critical CHD. A total of 153 patients with transposition of the great arteries and single ventricle physiology were included in this analysis. MAIN OUTCOMES AND MEASURES: The presence of brain injury on the preoperative brain magnetic resonance imaging and the trajectory of postnatal brain microstructural development. RESULTS: Among 153 patients (67% male), 96 had transposition of the great arteries and 57 had single ventricle physiology. The presence of brain injury was significantly higher in patients with postnatal diagnosis of critical CHD (41 of 86 [48%]) than in those with prenatal diagnosis (16 of 67 [24%]) (P = .003). Patients with prenatal diagnosis demonstrated faster brain development in white matter fractional anisotropy (rate of increase, 2.2%; 95% CI, 0.1%-4.2%; P = .04) and gray matter apparent diffusion coefficient (rate of decrease, 0.6%; 95% CI, 0.1%-1.2%; P = .02). Patients with prenatal diagnosis had lower birth weight (mean, 3184.5 g; 95% CI, 3050.3-3318.6) than those with postnatal diagnosis (mean, 3397.6 g; 95% CI, 3277.6-3517.6) (P = .02). Those with prenatal diagnosis had an earlier estimated gestational age at delivery (mean, 38.6 weeks; 95% CI, 38.2-38.9) than those with postnatal diagnosis (mean, 39.1 weeks; 95% CI, 38.8-39.5) (P = .03). CONCLUSIONS AND RELEVANCE: Newborns with prenatal diagnosis of single ventricle physiology and transposition of the great arteries demonstrate less preoperative brain injury and more robust microstructural brain development than those with postnatal diagnosis. These results are likely secondary to improved cardiovascular stability. The impact of these findings on neurodevelopmental outcomes warrants further study.

Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants.

OBJECTIVE: Very preterm-born neonates (24-32 weeks of gestation) are exposed to stressful and painful procedures during neonatal intensive care. Analgesic and sedation therapies are essential, and opiates and benzodiazepines are commonly used. These medications may negatively impact brain development. The hippocampus may be especially vulnerable to the effects of pain and analgesic and/or sedative therapies and contribute to adverse outcomes. The effect of invasive procedures and analgesic-sedative exposure on hippocampal growth was assessed, as was that of hippocampal growth on neurodevelopmental outcome. METHODS: A total of 138 neonates (51% male, median gestational age = 27.7 weeks) underwent magnetic resonance imaging and diffusion tensor imaging (DTI) scans, early in life (postmenstrual age [PMA] = 32.3 weeks) and at term-equivalent age (PMA = 40.2 weeks). Volumes and DTI measures of axial diffusivity, radial diffusivity, and mean diffusivity (MD) were obtained from the hippocampus. Cognitive, language, and motor abilities were assessed using the Bayley Scales of Infant Development-III at 18.7 months median corrected age. Models testing the association of invasive procedures with hippocampal volumes and DTI measures accounted for birth gestational age, sex, PMA, dose of analgesics/sedatives (fentanyl, morphine, midazolam), mechanical ventilation, hypotension, and surgeries. RESULTS: Total midazolam dose predicted decreased hippocampal volumes (ß = -1.8, p < 0.001) and increased MD (ß = 0.002, p = 0.02), whereas invasive procedures did not (ß = 0, p > 0.5 each). Lower cognitive scores were associated with hippocampal growth (ß = -0.31, p = 0.003), midazolam dose (ß = -0.27, p = 0.03), and surgery (ß = -8.32, p = 0.04). INTERPRETATION: Midazolam exposure was associated with macro- and microstructural alterations in hippocampal development and poorer outcomes consistent with hippocampal dysmaturation. Use of midazolam in preterm neonates, particularly those not undergoing surgery, is cautioned.

Smaller Cerebellar Growth and Poorer Neurodevelopmental Outcomes in Very Preterm Infants Exposed to Neonatal Morphine.

OBJECTIVE: To examine the relationship between morphine exposure and growth of the cerebellum and cerebrum in very preterm neonates from early in life to term-equivalent age, as well as to examine morphine exposure and brain volumes in relation to neurodevelopmental outcomes at 18 months corrected age (CA). STUDY DESIGN: A prospective cohort of 136 very preterm neonates (24-32 weeks gestational age) was serially scanned with magnetic resonance imaging near birth and at term-equivalent age for volumetric measurements of the cerebellum and cerebrum. Motor outcomes were assessed with the Peabody Developmental Motor Scales, Second Edition and cognitive outcomes with the Bayley Scales of Infant and Toddler Development, Third Edition at 18 months CA. Generalized least squares models and linear regression models were used to assess relationships between morphine exposure, brain volumes, and neurodevelopmental outcomes. RESULTS: A 10-fold increase in morphine exposure was associated with a 5.5% decrease in cerebellar volume, after adjustment for multiple clinical confounders and total brain volume (P = .04). When infants exposed to glucocorticoids were excluded, the association of morphine was more pronounced, with an 8.1% decrease in cerebellar volume. Morphine exposure was not associated with cerebral volume (P = .30). Greater morphine exposure also predicted poorer motor (P < .001) and cognitive outcomes (P = .006) at 18 months CA, an association mediated, in part, by slower brain growth. CONCLUSIONS: Morphine exposure in very preterm neonates is independently associated with impaired cerebellar growth in the neonatal period and poorer neurodevelopmental outcomes in early childhood. Alternatives to better manage pain in preterm neonates that optimize brain development and functional outcomes are urgently needed.

STEAM - Statistical Template Estimation for Abnormality Mapping: A personalized DTI analysis technique with applications to the screening of preterm infants.

We introduce the STEAM DTI analysis engine: a whole brain voxel-based analysis technique for the examination of diffusion tensor images (DTIs). Our STEAM analysis technique consists of two parts. First, we introduce a collection of statistical templates that represent the distribution of DTIs for a normative population. These templates include various diffusion measures from the full tensor, to fractional anisotropy, to 12 other tensor features. Second, we propose a voxel-based analysis (VBA) pipeline that is reliable enough to identify areas in individual DTI scans that differ significantly from the normative group represented in the STEAM statistical templates. We identify and justify choices in the VBA pipeline relating to multiple comparison correction, image smoothing, and dealing with non-normally distributed data. Finally, we provide a proof of concept for the utility of STEAM on a cohort of 134 very preterm infants. We generated templates from scans of 55 very preterm infants whose T1 MRI scans show no abnormalities and who have normal neurodevelopmental outcome. The remaining 79 infants were then compared to the templates using our VBA technique. We show: (a) that our statistical templates display the white matter development expected over the modeled time period, and (b) that our VBA results detect abnormalities in the diffusion measurements that relate significantly with both the presence of white matter lesions and with neurodevelopmental outcomes at 18months. Most notably, we show that STEAM produces personalized results while also being able to highlight abnormalities across the whole brain and at the scale of individual voxels. While we show the value of STEAM on DTI scans from a preterm infant cohort, STEAM can be equally applied to other cohorts as well. To facilitate this whole-brain personalized DTI analysis, we made STEAM publicly available at http://www.sfu.ca/bgb2/steam.

Reliability of Early Magnetic Resonance Imaging (MRI) and Necessity of Repeating MRI in Noncooled and Cooled Infants With Neonatal Encephalopathy.

In cooled newborns with encephalopathy, although late magnetic resonance imaging (MRI) scan (10-14 days of age) is reliable in predicting long-term outcome, it is unknown whether early scan (3-6 days of life) is. We compared the predominant pattern and extent of lesion between early and late MRI in 89 term neonates with neonatal encephalopathy. Forty-three neonates (48%) were cooled. The predominant pattern of lesions and the extent of lesion in the watershed region agreed near perfectly in noncooled (kappa = 0.94; k = 0.88) and cooled (k = 0.89; k = 0.87) infants respectively. There was perfect agreement in the extent of lesion in the basal nuclei in noncooled infants (k = 0.83) and excellent agreement in cooled infants (k = 0.67). Changes in extent of lesions on late MRI occurred in 19 of 89 infants, with higher risk in infants with hypoglycemia and moderate-severe lesions in basal nuclei. In most term neonates with neonatal encephalopathy, early MRI (relative to late scan) robustly predicts the predominant pattern and extent of injury.

Stochastic process for white matter injury detection in preterm neonates.

Preterm births are rising in Canada and worldwide. As clinicians strive to identify preterm neonates at greatest risk of significant developmental or motor problems, accurate predictive tools are required. Infants at highest risk will be able to receive early developmental interventions, and will also enable clinicians to implement and evaluate new methods to improve outcomes. While severe white matter injury (WMI) is associated with adverse developmental outcome, more subtle injuries are difficult to identify and the association with later impairments remains unknown. Thus, our goal was to develop an automated method for detection and visualization of brain abnormalities in MR images acquired in very preterm born neonates. We have developed a technique to detect WMI in T1-weighted images acquired in 177 very preterm born infants (24-32 weeks gestation). Our approach uses a stochastic process that estimates the likelihood of intensity variations in nearby pixels; with small variations being more likely than large variations. We first detect the boundaries between normal and injured regions of the white matter. Following this we use a measure of pixel similarity to identify WMI regions. Our algorithm is able to detect WMI in all of the images in the ground truth dataset with some false positives in situations where the white matter region is not segmented accurately.

Automatic segmentation of the hippocampus for preterm neonates from early-in-life to term-equivalent age.

INTRODUCTION: The hippocampus, a medial temporal lobe structure central to learning and memory, is particularly vulnerable in preterm-born neonates. To date, segmentation of the hippocampus for preterm-born neonates has not yet been performed early-in-life (shortly after birth when clinically stable). The present study focuses on the development and validation of an automatic segmentation protocol that is based on the MAGeT-Brain (Multiple Automatically Generated Templates) algorithm to delineate the hippocampi of preterm neonates on their brain MRIs acquired at not only term-equivalent age but also early-in-life. METHODS: First, we present a three-step manual segmentation protocol to delineate the hippocampus for preterm neonates and apply this protocol on 22 early-in-life and 22 term images. These manual segmentations are considered the gold standard in assessing the automatic segmentations. MAGeT-Brain, automatic hippocampal segmentation pipeline, requires only a small number of input atlases and reduces the registration and resampling errors by employing an intermediate template library. We assess the segmentation accuracy of MAGeT-Brain in three validation studies, evaluate the hippocampal growth from early-in-life to term-equivalent age, and study the effect of preterm birth on the hippocampal volume. The first experiment thoroughly validates MAGeT-Brain segmentation in three sets of 10-fold Monte Carlo cross-validation (MCCV) analyses with 187 different groups of input atlases and templates. The second experiment segments the neonatal hippocampi on 168 early-in-life and 154 term images and evaluates the hippocampal growth rate of 125 infants from early-in-life to term-equivalent age. The third experiment analyzes the effect of gestational age (GA) at birth on the average hippocampal volume at early-in-life and term-equivalent age using linear regression. RESULTS: The final segmentations demonstrate that MAGeT-Brain consistently provides accurate segmentations in comparison to manually derived gold standards (mean Dice's Kappa > 0.79 and Euclidean distance <1.3 mm between centroids). Using this method, we demonstrate that the average volume of the hippocampus is significantly different (p < 0.0001) in early-in-life (621.8 mm(3)) and term-equivalent age (958.8 mm(3)). Using these differences, we generalize the hippocampal growth rate to 38.3 ± 11.7 mm(3)/week and 40.5 ± 12.9 mm(3)/week for the left and right hippocampi respectively. Not surprisingly, younger gestational age at birth is associated with smaller volumes of the hippocampi (p = 0.001). CONCLUSIONS: MAGeT-Brain is capable of segmenting hippocampi accurately in preterm neonates, even at early-in-life. Hippocampal asymmetry with a larger right side is demonstrated on early-in-life images, suggesting that this phenomenon has its onset in the 3rd trimester of gestation. Hippocampal volume assessed at the time of early-in-life and term-equivalent age is linearly associated with GA at birth, whereby smaller volumes are associated with earlier birth.

Minimizing the risk of preoperative brain injury in neonates with aortic arch obstruction.

OBJECTIVE: To determine whether prenatal diagnosis lowers the risk of preoperative brain injury by assessing differences in the incidence of preoperative brain injury across centers. STUDY DESIGN: From 2 prospective cohorts of newborns with complex congenital heart disease studied by preoperative cerebral magnetic resonance imaging, one cohort from the University Medical Center Utrecht (UMCU) and a combined cohort from the University of California San Francisco (UCSF) and University of British Columbia (UBC), patients with aortic arch obstruction were selected and their imaging and clinical course reviewed. RESULTS: Birth characteristics were comparable between UMCU (n = 33) and UCSF/UBC (n = 54). Patients had a hypoplastic aortic arch with either coarctation/interruption or hypoplastic left heart syndrome. In subjects with prenatal diagnosis, there was a significant difference in the prevalence of white matter injury (WMI) between centers (11 of 22 [50%] at UMCU vs 4 of 30 [13%] at UCSF/UBC; P < .01). Prenatal diagnosis was protective for WMI at UCSF/UBC (13% prenatal diagnoses vs 50% postnatal diagnoses; P < .01), but not at UMCU (50% vs 46%, respectively; P > .99). Differences in clinical practice between prenatally diagnosed subjects at UMCU vs UCSF/UBC included older age at surgery, less time spent in the intensive care unit, greater use of diuretics, less use of total parenteral nutrition (P < .01), and a greater incidence of infections (P = .01). In patients diagnosed postnatally, the prevalence of WMI was similar in the 2 centers (46% at UMCU vs 50% at UCSF/UBC; P > .99). Stroke prevalence was similar in the 2 centers regardless of prenatal diagnosis (prenatal diagnosis: 4.5% at Utrecht vs 6.7% at UCSF/UBC, P = .75; postnatal diagnosis: 9.1% vs 13%, respectively, P > .99). CONCLUSION: Prenatal diagnosis can be protective for WMI, but this protection may be dependent on specific clinical management practices that differ across centers.

Structural network analysis of brain development in young preterm neonates.

Preterm infants develop differently than those born at term and are at higher risk of brain pathology. Thus, an understanding of their development is of particular importance. Diffusion tensor imaging (DTI) of preterm infants offers a window into brain development at a very early age, an age at which that development is not yet fully understood. Recent works have used DTI to analyze structural connectome of the brain scans using network analysis. These studies have shown that, even from infancy, the brain exhibits small-world properties. Here we examine a cohort of 47 normal preterm neonates (i.e., without brain injury and with normal neurodevelopment at 18 months of age) scanned between 27 and 45 weeks post-menstrual age to further the understanding of how the structural connectome develops. We use full-brain tractography to find white matter tracts between the 90 cortical and sub-cortical regions defined in the University of North Carolina Chapel Hill neonatal atlas. We then analyze the resulting connectomes and explore the differences between weighting edges by tract count versus fractional anisotropy. We observe that the brain networks in preterm infants, much like infants born at term, show high efficiency and clustering measures across a range of network scales. Further, the development of many individual region-pair connections, particularly in the frontal and occipital lobes, is significantly correlated with age. Finally, we observe that the preterm infant connectome remains highly efficient yet becomes more clustered across this age range, leading to a significant increase in its small-world structure.

Cranial fasciitis: a rare pediatric non-neoplastic lesion with 14-year follow up.

Cranial fasciitis is a fibroblastic lesion found in the cranium of children three weeks to six years of age. It most commonly manifests as a solitary, rapid growing mass on the scalp with frequent involvement of underlying bone and occasional intracranial expansion. Patients with cranial fasciitis may present with a wide range of associated symptoms. Otologic symptoms such as otalgia, otorrhea, hearing loss and middle ear effusion are not frequently encountered. We present a case of cranial fasciitis with intracranial involvement and associated otologic symptoms in a four year old boy with subsequent follow up 14 years later.

Invasive procedures in preterm children: brain and cognitive development at school age.

BACKGROUND: Very preterm infants (born 24-32 weeks' gestation) undergo numerous invasive procedures during neonatal care. Repeated skin-breaking procedures in rodents cause neuronal cell death, and in human preterm neonates higher numbers of invasive procedures from birth to term-equivalent age are associated with abnormal brain development, even after controlling for other clinical risk factors. It is unknown whether higher numbers of invasive procedures are associated with long-term alterations in brain microstructure and cognitive outcome at school age in children born very preterm. METHODS: Fifty children born very preterm underwent MRI and cognitive testing at median age 7.6 years (interquartile range, 7.5-7.7). T1- and T2-weighted images were assessed for the severity of brain injury. Magnetic resonance diffusion tensor sequences were used to measure fractional anisotropy (FA), an index of white matter (WM) maturation, from 7 anatomically defined WM regions. Child cognition was assessed using the Wechsler Intelligence Scale for Children-IV. Multivariate modeling was used to examine relationships between invasive procedures, brain microstructure, and cognition, adjusting for clinical confounders (eg, infection, ventilation, brain injury). RESULTS: Greater numbers of invasive procedures were associated with lower FA values of the WM at age 7 years (P = .01). The interaction between the number of procedures and FA was associated with IQ (P = .02), such that greater numbers of invasive procedures and lower FA of the superior WM were related to lower IQ. CONCLUSIONS: Invasive procedures during neonatal care contribute to long-term abnormalities in WM microstructure and lower IQ.

Chorioamnionitis in the pathogenesis of brain injury in preterm infants.

Chorioamnionitis (or placental infection) is suspected to be a risk factor for brain injury in premature infants. The suggested association between chorioamnionitis and cystic periventricular leukomalacia and cerebral palsy is uncertain because of the variability of study designs and definitions of chorioamnionitis. Improvements in neonatal intensive care may have attenuated the impact of chorioamnionitis on brain health outcomes. Large multicenter studies using rigorous definitions of chorioamnionitis on placental pathologies and quantitative magnetic resonance techniques may offer the optimal way to clarify the complex role of chorioamnionitis in modifying brain health and long-term outcomes.