Evaluating Injury Severity in Neonatal Encephalopathy Using Automated Quantitative Electroencephalography Analysis: A Pilot Study.

Quantitative analysis of electroencephalography (qEEG) is a potential source of biomarkers for neonatal encephalopathy (NE). However, prior studies using qEEG in NE were limited in their generalizability due to individualized techniques for calculating qEEG features or labor-intensive pre-selection of EEG data. We piloted a fully automated method using commercially available software to calculate the suppression ratio (SR), absolute delta power, and relative delta, theta, alpha, and beta power from EEG of neonates undergoing 72 h of therapeutic hypothermia (TH) for NE between April 20, 2018, and November 4, 2019. We investigated the association of qEEG with degree of encephalopathy (modified Sarnat score), severity of neuroimaging abnormalities following TH (National Institutes of Child Health and Development Neonatal Research Network [NICHD-NRN] score), and presence of seizures. Thirty out of 38 patients met inclusion criteria. A more severe modified Sarnat score was associated with higher SR during all phases of TH, lower absolute delta power during all phases except rewarming, and lower relative delta power during the last 24 h of TH. In 21 patients with neuroimaging data, a worse NICHD-NRN score was associated with higher SR, lower absolute delta power, and higher relative beta power during all phases. QEEG features were not significantly associated with the presence of seizures after correction for multiple comparisons. Our results are consistent with those of prior studies using qEEG in NE and support automated qEEG analysis as an accessible, generalizable method for generating biomarkers of NE and response to TH. Additionally, we found evidence of an immature relative frequency composition in neonates with more severe brain injury, suggesting that automated qEEG analysis may have a use in the assessment of brain maturity.

Automatic Rejection based on Tissue Signal (ARTS) for motion-corrected quantification of cerebral venous oxygenation in neonates and older adults.

OBJECTIVE: Cerebral venous oxygenation (Yv) is a key parameter for the brain's oxygen utilization and has been suggested to be a valuable biomarker in various brain diseases including hypoxic ischemic encephalopathy in neonates and Alzheimer's disease in older adults. T2-Relaxation-Under-Spin-Tagging (TRUST) MRI is a widely used technique to measure global Yv level and has been validated against gold-standard PET. However, subject motion during TRUST MRI scan can introduce considerable errors in Yv quantification, especially for noncompliant subjects. The aim of this study was to develop an Automatic Rejection based on Tissue Signal (ARTS) algorithm for automatic detection and exclusion of motion-contaminated images to improve the precision of Yv quantification. METHODS: TRUST MRI data were collected from a neonatal cohort (N = 37, 16 females, gestational age = 39.12 ± 1.11 weeks, postnatal age = 1.89 ± 0.74 days) and an older adult cohort (N = 223, 134 females, age = 68.02 ± 9.01 years). Manual identification of motion-corrupted images was conducted for both cohorts to serve as a gold-standard. 9.3% of the images in the neonatal datasets and 0.4% of the images in the older adult datasets were manually identified as motion-contaminated. The ARTS algorithm was trained using the neonatal datasets. TRUST Yv values, as well as the estimation uncertainty (ΔR2) and test-retest coefficient-of-variation (CoV) of Yv, were calculated with and without ARTS motion exclusion. The ARTS algorithm was tested on datasets of older adults: first on the original adult datasets with little motion, and then on simulated adult datasets where the percentage of motion-corrupted images matched that of the neonatal datasets. RESULTS: In the neonatal datasets, the ARTS algorithm exhibited a sensitivity of 0.95 and a specificity of 0.97 in detecting motion-contaminated images. Compared to no motion exclusion, ARTS significantly reduced the ΔR2 (median = 3.68 Hz vs. 4.89 Hz, P = 0.0002) and CoV (median = 2.57% vs. 6.87%, P = 0.0005) of Yv measurements. In the original older adult datasets, the sensitivity and specificity of ARTS were 0.70 and 1.00, respectively. In the simulated adult datasets, ARTS demonstrated a sensitivity of 0.91 and a specificity of 1.00. Additionally, ARTS significantly reduced the ΔR2 compared to no motion exclusion (median = 2.15 Hz vs. 3.54 Hz, P < 0.0001). CONCLUSION: ARTS can improve the reliability of Yv estimation in noncompliant subjects, which may enhance the utility of Yv as a biomarker for brain diseases.

Serum brain injury biomarkers are gestationally and post-natally regulated in non-brain injured neonates.

BACKGROUND: To determine the association of gestational age (GA) and day of life (DOL) with the circulating serum concentration of six brain injury-associated biomarkers in non-brain injured neonates born between 23 and 41 weeks' GA. METHODS: In a multicenter prospective observational cohort study, serum CNS-insult, inflammatory and trophic proteins concentrations were measured daily in the first 7 DOL. RESULTS: Overall, 3232 serum samples were analyzed from 745 enrollees, median GA 32.3 weeks. BDNF increased 3.7% and IL-8 increased 8.9% each week of gestation. VEGF, IL-6, and IL-10 showed no relationship with GA. VEGF increased 10.8% and IL-8 18.9%, each DOL. IL-6 decreased by 15.8% each DOL. IL-10 decreased by 81.4% each DOL for DOL 0-3. BDNF did not change with DOL. Only 49.67% of samples had detectable GFAP and 33.15% had detectable NRGN. The odds of having detectable GFAP and NRGN increased by 53% and 11%, respectively, each week after 36 weeks' GA. The odds of having detectable GFAP and NRGN decreased by 15% and 8%, respectively, each DOL. CONCLUSIONS: BDNF and IL-8 serum concentrations vary with GA. VEGF and interleukin concentrations are dynamic in the first week of life, suggesting circulating levels should be adjusted for GA and DOL for clinically relevant assessment of brain injury. IMPACT: Normative data of six brain injury-related biomarkers is being proposed. When interpreting serum concentrations of brain injury biomarkers, it is key to adjust for gestational age at birth and day of life during the first week to correctly assess for clinical brain injury in neonates. Variation in levels of some biomarkers may be related to gestational and postnatal age and not necessarily pathology.

Plasma Biomarkers of Evolving Encephalopathy and Brain Injury in Neonates with Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: The objective of the study was to evaluate the relationship between a panel of candidate plasma biomarkers and (1) death or severe brain injury on magnetic resonance imaging (MRI) and (2) dysfunctional cerebral pressure autoregulation as a measure of evolving encephalopathy. STUDY DESIGN: Neonates with moderate-to-severe hypoxic-ischemic encephalopathy (HIE) at 2 level IV neonatal intensive care units were enrolled into this observational study. Patients were treated with therapeutic hypothermia (TH) and monitored with continuous blood pressure monitoring and near-infrared spectroscopy. Cerebral pressure autoregulation was measured by the hemoglobin volume phase (HVP) index; a higher HVP index indicates poorer autoregulation. Serial blood samples were collected during TH and assayed for Tau, glial fibrillary acidic protein, and neurogranin. MRIs were assessed using National Institutes of Child Health and Human Development scores. The relationships between the candidate biomarkers and (1) death or severe brain injury on MRI (defined as a National Institutes of Child Health and Human Development score of ≥ 2B) and (2) autoregulation were evaluated using bivariate and adjusted logistic regression models. RESULTS: Sixty-two patients were included. Elevated Tau levels on days 2-3 of TH were associated with death or severe injury on MRI (aOR: 1.06, 95% CI: 1.03-1.09; aOR: 1.04, 95% CI: 1.01-1.06, respectively). Higher Tau was also associated with poorer autoregulation (higher HVP index) on the same day (P = .022). CONCLUSIONS: Elevated plasma levels of Tau are associated with death or severe brain injury by MRI and dysfunctional cerebral autoregulation in neonates with HIE. Larger-scale validation of Tau as a biomarker of brain injury in neonates with HIE is warranted.

Risk Factors and Imaging Biomarkers Associated With Perioperative Stroke in Pediatric Moyamoya Arteriopathy.

Patients with moyamoya arteriopathy are at high risk for developing ischemic stroke in the perioperative period. We sought to evaluate whether preoperative clinical and neuroimaging biomarkers are associated with postoperative stroke and transient ischemic attack in children with moyamoya following revascularization surgery. We performed a retrospective chart review of pediatric patients who underwent revascularization surgery for moyamoya in the last 15 years. Fifty-three patients who underwent 69 surgeries met the inclusion criteria. We recorded clinical predictors of stroke or transient ischemic attack within 7 days following surgery. We used Suzuki stage and Composite Cerebrovascular Stenosis Score to analyze neuroimaging. Significant risk factors for developing postoperative stroke or transient ischemic attack were younger age at surgery (P = .004) and transient ischemic attack less than 1 month prior to surgery (P < .001). Children under 5 and those with recent preoperative ischemic events should be the focus of investigation to evaluate modifiable risk factors and targeted interventions.

Development of a composite diffusion tensor imaging score correlating with short-term neurological status in neonatal hypoxic-ischemic encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is the most common cause of neonatal acquired brain injury. Although conventional MRI may predict neurodevelopmental outcomes, accurate prognostication remains difficult. As diffusion tensor imaging (DTI) may provide an additional diagnostic and prognostic value over conventional MRI, we aimed to develop a composite DTI (cDTI) score to relate to short-term neurological function. Sixty prospective neonates treated with therapeutic hypothermia (TH) for HIE were evaluated with DTI, with a voxel size of 1 × 1 × 2 mm. Fractional anisotropy (FA) and mean diffusivity (MD) from 100 neuroanatomical regions (FA/MD *100 = 200 DTI parameters in total) were quantified using an atlas-based image parcellation technique. A least absolute shrinkage and selection operator (LASSO) regression was applied to the DTI parameters to generate the cDTI score. Time to full oral nutrition [short-term oral feeding (STO) score] was used as a measure of short-term neurological function and was correlated with extracted DTI features. Seventeen DTI parameters were selected with LASSO and built into the final unbiased regression model. The selected factors included FA or MD values of the limbic structures, the corticospinal tract, and the frontotemporal cortices. While the cDTI score strongly correlated with the STO score (rho = 0.83, p = 2.8 × 10-16), it only weakly correlated with the Sarnat score (rho = 0.27, p = 0.035) and moderately with the NICHD-NRN neuroimaging score (rho = 0.43, p = 6.6 × 10-04). In contrast to the cDTI score, the NICHD-NRN score only moderately correlated with the STO score (rho = 0.37, p = 0.0037). Using a mixed-model analysis, interleukin-10 at admission to the NICU (p = 1.5 × 10-13) and tau protein at the end of TH/rewarming (p = 0.036) and after rewarming (p = 0.0015) were significantly associated with higher cDTI scores, suggesting that high cDTI scores were related to the intensity of the early inflammatory response and the severity of neuronal impairment after TH. In conclusion, a data-driven unbiased approach was applied to identify anatomical structures associated with some aspects of neurological function of HIE neonates after cooling and to build a cDTI score, which was correlated with the severity of short-term neurological functions.

Brain Oxygen Extraction and Metabolism in Pediatric Patients With Sickle Cell Disease: Comparison of Four Calibration Models.

Sickle cell disease (SCD) is an inherited hemoglobinopathy with an increased risk of neurological complications. Due to anemia and other factors related to the underlying hemoglobinopathy, cerebral blood flow (CBF) increases as compensation; however, the nature of alterations in oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) in SCD remains controversial, largely attributed to the different calibration models. In addition, limited studies have been done to investigate oxygen metabolism in pediatric patients. Thus, this study used a non-invasive T2-based MR oximetry, T2-Relaxation-Under-Spin-Tagging (TRUST) MRI, to measure oxygen homeostasis in pediatric patients with SCD using four different calibration models and examined its relationship to hematological measures. It was found that, compared with controls, SCD patients showed an increased CBF, unchanged total oxygen delivery and increased venous blood T2. The results of OEF and CMRO2 were dependent on the calibration models used. When using sickle-specific, hemoglobin S (HbS) level-dependent calibration, there was a decreased OEF and CMRO2, while the bovine model showed an opposite result. OEF and CMRO2 were also associated with hemoglobin and HbS level; the direction of the relationship was again dependent on the model. Future studies with in vivo calibration are needed to provide more accurate information on the T2-Y v relationship.

Lymphatic Anomalies in Children: Update on Imaging Diagnosis, Genetics, and Treatment.

Lymphatic anomalies comprise a spectrum of disorders ranging from common localized microcystic and macrocystic lymphatic malformations (LMs) to rare complex lymphatic anomalies, including generalized lymphatic anomaly, Kaposiform lymph-angiomatosis, central conducting lymphatic anomaly, and Gorham-Stout disease. Imaging diagnosis of cystic LMs is generally straightforward, but complex lymphatic anomalies, particularly those with multiorgan involvement or diffuse disease, may be more challenging to diagnose. Complex lymphatic anomalies are rare but associated with high morbidity. Imaging plays an important role in their diagnosis, and radiologists may be the first clinicians to suggest the diagnosis. Furthermore, radiologists are regularly involved in management given the frequent need for image-guided interventions. For these reasons, it is crucial for radiologists to be familiar with the spectrum of entities comprising complex lymphatic anomalies and their typical imaging findings. In this article, we review the imaging findings of lymphatic anomalies, including LMs and complex lymphatic anomalies. We discuss characteristic imaging findings, multimodality imaging techniques used for evaluation, pearls and pitfalls in diagnosis, and potential complications. We also review recently discovered genetic changes underlying lymphatic anomaly development and the advent of new molecularly targeted therapies.

The Utility of Cerebral Autoregulation Indices in Detecting Severe Brain Injury Varies by Cooling Treatment Phase in Neonates with Hypoxic-Ischemic Encephalopathy.

Identifying the hemodynamic range that best supports cerebral perfusion using near infrared spectroscopy (NIRS) autoregulation monitoring is a potential physiologic marker for neonatal hypoxic-ischemic encephalopathy (HIE) during therapeutic hypothermia. However, an optimal autoregulation monitoring algorithm has not been identified for neonatal clinical medicine. We tested whether the hemoglobin volume phase (HVP), hemoglobin volume (HVx), and pressure passivity index (PPI) identify changes in autoregulation that are associated with brain injury on MRI or death. The HVP measures the phase difference between a NIRS metric of cerebral blood volume, the total hemoglobin (THb), and mean arterial blood pressure (MAP) at the frequency of maximum coherence. The HVx is the correlation coefficient between MAP and THb. The PPI is the percentage of coherent MAP-DHb (difference between oxygenated and deoxygenated hemoglobin, a marker of cerebral blood flow) epochs in a chosen time period. Neonates cooled for HIE were prospectively enrolled in an observational study in two neonatal intensive care units. In analyses adjusted for study site and encephalopathy level, all indices detected relationships between poor autoregulation in the first 6 h after rewarming with a higher injury score on MRI. Only HVx and PPI during hypothermia and the PPI during rewarming identified autoregulatory dysfunction associated with a poor outcome independent of study site and encephalopathy level. Our findings suggest that the accuracy of mathematical autoregulation algorithms in detecting the risk of brain injury or death may depend on temperature and postnatal age. Extending autoregulation monitoring beyond the standard 72 h of therapeutic hypothermia may serve as a method to provide personalized care by assessing the need for and efficacy of future therapies after the hypothermia treatment phase.

Imaging Blood-Brain Barrier Permeability Through MRI in Pediatric Sickle Cell Disease: A Feasibility Study.

BACKGROUND: Blood-brain barrier (BBB) disruption may lead to endothelium dysfunction and inflammation in sickle cell disease (SCD). However, abnormalities of BBB in SCD, especially in pediatric patients for whom contrast agent administration less than optimal, have not been fully characterized. PURPOSE: To examine BBB permeability to water in a group of pediatric SCD participants using a non-invasive magnetic resonance imaging technique. We hypothesized that SCD participants will have increased BBB permeability. STUDY TYPE: Prospective cross-sectional. POPULATION: Twenty-six pediatric participants (10 ± 1 years, 15F/11M) were enrolled, including 21 SCD participants and 5 sickle cell trait (SCT) participants, who were siblings of SCD patients. FIELD STRENGTH/SEQUENCE: 3 T. Water extraction with phase-contrast arterial spin tagging with echo-planer imaging, phase-contrast and T1 -weighted magnetization-prepared rapid acquisition of gradient echo. ASSESSMENT: Water extraction fraction (E), BBB permeability-surface area product (PS), cerebral blood flow, hematological measures (hemoglobin, hematocrit, hemoglobin S), neuropsychological scores (including domains of intellectual ability, attention and executive function, academic achievement and adaptive function, and a composite score). Regions of interest were drawn by Z.L. (6 years of experience). STATISTICAL TESTS: Wilcoxon rank sum test and chi-square test for group comparison of demographics. Multiple linear regression analysis of PS with diagnostic category (SCD or SCT), hematological measures, and neuropsychological scores. A two-tailed P value of 0.05 or less was considered statistically significant. RESULTS: Compared with SCT participants, SCD participants had a significantly higher BBB permeability to water (SCD: 207.0 ± 33.3 mL/100 g/minute, SCT: 171.2 ± 27.2 mL/100 g/minute). SCD participants with typically more severe phenotypes also had a significantly leakier BBB than those with typically milder phenotypes (severe: 217.3 ± 31.7 mL/100 g/minute, mild: 193.3 ± 31.8 mL/100 g/minute). Furthermore, more severe BBB disruption was associated with worse hematological symptoms, including lower hemoglobin concentrations (ß = -8.84, 95% confidence interval [CI] [-14.69, -3.00]), lower hematocrits (ß = -2.96, 95% CI [-4.84, -1.08]), and higher hemoglobin S fraction (ß = 0.77, 95% CI [0.014, 1.53]). DATA CONCLUSION: These findings support a potential role for BBB dysfunction in SCD pathogenesis of ischemic injury. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

EVALUATION OF MACULAR FLOW VOIDS ON OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY AS POTENTIAL BIOMARKERS FOR SILENT CEREBRAL INFARCTION IN SICKLE CELL DISEASE.

PURPOSE: To determine the relationship between macular microvascular abnormalities on optical coherence tomography angiography and silent cerebral infarctions (SCIs) on cerebral magnetic resonance imaging in sickle cell disease. METHODS: Patients (age <18 years old) from our previous pediatric sickle cell disease study cohort who had prior optical coherence tomography angiography and brain magnetic resonance imaging were identified. Brain magnetic resonance imaging images were compared with macular optical coherence tomography angiography scans to identify macular vascular density differences between patients with SCI and without SCI. RESULTS: Sixty-eight eyes from 34 patients who underwent optical coherence tomography angiography were evaluated, of whom 28 eyes from 14 patients met the inclusion criteria for this study. Eight patients (57%) with SCI and 6 patients (43%) without SCI were identified. The mean age (17 years in SCI and 16.3 years in non-SCI) was comparable between groups. There was no statistically significant difference in systemic complications. Deep capillary plexus vessel density was lower in the temporal quadrant in patients with SCI (49.3% vs. 53.7%, P = 0.014). CONCLUSION: Patients with SCI were found to have lower vessel density in the deep capillary plexus compared with those without SCI. This finding suggests that deep capillary plexus vessel density may have utility as an imaging biomarker to predict the presence of SCI.

Pediatric ECMO: unfavorable outcomes are associated with inflammation and endothelial activation.

BACKGROUND: Inflammatory and endothelial activation responses during extracorporeal membrane oxygenation (ECMO) support in children are poorly understood. In this study, we aimed to determine if circulating inflammatory, endothelial activation, and fibrinolytic markers are associated with mortality and with neurologic outcomes in children on ECMO. METHODS: We conducted a secondary analysis of a two-center prospective observational study of 99 neonatal and pediatric ECMO patients. Inflammatory (interferon gamma [IFNγ], interleukin-6 [IL-6], IL-1ß, tumor necrosis factor alpha [TNFα]), endothelial activation (E-selectin, P-selectin, intercellular adhesion molecule-3 [ICAM-3], thrombomodulin [TM]), and fibrinolytic markers (tissue plasminogen activator [tPA], plasminogen activator inhibitor-1 [PAI-1]) were measured in plasma on days 1, 2, 3, 5, 7, and every third day thereafter during the ECMO course. RESULTS: All ECMO day 1 inflammatory biomarkers were significantly elevated in children with abnormal vs. normal neuroimaging. ECMO day 1 and peak levels of IL-6 and PAI-1 were significantly elevated in children who died compared to those who survived to hospital discharge. Tested biomarkers showed no significant association with long-term neurobehavioral outcomes measured using the Vineland Adaptive Behavioral Scales, Second Edition. CONCLUSIONS: High levels of circulating inflammatory, endothelial activation, and fibrinolytic markers are associated with mortality and abnormal neuroimaging in children on ECMO. IMPACT: The inflammatory, endothelial activation, and fibrinolytic profile of children on ECMO differs by primary indication for extracorporeal support. Proinflammatory biomarkers on ECMO day 1 are associated with abnormal neurologic imaging in children on ECMO in univariable but not multivariable models. In multivariable models, a pronounced proinflammatory and prothrombotic biomarker profile on ECMO day 1 and longitudinally was significantly associated with mortality. Further studies are needed to identify inflammatory, endothelial, and fibrinolytic profiles associated with increased risk for neurologic injury and mortality through potential mediation of bleeding and thrombosis.

Therapeutic Hypothermia Modulates the Relationships Between Indicators of Severity of Neonatal Hypoxic Ischemic Encephalopathy and Serum Biomarkers.

Objective: To determine the changes due to therapeutic hypothermia (TH) exposure in the strength of association between traditional clinical and biochemical indicators of severity of neonatal hypoxic-ischemic encephalopathy (HIE) and serum biomarkers. We hypothesized that culmination of TH changes the strength of the relationships between traditional indicators of severity of HIE and serum biomarkers. Methods: This was a single-center observational cohort study of 178 neonates with HIE treated with TH and followed with serum biomarkers: (i) brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) (neurotrophins); (ii) tau and glial fibrillary acidic protein (GFAP) (neural cell injury); and (iii) interleukin 6 (IL-6), IL-8, and IL-10 (cytokines), during their first week of life. Adjusted mixed-effect models tested associations with HIE indicators in relation to TH exposure. Results: At admission, lower Apgar scores and base excess (BE) and higher lactate and nucleated red blood cell (NRBC) count correlated with higher Sarnat scores. These indicators of worse HIE severity, including higher Sarnat score, correlated with lower VEGF and higher tau, GFAP, and IL-10 levels at different time points. Within the first 24 h of life, patients with a Sarnat score >2 had lower VEGF levels, whereas only those with score of 3 also had higher GFAP and IL-10 levels. Tau levels increased during TH in patients with Sarnat score of 3, whereas tau and GFAP increased after TH in those with scores of 2. After adjustments, lower VEGF levels during TH and higher tau, GFAP, and IL-10 levels during and after TH were associated with worse Sarnat scores. Tau and GFAP relationship with Sarnat score became stronger after TH. Conclusion: Therapeutic hypothermia exerts an independent modulatory effect in the relationships between traditional indicators of severity of HIE and serum biomarkers after adjustments. Thus, the timing of biomarker testing in relation to TH exposure must be carefully considered if biomarkers are proposed for patient stratification in novel clinical trials.

Implementation Process and Evolution of a Laparotomy-Assisted 2-Port Fetoscopic Spina Bifida Closure Program.

INTRODUCTION: Prenatal closure of open spina bifida via open fetal surgery improves neurologic outcomes for infants in selected pregnancies. Fetoscopic techniques that are minimally invasive to the uterus aim to provide equivalent fetal benefits while minimizing maternal morbidities, but the optimal technique is undetermined. We describe the development, evolution, and feasibility of the laparotomy-assisted 2-port fetoscopic technique for prenatal closure of fetal spina bifida in a newly established program. METHODS: We conducted a retrospective cohort study of women consented for laparotomy-assisted fetoscopic closure of isolated fetal spina bifida. Inclusion and exclusion criteria followed the Management of Myelomeningocele Study (MOMS). Team preparation involved observation at the originating center, protocol development, ancillary staff training, and surgical rehearsal using patient-matched models through simulation prior to program implementation. The primary outcome was the ability to complete the repair fetoscopically. Secondary maternal and fetal outcomes to assess performance of the technique were collected prospectively. RESULTS: Of 57 women screened, 19 (33%) consented for laparotomy-assisted 2-port fetoscopy between February 2017 and December 2019. Fetoscopic closure was completed in 84% (16/19) cases. Over time, the technique was modified from a single- to a multilayer closure. In utero hindbrain herniation improved in 86% (12/14) of undelivered patients at 6 weeks postoperatively. Spontaneous rupture of membranes occurred in 31% (5/16) of fetoscopic cases. For completed cases, median gestational age at birth was 37 (range 27-39.6) weeks and 50% (8/16) of women delivered at term. Vaginal birth was achieved in 56% (9/16) of patients. One newborn had a cerebrospinal fluid leak that required postnatal surgical repair. CONCLUSION: Implementation of a laparotomy-assisted 2-port fetoscopic spina bifida closure program through rigorous preparation and multispecialty team training may accelerate the learning curve and demonstrates favorable obstetric and perinatal outcomes.

Wavelet Autoregulation Monitoring Identifies Blood Pressures Associated With Brain Injury in Neonatal Hypoxic-Ischemic Encephalopathy.

Dysfunctional cerebrovascular autoregulation may contribute to neurologic injury in neonatal hypoxic-ischemic encephalopathy (HIE). Identifying the optimal mean arterial blood pressure (MAPopt) that best supports autoregulation could help identify hemodynamic goals that support neurologic recovery. In neonates who received therapeutic hypothermia for HIE, we hypothesized that the wavelet hemoglobin volume index (wHVx) would identify MAPopt and that blood pressures closer to MAPopt would be associated with less brain injury on MRI. We also tested a correlation-derived hemoglobin volume index (HVx) and single- and multi-window data processing methodology. Autoregulation was monitored in consecutive 3-h periods using near infrared spectroscopy in an observational study. The neonates had a mean MAP of 54 mmHg (standard deviation: 9) during hypothermia. Greater blood pressure above the MAPopt from single-window wHVx was associated with less injury in the paracentral gyri (p = 0.044; n = 63), basal ganglia (p = 0.015), thalamus (p = 0.013), and brainstem (p = 0.041) after adjustments for sex, vasopressor use, seizures, arterial carbon dioxide level, and a perinatal insult score. Blood pressure exceeding MAPopt from the multi-window, correlation HVx was associated with less injury in the brainstem (p = 0.021) but not in other brain regions. We conclude that applying wavelet methodology to short autoregulation monitoring periods may improve the identification of MAPopt values that are associated with brain injury. Having blood pressure above MAPopt with an upper MAP of ~50-60 mmHg may reduce the risk of brain injury during therapeutic hypothermia. Though a cause-and-effect relationship cannot be inferred, the data support the need for randomized studies of autoregulation and brain injury in neonates with HIE.

Multi-Parametric Evaluation of Cerebral Hemodynamics in Neonatal Piglets Using Non-Contrast-Enhanced Magnetic Resonance Imaging Methods.

BACKGROUND: Disruption of brain oxygen delivery and consumption after hypoxic-ischemic injury contributes to neonatal mortality and neurological impairment. Measuring cerebral hemodynamic parameters, including cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2 ), is clinically important. PURPOSE: Phase-contrast (PC), velocity-selective arterial spin labeling (VSASL), and T2 -relaxation-under-phase-contrast (TRUPC) are magnetic resonance imaging (MRI) techniques that have shown promising results in assessing cerebral hemodynamics in humans. We aimed to test their feasibility in quantifying CBF, OEF, and CMRO2 in piglets. STUDY TYPE: Prospective. ANIMAL MODEL: Ten neonatal piglets subacutely recovered from global hypoxia-ischemia (N = 2), excitotoxic brain injury (N = 6), or sham procedure (N = 2). FIELD STRENGTH/SEQUENCE: VSASL, TRUPC, and PC MRI acquired at 3.0 T. ASSESSMENT: Regional CBF was measured by VSASL. Global CBF was quantified by both PC and VSASL. TRUPC assessed OEF at the superior sagittal sinus (SSS) and internal cerebral veins (ICVs). CMRO2 was calculated from global CBF and SSS-derived OEF. End-tidal carbon dioxide (EtCO2 ) levels of the piglets were also measured. Brain damage was assessed in tissue sections postmortem by counting damaged neurons. STATISTICAL TESTS: Spearman correlations were performed to evaluate associations among CBF (by PC or VSASL), OEF, CMRO2 , EtCO2 , and the pathological neuron counts. Paired t-test was used to compare OEF at SSS with OEF at ICV. RESULTS: Global CBF was 32.1 ± 14.9 mL/100 g/minute and 30.9 ± 8.3 mL/100 g/minute for PC and VSASL, respectively, showing a significant correlation (r = 0.82, P < 0.05). OEF was 54.9 ± 8.8% at SSS and 46.1 ± 5.6% at ICV, showing a significant difference (P < 0.05). Global CMRO2 was 79.1 ± 26.2 µmol/100 g/minute and 77.2 ± 12.2 µmol/100 g/minute using PC and VSASL-derived CBF, respectively. EtCO2 correlated positively with PC-based CBF (r = 0.81, P < 0.05) but negatively with OEF at SSS (r = -0.84, P < 0.05). Relative CBF of subcortical brain regions and OEF at ICV did not significantly correlate, respectively, with the ratios of degenerating-to-total neurons (P = 0.30, P = 0.10). DATA CONCLUSION: Non-contrast MRI can quantify cerebral hemodynamic parameters in normal and brain-injured neonatal piglets. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Neonatal Subpial Hemorrhage: Clinical Factors, Neuroimaging, and Outcomes in a Quaternary Care Children's Center.

BACKGROUND: Subpial hemorrhages are underrecognized, underreported, and poorly understood. The spectrum of their clinical manifestations and consequences in neonates has not been fully described. Here, we describe the demographic, clinical, and radiographic characteristics of neonates with subpial hemorrhages. METHODS: We reviewed the medical records and neuroimaging studies of neonates with subpial hemorrhage who were admitted to our neonatal intensive care unit between September 2009 and December 2020. RESULTS: Of 114 neonates with intracranial hemorrhage, 31 (27%) had subpial hemorrhage. The majority of neonates in our cohort were male (68%) and born at term (55%). The most common imaging indication was apneas and/or seizures in 58%. Common comorbid conditions included cardiorespiratory failure (42%), hypoxic-ischemic encephalopathy (26%), and coagulopathy (23%). Subpial hemorrhages were multifocal in 45% of neonates, located in the temporal lobe in 45% of neonates, and tended to be larger in neonates with coagulopathy, birth trauma, or hydrocephalus requiring neurosurgical intervention. Subpial hemorrhage was associated with another type of intracranial bleed in 77% of cases and with arterial ischemic stroke in 16% of cases. Of 17 patients with more than one year of follow-up data, 14 (82%) have developmental delay and four (24%) have epilepsy. Of 14 patients with follow-up imaging, 10 (71%) had encephalomalacia subjacent to the subpial hemorrhage. CONCLUSIONS: This is the largest cohort of neonates with subpial hemorrhages to date. Outcome data are limited by duration of follow-up and may be confounded by comorbid conditions and other concurrent hemorrhages. Further study is needed to define the spectrum of risk factors and expected neurological outcomes.

Fractional anisotropy from diffusion tensor imaging correlates with acute astrocyte and myelin swelling in neonatal swine models of excitotoxic and hypoxic-ischemic brain injury.

The specific cytopathology that causes abnormal fractional anisotropy (FA) and mean diffusivity (MD) from diffusion tensor imaging (DTI) after neonatal hypoxia-ischemia (HI) is not completely understood. The panoply of cell types in the brain might contribute differentially to changes in DTI metrics. Because glia are the predominant cell type in brain, we hypothesized that changes in FA and MD would signify perturbations in glial microstructure. Using a 3-Tesla clinical scanner, we conducted in vivo DTI MRI in nine neonatal piglets at 20-96 h after excitotoxic brain injury from striatal quinolinic acid injection or global HI. FA and MD from putamen, caudate, and internal capsule in toto were correlated with astrocyte swelling, neuronal excitotoxicity, and white matter injury. Low FA correlated with more swollen astrocytes immunophenotyped by aquaporin-4 (AQP4), glial fibrillary acidic protein (GFAP), and glutamate transporter-1 (GLT-1). Low FA was also related to the loss of neurons with perineuronal GLT-1+ astrocyte decorations, large myelin swellings, lower myelin density, and oligodendrocyte cell death identified by 2',3'-cyclic nucleotide 3'-phosphodiesterase, bridging integrator-1, and nuclear morphology. MD correlated with degenerating oligodendrocytes and depletion of normal GFAP+ astrocytes but not with astrocyte or myelin swelling. We conclude that FA is associated with cytotoxic edema in astrocytes and oligodendrocyte processes as well as myelin injury at the cellular level. MD can detect glial cell death and loss, but it may not discern subtle pathology in swollen astrocytes, oligodendrocytes, or myelin. This study provides a cytopathologic basis for interpreting DTI in the neonatal brain after HI.

Subpial Hemorrhage in Neonates: What Radiologists Need to Know.

OBJECTIVE. Subpial hemorrhages, typically seen in neonates, are rare but can harm the adjacent brain parenchyma. The purpose of this review is to summarize the anatomy and pathophysiology of subpial hemorrhage and highlight its characteristic neuro-imaging pattern. CONCLUSION. The distinctive neuroimaging pattern of subpial hemorrhage is best appreciated on brain MRI, which shows the morphology over the cortex and injury to adjacent cortex and subcortical white matter. These findings do not occur in subarachnoid and subdural hemorrhages. Recognizing the pattern of subpial hemorrhages should guide prognostic precision, prognostication, and counseling.