Quantitative noninvasive measurement of cerebrospinal fluid flow in shunted hydrocephalus.

OBJECTIVE: Standard MRI protocols lack a quantitative sequence that can be used to evaluate shunt-treated patients with a history of hydrocephalus. The objective of this study was to investigate the use of phase-contrast MRI (PC-MRI), a quantitative MR sequence, to measure CSF flow through the shunt and demonstrate PC-MRI as a useful adjunct in the clinical monitoring of shunt-treated patients. METHODS: The rapid (96 seconds) PC-MRI sequence was calibrated using a flow phantom with known flow rates ranging from 0 to 24 mL/hr. Following phantom calibration, 21 patients were scanned with the PC-MRI sequence. Multiple, successive proximal and distal measurements were gathered in 5 patients to test for measurement error in different portions of the shunt system and to determine intrapatient CSF flow variability. The study also includes the first in vivo validations of PC-MRI for CSF shunt flow by comparing phase-contrast-measured flow rate with CSF accumulation in a collection burette obtained in patients with externalized distal shunts. RESULTS: The PC-MRI sequence successfully measured CSF flow rates ranging from 6 to 54 mL/hr in 21 consecutive pediatric patients. Comparison of PC-MRI flow measurement and CSF volume collected in a bedside burette showed good agreement in a patient with an externalized distal shunt. Notably, the distal portion of the shunt demonstrated lower measurement error when compared with PC-MRI measurements acquired in the proximal catheter. CONCLUSIONS: The PC-MRI sequence provided accurate and reliable clinical measurements of CSF flow in shunt-treated patients. This work provides the necessary framework to include PC-MRI as an immediate addition to the clinical setting in the noninvasive evaluation of shunt function and in future clinical investigations of CSF physiology.

Brain Injury Outcomes after Adjuvant Erythropoietin Neuroprotection for Moderate or Severe Neonatal Hypoxic-Ischemic Encephalopathy: A Report from the HEAL Trial.

INTRODUCTION: Erythropoietin (Epo) is a putative neuroprotective therapy that did not improve overall outcomes in a phase 3 randomized controlled trial for neonates with moderate or severe hypoxic-ischemic encephalopathy (HIE). However, HIE is a heterogeneous disorder, and it remains to be determined whether Epo had beneficial effects on a subset of perinatal brain injuries. METHODS: This study was a secondary analysis of neuroimaging data from the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, which was conducted from 2016 - 2021 at 17 sites involving 23 US academic medical centers. Participants were neonates >36 weeks' gestation undergoing therapeutic hypothermia for moderate or severe HIE who received 5 doses of study drug (Epoetin alpha 1000 U/kg/dose) or placebo in the first week of life. Treatment assignment was stratified by trial site and severity of encephalopathy. The primary outcome was the locus, pattern and acuity of brain injury as determined by three independent readers using a validated HIE Magnetic Resonance Imaging (MRI) scoring system. RESULTS: Of the 500 infants enrolled in HEAL, 470 (94%) had high quality MRI data obtained at a median of 4.9 days of age (IQR 4.5 - 5.8). The incidence of injury to the deep grey nuclei, cortex, white matter, brainstem and cerebellum was similar between Epo and placebo groups. Likewise, the distribution of injury patterns was similar between groups. Among infants imaged at less than 8 days (n=414), 94 (23%) evidenced only acute, 93 (22%) only subacute and 89 (21%) both acute and subacute injuries, with similar distribution across treatment groups. CONCLUSION: Adjuvant erythropoietin did not reduce the incidence of regional brain injury. Subacute brain injury was more common than previously reported, which has key implications for the development of adjuvant neuroprotective therapies for this population.

Brain Glutathione Increase and Seizure Burden Decrease in Patients with Intractable Epilepsy on Ketogenic Diet.

Background and Purpose: Ketogenic diet (KD) improves seizure control in patients with drug-resistant epilepsy. As increased mitochondrial levels of glutathione (GSH) might contribute to a change in seizure susceptibility, we quantified changes of absolute GSH levels in the brain by in vivo 1H magnetic resonance spectroscopy (1H MRS) and correlate that with degree of seizure control in patients on KD. Methods: Five cognitively normal adult patients with drug-resistant epilepsy were initially included and 2 completed the study. Each patient was evaluated by a neurologist and registered dietitian at baseline, 1, 3, and 6 months for seizure status and diet adherence after initiation of a modified atkins diet. Multiple metabolites including GSH were quantified using LCModel (version 6.3-1P; Stephen Provencher, Oakville, ON, CA) on a short echo time single-voxel 1H MRS in parieto/occipital grey matter and parietal white matter on a 3 Tesla General Electric magnet prior to starting the ketogenic diet and at 6 months. Results: Both patients (42-years-old male and 35-years-old female) demonstrated marked increases in absolute GSH level in both gray matter (0.12 to 1.40 and 0.10 to 0.70 international unit [IU]) and white matter (0.65 to 1.50 and 0.80 to 2.00 IU), as well as 50% improvements in seizure duration and frequency. Other metabolites including ketone bodies did not demonstrate consistent changes. Conclusions: Markedly increased levels of GSH (7-fold and 14-fold) were observed in longitudinal prospective study of two adult patients with intractable epilepsy with 50% seizure improvement after initiation of ketogenic diets. This pilot study supports the possible anticonvulsant role of GSH in the brain.

Cerebral Glucose Concentration in Neonatal Hypoxic-Ischemic Encephalopathy during Therapeutic Hypothermia.

OBJECTIVE: To determine cerebral glucose concentration and its relationship with glucose infusion rate (GIR) and blood glucose concentration in neonatal encephalopathy during therapeutic hypothermia (TH). METHODS: This was an observational study in which cerebral glucose during TH was quantified by magnetic resonance (MR) spectroscopy and compared with mean blood glucose at the time of scan. Clinical data (gestational age, birth weight, GIR, sedative use) that could affect glucose use were collected. The severity and pattern of brain injury on MR imaging were scored by a neuroradiologist. Student t test, Pearson correlation, repeated measures ANOVA, and multiple regression analysis were performed. RESULTS: Three-hundred-sixty blood glucose values and 402 MR spectra from 54 infants (30 female infants; mean gestational age 38.6 ± 1.9 weeks) were analyzed. In total, 41 infants had normal-mild and 13 had moderate-severe injury. Median GIR and blood glucose during TH were 6.0 mg/kg/min (IQR 5-7) and 90 mg/dL (IQR 80-102), respectively. GIR did not correlate with blood or cerebral glucose. Cerebral glucose was significantly greater during than after TH (65.9 ± 22.9 vs 60.0 ± 25.2 mg/dL, P < .01), and there was a significant correlation between blood glucose and cerebral glucose during TH (basal ganglia: r = 0.42, thalamus: r = 0.42, cortical gray matter: r = 0.39, white matter: r = 0.39, all P < .01). There was no significant difference in cerebral glucose concentration in relation to injury severity or pattern. CONCLUSIONS: During TH, cerebral glucose concentration is partly dependent on blood glucose concentration. Further studies to understand brain glucose use and optimal glucose concentrations during hypothermic neuroprotection are needed.

Neuroimaging of complications arising after CD19 chimeric antigen receptor T-cell therapy: A review.

Chimeric antigen receptor (CAR) T cells targeting the CD19 (cluster of differentiation 19) cell surface glycoprotein have emerged as a highly effective immunologic therapy in patients with relapsed or refractory B-cell malignancies. The engagement of CAR T cells with CD19 on the surface of neoplastic B cells causes a systemic cytokine release, which can compromise the blood-brain barrier and cause an immune effector cell-associated neurotoxicity syndrome (ICANS). In a small proportion of ICANS patients who demonstrate neuroimaging abnormalities, certain distinct patterns have been recognized, including signal changes in the thalami, external capsule, and brainstem, the subcortical and/or periventricular white matter, the splenium of the corpus callosum, and the cerebellum. On careful review of the underlying pathophysiology of ICANS, we noticed that these changes closely mirror the underlying blood-brain barrier disruption and neuroinflammatory and excitotoxic effects of the offending cytokines released during ICANS. Furthermore, other uncommon complications of CD19 CAR T-cell therapy such as posterior reversible encephalopathy syndrome, ocular complications, and opportunistic fungal infections can be catastrophic if not diagnosed in a timely manner, with neuroimaging playing a significant role in management. In this narrative review, we will summarize the current literature on the spectrum of neuroimaging findings in ICANS, list appropriate differential diagnoses, and explore the imaging features of other uncommon central nervous system complications of CD19 CAR T-cell therapy using illustrative cases from two tertiary care institutions.

Assessment of Brain Magnetic Resonance and Spectroscopy Imaging Findings and Outcomes After Pediatric Cardiac Arrest.

Importance: Morbidity and mortality after pediatric cardiac arrest are chiefly due to hypoxic-ischemic brain injury. Brain features seen on magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) after arrest may identify injury and aid in outcome assessments. Objective: To analyze the association of brain lesions seen on T2-weighted MRI and diffusion-weighted imaging and N-acetylaspartate (NAA) and lactate concentrations seen on MRS with 1-year outcomes after pediatric cardiac arrest. Design, Setting, and Participants: This multicenter cohort study took place in pediatric intensive care units at 14 US hospitals between May 16, 2017, and August 19, 2020. Children aged 48 hours to 17 years who were resuscitated from in-hospital or out-of-hospital cardiac arrest and who had a clinical brain MRI or MRS performed within 14 days postarrest were included in the study. Data were analyzed from January 2022 to February 2023. Exposure: Brain MRI or MRS. Main Outcomes and Measures: The primary outcome was an unfavorable outcome (either death or survival with a Vineland Adaptive Behavior Scales, Third Edition, score of <70) at 1 year after cardiac arrest. MRI brain lesions were scored according to region and severity (0 = none, 1 = mild, 2 = moderate, 3 = severe) by 2 blinded pediatric neuroradiologists. MRI Injury Score was a sum of T2-weighted and diffusion-weighted imaging lesions in gray and white matter (maximum score, 34). MRS lactate and NAA concentrations in the basal ganglia, thalamus, and occipital-parietal white and gray matter were quantified. Logistic regression was performed to determine the association of MRI and MRS features with patient outcomes. Results: A total of 98 children, including 66 children who underwent brain MRI (median [IQR] age, 1.0 [0.0-3.0] years; 28 girls [42.4%]; 46 White children [69.7%]) and 32 children who underwent brain MRS (median [IQR] age, 1.0 [0.0-9.5] years; 13 girls [40.6%]; 21 White children [65.6%]) were included in the study. In the MRI group, 23 children (34.8%) had an unfavorable outcome, and in the MRS group, 12 children (37.5%) had an unfavorable outcome. MRI Injury Scores were higher among children with an unfavorable outcome (median [IQR] score, 22 [7-32]) than children with a favorable outcome (median [IQR] score, 1 [0-8]). Increased lactate and decreased NAA in all 4 regions of interest were associated with an unfavorable outcome. In a multivariable logistic regression adjusted for clinical characteristics, increased MRI Injury Score (odds ratio, 1.12; 95% CI, 1.04-1.20) was associated with an unfavorable outcome. Conclusions and Relevance: In this cohort study of children with cardiac arrest, brain features seen on MRI and MRS performed within 2 weeks after arrest were associated with 1-year outcomes, suggesting the utility of these imaging modalities to identify injury and assess outcomes.

How well does neonatal neuroimaging correlate with neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy?

BACKGROUND: In newborns with hypoxic-ischemic encephalopathy (HIE), the correlation between neonatal neuroimaging and the degree of neurodevelopmental impairment (NDI) is unclear. METHODS: Infants with HIE enrolled in a randomized controlled trial underwent neonatal MRI/MR spectroscopy (MRS) using a harmonized protocol at 4-6 days of age. The severity of brain injury was measured with a validated scoring system. Using proportional odds regression, we calculated adjusted odds ratios (aOR) for the associations between MRI/MRS measures of injury and primary ordinal outcome (i.e., normal, mild NDI, moderate NDI, severe NDI, or death) at age 2 years. RESULTS: Of 451 infants with MRI/MRS at a median age of 5 days (IQR 4.5-5.8), outcomes were normal (51%); mild (12%), moderate (14%), severe NDI (13%); or death (9%). MRI injury score (aOR 1.06, 95% CI 1.05, 1.07), severe brain injury (aOR 39.6, 95% CI 16.4, 95.6), and MRS lactate/n-acetylaspartate (NAA) ratio (aOR 1.6, 95% CI 1.4,1.8) were associated with worse primary outcomes. Infants with mild/moderate MRI brain injury had similar BSID-III cognitive, language, and motor scores as infants with no injury. CONCLUSION: In the absence of severe injury, brain MRI/MRS does not accurately discriminate the degree of NDI. Given diagnostic uncertainty, families need to be counseled regarding a range of possible neurodevelopmental outcomes. IMPACT: Half of all infants with hypoxic-ischemic encephalopathy (HIE) enrolled in a large clinical trial either died or had neurodevelopmental impairment at age 2 years despite receiving therapeutic hypothermia. Severe brain injury and a global pattern of brain injury on MRI were both strongly associated with death or neurodevelopmental impairment. Infants with mild or moderate brain injury had similar mean BSID-III cognitive, language, and motor scores as infants with no brain injury on MRI. Given the prognostic uncertainty of brain MRI among infants with less severe degrees of brain injury, families should be counseled regarding a range of possible neurodevelopmental outcomes.

Corrigendum to: Glutathione Increase and Seizure Burden Decrease in Patients with Intractable Epilepsy on Ketogenic Diet.

[This corrects the article DOI: 10.14581/jer.23001.].

Quantitative Susceptibility Mapping: Translating an Investigative Research Tool into High Volume Clinical Diagnostic Imaging.

Quantitative susceptibility mapping (QSM) is an MRI-based technique for iron quantification of targeted tissue. QSM provides information relevant to clinicians in a broad range of diagnostic contexts, including sickle cell disease, inflammatory/demyelinating processes, and neoplasms. However, major MRI vendors do not offer QSM post-processing in a form ready for general use. This work describes a vendor-agnostic approach for scaling QSM analysis from a research technique to a routine diagnostic test. We provide the details needed to seamlessly integrate hardware, software, and clinical systems to provide QSM processing for a busy clinical radiology workflow. This approach can be generalized to other advanced MRI acquisitions and analyses with proven diagnostic utility, yet without crucial MR vendor support.

Magnetic Resonance Spectroscopy Metabolites as Biomarkers of Disease Status in Pediatric Diffuse Intrinsic Pontine Gliomas (DIPG) Treated with Glioma-Associated Antigen Peptide Vaccines.

PURPOSE: Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive tumors with no currently available curative therapy. This study evaluated whether measurements of in vivo cell metabolites using magnetic resonance spectroscopy (MRS) may serve as biomarkers of response to therapy, including progression. METHODS: Single-voxel MR spectra were serially acquired in two cohorts of patients with DIPG treated with radiation therapy (RT) with or without concurrent chemotherapy and prior to progression: 14 participants were enrolled in a clinical trial of adjuvant glioma-associated antigen peptide vaccines and 32 patients were enrolled who did not receive adjuvant vaccine therapy. Spearman correlations measured overall survival associations with absolute metabolite concentrations of myo-inositol (mI), creatine (Cr), and n-acetyl-aspartate (NAA) and their ratios relative to choline (Cho) during three specified time periods following completion of RT. Linear mixed-effects regression models evaluated the longitudinal associations between metabolite ratios and time from death (terminal decline). RESULTS: Overall survival was not associated with metabolite ratios obtained shortly after RT (1.9-3.8 months post-diagnosis) in either cohort. In the vaccine cohort, an elevated mI/Cho ratio after 2-3 doses (3.9-5.2 months post-diagnosis) was associated with longer survival (rho = 0.92, 95% CI 0.67-0.98). Scans performed up to 6 months before death showed a terminal decline in the mI/Cho ratio, with an average of 0.37 ratio/month in vaccine patients (95% CI 0.11-0.63) and 0.26 (0.04-0.48) in the non-vaccine cohort. CONCLUSION: Higher mI/Cho ratios following RT, consistent with less proliferate tumors and decreased cell turnover, were associated with longer survival, suggesting that this ratio can serve as a biomarker of prognosis following RT. This finding was seen in both cohorts, although the association with OS was detected earlier in the vaccine cohort. Increased mI/Cho (possibly reflecting immune-effector cell influx into the tumor as a mechanism of tumor response) requires further study.

Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57). CONCLUSIONS: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).

Proton MR Spectroscopy of Pediatric Brain Disorders.

In vivo MR spectroscopy is a non -invasive methodology that provides information about the biochemistry of tissues. It is available as a "push-button" application on state-of-the-art clinical MR scanners. MR spectroscopy has been used to study various brain diseases including tumors, stroke, trauma, degenerative disorders, epilepsy/seizures, inborn errors, neuropsychiatric disorders, and others. The purpose of this review is to provide an overview of MR spectroscopy findings in the pediatric population and its clinical use.

Clinical 1H MRS in childhood neurometabolic diseases-part 1: technique and age-related normal spectra.

Despite its vigorous ability to detect and measure metabolic disturbances, 1H MRS remains underutilized in clinical practice. MRS increases diagnostic yield and provides therapeutic measures. Because many inborn metabolic errors are now treatable, early diagnosis is crucial to prevent or curb permanent brain injury. Therefore, patients with known or suspected inborn metabolic errors stand to benefit from the addition of MRS. With education and practice, all neuroradiologists can perform and interpret MRS notwithstanding their training and prior experience. In this two-part review, we cover the requisite concepts for clinical MRS interpretation including technical considerations and normal brain spectral patterns based on age, location, and methodology.

Clinical 1H MRS in childhood neurometabolic diseases - part 2: MRS signatures.

Proton MRS of the brain provides the ability to gather direct information regarding the metabolic status of the brain at the time of MRI. Although selective vulnerability of brain tissue may yield distinct imaging patterns in neurometabolic disorders, it is not uncommon for the brain MRI to be normal, nonspecific, or show ambiguous abnormalities among several possible diagnoses, metabolic, or otherwise. This review highlights childhood neurometabolic diseases in which 1H MRS may show diagnostic or suggestive metabolic profiles without complicated acquisition or postprocessing techniques.

Targeting integrated epigenetic and metabolic pathways in lethal childhood PFA ependymomas.

Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cycle­related genes including hexokinase-2 and pyruvate dehydrogenase. Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at hexokinase-2 and pyruvate dehydrogenase, accompanied by enhanced glycolysis and TCA cycle metabolism. AMPKα-2, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WT­expressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.

Proton and Multinuclear Spectroscopy of the Pediatric Brain.

Magnetic resonance spectroscopy (MRS) is a valuable adjunct to structural brain imaging. State-of-the-art MRS has benefited greatly from recent technical advancements. Neurometabolic alterations in pediatric brain diseases have implications for diagnosis, prognosis, and therapy. Herein, the authors discuss MRS technical considerations and applications in the setting of various pediatric disease processes including tumors, metabolic diseases, hypoxic/ischemic encephalopathy/stroke, epilepsy, demyelinating disease, and infection.

Algorithms for segmenting cerebral time-of-flight magnetic resonance angiograms from volunteers and anemic patients.

Purpose: To evaluate six cerebral arterial segmentation algorithms in a set of patients with a wide range of hemodynamic characteristics to determine real-world performance. Approach: Time-of-flight magnetic resonance angiograms were acquired from 33 subjects: normal controls ( N = 11 ), sickle cell disease ( N = 11 ), and non-sickle anemia ( N = 11 ) using a 3 Tesla Philips Achieva scanner. Six segmentation algorithms were tested: (1) Otsu's method, (2) K-means, (3) region growing, (4) active contours, (5) minimum cost path, and (6) U-net machine learning. Segmentation algorithms were tested with two region-selection methods: global, which selects the entire volume; and local, which iteratively tracks the arteries. Five slices were manually segmented from each patient by two readers. Agreement between manual and automatic segmentation was measured using Matthew's correlation coefficient (MCC). Results: Median algorithm segmentation times ranged from 0.1 to 172.9 s for a single angiogram versus 10 h for manual segmentation. Algorithms had inferior performance to inter-observer vessel-based ( p < 0.0001 , MCC = 0.65 ) and voxel-based ( p < 0.0001 , MCC = 0.73 ) measurements. There were significant differences between algorithms ( p < 0.0001 ) and between patients ( p < 0.0042 ). Post-hoc analyses indicated (1) local minimum cost path performed best with vessel-based ( p = 0.0261 , MCC = 0.50 ) and voxel-based ( p = 0.0131 , MCC = 0.66 ) analyses; and (2) higher vessel-based performance in non-sickle anemia ( p = 0.0002 ) and lower voxel-based performance in sickle cell ( p = 0.0422 ) compared with normal controls. All reported MCCs are medians. Conclusions: The best-performing algorithm (local minimum cost path, voxel-based) had 9.59% worse performance than inter-observer agreement but was 3 orders of magnitude faster. Automatic segmentation was non-inferior in patients with sickle cell disease and superior in non-sickle anemia.

Integrating neuroimaging biomarkers into the multicentre, high-dose erythropoietin for asphyxia and encephalopathy (HEAL) trial: rationale, protocol and harmonisation.

INTRODUCTION: MRI and MR spectroscopy (MRS) provide early biomarkers of brain injury and treatment response in neonates with hypoxic-ischaemic encephalopathy). Still, there are challenges to incorporating neuroimaging biomarkers into multisite randomised controlled trials. In this paper, we provide the rationale for incorporating MRI and MRS biomarkers into the multisite, phase III high-dose erythropoietin for asphyxia and encephalopathy (HEAL) Trial, the MRI/S protocol and describe the strategies used for harmonisation across multiple MRI platforms. METHODS AND ANALYSIS: Neonates with moderate or severe encephalopathy enrolled in the multisite HEAL trial undergo MRI and MRS between 96 and 144 hours of age using standardised neuroimaging protocols. MRI and MRS data are processed centrally and used to determine a brain injury score and quantitative measures of lactate and n-acetylaspartate. Harmonisation is achieved through standardisation-thereby reducing intrasite and intersite variance, real-time quality assurance monitoring and phantom scans. ETHICS AND DISSEMINATION: IRB approval was obtained at each participating site and written consent obtained from parents prior to participation in HEAL. Additional oversight is provided by an National Institutes of Health-appointed data safety monitoring board and medical monitor. TRIAL REGISTRATION NUMBER: NCT02811263; Pre-result.

Fetal neurodevelopmental recovery in donors after laser surgery for twin-twin transfusion syndrome.

BACKGROUND: Fetal magnetic resonance imaging (MRI) and spectroscopy (MRS) provide a unique opportunity to non-invasively measure markers of neurodevelopment in survivors of twin-twin transfusion syndrome (TTTS). OBJECTIVE: To characterize fetal brain maturation after laser surgery for TTTS by measuring brain volumes and cerebral metabolite concentrations using fetal MRI + MRS. STUDY DESIGN: Prospective study of dual surviving fetuses treated with laser surgery for TTTS. At 4-5 postoperative weeks, fetal MRI was used together with novel image analysis to automatically extract major brain tissue volumes. Fetal MRS was used to measure major metabolite concentrations in the fetal brain. RESULTS: Twenty-one twin pairs were studied. The average (±SD) gestational age at MRI was 25.89 (±2.37) weeks. Total brain volume (TBV) was lower in the donors, although cerebral volumes were not different between twin pairs. Recipients showed lower proportions of cortical and cerebellar volumes, normalized to TBV and cerebral volumes. MRS data showed that biochemical differences between twin brains were related to discrepancy in their brain volumes. CONCLUSION: Although donors have a smaller TBV compared to recipients, proportionality of brain tissue volumes are preserved in donors. MRS maturational markers of fetal brain development show that recovery in donors persists 4 weeks after surgery.