Brain MRIs Research Articles

Lesion distribution pattern of parenchymal Neuro-Behçet's disease using probability mapping

Background and PurposeBehçet's disease (BD) is an inflammatory disorder with multisystemic involvement. The most disabling aspect of BD is Neuro-Behçet's disease (NBD). In NBD, parenchymal lesions tend to occur in the mesodiencephalic region and brainstem, as reported in large series of NBD. Our study aimed to generate probability maps of parenchymal lesions to compare patient subgroups with different clinical and laboratory features. MethodWe included 66 non-standardized acute relapse MRIs of 55 patients with parenchymal NBD (p-NBD). We used T2-weighted axial images to digitalize the lesions using the CAD software. Boundaries of lesions were determined as polygons and converted into high-definition raster datasets. Then, digitalized lesion maps were transferred into the ICBM-152 brain template to perform spatial analyses. Finally, we created subtraction maps to compare the patient subgroups. ResultsWe used a total of 66 MRIs of 55 patients to generate the probability maps. The most frequently affected parenchymal structures were the rostral pons, mesencephalon, and diencephalic region. Interestingly, the brainstem was more commonly affected in females than males (p<0.01). In the late-onset disease, lesions were localized in the corticospinal tracts and caudal brainstem (p<0.01). Progressive disease and severe disability at the end of the follow-up period were associated with corticospinal tract lesions during relapses (p<0.01). Patients with positive pathergy tests were more likely to present right hemisphere involvement (p<0.01). Additionally, cyclosporine-induced lesions tend to be in atypical locations such as hemispheric white matter. ConclusionsIn the published studies, lesions in NBD were localized according to coarse anatomical regions. Our study uses visual maps to offer accurate lesion localizations using non-standardized brain MRIs, allowing comparisons across different NBD subgroups. By using this technique, we investigated the relationship of the clinical and laboratory features with the lesion locations. We found that the late age of onset was associated with a poor prognosis. Additionally, corticospinal lesions may predict severe and progressive disease course, requiring aggressive treatment. Interestingly, females had more brainstem lesions and lesion lateralization might be influenced by the pathergy test status.

Spatial and time domain analysis of eye-tracking data during screening of brain magnetic resonance images.

IntroductionEye-tracking research has been widely used in radiology applications. Prior studies exclusively analysed either temporal or spatial eye-tracking features, both of which alone do not completely characterise the spatiotemporal dynamics of radiologists’ gaze features.PurposeOur research aims to quantify human visual search dynamics in both domains during brain stimuli screening to explore the relationship between reader characteristics and stimuli complexity. The methodology can be used to discover strategies to aid trainee radiologists in identifying pathology, and to select regions of interest for machine vision applications.MethodThe study was performed using eye-tracking data 5 seconds in duration from 57 readers (15 Brain-experts, 11 Other-experts, 5 Registrars and 26 Naïves) for 40 neuroradiological images as stimuli (i.e., 20 normal and 20 pathological brain MRIs). The visual scanning patterns were analysed by calculating the fractal dimension (FD) and Hurst exponent (HE) using re-scaled range (R/S) and detrended fluctuation analysis (DFA) methods. The FD was used to measure the spatial geometrical complexity of the gaze patterns, and the HE analysis was used to measure participants’ focusing skill. The focusing skill is referred to persistence/anti-persistence of the participants’ gaze on the stimulus over time. Pathological and normal stimuli were analysed separately both at the “First Second” and full “Five Seconds” viewing duration.ResultsAll experts were more focused and a had higher visual search complexity compared to Registrars and Naïves. This was seen in both the pathological and normal stimuli in the first and five second analyses. The Brain-experts subgroup was shown to achieve better focusing skill than Other-experts due to their domain specific expertise. Indeed, the FDs found when viewing pathological stimuli were higher than those in normal ones. Viewing normal stimuli resulted in an increase of FD found in five second data, unlike pathological stimuli, which did not change. In contrast to the FDs, the scanpath HEs of pathological and normal stimuli were similar. However, participants’ gaze was more focused for “Five Seconds” than “First Second” data.ConclusionsThe HE analysis of the scanpaths belonging to all experts showed that they have greater focus than Registrars and Naïves. This may be related to their higher visual search complexity than non-experts due to their training and expertise.

Impact on ALFF and ReHO mapping of lifestyle multidomain intervention: The SUPERBRAIN study

AbstractBackgroundIn the South Korean study to prevent cognitive impairment and protect brain health through lifestyle intervention in at‐risk elderly people (SUPERBRAIN), we explored impact on amplitude of low‐frequency fluctuation (ALFF) and regional homogeneity (ReHo) mapping of 24‐week facility‐based multidomain intervention (FMI) and home‐based MI (HMI).MethodA total of 152 participants, aged 60‐79 years without dementia but with ≥ 1 modifiable dementia risk factor, were randomly assigned to the FMI, HMI, or control groups. Among them, 56 participants (20 FMI, 20 HMI, and 16 control) took brain MRIs at baseline and 24 weeks. We compared between each intervention and control groups in change of ALFF and ReHo mapping. The changes in ALFF and ReHo mapping were compared using analysis of covariance with age, sex, education, and scan centers as covariates. ROI‐based analysis was controlled for multiple comparisons with a false discovery rate threshold of P &lt; 0.05.ResultOnly in the FMI group, a significant increase of ALFF in left medial orbitofrontal gyrus was observed after intervention. When 24‐week ALFF change in the left medial orbitofrontal gyrus was compared between each intervention and control groups, there was no difference. In HMI, increased ReHo was evident in right cuneus at follow‐up, whereas increased ReHo in left medial orbitofrontal gyrus and left anterior cingulate and decreased ReHo in right superior parietal lobule and right precuneus were observed in FMI group. The ReHo change in right cuneus was significantly higher in HMI group compared to the control group. The ReHo change in left medial orbitofrontal gyrus was notably higher in FMI compared to the control group. The correlation analysis revealed a positive correlation between the ReHo change in left medial orbitofrontal gyrus and change of serum brain‐derived neurotrophic factor (BDNF) levels in FMI group.ConclusionSignificant differences between the FMI and control groups on changes in ReHo in at‐risk elderly without substantial impairment in the SUPERBRAIN suggest that group preventive strategies at the facility may be beneficial on cognition through neuroplastic changes of functional processing circuits in the brain areas which play a crucial role in processing social information.

Impact on cerebral cortical thickness of lifestyle multidomain intervention: The SUPERBRAIN study

AbstractBackgroundIn the South Korean study to prevent cognitive impairment and protect brain health through lifestyle intervention in at‐risk elderly people (SUPERBRAIN), we explored impact on cortical thickness of 24‐week facility‐based multidomain intervention (FMI) and home‐based MI (HMI).MethodA total of 152 participants, aged 60‐79 years without dementia but with ≥ 1 modifiable dementia risk factor, were randomly assigned to the FMI, HMI, or control groups. Among them, 55 participants (20 FMI, 19 HMI, and 16 control) took brain MRIs at baseline and 24 weeks. We compared between each intervention and control groups in change of global/regional mean cortical thickness at 76 region‐of‐interest (ROI)s of the automated anatomical labelling (AAL); the total scale index score of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS); and Serum brain‐derived neurotrophic factor (BDNF) levels. The changes in mean cortical thickness were compared using analysis of covariance with age, sex, education, and scan centers as covariates. ROI‐based analysis was controlled for multiple comparisons with a false discovery rate threshold of P &lt; 0.05.ResultComparing with the control group, the total scale index score of RBANS was more significantly improved in both FMI group (p=0.002) and HMI group (p=0.013), respectively. The serum BDNF more significantly increased only in the FMI group (p=0.029). Mean global cortical thickness more significantly increased only in the FMI group (0.033±0.070 vs ‐0.003±0.040, p=0.035). ROI‐based analysis showed more significantly increased cortical thickness of the orbital, medial, medial orbital parts of right superior frontal gyrus, right olfactory cortex, right rectal gyrus, right anterior cingulate and paracingulate gyri, right middle temporal gyrus, medial orbital and dorsolateral parts of the left superior frontal gyrus, the orbital part of the left middle frontal gyrus, left middle occipital gyrus, and left middle temporal gyrus in the FMI group.ConclusionSignificant differences between the FMI and control groups on changes in cortical thicknesses in at‐risk elderly without substantial impairment in the SUPERBRAIN suggest that group preventive strategies at the facility may be beneficial on cognition through structural neuroplastic changes in the brain areas which play a crucial role in processing social information.

Get Your Molar Tooth Right: Joubert Syndrome Misdiagnosis Unmasked by Whole-Exome Sequencing

Joubert syndrome (JS) is a recessively inherited ciliopathy, characterized by a specific cerebellar and brainstem malformation recognizable on brain imaging as the "molar tooth sign" (MTS). Clinical signs include hypotonia, developmental delay, breathing abnormalities, and ocular motor apraxia. Older patients develop ataxia, intellectual impairment, and variable organ involvement. JS is genetically heterogeneous, with over 40 ciliary genes overall accounting for 65-75% cases. Thus, in recent years, the genetic diagnosis of JS has been based on the analysis of next-generation sequencing targeted gene panels. Since clinical features are unspecific and undistinguishable from other neurodevelopmental syndromes, the recognition of the MTS is crucial to address the patient to the appropriate genetic testing. However, the MTS is not always properly diagnosed, resulting either in false negative diagnoses (patients with the MTS not addressed to JS genetic testing) or in false positive diagnoses (patients with a different brain malformation wrongly addressed to JS genetic testing). Here, we present six cases referred for JS genetic testing based on inappropriate recognition of MTS. While the analysis of JS-related genes was negative, whole-exome sequencing (WES) disclosed pathogenic variants in other genes causative of distinct brain malformative conditions with partial clinical and neuroradiological overlap with JS. Reassessment of brain MRIs from five patients by a panel of expert pediatric neuroradiologists blinded to the genetic diagnosis excluded the MTS in all cases but one, which raised conflicting interpretations. This study highlights that the diagnostic yield of NGS-based targeted panels is strictly related to the accuracy of the diagnostic referral based on clinical and imaging assessment and that WES has an advantage over targeted panel analysis when the diagnostic suspicion is not straightforward.

An MRI Study on Effects of Math Education on Brain Development Using Multi-Instance Contrastive Learning.

This paper explores whether mathematical education has effects on brain development from the perspective of brain MRIs. While biochemical changes in the left middle front gyrus region of the brain have been investigated, we proposed to classify students by using MRIs from the intraparietal sulcus (IPS) region that was left untouched in the previous study. On the cropped IPS regions, the proposed model developed popular contrastive learning (CL) to solve the problem of multi-instance representation learning. The resulted data representations were then fed into a linear neural network to identify whether students were in the math group or the non-math group. Experiments were conducted on 123 adolescent students, including 72 math students and 51 non-math students. The proposed model achieved an accuracy of 90.24 % for student classification, gaining more than 5% improvements compared to the classical CL frame. Our study provides not only a multi-instance extension to CL and but also an MRI insight into the impact of mathematical studying on brain development.

MeTiS: A Modular Pipeline for Extracting 3D-Printable Brain-Surface Models from Conventional and Ultra-High Field MRI

Aim: To develop a modular software pipeline for robustly extracting 3D brain-surface models from MRIs for visualization or printing. No other end-to-end pipeline specialized for neuroimaging does this directly with an interchangeable combination of methods. Materials &amp; methods: A software application was developed to dynamically generate Nipype workflows using interfaces from the Analysis of Functional NeuroImages, Advanced Normalization Tools, FreeSurfer, BrainSuite, Nighres and the FMRIB Software Library suites. The application was deployed for public use via the LONI pipeline environment. Results: In a small, head-to-head comparison test, a pipeline using FreeSurfer for both the skull stripping and cortical-mesh extraction stages earned the highest subjective quality scores. Conclusion: We have deployed a publicly available and modular software tool for extracting 3D models from brain MRIs to use in medical education.

Abstract 13579: Serum Neural Biomarkers and Neuroimaging Markers in Neonates With Congenital Heart Disease Undergoing Cardiac Surgery

Introduction: Congenital heart disease (CHD) patients requiring neonatal cardiopulmonary bypass (CPB) surgery often experience abnormal neurodevelopment. Open heart surgery and anesthesia induce changes in the developing brain concomitant with an increase in the level of neuromarkers. The aim of this study is to assess the relationship between neuromarkers, brain dysplasia and neurodevelopmental outcomes for CHD patients undergoing neonatal CPB. Hypothesis: Neuromarkers and neuroimaging brain dysplasia can predict the neurodevelopmental outcomes for CHD patients undergoing neonatal CPB. Methods: 42 neonates with CHD requiring CPB were included in this prospective, observational study. Using the Neurology 4-Plex A Assay, serum levels of glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), neurofilament light (NF-L), and Tau protein were measured pre-operatively and at 0 hours, 24 hours, and 48 hours post-operatively. Brain MRIs were obtained in 24 neonates. Neurodevelopment testing was completed at 6 months to 36 months of age using the Bayley-III Scales of infant. Findings of brain MRI were scored using an internally developed scoring system which evaluates the brains structures individually on degrees of dysplasia, hypoplasia, and abnormalities, as well as providing a comprehensive assessment of overall brain development combining the individual structural abnormalities into a composite total brain dysplasia score (TBDS). Results: Bayley-III scales were negatively correlated with NF-L and Tau. For UCH-L1, a positive correlation was seen at immediate postop. Hemorrhage is associated with low language score (P=0.009) and elevated UCH-L1 levels at 24 hours and 48 hours. Infraction (P=0.0375) and lower maturation (P=0.03) are associated with low fine motor scores. Lower maturation is related to more domains below average (P=0.01). Infarction is associated with high postoperative Tau level (P=0.04).TBDS is associated with high levels of GFAP, NFL-1, and decreased language development. Conclusion: A negative correlation of Tau and NF-L to Bayley-III scales was consistent with their known roles as markers of neural injury. High NF-L and GFAP are associated with brain dysplasia.

Abstract 10700: Inverse Relationship Between Cerebral Blood Flow and Systemic to Pulmonary Collateral Flow in Fontans Adjusting for Brain Injury: What Goes up Must Come Down - and Visa Versa

Introduction: Single ventricle patients develop aortopulmonary collaterals (APC) whose flow (APCF) has been shown, in a cross-sectional study, to be inversely proportional to cerebral blood flow (CBF). Serial longitudinal CBF and APCF data in Fontan patients taking into account brain injury (BI) has never been reported. Decreased CBF may adversely impact neurodevelopmental outcome. Methods: A prospective longitudinal cohort of 27 Fontan patients (age 10 + 1.9 years, 74% male) underwent cardiac and brain MRIs 3-9 months after Fontan and 6.0 + 1.86 years afterwards to measure CBF, APCF and to assess BI (grouped into focal brain injury (FBI), generalized insult (GI) and hemorrhage). CBF was measured using jugular venous flow and APCF was measured by the difference between aortic flow and caval return. A multivariate linear regression model was used to assess the relationship between change in APCF and change in CBF controlling for time since Fontan, sex, and changes in BI. Results: Demographics, flow and BI data are shown in table 1. A strong inverse relationship was found between CBF and APCF when CBF was indexed to aortic flow and APCF was indexed to BSA (R^2 = 0.72, P&lt;0.01). Overall, CBF decreased by 9 + 11% and APCF decreased by 0.73 + 0.67 l/min/m^2 (12% when indexed to aortic flow). CBF and APCF were significantly and inversely related when adjusting for time since Fontan, sex, and change in the visibility of BI on MRI. Each one unit increase in APCF was associated with an 8% decrease in CBF. Change in CBF was smaller for those with longer times since Fontan and was larger for males. Change in CBF was larger for those whose FBI or GI became less visible, but smaller for those whose hemorrhages became less visible. See table 2. Conclusion: CBF and APCF are inversely related across serial imaging, adjusting for time from Fontan, sex and BI. This may adversely impact neurodevelopment. As APCs can be embolized, this may be a modifiable risk factor. A large scale trial is warranted.

Abstract 10072: Stroke Topology and Neurodevelopment in Infants with Congenital Heart Disease: Does it Differ by Cardiac Physiology?

Objectives: Vulnerability to brain injury in infants with congenital heart disease (CHD) may differ by CHD lesion. However, the link between arterial ischemic stroke (AIS) and neurodevelopment, and whether it differs by CHD lesion, is unknown. We sought to determine whether: (1) Stroke topology differs between infants with Transposition of the Great Arteries (TGA) and single ventricle physiology (SVP), and relationship with neurodevelopment;(2) Associations between stroke volume and neurodevelopment are CHD lesion specific. Methods: 64 of 312 CHD infants (TGA n=38, SVP n=26) studied prospectively with pre- and/or post-operative brain MRIs had AIS. AIS were segmented on 3DT1 and/or ADC images. 39 infants completed 18-month neurodevelopmental assessments with Bayley Scales (2 nd or 3 rd Edition); scores were adjusted to account for differences between versions. Adverse neurodevelopment was defined as &lt;85 points. We used multivariable linear regression models to study associations between AIS volume and neurodevelopment, stratifying by CHD lesion and adjusting for study site. Probability maps demonstrating areas vulnerable to AIS and odds ratio maps reflecting likelihood of a lesion predicting adverse outcomes were developed. Results: Most AIS were in MCA territories, with a left-sided predominance (Fig 1A). Stroke volume did not differ between CHD groups (p=0.8). Basal ganglia lesions were most predictive of cognitive (max OR=11) and motor (max OR=6) outcomes (Fig 1B). Stratifying by CHD lesion, AIS volume predicted 18-month cognitive outcomes in infants with TGA (β=-0.6, 95%CI -1.0-(-0.1), p=0.02) but not SVP (β=7.9, 95%CI -72-88). AIS volume did not predict motor outcomes in infants with TGA (β=-0.6, 95%CI -1.6-0.3) or SVP (β=-19.7, 95%CI -91-52). Conclusions: Neonatal AIS topology does not differ between infants with TGA and SVP. AIS location and size are important predictors of neurodevelopment at 18 months though this association differs by CHD lesion.

INNV-28. POTENTIAL EFFECTIVE CONSOLIDATION THERAPY WITH SINGLE AGENT IBRUTINIB FOR A CASE WITH PRIMARY CNS LYMPHOMA AFTER INITIAL HD-MTX AND RITUXIMAB INDUCTION THERAPY

Abstract INTRODUCTION Primary CNS Lymphoma (PCNSL) is a rare and aggressive cancer that originates from lymphocytes and develops in the central nervous system. Standard induction therapy involves high-dose methotrexate (HD-MTX)-based chemotherapy, which achieves complete or partial response in most PCNSL patients. However, there is no standard consolidation therapy. We report one case in which ibrutinib, a Bruton’s tyrosine kinase inhibitor, replaced low-dose WBRT as consolidation therapy after induction by HD-MTX and rituximab. Ibrutinib treatment yielded good tolerance and further resolution of small residue lymphoma. CASE REPORT The patient is a 77-year-old female who presented with slurred speech, right-sided weakness, and difficulty word-finding in early 2020. Brain MRI found multifocal lesions, and biopsy of the largest lesion near the left lateral ventricle revealed diffuse large B cell lymphoma. The patient began HD-MTX at 6 g/m2 for the first cycle of induction therapy. She continued HD-MTX every two weeks, but dosage was reduced every cycle due to worsening renal function. Ultimately, MTX was discontinued after 6 cycles. Brain MRI showed significant response after HD-MTX except for small residue lymphoma at the biopsy area. 2nd line regimen rituximab and temozolomide was given to complete induction. Brain MRI was stable, but the small enhancing residue lymphoma at left peri-ventricle area was persistent after the induction therapy (uCR). Ibrutinib as consolidation therapy began after discussion with the patient. The patient tolerated 560 mg ibrutinib for 6 cycles initially, then switched to a reduced dose of 420 mg for cycles 7 and 8 due to neutropenia. Brain MRIs have been stable with resolution of the small lymphoma residue after 6 cycles of ibrutinib. The patient continues ibrutinib for the goal of one year of consolidation therapy. DISCUSSION Our case highlights the potential of single-agent ibrutinib as consolidation therapy for PCNSL after HD-MTX and rituximab/temzolomide induction therapy.

IMMU-27. LONG TERM STABILIZATION OF RECURRENT HIGH-GRADE GLIOMA WITH PD-1 INHIBITOR PEMBROLIZUMAB IN TWO CASES

Abstract INTRODUCTION Despite PD-1 inhibition having success in many cancers, it has uncertain effects in brain tumors. We report two cases of recurrent high-grade gliomas that have remained stable for over one year since starting pembrolizumab. CASE REPORTS Case 1: A 59-year-old male was diagnosed with glioblastoma (GBM) without MGMT methylation or IDH mutation in late 2018 after surgery. He received radiation and temozolomide (TMZ) followed by adjuvant TMZ before tumor progression. He underwent second tumor debulking with recurrent GBM on pathology with negative PD-L1 expression. He started carboplatin. Progression was noticed after 7 to 8 cycles. Pembrolizumab was added. Tumor was stabilized. Carboplatin was completed after total 12 cycles and the patient has continued single agent of pembrolizumab for more than one year with stable brain MRIs. The patient has survived for 24 months since recurrence and 30 months since diagnosis. Case 2: A 53-year-old male had a brain tumor discovered on MRI in 2012 and received no treatment until resection in 2014. In 2016, he underwent second tumor debulking and was diagnosed with anaplastic oligodendroglioma with negative PD-L1 expression. He received radiation followed by PCV regimen. 17 months since diagnosis, he had first tumor progression on PCV. TMZ was started. 22 months since diagnosis, bevacizumab was initiated due to further growth. 33 months since diagnosis, pembrolizumab was added due to new lesions after 12-months of bevacizumab therapy. His tumor was stabilized. Bevacizumab was eventually discontinued. He has continued single agent pembrolizumab for 6 months so far. His tumor has been stable for 22 months since starting pembrolizumab. Survival has been 38 months from first recurrence and 7 years since tissue diagnosis. DISCUSSION These cases demonstrate the potential effects of anti-PD-1 immunotherapy in stabilizing recurrent high-grade glioma with combination of other treatment agents followed by single agent as maintenance therapy.

Longitudinal analysis of regional brain changes in anti-NMDAR encephalitis: a case report

BackgroundAnti-NMDA receptor encephalitis is an immune-mediated disorder characterized by antibodies against the GluN1 subunit of the NMDA receptor that is increasingly recognized as a treatable cause of childhood epileptic encephalopathy. In adults, the disorder has been associated with reversible changes in brain volume over the course of treatment and recovery, but in children, little is known about its time course and associated imaging manifestations.Case presentationA previously healthy 20-month-old boy presented with first-time unprovoked seizures, dysautonomia, and dyskinesia. Paraneoplastic workup was negative, but CSF was positive for anti-NMDAR antibodies. The patient’s clinical condition waxed and waned over a 14-month course of treatment with first- and second-line immunotherapies (including steroids, IVIG, rituximab, and cyclophosphamide). Serial brain MRIs scans obtained at 5 time points spanning this same period showed no abnormal signal or enhancement but were remarkable for cycles of reversible regional cortical volume loss. All scans included identical 1-mm resolution 3D T1-weighted sequences obtained on the same 3 T scanner. Using a novel longitudinal processing stream in FreeSurfer6 (Reuter M, et. al, Neuroimage 61:1402–18, 2012) we quantified the rate of change in cortical volume at each vertex (% volume change per month) between consecutive scans and correlated these changes with the time course of the patient’s treatment and clinical response. We found regionally specific changes in cortical volume (up to 7% per month) that preferentially affected the frontal and occipital lobes and paralleled the patient’s clinical course, with clinical decline associated with volume loss and clinical improvement associated with volume gain.ConclusionsOur results suggest that reversible cortical volume loss in anti-NMDA encephalitis has a regional specificity that mirrors many of the clinical symptoms associated with the disorder and tracks the dynamics of disease severity over time. This case illustrates how quantitative morphometric techniques can be applied to clinical imaging data to reveal patterns of brain change that may provide insight into disease pathophysiology. More widespread application of this approach might reveal regional and temporal patterns specific to different types of autoimmune encephalitis, providing a tool for diagnosis and a surrogate marker for monitoring treatment response.

Patterns of Failure in Patients With Recurrent High-Grade Glioma Treated With Hypofractionated Stereotactic Re-Irradiation, Pembrolizumab, and Bevacizumab

Patients with high-grade gliomas (HGG) progress despite multimodality therapy. Hypofractionated stereotactic re-irradiation therapy (HFSRT) has been used with promising efficacy as a salvage treatment in the setting of recurrent HGG (rHGG). We recently completed a phase I study combining HFSRT with concurrent pembrolizumab and bevacizumab (Bev) for patients with rHGG (NCT02313272). The main objective of this study is to identify patterns of failure in the above regimen.Data from 32 patients enrolled in the phase I trial from June 2015 to January 2018 were reviewed. Patient characteristics, time to progression, and treatment outcomes were evaluated. Brain MRIs were taken at baseline, and every 6 to 8 weeks until progression. T1 post-contrast and T2- FLAIR images at baseline and at progression were imported into commercial software and the extent of hyperintensity was contoured by a single physician and reviewed by a second physician. An automated algorithm was used to compare the volumetric similarities between the pre- and post-treatment structures. This algorithm used Dice similarity coefficient (DSC), a statistical validating index for evaluating reproducibility and spatial overlap accuracy in the MRI image segmentation. A DSC value of 0.3 or greater indicated significant spatial overlap accuracy. Pearson's single and two-tailed tests were used to identify correlation between time to progression and volumetric parameters.The median age of patients at re-irradiation was 56 years (22-68).24 patients had Bev naïve tumor. The median radiation dose was 35 Gy in 5 fractions (25-40). The median progression free survival was 7.92 months (95% CI:6.31-12.45). A total of 22 (68%) patients with radiological progression were included for this analysis. Considerable similarities were observed (11/22) between the pretreatment T2- FLAIR and the post-treatment T1 contrast: with a median DSC of 0.31(range 0.05-0.6) and pre-treatment T2-FLAIR and post-treatment T2-FLAIR; DSC 0.66 (range 0.15-0.7). The median DSC value comparing pre- and post-treatment T1 contrast volumes were 0.24 (range 0-0.5). These findings suggest that recurrence or progression occurred in the pretreatment T2-FLAIR region outside the pre-treatment post-contrast T1 region. A positive correlation between time to progression with maximum dose received by pre-treatment (P = 0.02) and post-treatment T2-FLAIR (P = 0.02) volumes was observed.Our analysis of a prospective trial of HSFRT with concurrent pembrolizumab and bevacizumab showed recurrences occurred outside the radiation field (i.e., region of T1post contrast abnormality). Recurrences predominantly occurred in the pre-treatment T2-FLAIR region. Including T2-FLAIR region in the pre-treatment GTV contours may be needed in achieving optimal local control.R. Padmanabhan: None. G.G. Zhang: None. D.E. Oliver: None. J. Graham: None. D. Grass: None. S. Sahebjam: Research Grant; Merck, Bristol Myers Squibb and Brooklyn Immuno Therapeutics. Advisory Board; Merck, Boehringer Ingelheim. Travel Expenses; Eli Lilly. H.M. Yu: Honoraria; UpToDate. Speaker's Bureau; BrainLab. Advisory Board; Novocure, AbbVie.

The presentation of brain metastases in melanoma, non-small cell lung cancer, and breast cancer and potential implications for screening brain MRIs.

This study assessed the presentation and institutional outcomes treating brain metastases (BM) of breast cancer (BC), non-small cell lung cancer (NSCLC), and melanoma origin. Patients with brain metastases treated between 2014 and 2019 with primary melanoma, NSCLC, and BC were identified. Overall survival (OS) was calculated from dates of initial BM diagnosis using the Kaplan-Meier method. A total of 959 patients were identified including melanoma (31%), NSCLC (51%), and BC (18%). Patients with BC were younger at BM diagnosis (median age: 57) than NSCLC (65) and melanoma patients (62, p < 0.0001). Breast cancer patients were more likely to present with at least 5 BM (27%) than NSCLC (14%) and melanoma (13%), leptomeningeal disease (23%, 6%, and 6%, p = 0.0004) and receive whole brain radiation therapy (WBRT) (58%, 37%, and 22%, p < 0.0001). There were no differences in surgical resection (24%, 24%, and 29%, p = 0.166). Median OS was shorter for BC patients (9.9, 10.3, and 13.7months, p = 0.0006). Breast cancer patients were more likely to be younger, present with advanced disease, require WBRT, and have poorer OS than NSCLC and melanoma patients. Further investigation is needed to determine which BC patients are at sufficient risk for brain MRI screening.

Accuracy of central neuro-imaging review of DIPG compared with histopathology in the International DIPG Registry.

Diffuse intrinsic pontine glioma (DIPG) remains a clinico-radiologic diagnosis without routine tissue acquisition. Reliable imaging distinction between DIPG and other pontine tumors with potentially more favorable prognoses and treatment considerations is essential. Cases submitted to the International DIPG registry (IDIPGR) with histopathologic and/or radiologic data were analyzed. Central imaging review was performed on diagnostic brain MRIs (if available) by two neuro-radiologists. Imaging features suggestive of alternative diagnoses included nonpontine origin, <50% pontine involvement, focally exophytic morphology, sharply defined margins, and/or marked diffusion restriction throughout. Among 286 patients with pathology from biopsy and/or autopsy, 23 (8%) had histologic diagnoses inconsistent with DIPG, most commonly nondiffuse low-grade gliomas and embryonal tumors. Among 569 patients with centrally-reviewed diagnostic MRIs, 40 (7%) were classified as non-DIPG, alternative diagnosis suspected. The combined analysis included 151 patients with both histopathology and centrally-reviewed MRI. Of 77 patients with imaging classified as characteristic of DIPG, 76 (99%) had histopathologic diagnoses consistent with DIPG (infiltrating grade II-IV gliomas). Of 57 patients classified as likely DIPG with some unusual imaging features, 55 (96%) had histopathologic diagnoses consistent with DIPG. Of 17 patients with imaging features suggestive of an alternative diagnosis, eight (47%) had histopathologic diagnoses inconsistent with DIPG (remaining patients were excluded due to nonpontine tumor origin). Association between central neuro-imaging review impression and histopathology was significant (p < 0.001), and central neuro-imaging impression was prognostic of overall survival. The accuracy and important role of central neuro-imaging review in confirming the diagnosis of DIPG is demonstrated.

Predictive value of brain MRI at term-equivalent age in extremely preterm children on neurodevelopmental outcome at school-age.

This study's objective was to correlate the abnormalities in brain MRIs performed at corrected-term age for minor or moderate neurocognitive disorders in children school-age born extremely premature (EPT) and without serious sequelae such as autism, cerebral palsy, mental impairment. Data were issued from a cross-sectional multicenter study (GP-Qol study, number NCT01675726). Clinical examination and psychometric assessments were performed when the children were between 7 and 10years old during a day-long evaluation. Term-equivalent age brain MRIs on EPT were analyzed with a standardized scoring system. There were 114 children included in the study. The mean age at the time of evaluation, was 8.47years old (± 0.70). 59% of children with at least one cognitive impairment and 53% who had a dysexecutive disorder. Only ten EPT (8.7%) presented moderate to severe white and grey matter abnormalities. These moderate to severe grey matter abnormalities were associated with at least two abnormal executive functions [OR 3.08 (95% CI 1.04-8.79), p = 0.04] and language delay [OR 3.25 (95% CI 1.03-9.80), p = 0.04]. These results remained significant in the multivariate analysis. Moderate to severe ventricular dilatation abnormalities (15%, n = 17) were associated with ideomotor dyspraxia [OR 7.49 (95% CI 1.48-35.95), p = 0.02] and remained significant in multivariate analysis [OR 11.2 (95% CI 1.45-131.4), p = 0.02]. Biparietal corrected diameters were moderate abnormal in 20% of cases (n = 23) and were associated to visuo spatial integration delay [OR 4.13 (95% CI 1.23-13.63), p = 0.02]. Cerebral MRI at term-equivalent age with scoring system analysis can provide information on long-term neuropsychological outcomes at school-age in EPTs children having no severe disability.

Study of montelukast in children with sickle cell disease (SMILES): a study protocol for a randomised controlled trial

BackgroundYoung children with sickle cell anaemia (SCA) often have slowed processing speed associated with reduced brain white matter integrity, low oxygen saturation, and sleep-disordered breathing (SDB), related in part to enlarged adenoids and tonsils. Common treatments for SDB include adenotonsillectomy and nocturnal continuous positive airway pressure (CPAP), but adenotonsillectomy is an invasive surgical procedure, and CPAP is rarely well-tolerated. Further, there is no current consensus on the ability of these treatments to improve cognitive function. Several double-blind, randomised controlled trials (RCTs) have demonstrated the efficacy of montelukast, a safe, well-tolerated anti-inflammatory agent, as a treatment for airway obstruction and reducing adenoid size for children who do not have SCA. However, we do not yet know whether montelukast reduces adenoid size and improves cognition function in young children with SCA.MethodsThe Study of Montelukast In Children with Sickle Cell Disease (SMILES) is a 12-week multicentre, double-blind, RCT. SMILES aims to recruit 200 paediatric patients with SCA and SDB aged 3–7.99 years to assess the extent to which montelukast can improve cognitive function (i.e. processing speed) and sleep and reduce adenoidal size and white matter damage compared to placebo. Patients will be randomised to either montelukast or placebo for 12 weeks. The primary objective of the SMILES trial is to assess the effect of montelukast on processing speed in young children with SCA. At baseline and post-treatment, we will administer a cognitive evaluation; caregivers will complete questionnaires (e.g. sleep, pain) and measures of demographics. Laboratory values will be obtained from medical records collected as part of standard care. If a family agrees, patients will undergo brain MRIs for adenoid size and other structural and haemodynamic quantitative measures at baseline and post-treatment, and we will obtain overnight oximetry.DiscussionFindings from this study will increase our understanding of whether montelukast is an effective treatment for young children with SCA. Using cognitive testing and MRI, the SMILES trial hopes to gain critical knowledge to help develop targeted interventions to improve the outcomes of young children with SCA.Trial registrationClinicalTrials.govNCT04351698. Registered on April 17, 2020. European Clinical Trials Database (EudraCT No. 2017-004539-36). Registered on May 19, 2020

Utility of paramagnetic rim lesions on 1.5-T susceptibility phase imaging for the diagnosis of pediatric multiple sclerosis.

Studies have suggested that paramagnetic rim lesions on 7-tesla (T) and 3-T susceptibility-based brain MRI are specific features of multiple sclerosis (MS) lesions in adults. The aim of this study was to investigate whether the presence of paramagnetic rim lesions on 1.5-T phase images can help discriminate pediatric patients with MS from those with other demyelinating diseases. In this retrospective study we reviewed brain MRIs performed on 1.5-T scanners that included susceptibility-weighted imaging (SWI) sequences with phase images in children younger than 18years diagnosed with MS and other acquired demyelinating syndromes. In each case, five white matter lesions were selected using T2/fluid-attenuated inversion recovery images for further paramagnetic rim evaluation on SWI. Two researchers performed independent assessments of the presence of paramagnetic rim lesions. Discrepancies between them were settled by consensus, with input from a senior neuroradiologist. We included 13 children diagnosed with MS and 16 children diagnosed with non-MS demyelinating diseases and analyzed a total of 132 focal white matter lesions. Seventy-one percent of the lesions in the MS group had paramagnetic rims, while none of the lesions in the non-MS group had rims. All but one of the children with MS had at least one lesion with a paramagnetic rim. The presence of one lesion with a paramagnetic rim on 1.5-T phase-contrast images resulted in 70% sensitivity and 100% specificity for MS. Paramagnetic rim lesions detected on 1.5-T phase-contrast MR images can help discriminate MS from other acquired demyelinating syndromes in the pediatric population.

Review of 37 patients with SOX2 pathogenic variants collected by the Anophthalmia/Microphthalmia Clinical Registry and DNA research study.

SOX2 variants and deletions are a common cause of anophthalmia and microphthalmia (A/M). This article presents data from a cohort of patients with SOX2 variants, some of whom have been followed for 20+ years. Medical records from patients enrolled in the A/M Research Registry and carrying SOX2 variants were reviewed. Thirty-seven patients were identified, ranging in age from infant to 30 years old. Eye anomalies were bilateral in 30 patients (81.1%), unilateral in 5 (13.5%), and absent in 2 (5.4%). Intellectual disability was present in all with data available and ranged from mild to profound. Seizures were noted in 18 of 27 (66.6%) patients, usually with abnormal brain MRIs (10/15, 66.7%). Growth issues were reported in 14 of 21 patients (66.7%) and 14 of 19 (73.7%) had gonadotropin deficiency. Genitourinary anomalies were seen in 15 of 19 (78.9%) male patients and 5 of 15 (33.3%) female patients. Patients with SOX2 nucleotide variants, whole gene deletions or translocations are typically affected with bilateral or unilateral microphthalmia and anophthalmia. Other associated features include intellectual disability, seizures, brain anomalies, growth hormone deficiency, gonadotropin deficiency, and genitourinary anomalies. Recommendations for newly diagnosed patients with SOX2 variants include eye exams, MRI of the brain and orbits, endocrine and neurology examinations. Since the clinical spectrum associated with SOX2 alleles has expanded beyond the originally reported phenotypes, we propose a broader term, SOX2-associated disorder, for this condition.