IL-11 antagonist suppresses Th17 cell-mediated neuroinflammation and demyelination in a mouse model of relapsing-remitting multiple sclerosis.

IL-11 induced differentiation and expansion of Th17 cells in patients with early relapsing-remitting multiple sclerosis (RRMS). In mice with relapsing-remitting experimental autoimmune encephalomyelitis (RREAE), IL-11 exacerbated disease, induced demyelination in the central nervous system (CNS), increased the percentage of IL-17A+CD4+ Th17 cells in the CNS in the early acute phase, and up-regulated serum IL-17A levels and the percentage of IL-17A+CD4+ Th17 cells in lymph nodes, and IFN-γ+CD4+ T cells in spinal cord in the RR phase. IL-11 antagonist suppressed RREAE disease activities, inhibited IL-17A+CD4+ cell infiltration and demyelination in the CNS, and decreased the percentage of IL-17A+CD4+ T cells in peripheral blood mononuclear cells and ICAM1+CD4+ T cells in brain and SC. Diffusion Tensor Imaging indicated that IL-11 antagonist inhibited demyelination in several brain regions. We conclude that by suppressing Th17 cell-mediated neuroinflammation and demyelination, IL-11 antagonist can be further studied as a potential selective and early therapy for RRMS.

The role of endogenous IFN-ß in the regulation of Th17 responses in patients with relapsing-remitting multiple sclerosis.

IFN-ß has been used as a first-line therapy for relapsing-remitting multiple sclerosis (RRMS). Because only a few studies have addressed the role of endogenous IFN-ß in the pathogenesis of the disease, our objective was to characterize its role in the transcriptional regulation of pathogenic Th17 cytokines in patients with RRMS. In vitro studies have demonstrated that IFN-ß inhibits IL-17A, IL-17F, IL-21, IL-22, and IFN-γ secretion in CD4(+) lymphocytes through the induction of suppressor of cytokine secretion 1 and suppressor of cytokine secretion 3. We found that patients with RRMS have increased serum and cerebrospinal fluid Th17 (IL-17A and IL-17F) cytokine levels in comparison with the control subjects, suggesting that deficient endogenous IFN-ß secretion or signaling can contribute to the dysregulation of those pathogenic cytokines in CD4(+) cells. We identified that the endogenous IFN-ß from serum of RRMS patients induced a significantly lower IFN-inducible gene expression in comparison with healthy controls. In addition, in vitro studies have revealed deficient endogenous and exogenous IFN-ß signaling in the CD4(+) cells derived from patients with MS. Interestingly, upon inhibition of the endogenous IFN-ß signaling by silencing IFN regulatory factor (IRF) 7 gene expression, the resting CD4(+) T cells secreted significantly higher level of IL-17A, IL-17F, IL-21, IL-22, and IL-9, suggesting that endogenous IFN-ß suppresses the secretion of these pathogenic cytokines. In vivo recombinant IFN-ß-1a treatment induced IFNAR1 and its downstream signaling molecules' gene expression, suggesting that treatment reconstitutes a deficient endogenous IFN-ß regulation of the CD4(+) T cells' pathogenic cytokine production in patients with MS.

Interactive and additive influences of Gender, BMI and Apolipoprotein 4 on cognition in children chronically exposed to high concentrations of PM2.5 and ozone. APOE 4 females are at highest risk in Mexico City.

Children's air pollution exposures are associated with systemic and brain inflammation and the early hallmarks of Alzheimer's disease (AD). The Apolipoprotein E (APOE) 4 allele is the most prevalent genetic risk for AD, with higher risk for women. We assessed whether gender, BMI, APOE and metabolic variables in healthy children with high exposures to ozone and fine particulate matter (PM2.5) influence cognition. The Wechsler Intelligence Scale for Children (WISC-R) was administered to 105 Mexico City children (12.32±5.4 years, 69 APOE 3/3 and 36 APOE 3/4). APOE 4v 3 children showed decrements on attention and short-term memory subscales, and below-average scores in Verbal, Performance and Full Scale IQ. APOE 4 females had higher BMI and females with normal BMI between 75-94% percentiles had the highest deficits in Total IQ, Performance IQ, Digit Span, Picture Arrangement, Block Design and Object Assembly. Fasting glucose was significantly higher in APOE 4 children p=0.006, while Gender was the main variable accounting for the difference in insulin, HOMA-IR and leptin (p<.05). Gender, BMI and APOE influence children's cognitive responses to air pollution and glucose is likely a key player. APOE 4 heterozygous females with >75% to <94% BMI percentiles are at the highest risk of severe cognitive deficits (1.5-2SD from average IQ). Young female results highlight the urgent need for gender-targeted health programmes to improve cognitive responses. Multidisciplinary intervention strategies could provide paths for prevention or amelioration of female air pollution targeted cognitive deficits and possible long-term AD progression.

The Relationship Between Cochleovestibular Orientation, Age, and Sensorineural Hearing Loss: Implications for Cochlear Implantation.

OBJECTIVES: To determine if spatial orientation of the cochlea within the temporal bone is related to age or sensorineural hearing loss (SNHL) and describe the implications for cochlear implantation. METHODS: Five angles of cochlear orientation were determined from computed tomography (CT) imaging of the temporal bones in adults with (n = 55) and without (n = 27) sensorineural hearing loss (SNHL) and children with (n = 45) and without (n = 12) SNHL: facial recess versus basal turn, posterior semicircular canal versus basal turn, round window versus basal turn (axial view), round window versus basal turn (coronal view), and the cochlear axis versus the mastoid facial nerve. RESULTS: All angles showed substantial variation between subjects and between ears. The angles between the round window and basal turn (coronal view) and the posterior semicircular canal and basal turn were significantly correlated with age for all subjects with SNHL (r = 0.22, P = .002 and r = 0.15, P = .03, respectively). Patients with SNHL had significantly more acute angles (46.6° vs 55.8°) between the round window versus basal turn (axial orientation) compared to controls (P < .001). CONCLUSIONS: Cochlear orientation within the temporal bone changes with age and the degree of SNHL. These results suggest that the approach to the round window for electrode insertion might differ between children and adults.

Diffusion tensor imaging based network analysis detects alterations of neuroconnectivity in patients with clinically early relapsing-remitting multiple sclerosis.

Although it is inarguable that conventional MRI (cMRI) has greatly contributed to the diagnosis and assessment of multiple sclerosis (MS), cMRI does not show close correlation with clinical findings or pathologic features, and is unable to predict prognosis or stratify disease severity. To this end, diffusion tensor imaging (DTI) with tractography and neuroconnectivity analysis may assist disease assessment in MS. We, therefore, attempted this pilot study for initial assessment of early relapsing-remitting MS (RRMS). Neuroconnectivity analysis was used for evaluation of 24 early RRMS patients within 2 years of presentation, and compared to the network measures of a group of 30 age-and-gender-matched normal control subjects. To account for the situation that the connections between two adjacent regions may be disrupted by an MS lesion, a new metric, network communicability, was adopted to measure both direct and indirect connections. For each anatomical area, the brain network communicability and average path length were computed and compared to characterize the network changes in efficiencies. Statistically significant (P < 0.05) loss of communicability was revealed in our RRMS cohort, particularly in the frontal and hippocampal/parahippocampal regions as well as the motor strip and occipital lobes. Correlation with the 25-foot Walk test with communicability measures in the left superior frontal (r = -0.71) as well as the left superior temporal gyrus (r = -0.43) and left postcentral gyrus (r = -0.41) were identified. Additionally identified were increased communicability between the deep gray matter structures (left thalamus and putamen) with the major interhemispheric and intrahemispheric white matter tracts, the corpus callosum, and cingulum, respectively. These foci of increased communicability are thought to represent compensatory changes. The proposed DTI-based neuroconnectivity analysis demonstrated quantifiable, structurally relevant alterations of fiber tract connections in early RRMS and paves the way for longitudinal studies in larger patient groups.

Pituitary adenoma associated with xanthogranuloma.

Xanthogranuloma (XG) of the sellar region is a non-neoplastic inflammatory lesion characterized histologically by recent and remote hemorrhage, necrotic debris, fibrosis, chronic inflammation, and cholesterol clefts with associated foreign-body giant cells. The inflammatory lesion was recognized by the World Health Organization in 2000. XG of the sellar region is rare. Cases of pituitary adenoma (PA) with an associated XG (PA/XG) are extremely rare, with a total of 16 cases in the literature. PA/XG lacks specific clinical and radiologic signs, making pre-operative diagnosis challenging. Herein, we report a case of PA/XG, describe the radiologic and pathologic findings, and discuss the role of so-called silent or "subclinical pituitary apoplexy" in the possible histogenesis of PA/XGs.

Recurrent acute hemorrhagic necrotizing encephalopathy associated with RAN-binding protein-2 gene mutation in a pediatric patient.

A young male child presented with recurrent episodes of seizures and altered mental status following febrile episodes on three separate occasions between his first and third birthdays. Laboratory evaluations identified SARS-CoV-2 infection during the first episode and no infective agents or antibodies in the cerebrospinal fluid during all the episodes. Brain imaging with CT and MRI revealed bilaterally symmetric patchy hemorrhagic necrotic foci in the deep brain nuclei and medial temporal lobes, prompting suspicion for an underlying predisposition to recurrent acute hemorrhagic necrotizing encephalopathy. Gene analysis confirmed a mutation in the RAN-binding protein-2 (RANBP2) gene. The patient made good recovery following treatment with IVIG, steroids and plasmapheresis, and follow-up brain imaging showed no progression of brain lesions. Early suspicion from characteristic imaging features in appropriate clinical settings will inform timely appropriate treatment and better outcome. We therefore provided short review of imaging features of acute hemorrhagic necrotizing encephalopathy.

Qualitative and quantitative methods in post-chemoradiation PET for head and neck cancer.

OBJECTIVE: The aim of this study was to determine whether quantitative methods could aid in the evaluation of post-treatment head and neck scans, particularly taking human papillomavirus status into account. METHODS: Clinical readings of positron emission tomography/computed tomography scans as well as standardized uptake value (SUV)max (and other metrics) of nodes visible on PET conducted on a total of 172 patients with head and neck squamous cell cancer were examined. Locoregional recurrence at 2 years was assessed. In total 88 of these patients had close enough follow-up to determine whether individual nodes were positive or negative, and 233 nodes on these patients were compared to surgical pathology notes or follow-up (if no path was available). RESULTS: General negative predictive value (NPV) of complete response was 93% and an equivocal response was 89%; focusing on nodal recurrence, NPV was found to be 97% and positive predictive value (PPV) 46% if equivocal reads were treated as negative and NPV 98% and PPV 16% if equivocal reads were treated as positive. Using SUVmax of the hottest node with a cutoff of 3.4 gave NPV 97% and PPV 26%; a direct re-read (using 2 observers) gave NPV 98% and PPV 32% if equivocal reads were treated as negative, and NPV 99% and PPV 18% if equivocal reads were treated as positive. Using other first-order radiomics data such as SD and skewness did not improve this. CONCLUSIONS: Quantitative data such as SUVmax does not show additional value over qualitative evaluation of response to chemoradiation in head and neck tumors.

Postoperative seizures following endoscopic third ventriculostomy and choroid plexus cauterization: a case series.

OBJECTIVE: In this study, the authors sought to investigate variables associated with postoperative seizures following endoscopic third ventriculostomy and choroid plexus cauterization (ETV/CPC) for treatment of pediatric hydrocephalus. METHODS: A retrospective analysis of 37 patients who underwent ETV/CPC for treatment of hydrocephalus at an academic medical center from September 2016 to March 2021 was conducted. Demographics, etiology of hydrocephalus, operative details, electroencephalography (EEG) data, MRI findings, need for subsequent procedures, perioperative laboratory tests, medical history, and presence of clinical postoperative seizures were collected. Postoperative seizures were defined as clinical seizures within 24 hours of surgery. Eighteen patients received levetiracetam intraoperatively as well as over the next 7 days postoperatively for seizure prophylaxis. RESULTS: Of 37 included patients, 9 (24%) developed clinical seizures within 24 hours after surgery, 5 of whom subsequently had electroclinical seizures captured on video-EEG. The clinical seizures in 4 of those 5 patients (80%) may have been associated with the hemisphere of the brain through which the endoscope was introduced. The median corrected age of the cohort was 3.4 months. The median corrected age of patients who did not develop postoperative seizures was 2.3 months compared with 0.7 months for patients who did develop postoperative seizures (p > 0.99). Postoperative seizures occurred in 43% (3/7) of prenatally repaired myelomeningocele patients versus 29% (2/7) of postnatally repaired myelomeningocele patients. Of the 18 patients who received prophylactic levetiracetam, none (0%) developed postoperative seizures compared with 9 of the 19 patients (47%) who did not receive prophylactic levetiracetam (p = 0.014). CONCLUSIONS: Postoperative seizures were recorded in 24% of the pediatric patients who underwent ETV/CPC for hydrocephalus, which is higher than previously reported rates in the literature of 5%. Since 80% of the postoperative electrographic seizures may have been associated with the hemisphere through which the endoscope was introduced, the surgical entry site may contribute to postoperative seizure development. In patients who received prophylactic perioperative levetiracetam, the postoperative seizure incidence dropped to 0% compared with 47% in those who did not receive prophylactic perioperative levetiracetam. This finding indicates that the use of prophylactic perioperative levetiracetam may be efficacious in the prevention of clinical seizures in this patient population.

Longitudinal regression analysis of spatial-temporal growth patterns of geometrical diffusion measures in early postnatal brain development with diffusion tensor imaging.

Although diffusion tensor imaging (DTI) has provided substantial insights into early brain development, most DTI studies based on fractional anisotropy (FA) and mean diffusivity (MD) may not capitalize on the information derived from the three principal diffusivities (e.g. eigenvalues). In this study, we explored the spatial and temporal evolution of white matter structures during early brain development using two geometrical diffusion measures, namely, linear (Cl) and planar (Cp) diffusion anisotropies, from 71 longitudinal datasets acquired from 29 healthy, full-term pediatric subjects. The growth trajectories were estimated with generalized estimating equations (GEE) using linear fitting with logarithm of age (days). The presence of the white matter structures in Cl and Cp was observed in neonates, suggesting that both the cylindrical and fanning or crossing structures in various white matter regions may already have been formed at birth. Moreover, we found that both Cl and Cp evolved in a temporally nonlinear and spatially inhomogeneous manner. The growth velocities of Cl in central white matter were significantly higher when compared to peripheral, or more laterally located, white matter: central growth velocity Cl=0.0465±0.0273/log(days), versus peripheral growth velocity Cl=0.0198±0.0127/log(days), p<10⁻6. In contrast, the growth velocities of Cp in central white matter were significantly lower than that in peripheral white matter: central growth velocity Cp=0.0014±0.0058/log(days), versus peripheral growth velocity Cp=0.0289±0.0101/log(days), p<10⁻6. Depending on the underlying white matter site which is analyzed, our findings suggest that ongoing physiologic and microstructural changes in the developing brain may exert different effects on the temporal evolution of these two geometrical diffusion measures. Thus, future studies utilizing DTI with correlative histological analysis in the study of early brain development are warranted.

Exposure to severe urban air pollution influences cognitive outcomes, brain volume and systemic inflammation in clinically healthy children.

Exposure to severe air pollution produces neuroinflammation and structural brain alterations in children. We tested whether patterns of brain growth, cognitive deficits and white matter hyperintensities (WMH) are associated with exposures to severe air pollution. Baseline and 1 year follow-up measurements of global and regional brain MRI volumes, cognitive abilities (Wechsler Intelligence Scale for Children-Revised, WISC-R), and serum inflammatory mediators were collected in 20 Mexico City (MC) children (10 with white matter hyperintensities, WMH(+), and 10 without, WMH(-)) and 10 matched controls (CTL) from a low polluted city. There were significant differences in white matter volumes between CTL and MC children - both WMH(+) and WMH(-) - in right parietal and bilateral temporal areas. Both WMH(-) and WMH(+) MC children showed progressive deficits, compared to CTL children, on the WISC-R Vocabulary and Digit Span subtests. The cognitive deficits in highly exposed children match the localization of the volumetric differences detected over the 1 year follow-up, since the deficits observed are consistent with impairment of parietal and temporal lobe functions. Regardless of the presence of prefrontal WMH, Mexico City children performed more poorly across a variety of cognitive tests, compared to CTL children, thus WMH(+) is likely only partially identifying underlying white matter pathology. Together these findings reveal that exposure to air pollution may perturb the trajectory of cerebral development and result in cognitive deficits during childhood.

Assessment of 18F-PBR-111 in the Cuprizone Mouse Model of Multiple Sclerosis.

The study aims to assess site assessment of the performance of 18F-PBR-111 as a neuroinflammation marker in the cuprizone mouse model of multiple sclerosis (MS). 18F-PBR-111 PET imaging has not been well evaluated in multiple sclerosis applications both in preclinical and clinical research. This study will help establish the potential utility of 18F-PBR-111 PET in preclinical MS research and future animal and future human applications. 18F-PBR-111 PET/CT was conducted at 3.5 weeks (n = 7) and 5.0 weeks (n = 7) after cuprizone treatment or sham control (n = 3) in the mouse model. A subgroup of mice underwent autoradiography with cryosectioned brain tissue. T2 weighted MRI was performed to obtain the brain structural data of each mouse. 18F-PBR-111 uptake was assessed in multiple brain regions with PET and autoradiography images. The correlation between autoradiography and immunofluorescence staining of neuroinflammation (F4/80 and CD11b) was measured. Compared to control mice, significant 18F-PBR-111 uptake in the corpus callosum (p < 0.001), striatum (caudate and internal capsule, p < 0.001), and hippocampus (p < 0.05) was identified with PET images at both 3.5 weeks and 5.0 weeks, and validated with autoradiography. No significant uptake differences were detected between 3.5 weeks and 5.0 weeks assessing these regions as a whole, although there was a trend of increased uptake at 5.0 weeks compared to 3.5 weeks in the CC. High 18F-PBR-111 uptake regions correlated with microglial/macrophage locations by immunofluorescence staining with F4/80 and CD11b antibodies. 18F-PBR-111 uptake in anatomic locations correlated with activated microglia at histology in the cuprizone mouse model of MS suggests that 18F-PBR-111 has potential for in vivo evaluation of therapy response and potential for use in MS patients and animal studies.

Fatal Pediatric COVID-19 Case With Seizures and Fulminant Cerebral Edema.

The novel coronavirus, SARS-CoV-2, can present with a wide range of neurological manifestations, in both adult and pediatric populations. We describe here the case of a previously healthy 8-year-old girl who presented with seizures, encephalopathy, and rapidly progressive, diffuse, and ultimately fatal cerebral edema in the setting of acute COVID-19 infection. CSF analysis, microbiological testing, and neuropathology yielded no evidence of infection or acute inflammation within the central nervous system. Acute fulminant cerebral edema (AFCE) is an often fatal pediatric clinical entity consisting of fever, encephalopathy, and new-onset seizures followed by rapid, diffuse, and medically-refractory cerebral edema. AFCE occurs as a rare complication of a variety of common pediatric infections and a CNS pathogen is identified in only a minority of cases, suggesting a para-infectious mechanism of edema. This report suggests that COVID-19 infection can precipitate AFCE, and highlights the need for high suspicion and early recognition thereof.

Multi-Site Infant Brain Segmentation Algorithms: The iSeg-2019 Challenge.

To better understand early brain development in health and disorder, it is critical to accurately segment infant brain magnetic resonance (MR) images into white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF). Deep learning-based methods have achieved state-of-the-art performance; h owever, one of the major limitations is that the learning-based methods may suffer from the multi-site issue, that is, the models trained on a dataset from one site may not be applicable to the datasets acquired from other sites with different imaging protocols/scanners. To promote methodological development in the community, the iSeg-2019 challenge (http://iseg2019.web.unc.edu) provides a set of 6-month infant subjects from multiple sites with different protocols/scanners for the participating methods. T raining/validation subjects are from UNC (MAP) and testing subjects are from UNC/UMN (BCP), Stanford University, and Emory University. By the time of writing, there are 30 automatic segmentation methods participated in the iSeg-2019. In this article, 8 top-ranked methods were reviewed by detailing their pipelines/implementations, presenting experimental results, and evaluating performance across different sites in terms of whole brain, regions of interest, and gyral landmark curves. We further pointed out their limitations and possible directions for addressing the multi-site issue. We find that multi-site consistency is still an open issue. We hope that the multi-site dataset in the iSeg-2019 and this review article will attract more researchers to address the challenging and critical multi-site issue in practice.

Multimodal Image Analysis for Assessing Multiple Sclerosis and Future Prospects Powered by Artificial Intelligence.

The purpose of this paper is to serve as a template for greater understanding for the practicing radiologist about key steps to perform multimodality computer analysis of MRI images, specifically in multiple sclerosis patients. With this understanding, radiologists will be better equipped about how best to process and analyze MRI imaging data and obtain accurate quantitative information for MS patient evaluation. A secondary intent of this article is to improve radiologist understanding of how artificial intelligence will be employed in the future for better patient stratification, and for evaluation of response to therapy in both clinical care and drug trials.

What Can Mimic Multiple Sclerosis?

This article discusses mimics of multiple sclerosis (MS). Excluded in this discussion are neuromyelitis optica and vasculitis, discussed in other articles in this journal. Covered entities include posterior reversible encephalopathy syndrome, reversible vasoconstriction syndrome, acute disseminated encephalomyelitis, Sussac's Syndrome, and chronic idiopathic demyelinating polyneuropathy. There are also multiple infectious entities that mimic MS including; progressive multi-focal leukoencephalopathy (PML), Toxoplasmosis, Tuberculosis, Herpes Simplex Virus, Cytomegalovirus, Varicella zoster virus, Epstein Barr virus, Cryptococcus and Human immunodeficiency virus. In addition, there are leukoencephalopathies that can present in adulthood including Adrenoleukodystrophy, Metachromatic leukodystrophy, Cerebral autosomal dominant idiopathic leukoencephalopathy, Leigh's and Alexanders disease that could be mistaken for MS.

CNS Vasculitis-An Overview of This Multiple Sclerosis Mimic: Clinical and MRI Implications.

This article discusses central nervous system vasculitis, a clinical and MRI mimic of multiple sclerosis (MS). There is a paucity of discussion of vasculitis in the radiology literature, and many MS neurologists believe that vasculitis is underdiagnosed. Therefore, the authors hope that the readers will find this paper increases their knowledge about CNS vasculitis and improves their ability to differentiate MS from vasculitis.

Detectable size of melanoma metastases to brain on PET/CT.

OBJECTIVE: We aimed to determine at what size melanoma metastases become detectable by PET/CT. METHODS: We reviewed a total of 293 whole-body PET/CT studies performed on 212 patients for staging of melanoma where there was an MRI within a month of the PET/CT. MR and PET/CT were reviewed independently by separate readers. RESULTS: PET/CT revealed an overall incidental true-positive rate of 1% on a per-patient basis, consistent with other studies, with 'hot' lesions (more avid than brain parenchyma) visible at smaller sizes than 'cold' lesions. CONCLUSIONS: PET/CT can detect metastatic melanoma lesions over about 2 cm in size, with hot lesions generally visible at smaller sizes.