Brain aerobic glycolysis and resilience in Alzheimer disease.

The distribution of brain aerobic glycolysis (AG) in normal young adults correlates spatially with amyloid-beta (Aß) deposition in individuals with symptomatic and preclinical Alzheimer disease (AD). Brain AG decreases with age, but the functional significance of this decrease with regard to the development of AD symptomatology is poorly understood. Using PET measurements of regional blood flow, oxygen consumption, and glucose utilization-from which we derive AG-we find that cognitive impairment is strongly associated with loss of the typical youthful pattern of AG. In contrast, amyloid positivity without cognitive impairment was associated with preservation of youthful brain AG, which was even higher than that seen in cognitively unimpaired, amyloid negative adults. Similar findings were not seen for blood flow nor oxygen consumption. Finally, in cognitively unimpaired adults, white matter hyperintensity burden was found to be specifically associated with decreased youthful brain AG. Our results suggest that AG may have a role in the resilience and/or response to early stages of amyloid pathology and that age-related white matter disease may impair this process.

Deep Learning for Grading Endometrial Cancer.

Endometrial cancer is the fourth most common cancer in women in the United States, with a lifetime risk of approximately 2.8%. Precise histologic evaluation and molecular classification of endometrial cancer are important for effective patient management and determining the best treatment options. This study introduces EndoNet, which uses convolutional neural networks for extracting histologic features and a vision transformer for aggregating these features and classifying slides into high- and low-grade cases. The model was trained on 929 digitized hematoxylin and eosin-stained whole-slide images of endometrial cancer from hysterectomy cases at Dartmouth-Health. It classifies these slides into low-grade (endometrioid grades 1 and 2) and high-grade (endometrioid carcinoma International Federation of Gynecology and Obstetrics grade 3, uterine serous carcinoma, or carcinosarcoma) categories. EndoNet was evaluated on an internal test set of 110 patients and an external test set of 100 patients from The Cancer Genome Atlas database. The model achieved a weighted average F1 score of 0.91 (95% CI, 0.86 to 0.95) and an area under the curve of 0.95 (95% CI, 0.89 to 0.99) on the internal test, and 0.86 (95% CI, 0.80 to 0.94) for F1 score and 0.86 (95% CI, 0.75 to 0.93) for area under the curve on the external test. Pending further validation, EndoNet has the potential to support pathologists without the need of manual annotations in classifying the grades of gynecologic pathology tumors.

Accuracy of TrUE-Net in comparison to established white matter hyperintensity segmentation methods: An independent validation study.

White matter hyperintensities (WMH) are nearly ubiquitous in the aging brain, and their topography and overall burden are associated with cognitive decline. Given their numerosity, accurate methods to automatically segment WMH are needed. Recent developments, including the availability of challenge data sets and improved deep learning algorithms, have led to a new promising deep-learning based automated segmentation model called TrUE-Net, which has yet to undergo rigorous independent validation. Here, we compare TrUE-Net to six established automated WMH segmentation tools, including a semi-manual method. We evaluated the techniques at both global and regional level to compare their ability to detect the established relationship between WMH burden and age. We found that TrUE-Net was highly reliable at identifying WMH regions with low false positive rates, when compared to semi-manual segmentation as the reference standard. TrUE-Net performed similarly or favorably when compared to the other automated techniques. Moreover, TrUE-Net was able to detect relationships between WMH and age to a similar degree as the reference standard semi-manual segmentation at both the global and regional level. These results support the use of TrUE-Net for identifying WMH at the global or regional level, including in large, combined datasets.

MOG and AQP4 Antibodies among Children with Multiple Sclerosis and Controls.

OBJECTIVE: The purpose of this study was to determine the frequency of myelin oligodendrocyte glycoprotein (MOG)-IgG and aquaporin-4 (AQP4)-IgG among patients with pediatric-onset multiple sclerosis (POMS) and healthy controls, to determine whether seropositive cases fulfilled their respective diagnostic criteria, to compare characteristics and outcomes in children with POMS versus MOG-IgG-associated disease (MOGAD), and identify clinical features associated with final diagnosis. METHODS: Patients with POMS and healthy controls were enrolled at 14 US sites through a prospective case-control study on POMS risk factors. Serum AQP4-IgG and MOG-IgG were assessed using live cell-based assays. RESULTS: AQP4-IgG was negative among all 1,196 participants, 493 with POMS and 703 healthy controls. MOG-IgG was positive in 30 of 493 cases (6%) and zero controls. Twenty-five of 30 patients positive with MOG-IgG (83%) had MOGAD, whereas 5 of 30 (17%) maintained a diagnosis of multiple sclerosis (MS) on re-review of records. MOGAD cases were more commonly in female patients (21/25 [84%] vs 301/468 [64%]; p = 0.044), younger age (mean = 8.2 ± 4.2 vs 14.7 ± 2.6 years; p < 0.001), more commonly had initial optic nerve symptoms (16/25 [64%] vs 129/391 [33%]; p = 0.002), or acute disseminated encephalomyelitis (ADEM; 8/25 [32%] vs 9/468 [2%]; p < 0.001), and less commonly had initial spinal cord symptoms (3/20 [15%] vs 194/381 [51%]; p = 0.002), serum Epstein-Barr virus (EBV) positivity (11/25 [44%] vs 445/468 [95%]; p < 0.001), or cerebrospinal fluid oligoclonal bands (5/25 [20%] vs 243/352 [69%]; p < 0.001). INTERPRETATION: MOG-IgG and AQP4-IgG were not identified among healthy controls confirming their high specificity for pediatric central nervous system (CNS) demyelinating disease. Five percent of those with prior POMS diagnoses ultimately had MOGAD; and none had AQP4-IgG positivity. Clinical features associated with a final diagnosis of MOGAD in those with suspected MS included initial ADEM phenotype, younger age at disease onset, and lack of EBV exposure. ANN NEUROL 2023;93:271-284.

Individual-level metabolic connectivity from dynamic [18F]FDG PET reveals glioma-induced impairments in brain architecture and offers novel insights beyond the SUVR clinical standard.

PURPOSE: This study evaluates the potential of within-individual Metabolic Connectivity (wi-MC), from dynamic [18F]FDG PET data, based on the Euclidean Similarity method. This approach leverages the biological information of the tracer's full temporal dynamics, enabling the direct extraction of individual metabolic connectomes. Specifically, the proposed framework, applied to glioma pathology, seeks to assess sensitivity to metabolic dysfunctions in the whole brain, while simultaneously providing further insights into the pathophysiological mechanisms regulating glioma progression. METHODS: We designed an index (Distance from Healthy Group, DfHG) based on the alteration of wi-MC in each patient (n = 44) compared to a healthy reference (from 57 healthy controls), to individually quantify metabolic connectivity abnormalities, resulting in an Impairment Map highlighting significantly compromised areas. We then assessed whether our measure of metabolic network alteration is associated with well-established markers of disease severity (tumor grade and volume, with and without edema). Subsequently, we investigated disruptions in wi-MC homotopic connectivity, assessing both affected and seemingly healthy tissue to deepen the pathology's impact on neural communication. Finally, we compared network impairments with local metabolic alterations determined from SUVR, a validated diagnostic tool in clinical practice. RESULTS: Our framework revealed how gliomas cause extensive alterations in the topography of brain networks, even in structurally unaffected regions outside the lesion area, with a significant reduction in connectivity between contralateral homologous regions. High-grade gliomas have a stronger impact on brain networks, and edema plays a mediating role in global metabolic alterations. As compared to the conventional SUVR-based analysis, our approach offers a more holistic view of the disease burden in individual patients, providing interesting additional insights into glioma-related alterations. CONCLUSION: Considering our results, individual PET connectivity estimates could hold significant clinical value, potentially allowing the identification of new prognostic factors and personalized treatment in gliomas or other focal pathologies.

Finding MeVO: Identifying Intracranial Medium-Vessel Occlusions at CT Angiography.

The development of methods to detect and treat intracranial large-vessel occlusions (LVOs) has revolutionized the management of acute ischemic stroke. CT angiography (CTA) of the head and neck is effective in depicting LVOs and widely used in the evaluation of patients who have had a stroke. Ongoing efforts are now focused on the potential to detect and treat intracranial medium-vessel occlusions (MeVOs), which by definition are smaller than LVOs and thus more difficult to detect with CTA. The authors review common and variant anatomies of medium-sized cerebral arteries and the appearance of a variety of MeVOs on CT angiograms. Possible pitfalls in MeVO detection include rare anatomic variants, calcified thrombi, and stump occlusions. Current recommendations for performing CTA and ancillary methods that might aid in MeVO detection are discussed. Understanding the relevant anatomy and the variety of appearances of MeVOs aids radiologists in identifying these occlusions, particularly in the setting of urgent stroke. ©RSNA, 2024 See the invited commentary by Ospel and Nguyen in this issue.

Validity and Reliability of Hindi version of Foot and Ankle Disability Index in patients with chronic recurrent lateral ankle sprain.

BACKGROUND: Lateral Ankle Sprain (LAS) is a recurrent musculoskeletal injury commonly noticed in primary care, podiatry, orthopaedics, and physical therapy centers. The Foot and Ankle Disability Index (FADI) is a self-reported and region-specific tool with no previous literature available on the translation of the FADI scale into Hindi language. AIM: The study aims to translate and evaluate each translated domain of FADI to see its cross-cultural adaptation, content validity and reliability for patients with chronic recurrent LAS. STUDY DESIGN: A Cross-Sectional Study. METHODS: The scale was translated from the reference language to the target language, Hindi, using the instructions provided in the literature. Delphi survey was conducted for content validation followed by recruitment of 51 participants with a history of long lasting repetitive lateral sprain of ankle to evaluate test-retest reliability of Hindi version of FADI. RESULT: The S-CVI/Ave and S-CVI/UA came out to be 0.988 and 0.884, respectively and I-CVI for all items of Hindi version of FADI were more than 0.90. The ICC (Intra-class Correlation Coefficient) and internal consistency was evaluated, which came out to 0.961 and 0.980, respectively for Hindi version of FADI. CONCLUSION: Hindi version of FADI is a valid and reliable scale that has been translated and adapted to be implemented among Indian population suffering from long lasting repetitive LAS.

Characteristics of pediatric patients with multiple sclerosis and related disorders infected with SARS-CoV-2.

BACKGROUND: Pediatric patients with multiple sclerosis (POMS) and related disorders, clinically isolated syndrome (CIS), myelin oligodendrocyte glycoprotein antibody disorder (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD), are commonly treated with immunosuppressants. Understanding the impact of SARS-CoV-2 infection in patients may inform treatment decisions. OBJECTIVE: Characterize SARS-CoV-2 infection prevalence and severity among a cohort of patients with POMS and related disorders, as well as the impact of disease-modifying therapies (DMTs). METHODS: POMS and related disorders patients enrolled in a large, prospective registry were screened for COVID-19 during standard-of-care neurology visits. If confirmed positive of having infection, further analysis was undertaken. RESULTS: Six hundred and sixty-nine patients were surveyed between March 2020 and August 2021. There were 73 confirmed COVID-19 infections. Eight of nine hospitalized patients (89%), and all patients admitted to the ICU were treated with B cell depleting therapy. The unadjusted odds ratio of hospitalization among those who tested positive of having had COVID-19 was 15.27 among those on B-cell-depleting therapy (p = 0.016). CONCLUSIONS: B-cell-depleting treatment was associated with a higher risk of COVID-19, higher rates of hospitalization, and ICU admission, suggesting this therapy carries a higher risk of severe infection in POMS and related disorders.

A new look at cognitive functioning in pediatric MS.

OBJECTIVE: Cognitive involvement in pediatric multiple sclerosis (MS) relative to adult MS is less defined. This study advances our understanding by measuring cognitive performances in pediatric MS, adult MS, and pediatric healthy controls. METHODS: Consecutive relapsing pediatric MS participants from the United States Network of Pediatric MS Centers were compared with pediatric healthy controls and adults with relapsing MS. Participants were compared on two screening batteries: the Brief International Cognitive Assessment for MS and the Cogstate Brief Battery. Results were transformed to age-normative z scores. RESULTS: The pediatric groups (MS vs. Healthy Controls) did not differ on either battery's composite mean score or individual test scores (ps > 0.32), nor in the proportions impaired on either battery, Brief International Cognitive Assessment for MS (26% vs. 24%, p = 0.83); Cogstate Brief Battery (26% vs. 32%, p = 0.41). The pediatric versus adult MS group even after controlling for differences in disease duration performed better on the Brief International Cognition Assessment for MS composite (p = 0.03), Symbol Digit Modalities Test (p = 0.02), Rey Auditory Verbal Learning Test (p = 0.01), and Cogstate choice reaction time (p < 0.001). CONCLUSION: Pediatric MS patients do not differ from healthy pediatric controls on cognitive screens but perform better than adults with MS.

Automated analysis of low-field brain MRI in cerebral malaria.

A central challenge of medical imaging studies is to extract biomarkers that characterize disease pathology or outcomes. Modern automated approaches have found tremendous success in high-resolution, high-quality magnetic resonance images. These methods, however, may not translate to low-resolution images acquired on magnetic resonance imaging (MRI) scanners with lower magnetic field strength. In low-resource settings where low-field scanners are more common and there is a shortage of radiologists to manually interpret MRI scans, it is critical to develop automated methods that can augment or replace manual interpretation, while accommodating reduced image quality. We present a fully automated framework for translating radiological diagnostic criteria into image-based biomarkers, inspired by a project in which children with cerebral malaria (CM) were imaged using low-field 0.35 Tesla MRI. We integrate multiatlas label fusion, which leverages high-resolution images from another sample as prior spatial information, with parametric Gaussian hidden Markov models based on image intensities, to create a robust method for determining ventricular cerebrospinal fluid volume. We also propose normalized image intensity and texture measurements to determine the loss of gray-to-white matter tissue differentiation and sulcal effacement. These integrated biomarkers have excellent classification performance for determining severe brain swelling due to CM.

White matter hyperintensity longitudinal morphometric analysis in association with Alzheimer disease.

INTRODUCTION: Vascular damage in Alzheimer's disease (AD) has shown conflicting findings particularly when analyzing longitudinal data. We introduce white matter hyperintensity (WMH) longitudinal morphometric analysis (WLMA) that quantifies WMH expansion as the distance from lesion voxels to a region of interest boundary. METHODS: WMH segmentation maps were derived from 270 longitudinal fluid-attenuated inversion recovery (FLAIR) ADNI images. WLMA was performed on five data-driven WMH patterns with distinct spatial distributions. Amyloid accumulation was evaluated with WMH expansion across the five WMH patterns. RESULTS: The preclinical group had significantly greater expansion in the posterior ventricular WM compared to controls. Amyloid significantly associated with frontal WMH expansion primarily within AD individuals. WLMA outperformed WMH volume changes for classifying AD from controls primarily in periventricular and posterior WMH. DISCUSSION: These data support the concept that localized WMH expansion continues to proliferate with amyloid accumulation throughout the entirety of the disease in distinct spatial locations.

Neuropathy-and foot-ulcer specific quality of life instrument (NeuroQoL): Translation, cross-cultural adaptation and content validation in Hindi.

BACKGROUND: Neuropathy-and foot ulcer-specific quality of life instrument (NeuroQoL) is not available in Hindi language which is one of the most spoken languages in the world. Hence, we aimed to translate, cross-culturally adapt and content validate NeuroQoL into Hindi language (NeuroQoL-H). METHODS: NeuroQoL is translated and cross-culturally adapted into Hindi language (NeuroQoL-H) using the guidelines proposed by Beaton and colleagues. Both item and scale levels content validity index (I-CVI & S-CVI) were reported for the validation and pretesting was performed with, n = 51 patients with diabetes. Floor and ceiling effects were reported. RESULT: Total score of content validated and pretested, NeuroQoL-H with, n = 51 patients with diabetes is, 60 (36,109). For all the items in NeuroQoL-H, I-CVI ≥ 0.8 and S-CVI = 0.95. The floor effect is (24 %) while the ceiling effect is (1 %). CONCLUSION: NeuroQoL-H scale is a valid outcome measure among Hindi speaking patients with diabetes.

ß-amyloid PET harmonisation across longitudinal studies: Application to AIBL, ADNI and OASIS3.

INTRODUCTION: The Centiloid scale was developed to harmonise the quantification of ß-amyloid (Aß) PET images across tracers, scanners, and processing pipelines. However, several groups have reported differences across tracers and scanners even after centiloid conversion. In this study, we aim to evaluate the impact of different pre and post-processing harmonisation steps on the robustness of longitudinal Centiloid data across three large international cohort studies. METHODS: All Aß PET data in AIBL (N = 3315), ADNI (N = 3442) and OASIS3 (N = 1398) were quantified using the MRI-based Centiloid standard SPM pipeline and the PET-only pipeline CapAIBL. SUVR were converted into Centiloids using each tracer's respective transform. Global Aß burden from pre-defined target cortical regions in Centiloid units were quantified for both raw PET scans and PET scans smoothed to a uniform 8 mm full width half maximum (FWHM) effective smoothness. For Florbetapir, we assessed the performance of using both the standard Whole Cerebellum (WCb) and a composite white matter (WM)+WCb reference region. Additionally, our recently proposed quantification based on Non-negative Matrix Factorisation (NMF) was applied to all spatially and SUVR normalised images. Correlation with clinical severity measured by the Mini-Mental State Examination (MMSE) and effect size, as well as tracer agreement in 11C-PiB-18F-Florbetapir pairs and longitudinal consistency were evaluated. RESULTS: The smoothing to a uniform resolution partially reduced longitudinal variability, but did not improve inter-tracer agreement, effect size or correlation with MMSE. Using a Composite reference region for 18F-Florbetapir improved inter-tracer agreement, effect size, correlation with MMSE, and longitudinal consistency. The best results were however obtained when using the NMF method which outperformed all other quantification approaches in all metrics used. CONCLUSIONS: FWHM smoothing has limited impact on longitudinal consistency or outliers. A Composite reference region including subcortical WM should be used for computing both cross-sectional and longitudinal Florbetapir Centiloid. NMF improves Centiloid quantification on all metrics examined.

Growth Differentiation Factor-15 as a Candidate Biomarker in Gynecologic Malignancies: A Meta-analysis.

Growth differentiation factor-15 (GDF-15), though emerged as a novel marker in gynecological cancers, is yet to be recognized in clinical diagnostics. Eligible studies were sorted from multiple online databases, namely PubMed, Cochrane, ClinicalTrials.gov, Google Scholar, Web of Science, Embase, Scopus, LILACS, and Opengrey. From six studies, histopathologically diagnosed cases without prior treatment, and with diagnostic accuracy data for GDF-15 in gynecological cancers, were included. Our meta-analysis shows that GDF-15 has pooled diagnostic odds ratio of 12.74 at 80.5% sensitivity and 74.1% specificity, and an area under the curve of 0.84. Hence, GDF-15 is a potential marker to differentiate gynecological malignancy from non-malignant tumors.

Mechanisms of Transcranial Doppler Ultrasound phenotypes in paediatric cerebral malaria remain elusive.

BACKGROUND: Cerebral malaria (CM) results in significant paediatric death and neurodisability in sub-Saharan Africa. Several different alterations to typical Transcranial Doppler Ultrasound (TCD) flow velocities and waveforms in CM have been described, but mechanistic contributors to these abnormalities are unknown. If identified, targeted, TCD-guided adjunctive therapy in CM may improve outcomes. METHODS: This was a prospective, observational study of children 6 months to 12 years with CM in Blantyre, Malawi recruited between January 2018 and June 2021. Medical history, physical examination, laboratory analysis, electroencephalogram, and magnetic resonance imaging were undertaken on presentation. Admission TCD results determined phenotypic grouping following a priori definitions. Evaluation of the relationship between haemodynamic, metabolic, or intracranial perturbations that lead to these observed phenotypes in other diseases was undertaken. Neurological outcomes at hospital discharge were evaluated using the Paediatric Cerebral Performance Categorization (PCPC) score. RESULTS: One hundred seventy-four patients were enrolled. Seven (4%) had a normal TCD examination, 57 (33%) met criteria for hyperaemia, 50 (29%) for low flow, 14 (8%) for microvascular obstruction, 11 (6%) for vasospasm, and 35 (20%) for isolated posterior circulation high flow. A lower cardiac index (CI) and higher systemic vascular resistive index (SVRI) were present in those with low flow than other groups (p < 0.003), though these values are normal for age (CI 4.4 [3.7,5] l/min/m2, SVRI 1552 [1197,1961] dscm-5m2). Other parameters were largely not significantly different between phenotypes. Overall, 118 children (68%) had a good neurological outcome. Twenty-three (13%) died, and 33 (19%) had neurological deficits. Outcomes were best for participants with hyperaemia and isolated posterior high flow (PCPC 1-2 in 77 and 89% respectively). Participants with low flow had the least likelihood of a good outcome (PCPC 1-2 in 42%) (p < 0.001). Cerebral autoregulation was significantly better in children with good outcome (transient hyperemic response ratio (THRR) 1.12 [1.04,1.2]) compared to a poor outcome (THRR 1.05 [0.98,1.02], p = 0.05). CONCLUSIONS: Common pathophysiological mechanisms leading to TCD phenotypes in non-malarial illness are not causative in children with CM. Alternative mechanistic contributors, including mechanical factors of the cerebrovasculature and biologically active regulators of vascular tone should be explored.

Performance of Automated RAPID Intracranial Hemorrhage Detection in Real-World Practice: A Single-Institution Experience.

BACKGROUND AND PURPOSE: Intracranial hemorrhage (ICH) is a common finding in patients presenting to the emergency department with acute neurological symptoms. Noncontrast head computed tomography (NCCT) is the primary modality for assessment and detection of ICH in the acute setting. RAPID ICH software aims to automatically detect ICH on NCCT and was previously shown to have high accuracy when applied to a curated test data set. Here, we measured the test performance characteristics of RAPID ICH software in detecting ICH on NCCT performed in patients undergoing emergency stroke evaluation at a tertiary academic comprehensive stroke center. MATERIALS AND METHODS: This retrospective study assessed consecutive patients over a 6-month period who presented with acute neurological symptoms suspicious for stroke and underwent NCCT with RAPID ICH postprocessing. RAPID ICH detection was compared with the interpretation of a reference standard comprising a board-certified or board-eligible neuroradiologist, or in cases of discrepancy, adjudicated by a consensus panel of 3 neuroradiologists. Accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of RAPID ICH for ICH detection were determined. RESULTS: Three hundred seven NCCT scans were included in the study. RAPID ICH correctly identified 34 of 37 cases with ICH and 228 of 270 without ICH. RAPID ICH had a sensitivity of 91.9% (78.1%-98.3%), specificity of 84.4% (79.6%-88.6%), NPV of 98.7% (96.3%-99.6%), PPV of 44.7% (37.6%-52.1%), and overall accuracy of 85.3% (80.9%-89.1%). CONCLUSIONS: In a real-world scenario, RAPID ICH software demonstrated high NPV but low PPV for the presence of ICH when evaluating possible stroke patients.

Persistent metabolic youth in the aging female brain.

Sex differences influence brain morphology and physiology during both development and aging. Here we apply a machine learning algorithm to a multiparametric brain PET imaging dataset acquired in a cohort of 20- to 82-year-old, cognitively normal adults (n = 205) to define their metabolic brain age. We find that throughout the adult life span the female brain has a persistently lower metabolic brain age-relative to their chronological age-compared with the male brain. The persistence of relatively younger metabolic brain age in females throughout adulthood suggests that development might in part influence sex differences in brain aging. Our results also demonstrate that trajectories of natural brain aging vary significantly among individuals and provide a method to measure this.

Pediatric Thrombectomy: Design and Workflow Lessons From Two Experienced Centers.

Endovascular thrombectomy has played a major role in advancing adult stroke care and may serve a similar role in pediatric stroke care. However, there is a need to develop better evidence and infrastructure for pediatric stroke care. In this work, we review 2 experienced pediatric endovascular thrombectomy programs and examine key design features in both care environments, including a formalized protocol and workflow, integration with an adult endovascular thrombectomy workflow, simplification and automation of workflow steps, pediatric adaptations of stroke imaging, advocacy of pediatric stroke care, and collaboration between providers, among others. These essential features transcend any single hospital environment and may provide an important foundation for other pediatric centers that aim to enhance the care of children with stroke.

Real-World Effectiveness of Initial Disease-Modifying Therapies in Pediatric Multiple Sclerosis.

OBJECTIVE: To assess real-world effectiveness of initial treatment with newer compared to injectable disease-modifying therapies (DMTs) on disease activity in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS). METHODS: This is a cohort study of children with MS/CIS followed at 12 clinics in the US Network of Pediatric MS Centers, who received initial therapy with newer (fingolimod, dimethyl fumarate, teriflunomide, natalizumab, rituximab, ocrelizumab) or injectable (interferon-ß, glatiramer acetate) DMTs. Propensity scores (PSs) were computed, including preidentified confounders. Relapse rate while on initial DMT was modeled with negative binomial regression, adjusted for PS-quintile. Time to new/enlarging T2-hyperintense and gadolinium-enhancing lesions on brain magnetic resonance imaging were modeled with midpoint survival analyses, adjusted for PS-quintile. RESULTS: A total of 741 children began therapy before 18 years, 197 with newer and 544 with injectable DMTs. Those started on newer DMTs were older (15.2 vs injectable 14.4 years, p = 0.001) and less likely to have a monofocal presentation. In PS-quintile-adjusted analysis, those on newer DMTs had a lower relapse rate than those on injectables (rate ratio = 0.45, 95% confidence interval (CI) = 0.29-0.70, p < 0.001; rate difference = 0.27, 95% CI = 0.14-0.40, p = 0.004). One would need to treat with newer rather than injectable DMTs for 3.7 person-years to prevent 1 relapse. Those started on newer DMTs had a lower rate of new/enlarging T2 (hazard ratio [HR] = 0.51, 95% CI = 0.36-0.72, p < 0.001) and gadolinium-enhancing lesions (HR = 0.38, 95% CI = 0.23-0.63, p < 0.001) than those on injectables. INTERPRETATION: Initial treatment of pediatric MS/CIS with newer DMTs led to better disease activity control compared to injectables, supporting greater effectiveness of newer therapies. Long-term safety data for newer DMTs are required. ANN NEUROL 2020 ANN NEUROL 2020;88:42-55.

Improved relapse recovery in paediatric compared to adult multiple sclerosis.

Incomplete relapse recovery contributes to disability accrual and earlier onset of secondary progressive multiple sclerosis. We sought to investigate the effect of age on relapse recovery. We identified patients with multiple sclerosis from two longitudinal prospective studies, with an Expanded Disability Status Scale (EDSS) score within 30 days after onset of an attack, and follow-up EDSS 6 months after attack. Adult patients with multiple sclerosis (n = 632) were identified from the Comprehensive Longitudinal Investigations in Multiple Sclerosis at Brigham study (CLIMB), and paediatric patients (n = 132) from the US Network of Paediatric Multiple Sclerosis Centers (NPMSC) registry. Change in EDSS was defined as the difference in EDSS between attack and follow-up. Change in EDSS at follow-up compared to baseline was significantly lower in children compared to adults (P = 0.001), as were several functional system scores. Stratification by decade at onset for change in EDSS versus age found for every 10 years of age, EDSS recovery is reduced by 0.15 points (P < 0.0001). A larger proportion of children versus adults demonstrated improvement in EDSS following an attack (P = 0.006). For every 10 years of age, odds of EDSS not improving increase by 1.33 times (P < 0.0001). Younger age is associated with improved recovery from relapses. Age-related mechanisms may provide novel therapeutic targets for disability accrual in multiple sclerosis.