Choroid plexus volume differentiates MS from its mimics.

This study aimed to determine whether choroid plexus volume (CPV) could differentiate multiple sclerosis (MS) from its mimics. A secondary analysis of two previously enrolled studies, 50 participants with MS and 64 with alternative diagnoses were included. CPV was automatically segmented from 3T magnetic resonance imaging (MRI), followed by manual review to remove misclassified tissue. Mean normalized choroid plexus volume (nCPV) to intracranial volume demonstrated relatively high specificity for MS participants in each cohort (0.80 and 0.76) with an area under the receiver-operator characteristic curve of 0.71 (95% confidence interval (CI) = 0.55-0.87) and 0.65 (95% CI = 0.52-0.77). In this preliminary study, nCPV differentiated MS from its mimics.

Emerging Cerebrospinal Fluid Biomarkers of Disease Activity and Progression in Multiple Sclerosis.

Importance: Biomarkers distinguishing nonrelapsing progressive disease biology from relapsing biology in multiple sclerosis (MS) are lacking. Cerebrospinal fluid (CSF) is an accessible fluid that most closely reflects central nervous system biology. Objective: To identify CSF biological measures associated with progressive MS pathobiology. Design, Setting, and Participants: This cohort study assessed data from 2 prospective MS cohorts: a test cohort provided serial CSF, clinical, and imaging assessments in a multicenter study of patients with relapsing MS (RMS) or primary progressive MS (PPMS) who were initiating anti-CD20 treatment (recruitment: 2016-2018; analysis: 2020-2023). A single-site confirmation cohort was used to assess CSF at baseline and long-term (>10 year) clinical follow-up (analysis: 2022-2023). Exposures: Test-cohort participants initiated standard-of-care ocrelizumab treatment. Confirmation-cohort participants were untreated or received standard-of-care disease-modifying MS therapies. Main Outcomes and Measures: Twenty-five CSF markers, including neurofilament light chain, neurofilament heavy chain, and glial fibrillary acid protein (GFAP); 24-week confirmed disability progression (CDP24); and brain magnetic resonance imaging measures reflecting focal injury, tissue loss, and progressive biology (slowly expanding lesions [SELs]). Results: The test cohort (n = 131) included 100 patients with RMS (mean [SD] age, 36.6 [10.4] years; 68 [68%] female and 32 [32%] male; Expanded Disability Status Scale [EDSS] score, 0-5.5), and 31 patients with PPMS (mean [SD] age, 44.9 [7.4] years; 15 [48%] female and 16 [52%] male; EDSS score, 3.0-6.5). The confirmation cohort (n = 68) included 41 patients with RMS and 27 with PPMS enrolled at diagnosis (age, 40 years [range, 20-61 years]; 47 [69%] female and 21 [31%] male). In the test cohort, GFAP was correlated with SEL count (r = 0.33), greater proportion of T2 lesion volume from SELs (r = 0.24), and lower T1-weighted intensity within SELs (r = -0.33) but not with acute inflammatory measures. Neurofilament heavy chain was correlated with SEL count (r = 0.25) and lower T1-weighted intensity within SELs (r = -0.28). Immune markers correlated with measures of acute inflammation and, unlike GFAP, were impacted by anti-CD20. In the confirmation cohort, higher baseline CSF GFAP levels were associated with long-term CDP24 (hazard ratio, 2.1; 95% CI, 1.3-3.4; P = .002). Conclusions and Relevance: In this study, activated glial markers (in particular GFAP) and neurofilament heavy chain were associated specifically with nonrelapsing progressive disease outcomes (independent of acute inflammatory activity). Elevated CSF GFAP was associated with long-term MS disease progression.

Shifting our attention earlier in the multiple sclerosis disease course.

PURPOSE OF REVIEW: Revisions of multiple sclerosis (MS) diagnostic criteria enable clinicians to diagnose patients earlier in the biologic disease course. Prompt initiation of therapy correlates with improved clinical outcomes. This has led to increased attention on the earliest stages of MS, including the MS prodrome and radiologically isolated syndrome (RIS). Here, we review current understanding and approach to patients with preclinical MS. RECENT FINDINGS: MS disease biology often begins well before the onset of typical MS symptoms, and we are increasingly able to recognize preclinical and prodromal stages of MS. RIS represents the best characterized aspect of preclinical MS, and its diagnostic criteria were recently revised to better capture patients at highest risk of conversion to clinical MS. The first two randomized control trials evaluating disease modifying therapy use in RIS also found that treatment could delay or prevent onset of clinical disease. SUMMARY: Despite progress in our understanding of the earliest stages of the MS disease course, additional research is needed to systematically identify patients with preclinical MS as well as capture those at risk for developing clinical disease. Recent data suggests that preventive immunomodulatory therapies may be beneficial for high-risk patients with RIS; though management remains controversial.

Systems Analysis of Immune Changes after B-cell Depletion in Autoimmune Multiple Sclerosis.

Multiple sclerosis (MS) is a complex genetically mediated autoimmune disease of the central nervous system where anti-CD20-mediated B cell depletion is remarkably effective in the treatment of early disease. While previous studies investigated the effect of B cell depletion on select immune cell subsets using flow cytometry-based methods, the therapeutic impact on patient immune landscape is unknown. In this study, we explored how a therapy-driven " in vivo perturbation " modulates the diverse immune landscape by measuring transcriptomic granularity with single-cell RNA sequencing (scRNAseq). We demonstrate that B cell depletion leads to cell type-specific changes in the abundance and function of CSF macrophages and peripheral blood monocytes. Specifically, a CSF-specific macrophage population with an anti-inflammatory transcriptomic signature and peripheral CD16 + monocytes increased in frequency post-B cell depletion. In addition, we observed increases in TNFα messenger RNA and protein in monocytes post-B cell depletion, consistent with the finding that anti-TNFα treatment exacerbates autoimmune activity in MS. In parallel, B cell depletion also induced changes in peripheral CD4 + T cell populations, including increases in the frequency of TIGIT + regulatory T cells and marked decreases in the frequency of myelin peptide loaded-tetramer binding CD4 + T cells. Collectively, this study provides an exhaustive transcriptomic map of immunological changes, revealing different mechanisms of action contributing to the high efficacy in B cell depletion treatment of MS.

A Noncanonical CD56dimCD16dim/- NK Cell Subset Indicative of Prior Cytotoxic Activity Is Elevated in Patients with Autoantibody-Mediated Neurologic Diseases.

Neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein Ab disease, and autoimmune myasthenia gravis (MG) are autoantibody-mediated neurologic conditions where autoantibodies can induce Ab-dependent cellular cytotoxicity (ADCC), a NK cell-mediated effector function. However, whether ADCC is a pathogenic mechanism in patients with these conditions has not been confirmed. We sought to characterize circulatory NK cells using functional assays, phenotyping, and transcriptomics to elucidate their role in pathology. NK cells from NMOSD patients and MG patients with elevated disease burden exhibited reduced ADCC and CD56dimCD16hi NK cells, along with an elevated frequency of CD56dimCD16dim/- NK cells. We determined that ADCC induces a similar phenotypic shift in vitro. Bulk RNA sequencing distinguished the CD56dimCD16dim/- population from the canonical CD56dimCD16hi cytotoxic and CD56hiCD16- immunomodulatory subsets, as well as CD56hiCD16+ NK cells. Multiparameter immunophenotyping of NK cell markers, functional proteins, and receptors similarly showed that the CD56dimCD16dim/- subset exhibits a unique profile while still maintaining expression of characteristic NK markers CD56, CD94, and NKp44. Notably, expression of perforin and granzyme is reduced in comparison with CD56dimCD16hi NK cells. Moreover, they exhibit elevated trogocytosis capability, HLA-DR expression, and many chemokine receptors, including CCR7. In contrast with NMOSD and MG, myelin oligodendrocyte glycoprotein Ab disease NK cells did not exhibit functional, phenotypic, or transcriptomic perturbations. In summary, CD56dimCD16dim/- NK cells are a distinct peripheral blood immune cell population in humans elevated upon prior cytotoxic activity by the CD56dimCD16hi NK cell subset. The elevation of this subset in NMOSD and MG patients suggests prior ADCC activity.

A multicenter pilot study evaluating simplified central vein assessment for the diagnosis of multiple sclerosis.

BACKGROUND: The central vein sign (CVS) is a proposed magnetic resonance imaging (MRI) biomarker for multiple sclerosis (MS); the optimal method for abbreviated CVS scoring is not yet established. OBJECTIVE: The aim of this study was to evaluate the performance of a simplified approach to CVS assessment in a multicenter study of patients being evaluated for suspected MS. METHODS: Adults referred for possible MS to 10 sites were recruited. A post-Gd 3D T2*-weighted MRI sequence (FLAIR*) was obtained in each subject. Trained raters at each site identified up to six CVS-positive lesions per FLAIR* scan. Diagnostic performance of CVS was evaluated for a diagnosis of MS which had been confirmed using the 2017 McDonald criteria at thresholds including three positive lesions (Select-3*) and six positive lesions (Select-6*). Inter-rater reliability assessments were performed. RESULTS: Overall, 78 participants were analyzed; 37 (47%) were diagnosed with MS, and 41 (53%) were not. The mean age of participants was 45 (range: 19-64) years, and most were female (n = 55, 71%). The area under the receiver operating characteristic curve (AUROC) for the simplified counting method was 0.83 (95% CI: 0.73-0.93). Select-3* and Select-6* had sensitivity of 81% and 65% and specificity of 68% and 98%, respectively. Inter-rater agreement was 78% for Select-3* and 83% for Select-6*. CONCLUSION: A simplified method for CVS assessment in patients referred for suspected MS demonstrated good diagnostic performance and inter-rater agreement.

Secondary hypogammaglobulinemia in patients with multiple sclerosis on anti-CD20 therapy: Pathogenesis, risk of infection, and disease management.

Hypogammaglobulinemia is characterized by reduced serum immunoglobulin levels. Secondary hypogammaglobulinemia is of considerable interest to the practicing physician because it is a potential complication of some medications and may predispose patients to serious infections. Patients with multiple sclerosis (MS) treated with B-cell-depleting anti-CD20 therapies are particularly at risk of developing hypogammaglobulinemia. Among these patients, hypogammaglobulinemia has been associated with an increased risk of infections. The mechanism by which hypogammaglobulinemia arises with anti-CD20 therapies (ocrelizumab, ofatumumab, ublituximab, rituximab) remains unclear and does not appear to be simply due to the reduction in circulating B-cell levels. Further, despite the association between anti-CD20 therapies, hypogammaglobulinemia, and infections, there is currently no generally accepted monitoring and treatment approach among clinicians treating patients with MS. Here, we review the literature and discuss possible mechanisms of secondary hypogammaglobulinemia in patients with MS, hypogammaglobulinemia results in MS anti-CD20 therapy clinical trials, the risk of infection for patients with hypogammaglobulinemia, and possible strategies for disease management. We also include a suggested best-practice approach to specifically address secondary hypogammaglobulinemia in patients with MS treated with anti-CD20 therapies.

Gut Microbiome Wellness Index 2 for Enhanced Health Status Prediction from Gut Microbiome Taxonomic Profiles.

Recent advancements in human gut microbiome research have revealed its crucial role in shaping innovative predictive healthcare applications. We introduce Gut Microbiome Wellness Index 2 (GMWI2), an advanced iteration of our original GMWI prototype, designed as a robust, disease-agnostic health status indicator based on gut microbiome taxonomic profiles. Our analysis involved pooling existing 8069 stool shotgun metagenome data across a global demographic landscape to effectively capture biological signals linking gut taxonomies to health. GMWI2 achieves a cross-validation balanced accuracy of 80% in distinguishing healthy (no disease) from non-healthy (diseased) individuals and surpasses 90% accuracy for samples with higher confidence (i.e., outside the "reject option"). The enhanced classification accuracy of GMWI2 outperforms both the original GMWI model and traditional species-level α-diversity indices, suggesting a more reliable tool for differentiating between healthy and non-healthy phenotypes using gut microbiome data. Furthermore, by reevaluating and reinterpreting previously published data, GMWI2 provides fresh insights into the established understanding of how diet, antibiotic exposure, and fecal microbiota transplantation influence gut health. Looking ahead, GMWI2 represents a timely pivotal tool for evaluating health based on an individual's unique gut microbial composition, paving the way for the early screening of adverse gut health shifts. GMWI2 is offered as an open-source command-line tool, ensuring it is both accessible to and adaptable for researchers interested in the translational applications of human gut microbiome science.

Anti-CD20 monoclonal antibody therapy in postpartum women with neurological conditions.

OBJECTIVE: Postpartum, patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) have increased risk for disease activity. Anti-CD20 IgG1 monoclonal antibodies (mAb) are increasingly used as disease-modifying therapies (DMTs). Patients may wish to both breastfeed and resume DMT postpartum. This study aimed to determine the transfer of anti-CD20 IgG1 mAbs, ocrelizumab, and rituximab (OCR/RTX), into mature breastmilk and describe maternal and infant outcomes. METHODS: Fifty-seven cis-women receiving OCR/RTX after 59 pregnancies and their infants were enrolled and followed up to 12M postpartum or 90 days post-infusion. Breastmilk was collected pre-infusion and serially up to 90 days and assayed for mAb concentration. Medical records and patients' questionnaire responses were obtained to assess neurologic, breastfeeding, and infant development outcomes. RESULTS: The median average concentration of mAb in breastmilk was low (OCR: 0.08 µg/mL, range 0.05-0.4; RTX: 0.03 µg/mL, range 0.005-0.3). Concentration peaked 1-7 days post-infusion in most (77%) and was nearly undetectable after 90 days. Median average relative infant dose was <1% (OCR: 0.1%, range 0.07-0.7; RTX: 0.04%, range 0.005-0.3). Forty-three participants continued to breastfeed post-infusion. At 8-12 months, the proportion of infants' growth between the 3rd and 97th World Health Organization percentiles did not differ for breastfed (36/40) and non-breastfed (14/16, p > 0.05) infants; neither did the proportion with normal development (breastfed: 37/41, non-breastfed: 11/13; p > 0.05). After postpartum infusion, two mothers experienced a clinical relapse. INTERPRETATION: These confirm minimal transfer of mAb into breastmilk. Anti-CD20 mAb therapy stabilizes MS activity before conception to the postpartum period, and postpartum treatments appears to be safe and well-tolerated for both mother and infant.

Prior cycles of anti-CD20 antibodies affect antibody responses after repeated SARS-CoV-2 mRNA vaccination.

BACKGROUNDWhile B cell depletion is associated with attenuated antibody responses to SARS-CoV-2 mRNA vaccination, responses vary among individuals. Thus, elucidating the factors that affect immune responses after repeated vaccination is an important clinical need.METHODSWe evaluated the quality and magnitude of the T cell, B cell, antibody, and cytokine responses to a third dose of BNT162b2 or mRNA-1273 mRNA vaccine in patients with B cell depletion.RESULTSIn contrast with control individuals (n = 10), most patients on anti-CD20 therapy (n = 48) did not demonstrate an increase in spike-specific B cells or antibodies after a third dose of vaccine. A third vaccine elicited significantly increased frequencies of spike-specific non-naive T cells. A small subset of B cell-depleted individuals effectively produced spike-specific antibodies, and logistic regression models identified time since last anti-CD20 treatment and lower cumulative exposure to anti-CD20 mAbs as predictors of those having a serologic response. B cell-depleted patients who mounted an antibody response to 3 vaccine doses had persistent humoral immunity 6 months later.CONCLUSIONThese results demonstrate that serial vaccination strategies can be effective for a subset of B cell-depleted patients.FUNDINGThe NIH (R25 NS079193, P01 AI073748, U24 AI11867, R01 AI22220, UM 1HG009390, P01 AI039671, P50 CA121974, R01 CA227473, U01CA260507, 75N93019C00065, K24 AG042489), NIH HIPC Consortium (U19 AI089992), the National Multiple Sclerosis Society (CA 1061-A-18, RG-1802-30153), the Nancy Taylor Foundation for Chronic Diseases, Erase MS, and the Claude D. Pepper Older Americans Independence Center at Yale (P30 AG21342).

Influence of menstrual cycle and hormonal contraceptive use on MS symptom fluctuations: A pilot study.

BACKGROUND: In clinical practice, females with MS often report menstrually-related symptom fluctuations. Hypothetically, use of oral contraceptives (OCs) could reduce these fluctuations, particularly continuous OCs (11+ weeks of consistent exogenous hormones followed by 1 week placebo). OBJECTIVES: To prospectively capture (1) whether neurologic and generalized symptoms vary with menstrual cycle phase and (2) whether type of contraception impacts symptom fluctuations. METHODS: In this two-center pilot study, females with MS and a regular menstrual cycle prospectively tracked their menstrual cycles and completed symptom surveys for up to 6 months. Participants were categorized as 1) users of oral contraceptives, either a) cyclic or b) continuous, or 2) endogenously cycling, either c) hormonal intrauterine device (IUD) users or d) "none users" (e.g. no hormonal contraception; included condoms, copper IUD, tubal ligation, "fertility awareness methods"). There was no correction for multiple analyses. RESULTS: Altogether, 47/70 participants (67%) provided >4 weeks of data and were included in the analyses. Mean (SD) age was 35.0 (0.9) years, median (IQR) EDSS was 1.5 (1-2) and mean (SD) SymptoMScreen score was 10.4 (9.6). For endogenously cycling patients (IUD and none users), fatigue (MFIS) was lower in the perimenstrual period than in the luteal period (p < 0.05). For continuous OC users, variability in symptoms was lower than for endogenously cycling females (MFIS: p < 0.01; Daily Hassles, from Uplift & Hassles Survey: p < 0.05) or cyclic OC users (MFIS: p < 0.001). CONCLUSIONS: In this pilot study, symptom severity did not definitively fluctuate in relationship to the menstrual cycle in endogenously cycling participants. However, fatigue and daily hassles were less variable for participants using continuous OC than for cyclic OC users or no-OC users. Future confirmatory studies are warranted to further examine whether contraceptive choice can be leveraged to manage symptom fluctuation in cycling females with MS. Such studies could enroll larger cohorts over fewer cycles or employ incentivization and hormonal measurements to enhance participant retention and statistical power.

Microfluidic Immuno-Serolomic Assay Reveals Systems Level Association with COVID-19 Pathology and Vaccine Protection.

How to develop highly informative serology assays to evaluate the quality of immune protection against coronavirus disease-19 (COVID-19) has been a global pursuit over the past years. Here, a microfluidic high-plex immuno-serolomic assay is developed to simultaneously measure50 plasma or serum samples for50 soluble markers including 35proteins, 11 anti-spike/receptor binding domian (RBD) IgG antibodies spanningmajor variants, and controls. This assay demonstrates the quintuplicate test in a single run with high throughput, low sample volume, high reproducibilityand accuracy. It is applied to the measurement of 1012 blood samples including in-depth analysis of sera from 127 patients and 21 healthy donors over multiple time points, either with acute COVID infection or vaccination. The protein analysis reveals distinct immune mediator modules that exhibit a reduced degree of diversity in protein-protein cooperation in patients with hematologic malignancies or receiving B cell depletion therapy. Serological analysis identifies that COVID-infected patients with hematologic malignancies display impaired anti-RBD antibody response despite high level of anti-spike IgG, which can be associated with limited clonotype diversity and functional deficiency in B cells. These findings underscore the importance to individualize immunization strategies for these high-risk patients and provide an informative tool to monitor their responses at the systems level.

MOGAD patient autoantibodies induce complement, phagocytosis, and cellular cytotoxicity.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an inflammatory demyelinating CNS condition characterized by the presence of MOG autoantibodies. We sought to investigate whether human MOG autoantibodies are capable of mediating damage to MOG-expressing cells through multiple mechanisms. We developed high-throughput assays to measure complement activity (CA), complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cellular cytotoxicity (ADCC) of live MOG-expressing cells. MOGAD patient sera effectively mediate all of these effector functions. Our collective analyses reveal that (a) cytotoxicity is not incumbent on MOG autoantibody quantity alone; (b) engagement of effector functions by MOGAD patient serum is bimodal, with some sera exhibiting cytotoxic capacity while others did not; (c) the magnitude of CDC and ADCP is elevated closer to relapse, while MOG-IgG binding is not; and (d) all IgG subclasses can damage MOG-expressing cells. Histopathology from a representative MOGAD case revealed congruence between lesion histology and serum CDC and ADCP, and we identified NK cells, mediators of ADCC, in the cerebrospinal fluid of relapsing patients with MOGAD. Thus, MOGAD-derived autoantibodies are cytotoxic to MOG-expressing cells through multiple mechanisms, and assays quantifying CDC and ADCP may prove to be effective tools for predicting risk of future relapses.

Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity.

A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20dimCD8+ T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20dimCD8+ T cells had a greater contribution to treatment-associated changes in the CD8+ T cell pool than was the case for CD4+ T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20dimCD8+ T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19+CD24highCD38high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20dimCD8+ T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8+ T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.

Future of Neurology & Technology: Neuroimaging Made Accessible Using Low-Field, Portable MRI.

In the 20th century, the advent of neuroimaging dramatically altered the field of neurologic care. However, despite iterative advances since the invention of CT and MRI, little progress has been made to bring MR neuroimaging to the point of care. Recently, the emergence of a low-field (<1 T) portable MRI (pMRI) is setting the stage to revolutionize the landscape of accessible neuroimaging. Users can transport the pMRI into a variety of locations, using a standard 110-220 V wall outlet. In this article, we discuss current applications for pMRI, including in the acute and critical care settings, the barriers to broad implementation, and future opportunities.

Effect of GBCA Use on Detection and Diagnostic Performance of the Central Vein Sign: Evaluation Using a 3-T FLAIR* Sequence in Patients With Suspected Multiple Sclerosis.

BACKGROUND. The central vein sign (CVS) is a proposed MRI biomarker of multiple sclerosis (MS). The impact of gadolinium-based contrast agent (GBCA) administration on CVS evaluation remains poorly investigated. OBJECTIVE. The purpose of this study was to assess the effect of GBCA use on CVS detection and on the diagnostic performance of the CVS for MS using a 3-T FLAIR* sequence. METHODS. This study was a secondary analysis of data from the pilot study for the prospective multicenter Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS), which recruited adults with suspected MS from April 2018 to February 2020. Participants underwent 3-T brain MRI including FLAIR and precontrast and post-contrast echo-planar imaging T2*-weighted acquisitions. Postprocessing was used to generate combined FLAIR and T2*-weighted images (hereafter, FLAIR*). MS diagnoses were established using the 2017 McDonald criteria. Thirty participants (23 women, seven men; mean age, 45 years) were randomly selected from the CAVS-MS pilot study cohort. White matter lesions (WMLs) were marked using FLAIR* images. A single observer, blinded to clinical data and GBCA use, reviewed marked WMLs on FLAIR* images for the presence of the CVS. RESULTS. Thirteen of 30 participants had MS. Across participants, on precontrast FLAIR* imaging, 218 CVS-positive and 517 CVS-negative WMLs were identified; on post-contrast FLAIR* imaging, 269 CVS-positive and 459 CVS-negative WMLs were identified. The fraction of WMLs that were CVS-positive on precontrast and postcontrast images was 48% and 58% in participants with MS and 7% and 10% in participants without MS, respectively. The median patient-level CVS-positivity rate on precontrast and postcontrast images was 43% and 67% for participants with MS and 4% and 8% for participants without MS, respectively. In a binomial model adjusting for MS diagnoses, GBCA use was associated with an increased likelihood of at least one CVS-positive WML (odds ratio, 1.6; p < .001). At a 40% CVS-positivity threshold, the sensitivity of the CVS for MS increased from 62% on precontrast images to 92% on postcontrast images (p = .046). Specificity was not significantly different between precontrast (88%) and postcontrast (82%) images (p = .32). CONCLUSION. GBCA use increased CVS detection on FLAIR* images, thereby increasing the sensitivity of the CVS for MS diagnoses. CLINICAL IMPACT. The postcontrast FLAIR* sequence should be considered for CVS evaluation in future investigational trials and clinical practice.

Infection risk in a real-world cohort of patients treated with long-term B-cell depletion for autoimmune neurologic disease.

BACKGROUND: B-cell depleting medications are effective disease-modifying therapies for multiple sclerosis. Prior studies have demonstrated that use of these medication is associated with infections and immunologic changes. Limited data suggest that infectious adverse effects may be more common with long-term use. We aimed to investigate rates of infections and laboratory abnormalities in a real-world cohort of patients treated with long term B-cell depletion and identify clinical factors associated with these outcomes. METHODS: In this retrospective, single-center observational study, patients with MS and other autoimmune neurologic disorders treated with rituximab or ocrelizumab for ≥2 years were identified. Linear regression analyses identified factors associated with increased risk of minor and severe infections. Rates of total and severe infections were compared between the first two years of treatment and years three and beyond. RESULTS: 291 patients, treated with rituximab or ocrelizumab for an average of 46 months, were included. Total infections and infections requiring hospitalization occurred at rates of 25.0 and 3.03 per 100 person-years, respectively. Female gender and current or former smoking status were associated with a higher rate of total infections. Hypogammaglobulinemia and higher BMI were associated with increased risk of hospitalization. Rates of total and serious infections were higher in years three and beyond compared to the first two years. CONCLUSIONS: Infections in patients with MS treated with long-term B-cell depletion may be more common with longer duration of therapy. This study provides additional information to help personalize care.

High-Efficacy Therapies for Treatment-Naïve Individuals with Relapsing-Remitting Multiple Sclerosis.

There are > 18 distinct disease-modifying therapy (DMT) options covering 10 mechanisms of action currently approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis (RRMS). Given the multitude of available treatment options, and recent international consensus guidelines offering differing recommendations, there is broad heterogeneity in how the DMTs are used in clinical practice. Choosing a DMT for newly diagnosed patients with MS is currently a topic of significant debate in MS care. Historically, an escalation approach to DMT was used for newly diagnosed patients with RRMS. However, the evidence for clinical benefits of early treatment with high-efficacy therapies (HETs) in this population is emerging. In this review, we provide an overview of the DMT options and MS treatment strategies, and discuss the clinical benefits of HETs (including ofatumumab, ocrelizumab, natalizumab, alemtuzumab, and cladribine) in the early stages of MS, along with safety concerns associated with these DMTs. By minimizing the accumulation of neurological damage early in the disease course, early treatment with HETs may enhance long-term clinical outcomes over the lifetime of the patient.

Disease-modifying therapies (DMTs) can help people with multiple sclerosis (MS) by changing the way that their MS develops over time. Some people with MS have relapses when their symptoms get worse, followed by recovery when their MS is remitting. This is called relapsing­remitting MS (RRMS). DMTs can reduce both the number and the severity of relapses. They can also delay the nerve damage that relapses cause. A range of DMTs are approved for treating people with RRMS. These treatments work in different ways, and international treatment guidelines vary on their recommendations for using DMTs in the clinic. Selecting DMTs for people with newly diagnosed RRMS is still a topic of discussion. Previously, people with RRMS only received the more effective high-efficacy therapies (HETs) if their first treatment was not effective. HETs include ofatumumab, ocrelizumab, natalizumab, alemtuzumab, and cladribine. Recently, using HETs at an earlier stage has shown promising results. In this review article, we provide an overview of the clinical strategies and the DMT options that are available for people with MS. Additionally, we discuss the benefits of using HETs for people with newly diagnosed MS and consider the safety issues related to DMTs. We summarize that using HETs to reduce the buildup of nerve damage during the early stages of MS may lead to improved long-term clinical outcomes over a person's lifetime.