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The success of clinical trials of selective B-cell depletion in patients with relapsing multiple sclerosis (MS) and primary progressive MS has led to a conceptual shift in the understanding of MS pathogenesis, away from the classical model in which T cells were the sole central actors and toward a more complex paradigm with B cells having an essential role in both the inflammatory and neurodegenerative components of the disease process. The role of B cells in MS was selected as the topic of the 27th Annual Meeting of the European Charcot Foundation. Results of the meeting are presented in this concise review, which recaps current concepts underlying the biology and therapeutic rationale behind B-cell–directed therapeutics in MS, and proposes strategies to optimize the use of existing anti–B-cell treatments and provide future directions for research in this area. ANN NEUROL 2021;89:13–23.

Background: White matter lesions (WMLs) on brain magnetic resonance imaging (MRI) in multiple sclerosis (MS) may contribute to misdiagnosis. In chronic active lesions, peripheral iron-laden macrophages appear as paramagnetic rim lesions (PRLs). Objective: To evaluate the sensitivity and specificity of PRLs in differentiating MS from mimics using clinical 3T MRI scanners. Method: This retrospective international study reviewed MRI scans of patients with MS ( n = 254), MS mimics ( n = 91) and older healthy controls ( n = 217). WMLs, detected using fluid-attenuated inversion recovery MRI, were analysed with phase-sensitive imaging. Sensitivity and specificity were assessed for PRLs. Results: At least one PRL was found in 22.9% of MS and 26.1% of clinically isolated syndrome (CIS) patients. Only one PRL was found elsewhere. The identification of ⩾1 PRL was the optimal cut-off and had high specificity (99.7%, confidence interval (CI) = 98.20%–99.99%) when distinguishing MS and CIS from mimics and healthy controls, but lower sensitivity (24.0%, CI = 18.9%–36.6%). All patients with a PRL showing a central vein sign (CVS) in the same lesion ( n = 54) had MS or CIS, giving a specificity of 100% (CI = 98.8%–100.0%) but equally low sensitivity (21.3%, CI = 16.4%–26.81%) Conclusion: PRLs may reduce diagnostic uncertainty in MS by being a highly specific imaging diagnostic biomarker, especially when used in conjunction with the CVS.

Background: Structural cortical networks (SCNs) represent patterns of coordinated morphological modifications in cortical areas, and they present the advantage of being extracted from previously acquired clinical magnetic resonance imaging (MRI) scans. SCNs have shown pathophysiological changes in many brain disorders, including multiple sclerosis. Objective: To investigate alterations of SCNs at the individual level in patients with clinically isolated syndrome (CIS), thereby assessing their clinical relevance. Methods: We analyzed baseline data collected in a prospective multicenter (MAGNIMS) study. CIS patients ( n = 60) and healthy controls ( n = 38) underwent high-resolution 3T MRI. Measures of disability and cognitive processing were obtained for patients. Single-subject SCNs were extracted from brain 3D-T1 weighted sequences; global and local network parameters were computed. Results: Compared to healthy controls, CIS patients showed altered small-world topology, an efficient network organization combining dense local clustering with relatively few long-distance connections. These disruptions were worse for patients with higher lesion load and worse cognitive processing speed. Alterations of centrality measures and clustering of connections were observed in specific cortical areas in CIS patients when compared with healthy controls. Conclusion: Our study indicates that SCNs can be used to demonstrate clinically relevant alterations of connectivity in CIS.

Background: Limited information is available on the use of natalizumab (NA) in pediatric multiple sclerosis (ped-MS) patients. Objective: The purpose of this study was to describe the long-term effects of NA in a large cohort of active ped-MS patients. Methods: Patients with definite ped-MS were treated with NA if in the previous year they had experienced at least two relapses or a severe relapse with incomplete recovery while on immunomodulating treatment, or at least two relapses and new magnetic resonance imaging (MRI) lesions regardless of any prior treatment. Results: The study included 55 patients (mean age: 14.4 years, mean number of relapses: 4.4, pre-treatment mean disease duration: 25.5 months). They received a median number of 26 infusions. Three relapses occurred during the follow-up, one female patient continued to deteriorate in cognitive functioning. Mean Expanded Disability Status Scale (EDSS) scores decreased from 2.7 to 1.9 at the last visit ( pConclusions: NA was well tolerated in all patients. A strong suppression of disease activity was observed in the majority of patients during the follow-up.

To provide new insights into the role of markers of response to interferon-β therapy in multiple sclerosis (MS) in a multicenter setting, focusing on the relevance of MRI lesions in combination with clinical variables.A large multicenter clinical dataset was collected within the Magnetic Resonance Imaging in MS (MAGNIMS) network. This included a large cohort of patients with relapsing-remitting MS on interferon-β treatment, MRI and clinical assessments during the first year of treatment, and clinical follow-up of at least 2 additional years. Heterogeneity among centers was assessed before pooling the data. The association of 1-year MRI or clinical relapses with the risk of treatment failure (defined as Expanded Disability Status Scale [EDSS] worsening or treatment switch for inefficacy) and of EDSS worsening alone was evaluated using multivariate Cox models.A pooled dataset of 1,280 patients with relapsing-remitting MS from 9 MAGNIMS centers was analyzed. The risk of failure had a relevant increase with 1 relapse (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.39-2.44, p0.001) and ≥3 new T2 lesions (HR 1.55, 95% CI 0.92-2.60, p = 0.09). In patients without relapses and less than 3 new T2 lesions, the 3-year risk of failure and EDSS worsening were 17% and 15%; in patients with 1 relapse or ≥3 new T2 lesions, the risks were 27% and 22%; in patients with both conditions or more than 1 relapse, the risks were 48% (p0.001) and 29% (p0.001).Substantial MRI activity, particularly if in combination with clinical relapses, during the first year of treatment with interferon-β indicates significant risk of treatment failure and EDSS worsening in the short term.

This book provides an overview of the practical aspects of diffusion tensor imaging (DTI), from understanding the basis of the technique through selection of the right protocols, trouble-shooting data quality, and analyzing DTI data optimally. DTI is a non-invasive magnetic resonance imaging (MRI) technique for visualizing and quantifying tissue microstructure based on diffusion. The book discusses the theoretical background underlying DTI and advanced techniques based on higher-order models and multi-shell diffusion imaging. It covers the practical implementation of DTI; derivation of information from DTI data; and a range of clinical applications, including neurosurgical planning and the assessment of brain tumors. Its practical utility is enhanced by decision schemes and a fully annotated DTI brain atlas, including color fractional anisotropy maps and 3D tractography reconstructions of major white matter fiber bundles. Featuring contributions from leading specialists in the field of DTI, Diffusion Tensor Imaging: A Practical Handbook is a valuable resource for radiologists, neuroradiologists, MRI technicians and clinicians.

To assess in a large population of patients with clinically isolated syndrome (CIS) the relevance of brain lesion location and frequency in predicting 1-year conversion to multiple sclerosis (MS).In this multicenter, retrospective study, clinical and MRI data at onset and clinical follow-up at 1 year were collected for 1,165 patients with CIS. On T2-weighted MRI, we generated lesion probability maps of white matter (WM) lesion location and frequency. Voxelwise analyses were performed with a nonparametric permutation-based approach (p0.05, cluster-corrected).In CIS patients with hemispheric, multifocal, and brainstem/cerebellar onset, lesion probability map clusters were seen in clinically eloquent brain regions. Significant lesion clusters were not found in CIS patients with optic nerve and spinal cord onset. At 1 year, clinically definite MS developed in 26% of patients. The converting group, despite a greater baseline lesion load compared with the nonconverting group (7 ± 8.1 cm3 vs. 4.6 ± 6.7 cm3, p0.001), showed less widespread lesion distribution (18% vs. 25% of brain voxels occupied by lesions). High lesion frequency was found in the converting group in projection, association, and commissural WM tracts, with larger clusters being in the corpus callosum, corona radiata, and cingulum.Higher frequency of lesion occurrence in clinically eloquent WM tracts can characterize CIS subjects with different types of onset. The involvement of specific WM tracts, in particular those traversed by fibers involved in motor function and near the corpus callosum, seems to be associated with a higher risk of clinical conversion to MS in the short term.

OBJECTIVES: To investigate, using resting state (RS) functional connectivity (FC), the selectivity of involvement of the sensorimotor network in patients with acquired (A) and with hereditary (H) peripheral neuropathies (PN) and the correlations of RS FC abnormalities with clinical impairment and structural brain damage. Temporal associations among RS networks were also explored. Experimental design: RS fMRI scans were acquired from 13 APN, 12 HPN, and 18 age‐ and sex‐matched healthy controls. Independent component analysis and functional network connectivity were used to investigate RS FC within and among RS networks with potential functional relevance. PRINCIPAL OBSERVATIONS: Compared to controls, patients had a decreased FC of the right precentral gyrus and an increased RS FC of the precuneus within the sensorimotor network. Both decreased and increased RS FC also involved the visual and auditory networks, which additionally had an increased coherence of function with the sensorimotor network (more pronounced in HPN). RS FC modifications in patients extended to several cognitive networks and were correlated with disease duration. In APN, they were also correlated with the severity of clinical impairment and corpus callosum atrophy. CONCLUSIONS: In PN, RS FC modifications extend beyond the sensorimotor network and involve other sensory and cognitive networks. The correlations between RS FC patterns and disease duration in patients as well as with clinical impairment in patients with APN suggest that modifications of FC might reflect an adaptive mechanism, which takes time to occur and helps to limit the clinical consequences of peripheral damage. Hum Brain Mapp 35:513–526, 2014. © 2012 Wiley Periodicals, Inc.

The development of therapeutic strategies that promote functional recovery is a major goal of multiple sclerosis (MS) research. Neuroscientific and methodological advances have improved our understanding of the brain's recovery from damage, generating novel hypotheses about potential targets and modes of intervention, and laying the foundation for development of scientifically informed recovery-promoting strategies in interventional studies. This Review aims to encourage the transition from characterization of recovery mechanisms to development of strategies that promote recovery in MS. We discuss current evidence for functional reorganization that underlies recovery and its implications for development of new recovery-oriented strategies in MS. Promotion of functional recovery requires an improved understanding of recovery mechanisms that can be modulated by interventions and the development of robust measurements of therapeutic effects. As imaging methods can be used to measure functional and structural alterations associated with recovery, this Review discusses their use to obtain reliable markers of the effects of interventions. © 2012 Macmillan Publishers Limited.

Objectives To study the safety and efficacy of vitamin D3 as an add on therapy to interferon b-1b (IFNB) in patients with multiple sclerosis (MS). Methods 1 year, double blind, placebo controlled, randomised study in 66 MS patients. The primary outcomes were T2 burden of disease (BOD) on MRI scans, proportion of patients with serum levels of 25-hydroxyvitamin D (25(OH)D) $85 nmol/l or intact parathyroid hormone (PTH) #20 ng/l, and number of adverse events. Secondary outcomes were number of MRI enhancing T1 lesions and new T2 lesions, annual relapse rate, changes in the Expanded Disability Status Scale score, timed 25 foot walk test and timed 10 foot tandem walk tests. Results Median change in BOD was 287 mm3 in the placebo group and 83 mm3 in the vitamin D group (p¼0.105). Serum levels of 25(OH)D increased from a mean of 54 (range 19e82) nmol/l to 110 (range 67e163) nmol/l in the vitamin D group. 84% of patients reached a serum 25(OH)D level >85 nmol/l in the vitamin D group and 3% in the placebo group (p

International audience; Objectives: The long-term impact of interferon-beta-1b (IFN) might be improved by short-term immunosuppression with mitoxantrone (MITOX) in aggressive relapsing-remitting multiple sclerosis (ARMS) patients. Methods: In this 3-year clinical and MRI study, 109 ARMS patients (two or more relapses in the previous 12 months and one or more gadolinium (Gd)-enhancing MRI lesion) were randomised into two groups: 54 patients received MITOX monthly (12 mg/m2; maximum 20 mg) combined with 1 g of methylprednisolone (MP) for 6 months followed by IFN for the last 27 months, and 55 patients received IFN for 3 years combined with 1 g of MP monthly for the first 6 months. The primary endpoint was the time to worsen by at least one Expanded Disability Status Scale point confirmed at 3 months. Results: The time to worsen by at least one Expanded Disability Status Scale point confirmed at 3 months was delayed by 18 months in the MITOX group compared with the IFN group (p

""In this multicentre study involving eight European centres, we characterized the spatial pattern of functional connectivity (FC) in the sensorimotor network from 61 right-handed patients with multiple sclerosis (MS) and 74 age-matched healthy subjects assessed with the use of functional magnetic resonance imaging (fMRI) and a simple motor task of their right dominant hand. FC was investigated by using: (i) voxel-wise correlations between the left sensorimotor cortex (SMC) and any other area in the brain; and (ii) bivariate correlations between time series extracted from several regions of interest (ROIs) belonging to the sensorimotor network. Both healthy controls and MS patients had significant FC between the left SMC and several areas of the sensorimotor network, including the bilateral postcentral and precentral gyri, supplementary motor area, middle frontal gyri, insulae, secondary somatosensory cortices, thalami, and right cerebellum. Voxel-wise assessment of FC revealed increased connectivity between the left SMC and the right precentral gyrus, right middle frontal gyrus (MFG) and bilateral postcentral gyri in MS patients as compared with controls. ROI analysis also showed a widespread pattern of altered connectivity, characterized by increased FC between the right MFG, the left insula and the right inferior frontal gyrus in comparison with many regions of the sensorimotor network. These results provide further evidence for increased bihemispheric contributions to motor control in patients with MS relative to healthy controls. They further suggest that multicentre fMRI studies of FC changes are possible, and provide a potential imaging biomarker for use in experimental therapeutic studies directed at enhancing adaptive plasticity in the disease.""

Background: Different double inversion recovery (DIR) sequences are currently used in multiple sclerosis (MS) research centers to visualize cortical lesions, making it difficult to compare published data. This study aimed to formulate consensus recommendations for scoring cortical lesions in patients with MS, using DIR images acquired in 6 European centers according to local protocols. Methods: Consensus recommendations were formulated and tested in a multinational meeting. Results: Cortical lesions were defined as focal abnormalities on DIR, hyperintense compared to adjacent normal-appearing gray matter, and were not scored unless ≥3 pixels in size, based on at least 1.0 mm 2 in-plane resolution. Besides these 2 obligatory criteria, additional, supportive recommendations concerned a priori artifact definition on DIR, use of additional MRI contrasts to verify suspected lesions, and a constant level of displayed image contrast. Robustness of the recommendations was tested in a small dataset of available, heterogeneous DIR images, provided by the different participating centers. An overall moderate agreement was reached when using the proposed recommendations: more than half of the readers agreed on slightly more than half (54%) of the cortical lesions scored, whereas complete agreement was reached in 19.4% of the lesions (usually larger, mixed white matter/gray matter lesions). Conclusions: Although not designed as a formal interobserver study, the current study suggests that comparing available literature data on cortical lesions may be problematic, and increased consistency in acquisition protocols may improve scoring agreement. Sensitivity and specificity of the proposed recommendations should now be studied in a more formal, prospective, multicenter setting using similar DIR protocols.

"Objective: To investigate whether cognitive impairment in multiple sclerosis (MS) patients is associated to different patterns of gray matter (GM) atrophy and T2-visible lesion distribution according to the clinical phenotype. Experimental Design: Twenty-two relapsing remitting (RR), 29 secondary progressive (SP), and 22 primary progressive (PP) MS patients, and 39 healthy controls underwent high-field structural magnetic resonance imaging and an extensive neuropsychological battery. Voxel-wise distribution of GM damage and T2-lesions was compared between cognitively impaired (CI) and cognitively preserved (CP) patients according to their clinical phenotype. Principal Observations: Thirty-nine MS patients were CI. In all MS groups, regional GM loss was correlated with cognitive impairment. Different patterns of regional distribution of GM atrophy and T2-visible lesions were found between CI vs. CP MS patients, according to their clinical phenotype. No areas were significantly more atrophied in CI SPMS vs. CI RRMS patients. Conversely, compared with CI PPMS, CI SPMS patients had a significant GM loss in several regions of the fronto-temporal lobes, the left hypothalamus and thalami. While in RRMS and SPMS patients there was a correspondence between presence of T2 visible lesions and GM atrophy in several areas, this was not the case in PPMS patients. Conclusion: Distinct patterns of regional distribution of GM damage and T2-visible lesions are associated with cognitive impairment in MS patients with different clinical phenotypes. The correspondence between lesion formation and GM atrophy distribution varies in the different forms of MS."