[TUMOR-LIKE EFFECT AS INITIAL PRESENTATION OF PEDIATRIC MULTIPLE SCLEROSIS].

INTRODUCTION: In both children and adults, magnetic resonance imaging of the brain in cases of multiple sclerosis (MS) has typical indications, where one of the key points for differentiating between demyelinating processes and place-taking processes is the fact that most of the lesions that appear in multiple sclerosis do not cause a mass effect or much edema around them. There are several uncommon subtypes of multiple sclerosis that can appear specifically in adolescents, presenting with a stormy clinical course and accompanied by brain lesions that resemble space-occupying lesions. These include Marburg disease, Balò's concentric sclerosis, and tumefactive MS. These unusual presentations raise the question regarding the ability to distinguish between neoplastic and demyelinating processes. In this article we present two case studies that illustrate this diagnostic dilemma and an accompanying literature review.

COVID-19 vaccination in patients with multiple sclerosis: What we have learnt by February 2021.

BACKGROUND: Since vaccination against coronavirus disease 2019 (COVID-19) became available, risks related to vaccinating patients with multiple sclerosis (MS) need to be carefully assessed. OBJECTIVE: Characterize safety and occurrence of immediate relapses following COVID-19 vaccination in a large cohort of MS patients. METHODS: We assessed the safety of BNT162b2 COVID-19 vaccination in adult MS patients. RESULTS: Between 20 December 2020 and 25 January 2021, 555 MS patients received the first dose of BNT162b2 vaccine and 435 received the second dose. There were three cases of COVID-19 infection encountered after the first dose. Safety profile of COVID-19 vaccine was characterized by pain at the injection site, fatigue, and headache. No increased risk of relapse activity was noted over a median follow-up of 20 and 38 days after first and second vaccine doses, respectively. The rate of patients with acute relapse was 2.1% and 1.6% following the first and second doses, respectively, similar to the rate in non-vaccinating patients during the corresponding period. Mild increase in the rate of adverse events was noted in younger patients (18-55 years), among patients with lower disability (Expanded Disability Status Scale (EDSS) ⩽3.0), and in patients treated with immunomodulatory drugs. CONCLUSION: COVID-19 BNT162b2 vaccine proved safe for MS patients. No increased risk of relapse activity was noted.

Focal cortical thinning in patients with stable relapsing-remitting multiple sclerosis: cross-sectional-based novel estimation of gray matter kinetics.

PURPOSE: The aim of our study is to identify radiological patterns of cortical gray matter atrophy (CGMA) that correlate with disease duration in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: RRMS patients were randomly selected from the Sheba Multiple Sclerosis (MS) center computerized data registry based on stratification of disease duration up to 10 years. Patients were scanned by 3.0 T (Signa, GE) MRI, using a T1 weighted 3D high resolution, FSPGR, MS protocol. Neurological disability was assessed by the Expanded Disability Status Scale (EDSS). FreeSurfer was used to obtain brain volumetric segmentation and to perform cortical thickness surface-based analysis. Clusters of change in cortical thickness with correlation to disease duration were produced. RESULTS: Two hundred seventy-one RRMS patients, mean ± SD age 33.0 ± 7.0 years, EDSS 1.6 ± 1.2, disease duration 5.0 ± 3.4 years. Cortical thickness analysis demonstrated focal areas of cerebral thinning that correlated with disease duration. Seven clusters accounting for 11.7% of the left hemisphere surface and eight clusters accounting for 10.6% of the right hemisphere surface were identified, with cluster-wise probability of p < 0.002 and p < 0.02, respectively.The clusters included bilateral involvement of areas within the cingulate, precentral, postcentral, paracentral, superior-parietal, superior-frontal gyri and insular cortex. Mean and cluster-wise cortical thickness negatively correlated with EDSS score, p < 0.001, with stronger Spearman rho for cluster-wise measurements. CONCLUSIONS: We identified CGMA patterns in sensitive brain regions which give insight and better understanding of the progression of cortical gray matter loss in relation to dissemination in space and time. These patterns may serve as markers to modulate therapeutic interventions to improve the management of MS patients.

COVID-19 vaccination in patients with multiple sclerosis: Safety and humoral efficacy of the third booster dose.

BACKGROUND: As immunity against SARS-COV-2 wanes following first and second doses of vaccination, a third dose is administered in several countries around the world. Similarly to the first doses, risks related to vaccination and humoral immune response in patients with multiple sclerosis (MS) need to be assessed. OBJECTIVE: Characterize safety and humoral immune response following the third dose of COVID-19 vaccination in a large cohort of MS patients. METHODS: We assessed the safety of the third dose of the BNT162b2-COVID-19 mRNA vaccination in adult MS patients and evaluated SARS-CoV-2 IgG response. RESULTS: Two hundred and eleven adult MS patients received a third dose of BNT162b2 COVID-19 vaccination. Median follow up time was 66 days from vaccine administration (IQR 54-84). The frequency of any adverse event was 54.5%, with the most common reported adverse events being fatigue, local pain at the injection site, fever and muscle or joint pain. Transient increase in MS symptoms was reported in 3.8% of patients, none of them requiring treatment. The rate of acute relapses treated with IV steroids was 3.3%. In a sub-group of 55 patients, 20 untreated and 35 treated with vaccination-safe disease-modifying treatments, SARS-CoV-2 IgG levels increased 21-fold (median ± SD 21.6 ± 53.05). CONCLUSIONS: The third dose of COVID-19-BNT162b2 vaccine proved safe for MS patients, with no increased risk of relapse activity. Untreated patients and patients treated with vaccination-safe disease-modifying treatments show significant increase in SARS-CoV-2 IgG levels following the third dose of vaccination.

Association Between White Matter Microstructure and Verbal Fluency in Patients With Multiple Sclerosis.

Verbal fluency refers to the ability to generate words quickly and efficiently according to predefined phonological or semantic criteria. Deficits in verbal fluency limit patients' ability to communicate effectively and to function well in social setups. Multiple sclerosis (MS) patients suffer from various cognitive impairments, and some of them experience language deficits as well. The goal of this study is to examine the contribution of the dorsal and ventral language pathways to verbal fluency in MS patients. All patients (N = 33) underwent diffusion MRI (dMRI) and fluency measurements. Diffusion parameters were calculated along dorsal and ventral language-related pathways and their right-hemispheric homologs, identified individually in each patient. Significant correlations were found between fluency measures and mean fractional anisotropy (FA) in several pathways, including the left fronto-temporal arcuate fasciculus (AFft), bilateral inferior fronto-occipital fasciculus (IFOF), and bilateral frontal aslant tract. Along-tract correlations revealed a more selective pattern of associations: letter-based fluency was associated with FA in a segment of the left AFft (dorsal pathway), while category-based fluency was associated with FA in a segment of the right IFOF (ventral pathway). The observed pattern of associations, mapping letter-based fluency to the dorsal stream and category-based fluency to the ventral stream, fits well within the dual stream framework of language processing. Further studies will be necessary to assess whether these associations generalize to the typical adult population or whether they are tied to the clinical state.

Brain Lesion Load and Anatomic Distribution in Patients With Juvenile Clinically Isolated Syndrome Predicts Rapidly Advanced to Multiple Sclerosis.

The aim was to assess brain lesion load and anatomical distribution in patients with juvenile clinically isolated syndrome and define magnetic resonance imaging (MRI) variables associated with rapidly advancing to multiple sclerosis. Patients were followed for one year after disease onset. Patients who experienced a second relapse were defined as those who rapidly advanced to multiple sclerosis. In all, 46 juvenile patients with a clinical presentation suggestive of multiple sclerosis were evaluated; 21 with gadolinium-enhancing lesions on initial brain MRI were excluded as they had already fulfilled the diagnosis criteria for multiple sclerosis. A total of 25 patients, 10 males and 15 females (mean ± SE age at onset 15.6 ± 0.6 years), met the definition of clinically isolated syndrome. The presence of a corpus callosum lesion at onset significantly differentiated between sustained clinically isolated syndrome and patients who rapidly advanced to multiple sclerosis.

Cerebellar volume as imaging outcome in progressive multiple sclerosis.

BACKGROUND AND PURPOSE: To assess whether cerebellar volumes changes could represent a sensitive outcome measure in primary-progressive MS. MATERIAL AND METHODS: Changes in cerebellar volumes over one-year follow-up, estimated in 26 primary-progressive MS patients and 20 controls with Freesurfer longitudinal pipeline, were assessed using Wilcoxon test and tested for their correlation with disability worsening by a logistic regression. Clinical worsening was defined as EDSS score increase or change of >20% for 25-foot walk test or 9-hole peg test scores at follow-up. Sample sizes for given treatment effects and power were calculated. The findings were validated in an independent cohort of 20 primary-progressive MS patients. RESULTS: Significant changes were detected in brain T1 lesion volume (p<0.01), cerebellar T2 and T1 lesion volume (p<0.01 and p<0.05), cerebellar volume, cerebellar cortex volume, and cerebellar WM volume (p<0.001). Only cerebellar volume and cerebellar cortex volume percentage change were significantly reduced in clinically progressed patients when compared to patients who did not progress (p<0.01; respectively AUC of 0.91 and 0.96). Cerebellar volume percentage changes were consistent in the exploration and validation cohorts (cerebellar volume -1.90±1.11% vs -1.47±2.30%; cerebellar cortex volume -1.68±1.41% vs -1.56±2.23%). Based on our results the numbers of patients required to detect a 30% effect are 81 per arm for cerebellar volume and 162 per arm for cerebellar cortex volume (90% power, type 1 error alpha = 0.05). CONCLUSIONS: Our results suggest a role for cerebellar cortex volume and cerebellar volume as potential short-term imaging metrics to monitor treatment effect in primary-progressive MS clinical trials.

Intravenous immunoglobulin and multiple sclerosis.

Intravenous immunoglobulin (IVIg) has been used as an immunomodulatory therapy for the treatment of multiple sclerosis (MS). In the current review, we summarize the up-to-date data related to IVIg clinical trials in MS, and the suggested mechanisms of action by which IVIg modulates the relevant immunological pathways impaired in MS.

Tumor necrosis factor (TNF)alpha and its soluble receptor (sTNFR) p75 during acute human parvovirus B19 infection in children.

Human parvovirus B19 (HPV) has been shown to be involved in the pathogenesis of various connective tissue and autoimmune diseases. In order to gain more information on HPV possible role in these diseases, we have investigated some immune responses in patients with acute HPV infection, mainly the secretion of the proinflammatory cytokine tumor necrosis factor (TNF)alpha and it's antagonist--the soluble TNF receptor (sTNFR) p75. Thirteen children with acute HPV infection and 13 healthy volunteers were investigated for the presence of autoantibodies, lymphocyte subpopulation counts, levels of total immunoglobulins, IgG subclasses and complement. The levels of TNFalpha and sTNFR p75 were determined in serum and conditioned medium (CM) from unstimulated and LPS stimulated peripheral blood mononuclear cell (PBMC) cultures. There was no difference between patients and controls regarding autoantibodies, lymphocytes, immunoglobulins, IgG subclasses and complement. A significant imbalance between TNFalpha and sTNFR p75 was found in the patients group. TNFalpha concentrations were significantly higher both in sera and in CM from the patients as compared with the controls. The levels of sTNFR concentrations were either similar (in sera) or significantly lower (in CM) in the patients compared with the controls. The TNF index, representing the biologically available TNFalpha, was significantly higher in patient's sera and CMs. In view of these results, it is conceivable that infection with human HPV in otherwise healthy children may lead to a proinflammatory state. The presence of high levels of biologically available TNFalpha, in susceptible individuals, may in turn play a role in the pathogenesis of systemic autoimmune diseases in HPV infected individuals.

Brain MRI lesion load quantification in multiple sclerosis: a comparison between automated multispectral and semi-automated thresholding computer-assisted techniques.

Brain magnetic resonance imaging (MRI) lesion volume measurement is an advantageous tool for assessing disease burden in multiple sclerosis (MS). We have evaluated two computer-assisted techniques: MSA multispectral automatic technique that is based on bayesian classification of brain tissue and NIH image analysis technique that is based on local (lesion by lesion) thresholding, to establish reliability and repeatability values for each technique. Brain MRIs were obtained for 30 clinically definite relapsing-remitting MS patients using a 2.0 Tesla MR scanner with contiguous, 3 mm thick axial, T1, T2 and PD weighted modalities. Digital (Dicom 3) images were analyzed independently by three observers; each analyzed the images twice, using the two different techniques (Total 360 analyses). Accuracy of lesion load measurements using phantom images of known volumes showed significantly better results for the MSA multispectral technique (p < 0.001). The mean intra-and inter-observer variances were, respectively, 0.04 +/- 0.4 (range 0.04-0.13), and 0.09 +/- 0.6 (range 0.01-0.26) for the multispectral MSA analysis technique, 0.24 +/- 2.27 (range 0.23-0.72) and 0.33 +/- 3.8 (range 0.47-1.36) for the NIH threshold technique. These data show that the MSA multispectral technique is significantly more accurate in lesion volume measurements, with better results of within and between observers' assessments, and the lesion load measurements are not influenced by increased disease burden. Measurements by the MSA multispectral technique were also faster and decreased analysis time by 43%. The MSA multispectral technique is a promising tool for evaluating MS patients. Non-biased recognition and delineation algorithms enable high accuracy, low intra-and inter-observer variances and fast assessment of MS related lesion load.

Diffusion tensor imaging analysis of tumefactive giant brain lesions in multiple sclerosis.

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) quantifies the motion of water within brain tissue. Inflammation leads to tissue disruption, resulting in increased diffusivity and decreased directionality. We aimed to quantify the damage within tumefactive giant brain lesions (TGL) in multiple sclerosis (MS) using MRI and DTI methodology. METHODS: Region of interest were determined on TGL and acute MS lesions to obtain metrics such as volume, apparent diffusion coefficient (ADC), fractional anisotropy (FA), axial diffusivity (λ|| ), and radial diffusivity (λ⊥ ). RESULTS: We identified 10 TGL in 10 patients with MS. The incidence of TGL was 2.8%. Comparing TGL to acute 16 MS lesions, DTI metrics demonstrated significantly higher ADC, λ|| and λ⊥ diffusivities and lower FA values in TGL (P <.001). Five TGL were reevaluated after 120 days by MRI and DTI metrics. Significant group changes were detected at 120 days: TGL volume decreased, ADC, λ|| and λ⊥ values were lower and FA was higher (P < .01). CONCLUSIONS: Within the spectrum of acute MS lesions, TGL present DTI metrics of an intense acute inflammatory process. Analysis of TGL progression proposes that DTI metrics sensitively detects micro-structural changes in TGL from acute inflammation towards lesion recovery and reorganization.

Co-registration of white matter tractographies by adaptive-mean-shift and Gaussian mixture modeling.

In this paper, we present a robust approach to the registration of white matter tractographies extracted from diffusion tensor-magnetic resonance imaging scans. The fibers are projected into a high dimensional feature space based on the sequence of their 3-D coordinates. Adaptive mean-shift clustering is applied to extract a compact set of representative fiber-modes (FM). Each FM is assigned to a multivariate Gaussian distribution according to its population thereby leading to a Gaussian mixture model (GMM) representation for the entire set of fibers. The registration between two fiber sets is treated as the alignment of two GMMs and is performed by maximizing their correlation ratio. A nine-parameters affine transform is recovered and eventually refined to a twelve-parameters affine transform using an innovative mean-shift based registration refinement scheme presented in this paper. The validation of the algorithm on synthetic intrasubject data demonstrates its robustness to interrupted and deviating fiber artifacts as well as outliers. Using real intrasubject data, a comparison is conducted to other intensity based and fiber-based registration algorithms, demonstrating competitive results. An option for tracking-in-time, on specific white matter fiber tracts, is also demonstrated on the real data.