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• SDQ assesses the frequency of dysphagic symptoms. • SDQ also evaluates dysphagia for saliva and different food textures. • SDQ may be used to investigate dysphagia in multiple sclerosis. The DYSPHAGIA IN MULTIPLE SCLEROSIS (DYMUS) questionnaire is the only specific tool developed to screen for dysphagia in people with Multiple Sclerosis (pwMS). However, some limitations of DYMUS could potentially be addressed by the SWALLOWING DISTURBANCE QUESTIONNAIRE (SDQ), which has not yet been validated in pwMS. The objective of this study was to translate and validate the SDQ into the Italian language for use in pwMS to detect swallowing disturbances. We translated the SDQ into Italian and adapted it for use in Italian pwMS. PwMS aged > 18 years, assessed for disability using the Expanded Disability Status Scale (EDSS), completed the SDQ and DYMUS questionnaires and performed the 3-OUNCE WATER SWALLOW TEST (WST). Clinical and demographic data were collected for each patient. The Italian version of the SDQ was retested after 30 days. A total of 84 pwMS were recruited for the study, consisting of 73.8 % women and 48.8 % with a relapsing-remitting form of MS. The mean age of participants was 44.5 years (SD: ±12.46), with a mean disease duration of 17 years (SD: ±10.27), and a median EDSS of 4 (range 1.5–7.5). The Cronbach's alpha for SDQ (to assess internal consistency) was 0.902, which increased to 0.908 after the elimination of item 15, resulting in the SDQ composed of 14 items. ROC analysis demonstrated good accuracy of the 14-item SDQ in pwMS (AUC: 0.811). By dividing the 14-item SDQ score into quartiles, three risk levels for dysphagia were identified: low (score 1–3), intermediate (score 4–8), and high (score ≥9). 14-item SDQ scores significantly correlated with DYMUS (r = 0.820; p <0.0001) and with EDSS (r = 0.541; p <0.0001). PwMS who reported dysphagia had a significantly higher mean 14-item SDQ score (8.27 ± SD 8.15) compared to those without swallowing problems (2.77 ± SD 4.25; p = 0.003). Additionally, pwMS with a positive WST had a significantly higher mean 14-item SDQ score (10.17 ± SD 8.96) than those with a negative WST (2.96 ± SD 3.93; p = 0.02). The Intraclass Correlation Coefficient for the retest, calculated on 48 pwMS in a stable phase of the disease, was 0.91 (95 % CI 0.84–0.95). The 14-item SDQ has demonstrated high internal consistency, good accuracy, and reliability in pwMS, making it a readily applicable tool for investigating dysphagia in MS. [ABSTRACT FROM AUTHOR]

Highlights • Gait analysis is able to detect preclinical motion impairment in MS. • The cognitive dual task condition worsened the gait parameters. • No significant correlation was found between gait abnormalities and cognitive status. • MRI measurements did not correlated with altered gait parameters. Abstract Background People with Relapsing-Remitting Multiple Sclerosis (pwRR-MS), may be affected by subclinical gait impairment. The Expanded Disability Status Scale, the most used scale to assess MS related disability, may be insensitive to subclinical gait disability. Minor gait abnormalities may be detected by three Dimensional-Gait Analysis (3D-GA). Objectives To investigate gait pattern in minimally disabled pwRR-MS by 3D-GA during walking (single task, SinT), and cognitive dual tasks (CogDT) and to evaluate correlations between altered gait parameters, cognitive scores, lesion load (LL) and brain atrophy measures. Methods Twenty-two pwRR-MS and twenty-one healthy controls (HCs), underwent neuropsychological (NP) evaluation, and brain MRI to assess brain volumes and lesion load (only in pwRR-MS) and 3D-GA. Results Both pwRR-MS and HCs were considered cognitively preserved (CP). During SinT pwRR-MS, compared to HCs, showed an impairment of velocity (increase of cycle time), stability (increase of stance time, swing time and coefficients of variability (CV) of swing time) and kinematic (increase of ankle dorsiflexion) parameters. During CogDT, the changes of velocity and stability parameters observed in SinT were confirmed. Moreover, a statistically significant increase of the double limb support was observed. Regarding the kinematic parameters, during CogDT, an increase of ankle dorsiflexion during mid and terminal stance phases of gait cycle was observed. No significant correlations were found between gait abnormalities and cognitive status or MRI structural damage in both groups. Conclusions The subclinical abnormal gait in asymptomatic and CP pwRR-MS, may be detected by 3D-GA. [ABSTRACT FROM AUTHOR]

Highlights • The improvement of the diagnostic process allowed the anticipation of MS diagnosis. • Earlier diagnoses of MS have really impacted on therapeutic management of the disease. • Web services may keep several aspects of patients' clinical history in an easy-to-use and easily connectable approach. Abstract Background In order to anticipate the diagnosis of Multiple Sclerosis (MS), the diagnostic criteria had been reviewed several times in the last years. Objective We wanted to understand whether earlier diagnoses of MS have impacted on therapeutic management of the disease. Methods We designed a 22-item survey posted on SMsocialnetwork, a webplatform with a medical supervision, dedicated to Italian MS patients. We collected socio-demographic data, disease and treatment-related information of 1000 patients. Results The median age at diagnosis significantly decreased over years. In the last decades the time delay between disease onset and diagnosis reduced, the disease phenotypes at diagnosis shifted from progressive form to relapsing ones and clinically isolated syndrome, the number of early treated patients increased over time. Conclusion We showed, verifying a large sample of patients in a reallife setting, that the improvement of the diagnostic process allowed the anticipation of MS diagnosis over years and had a huge impact in terms of treatment approach. [ABSTRACT FROM AUTHOR]

• The diagnosis of the progression phase of multiple sclerosis is still retrospective. • Identifying the progression as early as possible is crucial to maximize novel drug efficacy. • PROM scores could be useful for catching progressive disease onset early. • SF36 physical functioning was revealed to be an independent predictor of disease progression. The diagnosis of the progression phase of Multiple Sclerosis (MS) is still retrospective and based on the objectivation of clinical disability accumulation. To assess whether the Patient Reported Outcomes Measures (PROMs) scores predict the occurrence of disease progression within three years of follow-up. Observational prospective multicenter study. Stable Relapsing-Remitting MS (RRMS) patients were enrolled. At enrollment, patients completed the following PROMs: Beck Depression Inventory- II, The Treatment Satisfaction Questionnaire for Medications, Medical Outcomes Study Short Form 36- Item (SF36), Fatigue Severity Scale. EDSS was assessed at enrollment and three years later. The outcome measure was defined as the occurrence of confirmed disability progression (CDP) within three years of follow-up. Univariable and multivariable logistic regression models were performed to study the association between the final score of each test and the outcome. SF36-Physical Functioning (SF36-PF) was the only independent variable associated with the outcome. The ROC curve analysis determined a score of 77.5 at SF36-PF as the cut-off point identifying patients experiencing CDP within three years of follow-up [AUC: 0.66 (95% CI: 0.56–0.75)]. RRMS patients scoring higher (>77.5) at SF36-PF subscale have a higher likelihood to experience CDP within the next three years. [ABSTRACT FROM AUTHOR]

• The BICAMS is the most widely used screening tool for cognitive impairment in MS • We developed a tablet version of the BICAMS (iBICAMS) • The iBICAMS showed a high reliability over the paper version • iBICAMS could become a standard in clinical practice for cognitive assessment of MS The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) is the most widely used screening tool for cognitive impairment in Multiple Sclerosis (MS). However, the administration and scoring procedures of the paper version are time consuming and prone to errors. Aim of our study was to develop a tablet version of BICAMS (iBICAMS), and to assess its reliability compared to the paper version. We administered both BICAMS and iBICAMS to 139 MS patients in two different sessions. We compared scores on both versions using a paired t -test. We used a repeated measures ANOVA to test the impact of rater, order of administration and test-retest time on test-retest performances. We used the Intraclass Correlation Coefficient (ICC) to assess the reliability between BICAMS and iBICAMS. All three sub-tests of the BICAMS (SDMT, CVLT-II and BVMT-R) were different between the paper and the tablet versions. Order of administration influenced test-retest performances at the SDMT (p<0.001), CVLT- II (p<0.001) and BVMT-R (p<0.001). Intraclass coefficient correlation (ICC) revealed a high level of agreement between the paper BICAMS and the iPad version for all three tests: SDMT (0.92), CVLT-II (0.83) and BVMT-R (0.82). We found a high reliability between BICAMS and iBICAMS. Considering the inherent advantages of automated scoring, digital storage of data, standardized timing, the iBICAMS could become a standard in clinical practice. [ABSTRACT FROM AUTHOR]

Lesbian, gay, bisexual and transgender (LGBT) patients might experience unique difficulties and barriers to treatment of chronic diseases related to their sexual orientation. Thus, we investigated concerns experienced by LGBT patients with multiple sclerosis (MS). We conducted a web-based survey using a multi-choice questionnaire published in an Italian social-network ( www.smsocialnetwork.com ) for MS patients. The survey investigated: socio-demographic factors, lifestyle habits, MS-related health status and LGBT specific issues (e.g. friendliness to their sexual orientation and eventual homophobic behaviors in the MS Center). Among MS patients willing to use psychological services, LGBT patients were associated with a smaller number of psychological consultations, compared to heterosexuals (Coeff.=−0.449; p<0.001; 95%CI=−0.682 to −0.217). LGBT patients were more likely to change MS Center, compared to heterosexuals (OR=2.064; p=0.046; 95%CI=1.011–4.212). The number of MS Center changes was associated with MS Center friendliness (p=0.037; rho=−0.229) and with the occurrence of homophobic behaviors (p=0.036; rho=0.234). LGBT MS patients more frequently changed MS Center and had a reduced use of psychological services, compared to heterosexuals. The attitude towards LGBT MS patients might affect resource utilizations and LGBTs health status. [ABSTRACT FROM AUTHOR]

• Vitamin D has immunomodulatory effects. • Vitamin D deficiency is associated with a higher likelihood of disease activity in MS. • Low vitamin D serum levels might be associated to early B cell repopulation. Several observational studies have shown an association between low circulating levels of 25-hydroxy- vitamin D (25(OH)D) and an increase in inflammatory activity in Multiple Sclerosis (MS). Among its immunomodulatory functions, 25(OH)D suppresses proliferation and immunoglobulin production of B cells. 25(OH)D supplementation has been associated with better radiological outcomes in MS patients treated with interferon (IFN)-B, glatiramer acetate, fingolimod, natalizumab and rituximab. Our study is aimed at analyzing the association of 25(OH)D serum levels and supplementation with B cell kinetics and clinical-radiological outcomes of people with MS treated with ocrelizumab. We have retrospectively collected clinical and radiological data from 136 MS patients who have been treated with ocrelizumab, have undergone at least two treatment cycles and for whom data on serum 25(OH)D levels and intake were available. The patients were divided into three groups according to baseline 25(OH)D serum levels: deficient (≤19,9 ng/ml), insufficient (20-29,9 ng/ml), and normal range 25(OH)D (>30 ng/ml). According to 25(OH)D intake, we divided our population into users and non-users. To explore B cell kinetics at six- and twelve-month follow-ups, the patients were divided into two groups: with fast repopulation (FR) and slow repopulation rate (SR), based on the reappearance or non- appearance of CD19 at each time point. When considering the entire population, the mean 25(OH)D serum level (sd) was 26.27 ng/ml (14.15). 43 (31,62%) patients were classified as deficient, 52 (38,24%) were classified as insufficient, and 41 (30,14%) showed 25(OH)D serum levels within the normal range. 60.29% (82/136) of the patients were classified as users, and 39.70% (54/136) as non-users. Over the eighteen-month treatment period, we observed a significant difference between the 25(OH)D users and the non-users as concerns the number of scans with at least one new/enlarging T2 lesion (2% vs 15.38%, respectively; p= 0.025). In the multinomial regression model, 25(OH)D deficiency (serum levels ≤19,9 ng/ml) was significantly associated with a higher likelihood of disease activity during a follow-up of eighteen months (p = 0.029, RRR = 4.84, Confidence Interval (CI) 1.17 - 20.01). After six months, there were 30/136 FR patients (22,05%), whereas only 22/136 (16,17%) showed early B cell reappearance at twelve month follow up. 86.66% of the patients in the FR group showed 25(OH)D levels lower than 30 ng/ml (25(OH)D deficiency or insufficiency), whereas only 65.09% of the SR patients presented vitamin D levels lower than 30 ng/ml (p= 0.024). In the logistic regression model, 25(OH)D serum levels below 30 ng/ml were associated with a higher likelihood of early B cell reappearance at six month follow up (p= 0.042). 25(OH)D supplementation and serum levels might be associated with B cell kinetics and radiological activity of patients with MS treated with ocrelizumab. [ABSTRACT FROM AUTHOR]

Background The Dress picture recently has become a hot topic on the Internet, prompting a debate whether it was black and blue, or white and gold. Objective To investigate The Dress color perception in both multiple sclerosis (MS) patients, characterized by frequent visual system impairment with ensuing color vision effects, and general population. Methods We developed a questionnaire to record demographics, clinical features, and The Dress color perception, posted on general and MS-specific social networks. Results No statistically significant differences were observed in The Dress color perception between MS patients ( n =103) and general population ( n =441). Furthermore, white and gold color perception was positively associated with aging in the general population ( p =0.04), whereas negatively associated with progressive course ( p =0.03) and longer disease duration ( p <0.001) in MS patients, independently from patients' age. Conclusion The Dress black and blue or white and gold perception might be due to aging in the general population, whereas black and blue perception, despite of aging, might suggest a specific effect of the MS burden (i.e. disease duration and progression) on the visual structures specifically involved in the white and gold perception. [ABSTRACT FROM AUTHOR]

Objective We investigated the effect of glatiramer acetate (GA) on the modulation of immune cell subpopulations and serum levels of multiple immune/metabolic markers in patients with relapsing–remitting multiple sclerosis (RRMS) to understand whether the treatment with GA could induce a specific change in the immunometabolic asset of patients with RRMS. Material and methods We performed an extensive peripheral blood immunophenotyping and measured serum levels of several parameters involved in the pathogenesis of RRMS and also relevant in the pathogenesis of metabolic syndrome and obesity such as leptin, soluble leptin-receptor (sLep-R), myeloperoxidase (MPO), soluble CD40 ligand (sCD40-L), soluble tumor necrosis factor-receptor (sTNF-R), monocyte chemoattractant protein 1 (MCP-1), soluble Inter-Cellular Adhesion Molecule-1 (sICAM-1) and osteoprotegerin (OPG), in 20 naïve-to-treatment RRMS patients and 20 healthy controls. We repeated these analyses over time at 6 and 12 months after starting GA treatment. Results Our analysis showed that naïve-to-treatment RRMS patients had a lower number of CD16 + CD56 + NK cells, CD19 + B cells, CD4 + T cells co-expressing the MHC class II activation marker HLA-DR (CD4 + DR + ) and naïve CD4 + CD45RA + T cells in basal conditions. GA treatment induced a specific and significant decrease of circulating CD19 + B cells. Naïve-to-treatment RRMS patients also showed a significantly higher number of CD4 + T cells with a memory phenotype (CD4 + CD45RO + ) whose peripheral frequency was not affected by GA treatment. These changes over time associated with a higher serum concentration of leptin and lower levels of MPO. GA treatment also reduced significantly the circulating levels of sCD40-L and sTNF-R overtime. Conclusions Our data suggest that the clinical outcome of GA treatment is associated with changes in immune cell subpopulations and modulation of specific immunometabolic markers. These data add substantial evidence of the immune modulating effect of GA during RRMS and could be of relevance in understanding the pathogenesis of disease and its follow-up. [ABSTRACT FROM AUTHOR]

• Chronic immunosuppression is crucial in preventing NMSOD relapses. • CD27+ B cells might be a useful biomarker to guide RTX retreatment in AQP4-IgG positive patients. • Relapses in anti-MOG NMSOD occurred regardless of B cell depletion. Several studies have shown the efficacy of rituximab (RTX) in preventing relapses in patients suffering from Neuromyelitis Optica spectrum disorder (NMSOD) and have explored different therapeutic schemes. Given the extreme inter-individual variability of the disease course, there is the need to identify biomarkers to tailor the retreatment schedule and dosage. This review aimed to identify the most useful biomarker to guide reinfusion and, in turn, the optimal retreatment schedule of RTX for NMSOD. The literature search was conducted in the Web of Science, Scopus and Pubmed electronic databases. We limited document type to articles written in English and published up to 28 February 2022. Inclusion criteria were: (i) Patients affected by NMSOD and treated with RTX, (ii) followed up for at least one year and for whom Annualized Relapse rate (ARR) was collected over a period of at least 12 months before and after therapy initiation and (iii) induction protocols consisting of 375 mg / m2 / week for four weeks or 1000 mg infused once or twice two weeks apart. Collected information was: first authors' name, publication year, study design, sample size, sex, age, percentage of patients positive for antibodies to aquaporin 4 (AQP4-IgG), maintenance regimen, primary outcome, mean ARR pre-therapy and mean ARR post-therapy initiation, percentage of relapse-free patients. The primary outcome that we considered was the ARR reduction. Further, we considered the number of relapses that occurred when B cells and memory B cells were under the chosen threshold and the percentage of relapse-free patients when available. Among 31 potentially eligible studies, 9 fulfilled the inclusion criteria. ARR reduction was not comparable between studies. The studies that monitored CD19+ and CD27+ cell kinetics showed a higher number of relapses when CD19+ lymphocyte count was below the threshold compared to the number of relapses that occurred when CD27+ cell count was below the threshold. Further, a higher percentage of patients achieved the relapse-free condition with a reinfusion schedule when CD27+ reached 0, 05% of peripheral blood mononuclear cells (PBMCs) compared to the reinfusion when CD19+ reached 0, 1% of PBMCs. To date, the optimal retreatment schedule for RTX in NMOSD has not yet been determined. However, the presented findings suggest that CD27+ B cells might be a reliable biomarker to guide retreatment in AQP4-IgG positive patients, at least in the first six months from the infusion. Further effort is needed to identify those factors influencing anti-CD20 therapy effectiveness to tailor dosage and treatment schedule to achieve the most favourable risk/benefit ratio. [ABSTRACT FROM AUTHOR]

• The pandemic's negative aspects were associated with worse disability. • Greater endorsed post-traumatic growth was associated with lesser disability. • Greater self-protection against COVID-19 was associated more disability in the US. The present cross-national study addressed the relationship among three pandemic-related variables and multiple sclerosis (MS) disability outcomes among people with MS in Italy and the United States (US). This cross-sectional web-based study was administered to 708 patients with MS from the US and Italy in late Spring through mid-Summer of 2020. Pandemic-related variables assessed worry, self-protection, and post-traumatic growth. The Performance Scales© assessed MS disability. Multivariate multiple regression models addressed, separately by country, the relationship among worry, protection, and post-traumatic growth with MS disability, after covariate adjustment. The Italian sample (n = 292) was younger and less disabled than the US group (n = 416). After covariate adjustment, all three pandemic-related variables were associated with MS disability outcomes in the US sample, but only worry and post-traumatic growth were associated in the Italian sample. Worse cognitive and depression symptoms were associated with worry, and lesser mobility disability was associated with endorsed growth in both countries. More disability variables were associated with worry and growth in the Italian sample. The pandemic's negative aspects were associated with worse disability in both countries, and reported post-traumatic growth was associated with lesser disability. These findings may suggest directions for clinical intervention. [ABSTRACT FROM AUTHOR]

• Lymphopenia is reported in 20.7% of RRMS patients taking Ocrelizumab. • Among T cells, the treatment predominantly impacts CD8 cells. • CD8 T cell decrease is more pronounced in patients with lymphopenia. In the phase III, OPERA I and OPERA II, clinical trial lymphopenia was reported in 20.7% of relapsing–remitting multiple sclerosis (RRMS) patients taking Ocrelizumab (OCR). The objective of this study was to investigate the effect of OCR on lymphocyte subtypes in MS patients with and without lymphopenia. Retrospective study comparing lymphocyte subtypes in OCR-treated MS patients with low (G1) and normal (G2) absolute lymphocyte count (ALC) at the six-month follow-up (cut-off: 1000 × 106/L). Mann Whitney U test was used to compare ALC, CD19, CD4 T, CD8 T and NK cell counts at baseline and at the six-month follow up between the two groups. A linear mixed model was applied to compare changes in ALC, and subset counts and proportions between patients with and without lymphopenia. We performed the same analyses in a subpopulation of naïve to treatment patients to exclude the possible influence of the previous disease modifying therapy (DMT) in the different kinetics observed between the two groups. : One hundred sixty-seven patients were included (G1, n = 34; G2, n = 133). At the six-month follow-up, compared with baseline, in the whole population we observed a significant reduction in ALC (p <0.0001), CD19 (p <0.0001) and CD8 T (p <0.0288) lymphocytes. We also found and increase in CD4/CD8 ratio after six months of treatment (p = 0.0098). G1 showed a lower ALC than G2 at baseline. At six months, mean ALC was 896.41 ± 156.25 × 106/L in G1 and 1909.9 ± 629.07 × 106/L in G2. CD4 and CD8 T cell mean counts were lower (p < 0.0001) in G1 than G2. At the linear mixed model analysis, we found a more pronounced increase in CD8 T percentage in G2 than G1 (p = 0.008). In the naïve to treatment group fifty patients were included. CD4 and CD8 T cell mean counts at six months were lower (p = 0.0074 and p = 0.0032, respectively) in G1 than G2. At the linear mixed model analysis, we found a more pronounced decrease of CD8 T cell count in G1 than G2 (p = 0.0103). Furthermore, we found an increase in CD8 T percentage in G2 whereas a profound decrease of CD8 T percentage was observed in G1 (p = 0.0052). After adjusting for confounders, significantly positive correlations were noted between ALC and both CD4 and CD8 T cell counts. Negative correlation was observed between ALC and CD4/CD8 ratio driven by low CD8 T cell counts. OCR decreases ALC. Among T cells, the treatment predominantly impacts CD8 cells. However, CD8 T cell decrease was more pronounced in patients with lymphopenia. Further studies are needed to establish the relationship between the effect of OCR on ALC and CD8 T cells and its potential implication in the early clinical response and risk for viral infections. [ABSTRACT FROM AUTHOR]

• Patient's age is the most important factor in DMTs choice • Choice of oral drugs vs self-injectables ones is driven by unfavorable prognostic factors • Natalizumab preferred in early stage of severe disease and in younger patients The approval of an increasing number of disease modifying drugs for the treatment of Multiple Sclerosis (MS) creates new challenges for patients and clinicians on the first treatment choice. The main aim of this study was to assess factors impacting first therapy choice in a large Italian MS cohort. Newly diagnosed relapsing-remitting (RR) MS patients (2010-2018) followed in 24 Italian MS centres were included in the study. We evaluated the association of baseline demographics, clinical and MRI characteristics to the first treatment choice by logistic regression models applied to pre-defined binary alternatives: dimethyl fumarate vs injectables (interferon and glatiramer acetate), teriflunomide vs injectables, fingolimod vs dimethyl fumarate and fingolimod vs natalizumab. We enrolled 3025 patients in the period between January 2010 and June 2018. Relapses in the previous year (OR = 2.75; p = 0.001), presence of spinal cord lesions (OR = 1.80; p = 0.002) and higher number (>9) of T2 lesions on the baseline brain MRI scan (OR = 1.65; p = 0.022) were the factors associated to dimethyl fumarate choice as first therapy vs an injectable drug. Older age (OR = 1.06; p < 0.001), male sex (OR = 2.29; p = 0.001) and higher EDSS (OR = 1.36; p < 0.001) were the factors associated with the choice of teriflunomide vs injectables. In more recent years, dimethyl fumarate (OR = 3.23; p < 0.001) and teriflunomide (OR = 2.53; p < 0.001) were chosen more frequently than injectables therapies. The main determinant for the choice of fingolimod as compared with dimethyl fumarate was a higher EDSS (OR = 1.56; p = 0.001), while there was a weak association with a longer disease duration (p = 0.068) and a longer time from onset to diagnosis (p = 0.085). Compared to fingolimod, natalizumab was preferred in patients with a younger age (OR = 0.95; p = 0.003) and higher EDSS (OR = 1.45; p = 0.007) and a shorter disease duration (OR = 0.52; p = 0.076). Many factors guided therapeutic decision for our Italian cohort of MS patients; they are mainly related to MS disease activity, baseline EDSS, disease duration and age. [ABSTRACT FROM AUTHOR]