Search

Genome-wide association studies identified over 200 risk loci for multiple sclerosis (MS) focusing on common variants, which account for about 50% of disease heritability. The goal of this study was to investigate whether low-frequency and rare functional variants, located in MS-established associated loci, may contribute to disease risk in a relatively homogeneous population, testing their cumulative effect (burden) with gene-wise tests. We sequenced 98 genes in 588 Italian patients with MS and 408 matched healthy controls (HCs). Variants were selected using different filtering criteria based on allelic frequency and in silico functional impacts. Genes showing a significant burden (n = 17) were sequenced in an independent cohort of 504 MS and 504 HC. The highest signal in both cohorts was observed for the disruptive variants (stop-gain, stop-loss, or splicing variants) located in EFCAB13, a gene coding for a protein of an unknown function (p < 10–4). Among these variants, the minor allele of a stop-gain variant showed a significantly higher frequency in MS versus HC in both sequenced cohorts (p = 0.0093 and p = 0.025), confirmed by a meta-analysis on a third independent cohort of 1298 MS and 1430 HC (p = 0.001) assayed with an SNP array. Real-time PCR on 14 heterozygous individuals for this variant did not evidence the presence of the stop-gain allele, suggesting a transcript degradation by non-sense mediated decay, supported by the evidence that the carriers of the stop-gain variant had a lower expression of this gene (p = 0.0184). In conclusion, we identified a novel low-frequency functional variant associated with MS susceptibility, suggesting the possible role of rare/low-frequency variants in MS as reported for other complex diseases.

BACKGROUND:Depression occurs in about 50% of patients with multiple sclerosis. The aims of this study was to investigate the prevalence of depressive symptoms in a multicenter MS population using the Beck Depression Inventory II (BDI II) and to identify possible correlations between the BDI II score and demographic and clinical variables. METHODS:Data were collected in a multi-center, cross-sectional study over a period of six months in six MS centers in Italy using BDI II. RESULTS:1,011 MS patients participated in the study. 676 subjects were female, with a mean age of 34 years (SD 10.8), mean EDSS of 3.3 (0-8.5) and mean disease duration of 10.3 years (range 1-50 years). 668 (%) subjects scored lower than 14 on the BDI II and 343 (33.9%) scored greater than 14 (14 cut-off score). For patients with BDI>14 multivariate analysis showed a significant difference between EDSS and disease course. BDI II scores for subjects with secondary progressive (SP) MS were significantly different from primary progressive (PP) patients (p < 0.001) but similar to relapsing-remitting (RR) patients. Considering subjects with moderate to severe depressive symptoms (BDI II score from 20-63), in relation to disease course, 11.7% (83/710) had RR MS, 40.7% (96/236) SP and 13.6% (6/44) PP. CONCLUSIONS:Using the BDI II, 30% of the current sample had depressive symptoms. BDI II score correlates with disability and disease course, particularly in subjects with SP MS. The BDI II scale can be a useful tool in clinical practice to screen depressive symptoms in people with MS.

We report on the use of an ultracold ensemble of ^87 Rb atoms trapped in a vertical lattice as a source for a quantum force sensor based on a Ramsey–Raman type interferometer. We reach spatial resolution in the low micrometer range in the vertical direction thanks to evaporative cooling down to ultracold temperatures in a crossed optical dipole trap. In this configuration, the coherence time of the atomic ensemble is degraded by inhomogeneous dephasing arising from atomic interactions. By weakening the confinement in the transverse direction only, we dilute the cloud and drastically reduce the strength of these interactions, without affecting the vertical resolution. This allows us to maintain an excellent relative sensitivity on the Bloch frequency, which is related to the local gravitational force, of 5 × 10 ^−6 at 1 s which integrates down to 8 × 10 ^−8 after one hour averaging time.

Background: The study aims to examine the age and disability levels at diagnosis in people with multiple sclerosis (PwMS), with and without autoimmune comorbidities (AC), and the effect of AC on NEDA-3 status and to characterize AC associated with MS, comparing also therapeutic approaches between MS patients with and without other AC., Methods: This population-based, multicentric study enrolled patients with relapsing-remitting MS (RRMS) with AC (AC group) or without AC (reference group) from 14 MS centers. Demographical, clinical features, treatment information, MRI activity, EDSS, and no evidence of disease activity (NEDA-3) status were assessed at T36 (enrollment time) and T0 (36 months prior)., Results: Eight hundred seventy-three RRMS patients were included; 215 (24.7%) presented with at least one AC. The AC group was characterized by higher proportion of female patients than reference group (p = 0.008). Patients with AC, compared to reference group, exhibited older age at MS onset and MS diagnosis, and higher EDSS score at diagnosis, at T0 (all p < 0.001), and T36 (p = 0.03). The proportion of patients reaching EDSS 4 was higher in reference group than AC group (p = 0.03). People in AC group were more often treated with glatiramer acetate, natalizumab, and rituximab, whereas PwMS from reference group with interferon-beta and fingolimod at T0 and T36. The risk of losing NEDA-3 was lower in AC group (OR = 0.61, 95% CI 0.43-0.86, p = 0.005)., Conclusions: AC are common in PwMS and can be related to a delay in onset, diagnosis and higher disability at MS presentation. However, the coexistence of AC is not associated with a worse prognosis., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Disability progression is a key milestone in the disease evolution of people with multiple sclerosis (PwMS). Prediction models of the probability of disability progression have not yet reached the level of trust needed to be adopted in the clinic. A common benchmark to assess model development in multiple sclerosis is also currently lacking., Methods: Data of adult PwMS with a follow-up of at least three years from 146 MS centers, spread over 40 countries and collected by the MSBase consortium was used. With basic inclusion criteria for quality requirements, it represents a total of 15, 240 PwMS. External validation was performed and repeated five times to assess the significance of the results. Transparent Reporting for Individual Prognosis Or Diagnosis (TRIPOD) guidelines were followed. Confirmed disability progression after two years was predicted, with a confirmation window of six months. Only routinely collected variables were used such as the expanded disability status scale, treatment, relapse information, and MS course. To learn the probability of disability progression, state-of-the-art machine learning models were investigated. The discrimination performance of the models is evaluated with the area under the receiver operator curve (ROC-AUC) and under the precision recall curve (AUC-PR), and their calibration via the Brier score and the expected calibration error. All our preprocessing and model code are available at https://gitlab.com/edebrouwer/ms&#95;benchmark, making this task an ideal benchmark for predicting disability progression in MS., Findings: Machine learning models achieved a ROC-AUC of 0⋅71 ± 0⋅01, an AUC-PR of 0⋅26 ± 0⋅02, a Brier score of 0⋅1 ± 0⋅01 and an expected calibration error of 0⋅07 ± 0⋅04. The history of disability progression was identified as being more predictive for future disability progression than the treatment or relapses history., Conclusions: Good discrimination and calibration performance on an external validation set is achieved, using only routinely collected variables. This suggests machine-learning models can reliably inform clinicians about the future occurrence of progression and are mature for a clinical impact study., Competing Interests: The authors declare no competing non-financial interests but the following competing financial interests: - Dana Horakova received speaker honoraria and consulting fees from Biogen, Merck, Teva, Roche, Sanofi Genzyme, and Novartis, as well as support for research activities from Biogen and Czech Minsitry of Education [project Progres Q27/LF1]. - Francesco Patti received speaker honoraria and advisory board fees from Almirall, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and TEVA. He received research funding from Biogen, Merck, FISM (Fondazione Italiana Sclerosi Multipla), Reload Onlus Association and University of Catania. - Guillermo Izquierdo received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall and Teva. - Sara Eichau received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche and Teva. - Marc Girard received consulting fees from Teva Canada Innovation, Biogen, Novartis and Genzyme Sanofi; lecture payments from Teva Canada Innovation, Novartis and EMD. He has also received a research grant from Canadian Institutes of Health Research. - Alessandra Lugaresi has served as a Biogen, Bristol Myers Squibb, Merck Serono, Novartis, Roche, Sanofi/ Genzyme and Teva Advisory Board Member. She received congress and travel/accommodation expense compensations or speaker honoraria from Biogen, Merck, Mylan, Novartis, Roche, Sanofi/Genzyme, Teva and Fondazione Italiana Sclerosi Multipla (FISM). Her institutions received research grants from Novartis and Sanofi Genzyme. - Pierre Grammond has served in advisory boards for Novartis, EMD Serono, Roche, Biogen idec, Sanofi Genzyme, Pendopharm and has received grant support from Genzyme and Roche, has received research grants for his institution from Biogen idec, Sanofi Genzyme, EMD Serono. - Tomas Kalincik served on scientific advisory boards for BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. - Raed Alroughani received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. - Francois Grand’Maison received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi and ONO Pharmaceuticals. - Murat Terzi received travel grants from Novartis, Bayer-Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. - Jeannette Lechner-Scott travel compensation from Novartis, Biogen, Roche and Merck. Her institution receives the honoraria for talks and advisory board commitment as well as research grants from Biogen, Merck, Roche, TEVA and Novartis. - Samia J. Khoury received compensation for participation in the Novartis Maestro program. - Vincent van Pesch has received travel grants from Merck, Biogen, Sanofi, Bristol Myers Squibb, Almirall and Roche; his institution receives honoraria for consultancy and lectures and research grants from Roche, Biogen, Sanofi, Merck, Bristol Myers Squibb, Janssen, Almirall and Novartis Pharma. - Radek Ampapa received conference travel support from Novartis, Teva, Biogen, Bayer and Merck and has participated in a clinical trials by Biogen, Novartis, Teva and Actelion. - Daniele Spitaleri received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva and Merck. - Claudio Solaro served on scientific advisory boards for Merck, Genzyme, Almirall, and Biogen; received honoraria and travel grants from Sanofi Aventis, Novartis, Biogen, Merck, Genzyme and Teva. - Davide Maimone served on scientific advisory boards for Bayer, Biogen, Merck, Sanofi-Genzyme, Novartis, Roche, and Almirall; received honoraria and travel grants from Sanofi Genzyme, Novartis, Biogen, Merck, and Roche. - Gerardo Iuliano (retired - no PI successor but has approved ongoing use of data) had travel/accommodations/meeting expenses funded by Bayer Schering, Biogen, Merck, Novartis, Sanofi Aventis, and Teva. - Bart Van Wijmeersch received research and travel grants, honoraria for MS-Expert advisor and Speaker fees from Bayer-Schering, Biogen, Sanofi Genzyme, Merck, Novartis, Roche and Teva. - Tamara Castillo Triviño received speaking/consulting fees and/or travel funding from Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. - Jose Luis Sanchez-Menoyo accepted travel compensation from Novartis, Merck and Biogen, speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva and has participated in clinical trials by Biogen, Merck and Roche - Guy Laureys received travel and/or consultancy compensation from Sanofi-Genzyme, Roche, Teva, Merck, Novartis, Celgene, Biogen. - Anneke van der Walt served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck and Roche She has received speaker’s honoraria and travel support from Novartis, Roche, and Merck. She receives grant support from the National Health and Medical Research Council of Australia and MS Research Australia. - Jiwon Oh has received research funding from the MS Society of Canada, National MS Society, Brain Canada, Biogen, Roche, EMD Serono (an affiliate of Merck KGaA); and personal compensation for consulting or speaking from Alexion, Biogen, Celgene (BMS), EMD Serono (an affiliate of Merck KGaA), Novartis, Roche, and Sanofi-Genzyme. - Ayse Altintas received speaker honoraria from Merck, Alexion,; received travel and registration grants from Merck, Biogen - Gen Pharma, Roche, Sanofi-Genzyme. - Yara Fragoso received honoraria as a consultant on scientific advisory boards by Novartis, Teva, Roche and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva, Roche and Merck. - Tunde Csepany received speaker honoraria/ conference travel support from Bayer Schering, Biogen, Merck, Novartis, Roche, Sanofi-Aventis and Teva. - Suzanne Hodgkinson received honoraria and consulting fees from Novartis, Bayer Schering and Sanofi, and travel grants from Novartis, Biogen Idec and Bayer Schering. - Norma Deri received funding from Bayer, Merck, Biogen, Genzyme and Novartis. - Bruce Taylor received funding for travel and speaker honoraria from Bayer Schering Pharma, CSL Australia, Biogen and Novartis, and has served on advisory boards for Biogen, Novartis, Roche and CSL Australia. - Fraser Moore participated in clinical trials sponsored by EMD Serono and Novartis. - Orla Gray received honoraria as consultant on scientific advisory boards for Genzyme, Biogen, Merck, Roche and Novartis; has received travel grants from Biogen, Merck, Roche and Novartis; has participated in clinical trials by Biogen and Merck. - Csilla Rozsa received speaker honoraria from Bayer Schering, Novartis and Biogen, congress and travel expense compensations from Biogen, Teva, Merck and Bayer Schering. - Allan Kermode received speaker honoraria and scientific advisory board fees from Bayer, BioCSL, Biogen, Genzyme, Innate Immunotherapeutics, Merck, Novartis, Sanofi, Sanofi-Aventis, and Teva. - Magdolna Simo received speaker honoraria from Novartis, Biogen, Bayer Schering; congress/travel compensation from Teva, Biogen, Merck, Bayer Schering. - Todd Hardy has received speaking fees or received honoraria for serving on advisory boards for Biogen, Merck, Teva, Novartis, Roche, Bristol-Myers Squibb and Sanofi-Genzyme, is Co-Editor of Advances in Clinical Neurosciences and Rehabilitation, and serves on the editorial board of Journal of Neuroimmunology and Frontiers in Neurology. - Nikolaos Grigoriadis received honoraria, consultancy/lecture fees, travel support and research grants from Biogen Idec, Biologix, Novartis, TEVA, Bayer, Merck Serono, Genesis Pharma, Sanofi – Genzyme, ROCHE, Cellgene, ELPEN and research grants from Hellenic Ministry of Development., (Copyright: © 2024 De Brouwer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Treatment options for secondary progressive MS (SPMS) are limited, especially considering that the new drugs recently approved are licensed for actively relapsing patients. We aimed to compare the disability progression in a real-world cohort of SPMS patients treated with natalizumab (NTZ) or interferon beta-1b (IFNb-1b). This multicenter retrospective enrolled patients with a diagnosis of SPMS according to 2014 Lublin criteria, who received NTZ or IFNb-1b for at least 48 months between the 1st June 2012 and the 15th May 2018 ​at 33 Italian MS centers contributing to the Italian MS Registry NTZ or IFNb-1b. Confirmed Expanded Disability Status Scale worsening (CEW) and progression independent of relapse (PIRA) were evaluated. In order to correct for non-randomization, a propensity score matching of the groups was performed. Out of 5206 MS patients identified at the time of data extraction, 421 SPMS patients treated with NTZ (224 [53.2%] females, mean age 45.3 ​± ​25.4 years) and 353 with IFNb-1b (133 [37.8%] females, mean age 48.5 ​± ​19.8 years) were enrolled. After applying the matching procedure, 102 patients were retained in the NTZ group and 98 in the IFNb-2b group. The proportion of patients who reached the 48-month 1-point CEW was significantly higher in IFNb-1b compared to NTZ group (58.2% versus 30.4%, p ​= ​0.01). The proportion of patients who developed PIRA at 48 months were significantly higher in IFNb-1b compared to NTZ (72.4% versus 40.2%, p ​= ​0.01). EDSS before treatment initiation and SPMS duration were risk factors for disability progression in terms of PIRA (HR 2.54, 25%CI 1.67-5.7; p ​= ​0.006 and HR 2.04, 25%CI 1.22-3.35; p ​= ​0.01, respectively). Patients treated with IFNb-1b were 1.64 times more to likely to develop PIRA (HR 1.64, 25%CI 1.04-4.87; p ​= ​0.001). Treatment with NTZ in SPMS patients showed more favorable disability outcomes compared to IFNb-1b with beneficial effects over 48 months., Competing Interests: Declaration of competing interest CGC has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. UA reports no disclosures relevant to the manuscript. MPA has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. RB reports no disclosures relevant to the manuscript. AB has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. SB served as speaker and/or advisory board fee, and/or travel grant from Novartis, Teva, Sanofi-Genzyme, Roche, Biogen-Idec, Merck-Serono. VBM received fees for consultancies or public speaking from Merck, Novartis, Biogen, Roche, Genzyme and Biogen. PC has served as an advisory board member for Almirall, Biogen, Merck-Serono, Sanofi-Genzyme, Roche, Teva; she has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. EC reports no disclosures relevant to the manuscript. AC reports no disclosures relevant to the manuscript. SC has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. GDL reports no disclosures relevant to the manuscript. ADS reports no disclosures relevant to the manuscript. MF is Editor-in-Chief of the Journal of Neurology; received compensation for consulting services and/or speaking activities from Biogen Idec, Merck-Serono, Novartis, Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Teva Pharmaceutical Industries, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA(Fondazione Italiana di Ricerca per la SLA). AG reports no disclosures relevant to the manuscript. CG reports no disclosures relevant to the manuscript. FG received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. GL reports no disclosures relevant to the manuscript. DM reports no disclosures relevant to the manuscript. GTM has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. GAM has served as an advisory board member and received speaker honoraria, congress, travel and accommodation expense compensations from Merck, Teva, Mylan, Bayer, Novartis, Roche, Almirall, Biogen and Sanofi Genzyme. LM reports no disclosures relevant to the manuscript. DP has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. IP reports no disclosures relevant to the manuscript. PR reports no disclosures relevant to the manuscript. MR received travel grants and fees for consulting and public speaking from Almirall, Biogen, Genzyme-Sanofi, Merck Serono, Mylan and Novartis. GS has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. CS has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. RT reports no disclosures relevant to the manuscript. ST reports no disclosures relevant to the manuscript. MT has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. MV reports no disclosures relevant to the manuscript. VL reports no disclosures relevant to the manuscript. MZ has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. FP has received honoraria for speaking activities by Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA; he also served as advisory board member the following companies: Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA; he was also funded by Pfizer and FISM for epidemiological studies; he received grants for congress participation from Almirall, Bayer Shering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA., (Copyright © 2024. Published by Elsevier Inc.)

Aim: To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES-RRMS)., Methods: Real-world data from the MSBase Registry were obtained for patients with RES-RRMS who were previously either naive to disease-modifying therapies or had been treated with interferon-based therapies, glatiramer acetate, dimethyl fumarate, or teriflunomide (collectively known as BRACETD). Matched cohorts were selected by 3-way multinomial propensity score matching, and the annualized relapse rate (ARR) and 6-month-confirmed disability worsening (CDW6M) and improvement (CDI6M) were compared between treatment groups. Comparative effectiveness results were used in a cost-effectiveness model comparing natalizumab and fingolimod, using an established Markov structure over a lifetime horizon with health states based on the Expanded Disability Status Scale. Additional model data sources included the UK MS Survey 2015, published literature, and publicly available sources., Results: In the comparative effectiveness analysis, we found a significantly lower ARR for patients starting natalizumab compared with fingolimod (rate ratio [RR] = 0.65; 95% confidence interval [CI], 0.57-0.73) or BRACETD (RR = 0.46; 95% CI, 0.42-0.53). Similarly, CDI6M was higher for patients starting natalizumab compared with fingolimod (hazard ratio [HR] = 1.25; 95% CI, 1.01-1.55) and BRACETD (HR = 1.46; 95% CI, 1.16-1.85). In patients starting fingolimod, we found a lower ARR (RR = 0.72; 95% CI, 0.65-0.80) compared with starting BRACETD, but no difference in CDI6M (HR = 1.17; 95% CI, 0.91-1.50). Differences in CDW6M were not found between the treatment groups. In the base-case cost-effectiveness analysis, natalizumab dominated fingolimod (0.302 higher quality-adjusted life-years [QALYs] and £17,141 lower predicted lifetime costs). Similar cost-effectiveness results were observed across sensitivity analyses., Conclusions: This MSBase Registry analysis suggests that natalizumab improves clinical outcomes when compared with fingolimod, which translates to higher QALYs and lower costs in UK patients with RES-RRMS.

Limited longitudinal studies have been conducted on gait impairment progression overtime in non-disabled people with multiple sclerosis (PwMS). Therefore, a deeper understanding of gait changes with the progression of the disease is essential. The objective of the present study was to describe changes in gait quality in PwMS with a disease duration ≤ 5 years, and to verify whether a change in gait quality is associated with a change in disability and perception of gait deterioration. We conducted a multicenter prospective cohort study. Fifty-six subjects were assessed at baseline (age: 38.2 ± 10.7 years, Expanded Disability Status Scale (EDSS): 1.5 ± 0.7 points) and after 2 years, participants performed the six-minute walk test (6MWT) wearing inertial sensors. Quality of gait (regularity, symmetry, and instability), disability (EDSS), and walking perception (multiple sclerosis walking scale-12, MSWS-12) were collected. We found no differences on EDSS, 6MWT, and MSWS-12 between baseline and follow-up. A statistically significant correlation between increased EDSS scores and increased gait instability was found in the antero-posterior (AP) direction (r = 0.34, p = 0.01). Seventeen subjects (30%) deteriorated (increase of at least 0.5 point at EDSS) over 2 years. A multivariate analysis on deteriorated PwMS showed that changes in gait instability medio-lateral (ML) and stride regularity, and changes in ML gait symmetry were significantly associated with changes in EDSS (F = 7.80 (3,13), p = 0.003, R 2 = 0.56). Moreover, gait changes were associated with a decrease in PwMS perception on stability ( p < 0.05). Instrumented assessment can detect subtle changes in gait stability, regularity, and symmetry not revealed during EDSS neurological assessment. Moreover, instrumented changes in gait quality impact on subjects' perception of gait during activities of daily living.

Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients was 39 (95% confidence interval: 37 to 43) years. Higher latitude [median hazard ratio = 1.21, 95% credible interval (1.16, 1.26)], higher national multiple sclerosis prevalence [1.07 (1.03, 1.11)], male sex [1.30 (1.22, 1.39)], older age at onset [1.35 (1.30, 1.39)], higher disability [2.40 (2.34, 2.47)] and frequent relapses [1.18 (1.15, 1.21)] at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis [0.76 (0.73, 0.79)] and reduced the effect of latitude [interaction: 0.95 (0.92, 0.99)]. At the country-level, patients in Oman, Tunisia, Iran and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions. Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate efficacy immunotherapy can mitigate some of this geographically co-determined risk., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The balance of people with multiple sclerosis (PwMS) is commonly assessed during neurological examinations through clinical Romberg and tandem gait tests that are often not sensitive enough to unravel subtle deficits in early-stage PwMS. Inertial sensors (IMUs) could overcome this drawback. Nevertheless, IMUs are not yet fully integrated into clinical practice due to issues including the difficulty to understand/interpret the big number of parameters provided and the lack of cut-off values to identify possible abnormalities. In an attempt to overcome these limitations, an instrumented modified Romberg test (ImRomberg: standing on foam with eyes closed while wearing an IMU on the trunk) was administered to 81 early-stage PwMS and 38 healthy subjects (HS). To facilitate clinical interpretation, 21 IMU-based parameters were computed and reduced through principal component analysis into two components, sway complexity and sway intensity, descriptive of independent aspects of balance, presenting a clear clinical meaning and significant correlations with at least one clinical scale. Compared to HS, early-stage PwMS showed a 228% reduction in sway complexity and a 63% increase in sway intensity, indicating, respectively, a less automatic (more conscious) balance control and larger and faster trunk movements during upright posture. Cut-off values were derived to identify the presence of balance abnormalities and if these abnormalities are clinically meaningful. By applying these thresholds and integrating the ImRomberg test with the clinical tandem gait test, balance impairments were identified in 58% of PwMS versus the 17% detected by traditional Romberg and tandem gait tests. The higher sensitivity of the proposed approach would allow for the direct identification of early-stage PwMS who could benefit from preventive rehabilitation interventions aimed at slowing MS-related functional decline during neurological examinations and with minimal modifications to the tests commonly performed.

Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease resulting in motor impairments associated with muscle weakness and lack of movement coordination. The goal of this work was to quantify upper limb motor deficits in asymptomatic MS subjects with a robot-based assessment including performance and muscle synergies analysis. A total of 7 subjects (MS: 3 M-4 F; 42 ± 10 years) with clinically definite MS according to McDonald criteria, but with no clinical disability, and 7 age- and sex-matched subjects without a history of neurological disorders participated in the study. All subjects controlled a cursor on the computer screen by moving their hand or applying forces in 8 coplanar directions at their self-selected speed. They grasped the handle of a robotic planar manipulandum that generated four different environments: null, assistive or resistive forces, and rigid constraint. Simultaneously, the activity of 15 upper body muscles was recorded. Asymptomatic MS subjects generated less smooth and less accurate cursor trajectories than control subjects in controlling a force profile, while the end-point error was significantly different also in the other environments. The EMG analysis revealed different muscle activation patterns in MS subjects when exerting isometric forces or when moving in presence of external forces generated by a robot. While the two populations had the same number and similar structure of muscle synergies, they had different activation profiles. These results suggested that a task requiring to control forces against a rigid environment allows better than movement tasks to detect early sensory-motor signs related to the onset of symptoms of multiple sclerosis and to differentiate between stages of the disease., Competing Interests: MCo was employed by confinis ag. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pierella, Pellegrino, Muller, Inglese, Solaro, Coscia and Casadio.)

Background: Heat sensitivity occurs in a high percentage of people with multiple sclerosis (PwMS), in response to environmental or exercise-induced increase in body temperature. However, the kinetic and magnitude of adaptation of the internal load and of the core body temperature (CBT) to a submaximal continuous exercise has been poorly addressed in PwMS; this may be relevant for the brief exercise bouts usually occurring in normal daily life. The aim of this work was to evaluate whether multiple sclerosis influences the acute adaptation of the internal load, the CBT and the perceptual load in response to a constant submaximal work step., Methods: CBT has been continuously monitored (0.5 Hz) by a validated wearable heat-flux sensor and electrocardiography was recorded (250 Hz) by a wearable device during a standard 6-minute walk test (6MWT) in 14 PwMS (EDSS, 4.7 ± 1.2; disease duration: 13.0 ± 10.2 years; m ± SD) and 14 age, sex and BMI-matched healthy subjects (HS). The rate of perceived exertion (RPE) of the lower limbs was assessed during the 6MWT by the Borg scale (6-20)., Results: As expected, PwMS walked a significantly shorter distance (361 ± 98 m) than the HS group (613 ± 62 m, p<0.001 vs PwMS). However, the kinetics of adaptation of CBT and the magnitude of CBT change from baseline did not differ between groups. Similarly, heart rate (HR) kinetics and HR change from baseline were comparable between groups during the 6MWT. Finally, lower limbs RPE gradually increased during the exercise test, but without significant differences between groups., Conclusion: The internal load, the metabolic heat production, and the perceptive load due to a standard submaximal walking exercise seems to be preserved in PwMS, suggesting a comparable acute heat production and dissipation during exercise. Therefore, it is unlikely that the different distance achieved during the 6MWT may be caused by altered thermoregulatory responses to exercise. Rather, this appears to be a consequence of the known increased energy cost of locomotion in PwMS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gervasoni, Bertoni, Anastasi, Solaro, Di Giovanni, Grange, Gunga, Rovaris, Cattaneo, Maggioni and Merati.)

Objective: COVID-19 has been associated with neurological complications such as Guillain-Barre syndrome (GBS). Several cases have been reported but without functional outcome data after intensive rehabilitation and medium-term follow-up., Methods: In this observational study, patients were admitted in 2019 and 2020 to inpatient rehabilitation for GBS and were examined using the Barthel index, GBS-Disability Scale, and Medical Research Scale-sum score at admission, discharge, and at least 6 months after onset of symptoms. All the participants received personalized, goal-oriented inpatient rehabilitative treatment for the recovery of self-sufficiency in everyday life., Results: Eleven people with GBS-3 cases related to COVID-19-were admitted in 2019 and 2020 to inpatient rehabilitation. Eight patients with GBS not related to COVID-19 experienced a high complication rate during inpatient rehabilitation, with 2 deaths due to sepsis. In this cohort, a higher prevalence than expected of acute motor axonal neuropathy was also detected. The COVID-19-related GBS group did not have any complications. After a mean of 10.11 months (SD = 4.46 months), 55.55% of patients regained autonomous walking., Conclusion: COVID-19-related GBS appeared to have a better clinical outcome than GBS that was not COVID-19 related. A higher than usual prevalence of acute motor axonal neuropathy form was encountered. More follow-up studies are needed to understand whether the recovery of GBS related to COVID-19 might be different from that of GBS unrelated to COVID-19., Impact: No data are currently available on the follow-up of GBS in the COVID-19 era and on the functional outcome of those patients. This study provides important information indicating that GBS related to COVID-19 might have a better clinical outcome than GBS unrelated to COVID-19., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Turning the head while walking (an action often required during daily living) is particularly challenging to maintain balance. It can therefore potentially reveal subtle impairments in early-stage people with multiple sclerosis who still show normal locomotion (NW-PwMS). This would help in identifying those subjects who can benefit from early preventive exercise aimed at slowing the MS-related functional decline., Objectives: To analyze if the assessment of walking with horizontal head turns (WHHT) through inertial sensors can discriminate between healthy subjects (HS) and NW-PwMS and between NW-PwMS subgroups. To assess if the discriminant ability of the instrumented WHHT is higher compared to clinical scores. To assess the concurrent validity of the sensor-based metrics., Methods: In this multicenter study, 40 HS and 59 NW-PwMS [Expanded Disability Status Scale (EDSS) ≤ 2.5, disease duration ≤ 5 years] were tested. Participants executed Item-6 of the Fullerton Advanced Balance scale-short (FAB-s) wearing three inertial sensors on the trunk and ankles. The item required to horizontally turn the head at a beat of the metronome (100 bpm) while walking. Signals of the sensors were processed to compute spatiotemporal, regularity, symmetry, dynamic stability, and trunk sway metrics descriptive of WHHT., Results: Mediolateral regularity, anteroposterior symmetry, and mediolateral stability were reduced in NW-PwMS vs. HS ( p ≤ 0.001), and showed moderate discriminant ability (area under the receiver operator characteristic curve [AUC]: 0.71-0.73). AP symmetry and ML stability were reduced ( p ≤ 0.026) in EDSS: 2-2.5 vs. EDSS: 0-1.5 subgroup (AUC: 0.69-0.70). The number of NW-PwMS showing at least one abnormal instrumented metric (68%) was larger ( p ≤ 0.002) than the number of participants showing abnormal FAB-s-Item6 (32%) and FAB-s clinical scores (39%). EDSS: 2-2.5 subgroup included more individuals showing abnormal instrumented metrics (86%) compared to EDSS: 0-1.5 subgroup (57%). The instrumented metrics significantly correlated with FAB-s-Item6 and FAB-s scores (|Spearman's r s | ≥ 0.37, p < 0.001), thus demonstrating their concurrent validity., Conclusion: The instrumented assessment of WHHT provided valid objective metrics that discriminated, with higher sensitivity than clinical scores, between HS and NW-PwMS and between EDSS subgroups. The method is a promising tool to complement clinical evaluation, and reveal subclinical impairments in persons who can benefit from early preventive rehabilitative interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Carpinella, Gervasoni, Anastasi, Di Giovanni, Tacchino, Brichetto, Confalonieri, Solaro, Rovaris, Ferrarin and Cattaneo.)

Background: Motor and cognitive disorders appear early in the course of multiple sclerosis (MS) and develop gradually over time., Objective: To study the frequency and pattern of subtle functional disorders in people with MS (PwMS) with no overt signs of disability in an early phase of the disease and their association with walking impairments in daily activities., Methods: In this cross-sectional study, we recruited PwMS with an Expanded Disability Status Scale (EDSS) score≤2.5 and disease duration≤5years. Participants were assessed with functional scales rating walking endurance (6-Min Walk Test), perceived walking ability (Twelve-item Multiple Sclerosis Walking Scale), balance (Fullerton Advanced Balance scale&#95;short), manual dexterity (Nine Hole Peg Test), fatigue (Fatigue Severity Scale), and cognitive impairments (Brief International Cognitive Assessment)., Results: About 90% of the 82 PwMS (mean [SD] EDSS score 1.5 [0.7] and disease duration 2.2 [1.7] years) showed endurance values below the expected score; almost 30% showed impairment, and for 57%, perceived walking ability score was abnormal. Balance was impaired in 48% of participants, as was manual dexterity (29%) and fatigue (24%), but only a few showed cognitive impairments. Only 11% of PwMS had no abnormal score on the scales used in the assessment. As compared with EDSS score 0 to 1.5, with EDSS score 2 to 2.5, performance was worse for endurance (difference±61.0m, P=0.016), perceived walking ability (-11 points, P=0.002), balance (+1.9 points, P=0.005), manual dexterity (-2.8 s, P=0.004), and fatigue (-1.3 points, P=0.013). Factors that predicted perceived walking ability were balance (B=-1.37, P<0.001) and fatigue (B=5.11, P<0.001) rather than endurance (B=-0.01, P=048)., Conclusion: Even PwMS with no clinical disability and classified as having "no problem walking" present walking and other functional deficits when assessed with specific functional tests. The addition of specific tools could better identify subtle motor and cognitive deficits. Finally, the assessment of balance disorders and fatigue is important to understand individuals' perceived walking impairments in daily activities., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Introduction: Multiple sclerosis (MS) is the most common cause of progressive neurological disability in young adults. The use of advance care planning (ACP) for people with progressive MS (pwPMS) remains limited. The ConCure-SM project aims to assess the effectiveness of a structured ACP intervention for pwPMS. The intervention consists of a training programme on ACP for healthcare professionals caring for pwPMS, and a booklet to be used during the ACP conversation. Herein, we describe the first two project phases., Methods: In phase 1 we translated and adapted, to the Italian legislation and MS context, the ACP booklet of the National ACP Programme for New Zealand. Acceptability, comprehensibility and usefulness of the booklet were assessed via 13 personal cognitive interviews with pwPMS and significant others (SOs), and one health professional focus group. Based on these findings, we will revise the booklet. In phase 2 we will conduct a single-arm pilot/feasibility trial with nested qualitative study. Participants will be 40 pwPMS, their SOs, health professionals from six MS and rehabilitation centres in Italy. In the 6 months following the ACP conversation, we will assess completion of an advance care plan document (primary outcome), as well as safety of the intervention. Secondary outcomes will be a range of measures to capture the full process of ACP; patient-carer congruence in treatment preferences; quality of patient-clinician communication and caregiver burden. A qualitative process evaluation will help understand the factors likely to influence future implementation and scalability of the intervention., Ethics and Dissemination: The project is coleaded by a neurologist and a bioethicist. Phase 1 has received ethical approvals from each participating centre, while phase 2 will be submitted to the centres in May 2021. Findings from both phases will be disseminated widely through peer-reviewed publications, conferences and workshops., Trial Registration Number: ISRCTN48527663; Pre-results., Competing Interests: Competing interests: AL reports grants from Novartis, during the conduct of the study; personal fees from Biogen, Merck Serono, Mylan, Novartis, Roche, Sanofi/Genzyme, Teva and FISM. FP received personal compensation for serving on advisory board and/or speaking activities by Almirall, Bayer, Biogen, Bristol Meyers & Squibb, Merck, Novartis Roche, Sanofi and TEVA; he further received research grants by Biogen Italy, Biogen Global, Merck, University of Catania, FISM and Reload Onlus Patients Association. AS reports grants from FISM and European Academy of Neurology, during the conduct of the study; personal fees from Almirall and Merck Serono. This does not alter our adherence to BMJ Open policies on sharing data. All the other authors report no competing interests., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate prevalence of EMG patterns underlying hypertonia in multiple sclerosis (MS) and whether these patterns indicate different levels of spinal excitability., Methods: We investigated the EMG activity recorded from 108 hypertonic muscles of 59 consecutive MS patients. To investigate spastic dystonia (SD), we looked for the presence of EMG activity in muscles in a resting position. To investigate dynamic stretch reflex (DSR) and static stretch reflex (SSR), we looked for the presence of EMG activity in response to a manually performed passive stretch of the muscle., Results: DSR was evoked in 104 muscles. In 51 muscles, DSR was the sole EMG activity. This pattern corresponds to the classical notion of spasticity, and was predominant in extensors. In contrast, SSR was detected in 48 muscles - predominantly in flexors. SD was observed in 28 muscles, showing even distribution in flexor and extensor muscles. Only in the flexors, SSR was associated with a larger DSR compared to spasticity., Conclusions: These findings likely depend on the central effects of both flexor and extensor spindle afferents on the homonymous spinal motor neurons., Significance: Improving our capacity to assess spinal excitability in MS patients., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.)

Dominica, one of the most magmatically active islands of the Lesser Antilles through its four active volcanoes, is likely host under its central part, below Morne Trois Pitons-Micotrin, to a well-established transcrustal mush system. Pre-eruptive spatiotemporal magma dynamics are examined for five, explosive, pumiceous eruptions of this volcano in the last 24 kyrs through a combined Crystal System Analysis and intracrystalline Fe-Mg interdiffusion timescales modelling approaches. Before all eruptions, two magmatic environments of close compositions have interacted. These interactions began ~ 10-30 years prior to the four smaller of these eruptions, with more sustained mixing in the last decade, accelerated in the last 2 years. This contrasts with the largest pumiceous eruption, involving deeper magmas, with magma interaction starting over roughly a century but with various patterns. This suggests a possibility that increasing reactivation signals could be registered at the surface some years before future eruptions, having significant implications for volcanic risk mitigation.

Objective: We wanted to evaluate efficacy on inflammatory parameters of rituximab (RTX)-personalized reinfusion scheme using a memory B cell-based treatment regimen., Methods: This is a prospective, uncontrolled, open-label study including patients with MS treated with RTX in 2 Italian MS units. All patients were treated with RTX induction, followed by maintenance infusion at the dosage of 375 mg/m 2 , according to memory B cell repopulation (0.05% of peripheral-blood mononuclear cells [PBMCs] for the first 2 years, 0.1% of PBMC for the third year). MS activity was assessed as clinical or MRI activity., Results: One hundred two patients were included in the analysis. Mean follow-up was 2.40 years (range 0.57-7.15 years). The annualized relapse rate (ARR) was 0.67 in the year before RTX start and decreased to 0.01 in the 3 years after RTX initiation (global ARR). The proportion of patient with MS activity (i.e., relapse or MRI activity) was 63.16% in the year before RTX start and decreased to 8.7% (0-6 months), 1.3% (6-12 months), 0% (12-24 months), and 0% (24-36 months). Annualized RTX infusion rates were 1.67 (95% confidence interval [CI]: 1.43-1.94), 0.76 (95% CI: 0.58-0.98), and 0.78 (95% CI: 0.52-1.12) for the first 3 years after RTX initiation, respectively. Patients were reinfused with a mean infusion interval of 367 days (range 181-839 days)., Conclusion: The results of this study show that the memory B cell-based RTX reinfusion protocol is able to reduce the mean number of RTX reinfusions with persistent reduction of disease activity., Classification of Evidence: This study provides Class IV evidence that for patients with MS, a memory B cell-based RTX reinfusion protocol can reduce the mean number of RTX reinfusions with persistent reduction of disease activity., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Poor dynamic balance, such as poor walking stability, is a hallmark of multiple sclerosis. Instrumental measures of local dynamic stability (LDS, e.g. short-term Lyapunov's exponents, sLyEs) are genuine measures of walking stability and increasingly used as dynamic balance indicators. The current work aims to investigate if people with multiple sclerosis (PWMS) with no clinical evidence of gait impairment suffer poor LDS of gait. Eighty PWMS with minimal impairment (EDSS ≤2.5) and twenty controls completed the Six-Minute Walk Test (6MWT) at their maximum speed, wearing inertial sensors. sLyEs were calculated from trunk vertical, mediolateral and anteroposterior (sLyE AP ) acceleration. PWMS also completed a full clinical assessment including gait, balance and fatigue. Gait speed was lower in PWMS than controls (-15%), while sLyEs were larger in PWMS (+12%), even when adjusting for the different gait speed. High sLyE AP was associated with low gait speed, high impact of disease (including high fatigue) and poor balance, the three variables returned by a principal component analysis of the dataset of clinical measures. PWMS suffer poor LDS of gait, as indicated by large sLyEs. The association between high sLyE AP and poor balance supports the validity of sLyE AP as a dynamic balance measure. The inverse relationship between sLyE AP and gait speed is in line with the view that good balance is decisive for high gait speed. Finally, these findings are in line with the vicious circle linking poor balance and fatigue in PWMS, with fatigue worsening balance and poor balance leading to fatigue.

Background: The mechanisms underlying the therapeutic activity of interferon-β in multiple sclerosis are still not completely understood. In the present study, we evaluated the short and long-term effects of interferon-β treatment on different subsets of regulatory T cells in relapsing-remitting multiple sclerosis patients biologically responsive to treatment because of mixovirus resistance protein A inducibility., Methods: In this prospective longitudinal study, subsets of natural regulatory T cells (naïve, central memory and effector memory) and inducible regulatory T cells (Tr1), as well as in vitro-induced regulatory T cells (Tr1-like cells), were simultaneously quantified by flow cytometry in samples prepared from 148 therapy-naïve multiple sclerosis patients obtained before and after 6, 12, 18, and 24 months of interferon-β-1a treatment. mRNA for interleukin-10 and Tr1-related genes (CD18, CD49b, and CD46, together with Cyt-1 and Cyt-2 CD46-associated isoforms) were quantified in Tr1-like cells., Results: Despite profound inter-individual variations in the modulation of all regulatory T-cell subsets, the percentage of natural regulatory T cells increased after 6, 12, and 24 months of interferon-β treatment. This increase was characterized by the expansion of central and effector memory regulatory T-cell subsets. The percentage of Tr1 significantly enhanced at 12 months of therapy and continued to be high at the subsequent evaluation points. Patients experiencing relapses displayed a higher percentage of naïve regulatory T cells and a lower percentage of central memory regulatory T cells and of Tr1 before starting interferon-β therapy. In addition, an increase over time of central memory and of Tr1 was observed only in patients with stable disease. However, in vitro-induced Tr1-like cells, prepared from patients treated for 24 months, produced less amount of interleukin-10 mRNA compared with pre-treatment Tr1-like cells., Conclusion: Interferon-β induces the expansion of T regulatory subsets endowed with a high suppressive activity, especially in clinically stable patients. The overall concurrent modulation of natural and inducible regulatory T-cell subsets might explain the therapeutic effects of interferon-β in multiple sclerosis patients.

Behaviour is expected to be one of the most important factors driving urban living of bird species because it largely determines how animals interact with their environments. The contribution of different behavioural traits as facilitators of contemporary process of bird colonization of urban environments, however, is still unclear. Here we examined the differences in three behavioural traits: neophobia (avoidance of a new object) and solving success and solving latency of a problem solving test related to obtain food, in rural and urban living individuals of a common diurnal Neotropical raptor, the chimango caracara (Phalcoboenus chimango). Moreover, for solving success and solving latency behaviours, we tested the plasticity (i.e., habituation) in birds. Urban and rural chimangos showed similar neophobia of a new object. All chimangos showed an improvement in their output in problem-solving test as the five-day testing passed but urban chimangos showed higher solving capabilities than rural conspecifics as they were more successful in solving the problem test. More, urban birds shown lower solving latency than rural, as they were able to improve their test performance by opening doors in less time as the day passed; in rural birds this relation was not so abrupt. In addition, those individuals that opened more doors, opened these faster too. Lastly, both solving success and latency showed very low individual consistency (repeatability < 0.275). Our results provide evidence of plasticity in solving capabilities of chimango caracaras which reveal that a habituation process in these behavioural traits could be associated to establishment of birds in urban environments., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Multiple sclerosis is a chronic, autoimmune and neurodegenerative disease affecting multiple functional systems and resulting in motor impairments associated with muscle weakness and lack of movement coordination. We quantified upper limb motor deficits with a robot-based assessment including behavioral and muscle synergy analysis in 11 multiple sclerosis subjects with mild to moderate upper limb impairment (9 female; 50 ± 10 years) compared to 11 age- and gender- matched controls (9 female; 50 ± 9 years). All subjects performed planar reaching tasks by moving their upper limb or applying force while grasping the handle of a robotic manipulandum that generated four different environments: free space, assistive or resistive forces, and rigid constraint. We recorded the activity of 15 upper body muscles. Multiple sclerosis subjects generated irregular trajectories. While activities in isolated arm muscles appeared generally normal, shoulder muscle coordination with arm motions was impaired and there was a marked co-activation of the biceps and triceps in extension movements. Systematic differences in timing and organization of muscle synergies have also been observed. This study supports the definition of new biomarkers and rehabilitative treatments for improving upper limb motor coordination in multiple sclerosis.

Objective: To study the immunomodulatory effect of teriflunomide on innate and adaptive immune cell populations through a pilot, open-label, observational study in a cohort of patients with relapsing-remitting MS., Methods: Blood lymphocytes were isolated from 10 patients with MS before and after 3 or 12 months of treatment. Adaptive and innate immune cell subsets were analyzed by flow cytometry as follows: B cells (memory, regulatory, and mature subsets), T cells (effector and regulatory subsets), and natural killer (NK) cells (CD56 dim and CD56 bright subsets)., Results: Our results show that teriflunomide significantly reduces absolute counts of total CD19 + B cells and mature and regulatory B-cell subsets. T cells were affected to a lesser extent, with a trend in reduction of absolute counts for both T effector CD4 + cells (Th1, Th17 and Th1/17) and T regulatory CD8 + and CD4 + cells. Teriflunomide had no detectable effect on NK-cell numbers., Conclusions: In our small cohort, teriflunomide treatment affects mainly and significantly on B-cell numbers, while having a milder effect on T-cell numbers. Larger cohorts are necessary to confirm these findings and understand the effect of teriflunomide on the functionality of these cells.

Background: The approval of Sativex for the management of multiple sclerosis (MS) spasticity opened a new opportunity to many patients. In Italy, the healthcare payer can be fully reimbursed by the involved pharma company with the cost of treatment for patients not responding after a 4 week (28 days) trial period (Payment by Results, PbR), and 50% reimbursed with the cost of 6 weeks (42 days) treatment for other patients discontinuing (Cost Sharing, CS). The aim of our study was to describe the Sativex discontinuation profile from a large population of spasticity treated Italian MS patients., Methods: We collected data of patients from 30 MS centres across the country starting Sativex between January 2014 and February 2015. Data were collected from the mandatory Italian Medicines Agency (AIFA) web-registry. Predictors of treatment discontinuation were assessed using a multivariate Cox proportional regression analysis., Results: During the observation period 631 out of 1597 (39.5%) patients discontinued Sativex. The Kaplan-Meier estimates curve showed that 333 patients (20.8%) discontinued treatment at 4 weeks while 422 patients (26.4%) discontinued at 6 weeks. We found after adjusted modeling that a higher NRS score at T1 (adjHR 2.23, 95% 2.07-2.41, p<0.001) and a lower baseline NRS score (adjHR 0.51 95% CI 0.46-0.56, p<0.001) were predictive of treatment discontinuation., Conclusion: These data show that the first 6 weeks are useful in identifying those patients in which Sativex could be effective, thus avoiding the cost of longer term evaluation.

Objective. Gait impairment is commonly in people with multiple sclerosis (MS). The 12-item MS walking scale (MSWS-12) assesses patients' measurement of walking quality. The aim of this study was to cross-culturally adapt and validate the MSWS-12 for the Italian population with MS. Methods. Six MS out-patient clinics across Italy enrolled subjects between June 2013 and December 2013. Construct validity of MSWS-12 was determined by examining correlations with the Italian version of the EDSS, the timed 25-foot walk (T25FW), and the Fatigue Severity Scale (FSS). Results. 321 MS subjects were enrolled. Mean age was 47.55 years and mean disease duration was 13.8 years. Mean EDSS score was 4.46. 185 subjects had a relapsing-remitting course, 92 were secondary progressive, 43 were primary progressive, and 1 had a clinically isolated syndrome. The mean total score of the MSWS-12 was 49.6 (SD: 31) with values ranging between 0 and 100. Correlations between the MSWS-12 with age, disease duration, and disease course were found but not with gender. Values of the MSWS-12/IT were significantly related to EDSS (0.71), to the T25FW (0.65), and to the FSS (0.51). Conclusion. MSWS-12/IT has been adapted and validated, it is a reliable and reproducible scale for Italian patients with MS.

Background: Most of Multiple Sclerosis (MS) patients undergo disease modifying drug (DMD) therapy at childbearing age. The objective of this prospective, collaborative study, was to assess outcomes of pregnancies fathered by MS patients undergoing DMD., Methods: Structured interviews on pregnancies fathered by MS patients gathered in the Italian Pregnancy Dataset were collected; pregnancies were divided according to father exposure or unexposure to DMD at time of procreation. Treatment were compared with multivariable logistic and linear models., Results: Seventy-eight pregnancies fathered by MS patients were tracked. Forty-five patients were taking DMD at time of conception (39 beta-interferons, 6 glatiramer acetate), while 33 pregnancies were unexposed to DMD. Seventy-five pregnancies ended in live-births, 44 in the exposed and 31 in the unexposed group. No significant differences between the two groups were found in the risk of spontaneous abortion or malformations (p > 0.454), mean gestational age (p = 0.513), frequency of cesarean delivery (p = 0.644), birth weight (p = 0.821) and birth length (p = 0.649). In comparison with data of the Italian general population, the proportion of spontaneous abortion and caesarean delivery in exposed pregnancies fell within the estimates, while the proportion of pre-term delivery in the exposed group was higher than expected., Conclusions: Our data indicate no association between paternal DMD exposure at time of conception and risk of spontaneous abortion, adverse fetal outcomes and congenital malformations. Further studies clarifying the role of DMD fathers intake prior and during pregnancy are desirable, to supply guidelines for clinical practice.

Background: Optimal patient selection would improve the risk-benefit ratio of natalizumab treatment for relapsing-remitting multiple sclerosis (RR MS). Clinical features of subjects responding to natalizumab have not been univocally recognized., Methods: Longitudinal data on RR MS patients treated with natalizumab in Liguria, Italy are reported. Predictors of relapse occurrence and disability improvement were analyzed with a logistic regression method in subjects treated for one year (N = 62). A new score, called "Better EDSS Trend (BET)", was devised to describe the impact of the treatment on disability. Changes in annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) after one and two years and proportion of disease-free patients were evaluated., Results: Previous EDSS worsening plus ARR ≥ 2 increased the risk of relapse during the treatment [Odds Ratio (OR) 4.12, P = 0.04], but this was not associated with an increase in disability at one year. EDSS 3.0-3.5 or high disease activity were associated with neurological improvement in the first year of treatment (respectively OR 5.78, P = 0.05 and OR 4.80, P = 0.05). Positive BET score, i.e. improvement in the disability trend, was observed in 40.3% of patients, and correlated with high ARR in the year before treatment (OR 1.69, P = 0.03)., Conclusion: Subjects with EDSS 3.0-3.5 and those with very active disease in the year before treatment are most likely to improve in neurological function under natalizumab. A relapse in the first year of treatment is associated to high pre-treatment disease activity; however, since the occurrence of a relapse did not have a negative impact on clinical improvement at one year, we suggest that it should not lead to treatment discontinuation. We propose BET as an additional endpoint of treatment response in MS.

The purpose of this study was to assess the adherence to therapy in patients with relapsing remitting multiple sclerosis (RR-MS) and to analyze the possible influence of factors such as hospital care and patients socioeconomic status. Two hundred eighty-five patients with RR-MS according to Mc Donald's criteria and naïve disease-modifying drugs (DMDs) naïve were enrolled. Two self-administered questionnaires addressing the management of patients at therapy prescription and the personal perception of the daily life changes caused by DMDs were administered at months 3 and 12. Full adherence, considered as correct use of the therapy prescribed, was observed in a very high percentage of subjects (97.3% and 93.9% at 3 and 12 months). The main cause for reduced adherence was single dose forgetfulness, followed by anxiety, pain at the injection site, and tiredness of "doing all injections." Nurses and neurologists of MS Center were identified as the major resource in coping with the disease at 3 and 12 months by patients. The neurologist was the health professional involved in MS management in 95% of cases and the nurse appeared to play a central role in patient training and drug administration management (50.3%).

Evidence suggests that neurohormones such as GH and IGF-I are involved in the neuroreparative processes in multiple sclerosis (MS). GH and IGF-I blood levels in naïve MS patients with different disease courses were investigated in this study. Serum GH and IGF-I in untreated MS patients (n = 64), healthy controls (HC, n = 62), and patients affected by other neurological diseases (OND, n = 46) were evaluated with a solid-phase-enzyme-labeled-chemiluminescent-immunometric assay. No differences were detected in GH across MS, OND, and HC (MS = 0.87 ± 1.32 ng/mL; OND = 1.66 ± 3.7; and HC = 1.69 ± 3.35; P = 0.858) when considering gender, disease duration, and disease course. However, GH was lower (P = 0.007) in patients with more severe disease (expanded disability scale score, EDSS ≥ 4.0) compared with milder forms (EDSS < 4). IGF-I l did not differ across the 3 groups (P = 0.160), as far as concern disease course, disability, and gender were. Lower IGF-I levels were detected in subjects older than 50 years compared to younger ones for all 3 groups. Lower GH was detected in patients with more severe MS, and age was confirmed as the main factor driving IGF-I levels in all subjects. These findings, relying on the natural course of the disease, could help in shedding lights on the mechanisms involved in autoreparative failure associated with poorer prognosis in MS.

Background: Few studies have systematically addressed the role of epidural analgesia and caesarean delivery in predicting the post-partum disease activity in women with Multiple Sclerosis (MS).The objective of this study was to assess the impact of epidural analgesia (EA) and caesarean delivery (CD) on the risk of post-partum relapses and disability in women with MS., Methods: In the context of an Italian prospective study on the safety of immunomodulators in pregnancy, we included pregnancies occurred between 2002 and 2008 in women with MS regularly followed-up in 21 Italian MS centers. Data were gathered through a standardized, semi-structured interview, dealing with pregnancy outcomes, breastfeeding, type of delivery (vaginal or caesarean) and EA. The risk of post-partum relapses and disability progression (1 point on the Expanded Disability Status Sclae, EDSS, point, confirmed after six months) was assessed through a logistic multivariate regression analysis., Results: We collected data on 423 pregnancies in 415 women. Among these, 349 pregnancies resulted in full term deliveries, with a post-partum follow-up of at least one year (mean follow-up period 5.5±3.1 years). One hundred and fifty-five patients (44.4%) underwent CD and 65 (18.5%) EA. In the multivariate analysis neither CD, nor EA were associated with a higher risk of post-partum relapses. Post-partum relapses were related to a higher EDSS score at conception (OR=1.42; 95% CI 1.11-1.82; p=0.005), a higher number of relapses in the year before pregnancy (OR=1.62; 95% CI 1.15-2.29; p=0.006) and during pregnancy (OR=3.07; 95% CI 1.40-6.72; p=0.005). Likewise, CD and EA were not associated with disability progression on the EDSS after delivery. The only significant predictor of disability progression was the occurrence of relapses in the year after delivery (disability progression in the year after delivery: OR= 4.00; 95% CI 2.0-8.2; p<0.001; disability progression over the whole follow-up period: OR= 2.0; 95% CI 1.2-3.3; p=0.005)., Conclusions: Our findings, show no correlation between EA, CD and postpartum relapses and disability. Therefore these procedures can safely be applied in MS patients. On the other hand, post-partum relapses are significantly associated with increased disability, which calls for the need of preventive therapies after delivery.

Background: Only few studies have assessed safety of in utero exposure to glatiramer acetate (GA). Following a previous study assessing the safety of interferon beta (IFNB) pregnancy exposure in multiple sclerosis (MS), we aimed to assess pregnancy and fetal outcomes after in utero exposure to GA, using the same dataset, with a specific focus on the risk of spontaneous abortion., Materials and Methods: We recruited MS patients, prospectively followed-up in 21 Italian MS Centres, for whom a pregnancy was recorded in the period 2002-2008. Patients were divided into 2 groups: drug-exposed pregnancies (EP: suspension of the drug less than 4 weeks from conception); non-exposed pregnancies (NEP: suspension of the drug at least 4 weeks from conception or never treated pregnancies). All the patients were administered a structured interview which gathered detailed information on pregnancy course and outcomes, as well as on possible confounders. Multivariate logistic and linear models were used for treatment comparisons., Results: Data on 423 pregnancies were collected, 17 were classified as EP to GA, 88 as EP to IFNB, 318 as NEP. Pregnancies resulted in 16 live births in the GA EP, 75 live births in the IFNB EP, 295 live births in the NEP. GA exposure was not significantly associated with an increased risk of spontaneous abortion (OR = 0.44;95% CI 0.044-4.51;p = 0.49). Mean birth weight and length were not significantly different in pregnancies exposed to GA than in non exposed pregnancies (p = 0.751). The frequency of preterm delivery, observed in 4 subjects exposed to GA (25% of full term deliveries), was not significantly higher in pregnancies exposed to GA than in those non exposed (p > 0.735). These findings were confirmed in the multivariate analysis. There were neither major complications nor malformations after GA exposure., Conclusions: Data in our cohort show that mother's GA exposure is not associated with a higher frequency of spontaneous abortion, neither other negative pregnancy and fetal outcomes. Our findings point to the safety of in utero GA exposure and can support neurologists in the therapeutic counselling of MS women planning a pregnancy.

About half of patients with multiple sclerosis (MS) report pain; treatment for pain alone accounts for nearly 30% of the total use of medications for the management of all MS-related symptoms. Patients with MS can experience more than one type of pain simultaneously and at any point during the disease course, even in newly or recently diagnosed cases. Pain in MS can be associated with other symptoms, including spasticity, fatigue and mood disorder. Pain sufferers experience disruption in daily life activities, work, mood, recreation and general enjoyment of life, and report low satisfaction with pain management. Many clinical features of pain are often unrecognized by clinicians and are difficult for patients to describe. The majority of clinical evidence regarding treatment stems from small pilot and open-label studies; therefore, treatment of pain associated with MS is often based on anecdotal reports and clinicians' experience. The open-label design of the majority of studies, the unavailability of large samples and the difficulty of performing placebo-controlled studies because of ethical considerations result in insufficient evidence to support or refute the effectiveness of pain medications. This Review presents available data regarding pharmacological approaches for addressing pain in MS and highlights the shortcomings in pain management research.