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Background: In the absence of evidence from randomised controlled trials, observational data can be used to emulate clinical trials and guide clinical decisions. Observational studies are, however, susceptible to confounding and bias. Among the used techniques to reduce indication bias are propensity score matching and marginal structural models. Objective: To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models. Methods: Patients with clinically isolated syndrome or relapsing remitting MS who were treated with either fingolimod or natalizumab were identified in the MSBase registry. Patients were propensity score matched, and inverse probability of treatment weighted at six monthly intervals, using the following variables: age, sex, disability, MS duration, MS course, prior relapses, and prior therapies. Studied outcomes were cumulative hazard of relapse, disability accumulation, and disability improvement. Results: 4608 patients (1659 natalizumab, 2949 fingolimod) fulfilled inclusion criteria, and were propensity score matched or repeatedly reweighed with marginal structural models. Natalizumab treatment was associated with a lower probability of relapse (PS matching: HR 0.67 [95% CI 0.62-0.80]; marginal structural model: 0.71 [0.62-0.80]), and higher probability of disability improvement (PS matching: 1.21 [1.02 -1.43]; marginal structural model 1.43 1.19 -1.72]). There was no evidence of a difference in the magnitude of effect between the two methods. Conclusions: The relative effectiveness of two therapies can be efficiently compared by either marginal structural models or propensity score matching when applied in clearly defined clinical contexts and in sufficiently powered cohorts.

Aggressive neuromyelitis optica spectrum disorders (NMOSDs) with antibodies (Abs) against aquaporin-4 (AQP4) can be treated by blocking the interleukin 6 (IL6) pathways with tocilizumab. This IL6-inhibitor was employed to treat coronavirus disease 2019 (COVID-19) pneumonia with unconclusive results. We present a 52-year-old woman with AQP4 NMOSD, unresponsive to rituximab, that stabilized on tocilizumab one year after the disease onset. She was bed-bound and progressively recovered her mobility. During intensive rehabilitation, she presented fever and cough for one week with nasopharyngeal swabs positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This mild COVID-19 recovered spontaneously without sequelae, and the monthly tocilizumab infusions were continued for another 10 months. Subsequently, serious and prolonged respiratory and urinary infections caused treatment interruption, and then her disease re-activated. In our case, tocilizumab was effective in preventing NMOSD relapse and was safe to use during SARS-CoV-2 infection.

Double-blind randomized controlled trial.Carpal tunnel syndrome (CTS) is a common mononeuropathy that causes pain and disability in the affected hand. Kinesio taping (KT) has been recently proposed as a promising conservative approach in CTS patients.To investigate the effectiveness of KT compared to a sham taping on symptoms and hand function in patients affected by mild CTS.Patients affected by mild CTS with symptoms for at least 8 weeks were enrolled and randomly allocated into two groups: KT group, according to the technique proposed by Kase plus specific exercises; control group, undergoing a sham taping plus specific exercise. All patients performed 2 sessions/week for 5 weeks of exercises of mobilization of fingers and carpal joint. At the baseline, after 5 weeks (T1), and after 6 months (T2), a physician unaware of patients' allocation assessed the Boston Carpal Tunnel Questionnaire (BCTQ) symptom (BCTQ-S) and functional (BCTQ-F) subscales.Forty-two patients (mean age:54.3 ± 15.0 y) were randomly allocated into KT (n = 21) and control group (n = 21). At T1, in both groups we found a significant improvement in hand function and symptoms, as showed by BCTQ-F (KT:4.2 ± 0.7 vs 3.0 ± 0.6, P.001; sham: 2.2 ± 0.3 vs 1.7 ± 0.3, P = .012) and by BCTQ-S (KT: 2.2 ± 0.3 vs 1.7 ± 0.3, P.001; sham: 2.3 ± 0.4 vs 1.9 ± 0.5, P = .007). At T2, only in the KT group there was a significant difference in both sub-items of primary outcome. There were significantly better results in the KT group at T1 and T2.The present study showed that KT compared to a sham taping might be more effective in reducing perceived symptoms in mild CTS patients, reporting a clinically significant difference.KT might be considered as an effective technique combined to rehabilitative treatment in terms of hand function and symptoms in patients affected by mild CTS.

Background and purpose Some studies have shown that air pollution, often assessed by thin particulate matter with diameter below 2.5 µg/m3 (PM2.5), may contribute to severe COVID‐19 courses, as well as play a role in the onset and evolution of multiple sclerosis (MS). However, the impact of air pollution on COVID‐19 has never been explored specifically amongst patients with MS (PwMS). This retrospective observational study aims to explore associations between PM2.5 and COVID‐19 severity amongst PwMS. Methods Data were retrieved from an Italian web‐based platform (MuSC‐19) which includes PwMS with COVID‐19. PM2.5 2016–2018 average concentrations were provided by the Copernicus Atmospheric Monitoring Service. Italian patients inserted in the platform from 15 January 2020 to 9 April 2021 with a COVID‐19 positive test were included. Ordered logistic regression models were used to study associations between PM2.5 and COVID‐19 severity. Results In all, 1087 patients, of whom 13% required hospitalization and 2% were admitted to an intensive care unit or died, were included. Based on the multivariate analysis, higher concentrations of PM2.5 increased the risk of worse COVID‐19 course (odds ratio 1.90; p = 0.009). Conclusions Even if several other factors explain the unfavourable course of COVID‐19 in PwMS, the role of air pollutants must be considered and further investigated., Air pollution, often assessed by particulate matter with diameter below 2.5 µg/m3, may contribute to severe COVID‐19 courses. 1087 patients were included, of whom 13% required hospitalization and 2% were admitted to an intensive care unit or died. Even if several other factors explain the unfavourable course of COVID‐19 in patients with multiple sclerosis, the role of air pollutants must be considered and further investigated.

Objectives: To assess the impact of timing of natalizumab cessation/redosing on long-term maternal and infant outcomes in 72 out of the original 74 pregnancies of the Italian Pregnancy Dataset in multiple sclerosis (MS). Methods: Maternal outcomes in patients who received natalizumab until conception and restarted the drug within 1 month after delivery (“treatment approach,” (TA)) and patients who stopped natalizumab before conception and/or restarted the drug later than 1 month after delivery (“conservative approach,” (CA)) were compared through multivariable Cox regression analyses. Pediatric outcomes were assessed through a semi-structured questionnaire. Results: After a mean follow-up of 6.1 years, CA (hazard ratio (HR) = 4.1, 95% CI 1.6–10.6, p = 0.003) was the only predictor of relapse occurrence. Worsening on the Expanded Disability Status Scale (EDSS) was associated with higher annualized relapse-rate during the follow-up (HR = 3.3, 95% CI 1.4–7.9 p = 0.007). We found no major development abnormalities in children. Discussion: Our data confirm that TA reduces the risk of disease activity; we did not observe an increase in major development abnormalities in the child.

Background Patients with multiple sclerosis (MS) often receive disease-modifying therapies (DMTs) that can expose them to reactivation of potential occult hepatitis B virus (HBV) infection (pOBI). We aimed to evaluate the MS Centers behavior regarding HBV screening and prophylaxis in a large cohort of MS patients receiving anti-CD20 or cladribine. Methods Retrospective, multicentric study recruiting Italian MS patients treated with rituximab, ocrelizumab and cladribine. Results We included 931 MS patients from 15 centers. All but 38 patients performed a complete HBV screening. Patients’ age > 50 years was significantly associated with no history of vaccination and HBsAb titres p p = 0.5), pre-or post-therapy vaccination (p = 0.2) and number of previous DMTs (p = 0.2). Among pOBI patients (n = 53), 21 received antiviral prophylaxis, while only 13 had HBV DNA monitoring and 19 patients neither monitored HBV DNA nor received prophylaxis. Conclusions Baseline HBV screening in patients receiving anti-CD20 and cladribine is a consolidated practice. Nonetheless, HBV vaccination coverage is still lacking in such population and age is a significant factor associated with low HBV protection. Rituximab, ocrelizumab and cladribine did not impair HBV vaccine response. Almost 35% of pOBI patients fail to receive HBVr prevention. Management of HBV prophylaxis could be improved in MS patients and further prospective studies are needed to assess the effectiveness of prophylactic strategies in such patients.

Background and purpose: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS).Methods: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow -up >= 1 year, and Expanded Disability Status Scale (EDSS) score >= 3, with >= 1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12 -month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics.Results: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45- 0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41- 0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09- 1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity.Conclusions: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age. This study was financially supported by the National Health and Medical Research Council of Australia (1129189, 1140766, 1080518) We thank the patients and their carers who have agreed to participate in the global MSBase cohort study. The MSBase Foundation is a not-for-profit organization that receives support from Roche, Merck, Biogen, Novartis, Bayer-Schering, Sanofi-Genzyme, and Teva. The study was conducted separately and apart from the guidance of the sponsors. Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians.

Upper limb (UL) function is often affected in people with multiple sclerosis (PwMS) and is typically assessed through objective measures, including the Nine Hole Peg Test (9-HPT), Box and Block Test (BBT), and Hand Grip Strength (HGS). It is important to include the subjective perspective of PwMS in the assessment. This study aims to evaluate associations between Manual Ability Measure-36 (MAM-36) and 9-HPT, BBT, and HGS in MS.The cross-sectional study included five Italian centers. Inclusion criteria were age ≥ 18 years, MS diagnosis, and stable disease course. Exclusion criteria were bilateral UL paralysis, and concomitant orthopedic or neurological diseases.A total of 199 PwMS were included: 128 female, mean age = 50.7 ± 13.0 years, 119 relapsing-remitting MS (RRMS), 31 primary and 49 secondary progressive MS, mean disease duration = 14.0 ± 10.4, years, mean Expanded Disability Status Scale (EDSS) = 4.6 ± 2.0. The MAM-36 showed small correlations with 9-HPT, BBT, and HGS. Correlations between MAM-36 and 9-HPT and BBT were highest among subjects with EDSS ≥ 6 and progressive MS. MAM-36 and HGS showed the highest correlations in subjects with EDSS ≤ 5 and RRMS. Combining 9-HPT and HGS provided the strongest predictive power over the MAM-36.Correlations between objective measures and MAM-36 were small to moderate, meaning that objective measures do not match subjects' perception of UL function. The combination of 9-HPT and HGS measures can help improve the assessment of UL function in activities of daily living.

BackgroundDisability progression is a key milestone in the disease evolution of people with multiple sclerosis (PwMS). Prediction models 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.MethodsData 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. 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 expended 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 on their 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.FindingsA temporal attention model was the best model. It 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 is more predictive for future disability progression than the treatment or relapses.InterpretationGood discrimination and calibration performance on an external validation set is achieved, using only routinely collected variables. This makes these models ready for a clinical impact study. All our preprocessing and model code is available at https://gitlab.com/edebrouwer/ms_benchmark, making this task an ideal benchmark for predicting disability progression in MS.

Background and purpose The prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS); however, randomized clinical trials evaluate only short-term treatment effects on disability. This study aimed to define criteria for 6-month confirmed disability progression events of MS with a high probability of resulting in sustained long-term disability worsening. Methods In total, 14,802 6-month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6-month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long-term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial. Results The score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29-0.52; discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72%; 2: 88%; 3: 94%; 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was >88% likely to be sustained (events with score >1.5). Conclusions Clinicodemographic characteristics of 6-month confirmed disability progression events identify those at high risk of sustained long-term disability. This knowledge will allow future trials to better assess the effect of therapy on long-term disability accrual. NHMRC [1129189, 1157717, 1140766]; Merck; Biogen; Novartis; Roche; Bayer; Schering; Sanofi Genzyme; Teva Pharmaceutical Industries

BACKGROUND AND PURPOSE People with multiple sclerosis (PwMS) often report walking limitations even when the gold standard Expanded Disability Status Scale (EDSS) indicates normal walking endurance/autonomy. The present multicenter study on early-stage PwMS aims at analyzing which aspects are associated with patient-reported walking limitations measured with the 12-item Multiple Sclerosis Walking Scale (MSWS-12). METHODS Eighty-two PwMS (EDSS ≤ 2.5) were assessed using the Fullerton Advanced Balance Scale-short (FAB-s), the Fatigue Severity Scale (FSS) and the 6-min Walk Test (6MWT), the latter administered also to 21 healthy subjects. Participants performed the 6MWT wearing three inertial sensors on ankles and trunk. Instrumented metrics describing gait velocity (stride length and frequency) and quality (regularity, symmetry, instability) were computed from sensor data. Fatigue (FSS), balance (FAB-s), walking endurance (6MWT) and instrumented metrics were entered in a multiple regression model with MSWS-12 as dependent variable. RESULTS Gait symmetry, gait instability, fatigue and balance were significantly associated with self-rated walking ability, whilst walking endurance and velocity were not. Fatigue, balance, gait symmetry and instability were more impaired in participants reporting mild-to-moderate (MSMM-PWL , 25 ≤ MSWS-12

Background: Little is known about COVID-19 course and outcomes after a third booster dose of mRNA vaccine against SARS-CoV-2 (mRNA-Vax) in patients with multiple sclerosis (pwMS) treated with ocrelizumab (OCR) and fingolimod (FNG), which showed a weakened immune response to mRNA-vax. Objectives: The aim of this study was to evaluate COVID-19 course and outcomes in pwMS on OCR and FNG after receiving the third dose of mRNA-Vax and to compare it with pwMS on natalizumab (NTZ). Methods: Inclusion criteria: >18 years of age, being treated with OCR/FNG/NTZ since the first mRNA-Vax dose; COVID-19 after a third booster dose of mRNA-Vax; no steroids use. Results: Overall, 290 pwMS (79 NTZ, 126 OCR, and 85 FNG) from 17 Italian MS centers were included. Age, Expanded Disability Status Scale (EDSS) score, MS phenotype, disease, and treatment duration were significantly different across groups. PwMS who had COVID-19 on OCR and FNG compared with those on NTZ were slightly more symptomatic with higher hospitalization rates (11.1% vs 7.1% vs 1.3%, respectively). Regression models showed that the majority of the differences observed were not related to the disease-modifying treatments (DMTs) used. No fatal cases were observed. Conclusion: Our results support the effectiveness of the third booster dose of mRNA-Vax against severe forms of COVID-19 in pwMS treated with OCR and FNG.

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.

BackgroundThe exclusion of other diseases that can mimic multiple sclerosis (MS) is the cornerstone of current diagnostic criteria. However, data on the frequency of MS mimics in real life are incomplete.MethodsA total of 695 patients presenting with symptoms suggestive of MS in any of the 22 RIREMS centers underwent a detailed diagnostic workup, including a brain and spinal cord MRI scan, CSF and blood examinations, and a 3-year clinical and radiologic follow-up.FindingsA total of 667 patients completed the study. Alternative diagnoses were formulated in 163 (24.4%) cases, the most frequent being nonspecific neurologic symptoms in association with atypical MRI lesions of suspected vascular origin (40 patients), migraine with atypical lesions (24 patients), and neuromyelitis optica (14 patients). MS was diagnosed in 401 (60.1%) patients according to the 2017 diagnostic criteria. The multivariate analysis revealed that the absence of CSF oligoclonal immunoglobulin G bands (IgG-OB) (odds ratio [OR] 18.113), the presence of atypical MRI lesions (OR 10.977), the absence of dissemination in space (DIS) of the lesions (OR 5.164), and normal visual evoked potentials (OR 3.550) were all independent predictors of an alternative diagnosis.InterpretationThis observational, unsponsored, real-life study, based on clinical practice, showed that diseases that mimicked MS were many, but more than 45% were represented by nonspecific neurologic symptoms with atypical MRI lesions of suspected vascular origin, migraine, and neuromyelitis optica. The absence of IgG-OB and DIS, the presence of atypical MRI lesions, and normal visual evoked potentials should be considered suggestive of an alternative disease and red flags for the misdiagnosis of MS.

BACKGROUND AND PURPOSE The literature provides contrasting results on the efficacy of levetiracetam (LEV) in multiple sclerosis (MS) patients with cerebellar signs. It was sought to evaluate the efficacy of LEV on upper limb movement in MS patients. METHODS In this multicenter double-blind placebo-controlled crossover study, MS patients with prevalently cerebellar signs were randomly allocated into two groups: LEV followed by placebo (group 1) or placebo followed by LEV (group 2). Clinical assessments were performed by a blinded physician at T0 (day 1), T1 (day 22), T2 (2-week wash-out period, day 35) and T3 (day 56). The primary outcome was dexterity in the arm with greater deficit, assessed by the nine-hole peg test (9HPT). Secondary clinical outcomes included responders on the 9HPT (∆9HPT >20%), tremor activity of the daily living questionnaire and self-defined upper limb impairment, through a numeric rating scale. Kinematic evaluation was performed using a digitizing tablet, providing data on normalized jerk, aiming error and centripetal acceleration. RESULTS Forty-eight subjects (45.2 ± 10.4 years) were randomly allocated into two groups (n = 24 each). 9HPT significantly improved in the LEV phase in both groups (P

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 (sLyEAP) 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 sLyEAP 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 sLyEAP and poor balance supports the validity of sLyEAP as a dynamic balance measure. The inverse relationship between sLyEAP 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.

Introduction: The approval of 9-δ-tetrahydocannabinol (THC)+cannabidiol (CBD) oromucosal spray (Sativex®) in Italy as an add-on medication for the management of moderate to severe spasticity in multiple sclerosis (MS) has provided a new opportunity for MS patients with drug-resistant spasticity. We aimed to investigate the improvement of MS spasticity-related symptoms in a large cohort of patients with moderate to severe spasticity in daily clinical practice. Materials and methods: MS patients with drug-resistant spasticity were recruited from 30 Italian MS centers. All patients were eligible for THC:CBD treatment according to the approved label: ≥ 18 years of age, at least moderate spasticity (MS spasticity numerical rating scale [NRS] score ≥ 4) and not responding to the common antispastic drugs. Patients were evaluated at baseline (T0) and after 4 weeks of treatment (T1) with the spasticity NRS scale and were also asked about meaningful improvements in 6 key spasticity-related symptoms. Results: Out of 1615 enrolled patients, 1432 reached the end of the first month trial period (T1). Of these, 1010 patients (70.5%) reached a ≥ 20% NRS score reduction compared with baseline (initial responders; IR). We found that 627 (43.8% of 1432) patients showed an improvement in at least one spasticity-related symptom (SRSr group), 543 (86.6%) of them belonging to the IR group and 84 (13.4%) to the spasticity NRS non-responders group. Conclusion: Our study confirmed that the therapeutic benefit of cannabinoids may extend beyond spasticity, improving spasticity-related symptoms even in non-NRS responder patients. © 2020, Fondazione Società Italiana di Neurologia.

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.

none 26 no Background: The influence of pregnancy on long-term disability in multiple sclerosis (MS) is still controversial. Objective: To assess the risk of long-term disability worsening after pregnancy in MS women as compared with a propensity-score (PS) matched group of MS women without pregnancy. Methods: In the setting of the Italian Pregnancy Dataset, MS patients with (pregnancy group (PG)) and without pregnancy (control group (CG)) were recruited. Time to disability worsening on the Expanded Disability Status Scale (EDSS) was assessed through a multivariable Cox regression model. Results: The PS-matching retained 230 PG and 102 CG patients. After a follow-up of 6.5 +/- 3.1 years, disability worsening occurred in 87 (26.2%) women. In the multivariable analysis, disability worsening was associated with pregnancy in women with relapses in the year before conception (adjusted hazard ratio (aHR) = 1.74; 95% confidence interval (CI) 1.06-2.84; p = 0.027), higher EDSS (aHR = 1.39; 95% CI 1.12-1.74; p = 0.003), younger age (aHR = 0.95; 95% CI 0.91-0.99; p = 0.022) and shorter DMD exposure over the follow-up (p < 0.008). Conclusion: Pregnancy in MS women with relapses in the year before conception increases the risk of long-term disability worsening. Our findings underscore the importance of counselling in MS women facing a pregnancy that should be planned after a period of clinical stability, favouring treatment optimization in patients with recent disease activity. mixed Portaccio, Emilio; Tudisco, Laura; Pastò, Luisa; Razzolini, Lorenzo; Fonderico, Mattia; Bellinvia, Angelo; Ghezzi, Angelo; Annovazzi, Pietro; Zaffaroni, Mauro; Moiola, Lucia; Martinelli, Vittorio; Chisari, Clara Grazia; Patti, Francesco; Mancardi, Gianluigi; Pozzilli, Carlo; De Giglio, Laura; Totaro, Rocco; Lugaresi, Alessandra; Di Tommaso, Valeria; Paolicelli, Damiano; Cocco, Eleonora; Marrosu, Maria Giovanna; Comi, Giancarlo; Filippi, Massimo; Trojano, Maria; Amato, Maria Pia Portaccio, Emilio; Tudisco, Laura; Pastò, Luisa; Razzolini, Lorenzo; Fonderico, Mattia; Bellinvia, Angelo; Ghezzi, Angelo; Annovazzi, Pietro; Zaffaroni, Mauro; Moiola, Lucia; Martinelli, Vittorio; Chisari, Clara Grazia; Patti, Francesco; Mancardi, Gianluigi; Pozzilli, Carlo; De Giglio, Laura; Totaro, Rocco; Lugaresi, Alessandra; Di Tommaso, Valeria; Paolicelli, Damiano; Cocco, Eleonora; Marrosu, Maria Giovanna; Comi, Giancarlo; Filippi, Massimo; Trojano, Maria; Amato, Maria Pia

BackgroundHeat 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.MethodsCBT 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).ResultsAs expected, PwMS walked a significantly shorter distance (361 ± 98 m) than the HS group (613 ± 62 m, pConclusionThe 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.

The aim of the study was to explore the cognitive functions of a large sample of hospitalised subjects with mild symptomatic Coronavirus Disease (COVID-19) who were previously independent at home and without neurological diseases.Patients admitted in a COVID-19 Unit for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection between November 2020 and March 2021 were recruited. Inclusion criteria were: being independent at home before the infection, radiologically confirmed COVID-19 pneumonia, positive reverse transcriptase-polymerase chain reaction nasopharyngeal swab and no oxygen supplementation at the time of evaluation.cognitive impairment or neurological diseases previous to the infection, delirium episodes, and history of any mechanical ventilation use. They were evaluated with Montreal Cognitive Assessment (MoCA), Hamilton Depression Rating Scale (HAM-D) and Hamilton Anxiety Rating Scale (HAM-A).Out of 522 subjects admitted in the COVID-19 Unit, 90 were enrolled [mean age = 68.32(11.99); 46M/44F]. An impaired MoCA (cut-off 23) was found in 60 subjects (66.66 %). Pathological scores were obtained by 36.66 % of the subjects with65 years and 78.33 % of those older than 65 years. A high prevalence of executive function and memory impairment was detected.The results underline a high rate of cognitive impairment in previously independent mild COVID-19 patients. This might represent a potential threat for the everyday independence of these patients due to the consequences on everyday life activities and work following discharge from hospital. These subjects should, therefore, be monitored in order to allow a better understanding of the progression and consequences of the so-called "Long COVID".

BackgroundTurning 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.ObjectivesTo 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.MethodsIn 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.ResultsMediolateral 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 rs| ≥ 0.37, p < 0.001), thus demonstrating their concurrent validity.ConclusionThe 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.

The upper extremities limitation represents one of the essential functional impairments in patients with cervical spinal cord injury. Electromechanics assisted devices and robots are increasingly used in neurorehabilitation to help functional improvement in patients with neurological diseases. This review aimed to systematically report the evidence-based, state-of-art on clinical applications and robotic-assisted arm training (RAT) in motor and functional recovery in subjects affected by cervical spinal cord injury. The present study has been carried out within the framework of the Italian Consensus Conference on “Rehabilitation assisted by robotic and electromechanical devices for persons with disability of neurological origin” (CICERONE). PubMed/MEDLINE, Cochrane Library, and Physiotherapy Evidence Database (PEDro) databases were systematically searched from inception to September 2021. The 10-item PEDro scale assessed the study quality for the RCT and the AMSTAR-2 for the systematic review. Two different authors rated the studies included in this review. If consensus was not achieved after discussion, a third reviewer was interrogated. The five-item Oxford CEBM scale was used to rate the level of evidence. A total of 11 studies were included. The selected studies were: two systematic reviews, two RCTs, one parallel-group controlled trial, one longitudinal intervention study and five case series. One RCT was scored as a high-quality study, while the systematic review was of low quality. RAT was reported as feasible and safe. Initial positive effects of RAT were found for arm function and quality of movement in addition to conventional therapy. The high clinical heterogeneity of treatment programs and the variety of robot devices could severely affect the generalizability of the study results. Therefore, future studies are warranted to standardize the type of intervention and evaluate the role of robotic-assisted training in subjects affected by cervical spinal cord injury.

none 38 no BACKGROUND: Natalizumab (NTZ) is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). However, patients and physicians may consider discontinuing NTZ therapy due to safety or efficacy issues. The aim of our study was to evaluate the NTZ discontinuation rate and reasons of discontinuation in a large Italian population of RRMS patients. MATERIALS AND METHODS: The data were extracted from the Italian MS registry in May 2018 and were collected from 51,845 patients in 69 Italian multiple sclerosis centers. MS patients with at least one NTZ infusion in the period between June 1st 2012 to May 15th 2018 were included. Discontinuation rates at each time point were calculated. Reasons for NTZ discontinuation were classified as "lack of efficacy", "progressive multifocal leukoencephalopathy (PML) risk" or "other". RESULTS: Out of 51,845, 5151 patients, 3019 (58.6%) females, with a mean age of 43.6 ± 10.1years (median 40), were analyzed. Out of 2037 (39.5%) who discontinued NTZ, a significantly higher percentage suspended NTZ because of PML risk compared to lack of efficacy [1682 (32.7% of 5151) vs 221 (4.3%), p

Background There are few evidences on safety of Constraint-Induced Movement Therapy (CIMT), as well as its effects in neurological conditions, including multiple sclerosis (MS). Objective To evaluate safety and effectiveness of a 2-week CIMT protocol on upper limb activity of progressive MS patients through a three-dimensional (3D) kinematic analysis. Methods In this randomized single-blind pilot study, we randomly allocated patients affected by progressive MS reporting a reduced use of one upper limb into two different groups: CIMT group (less affected limb blocked by a splint) and control group (undergoing bi-manual treatment). Primary outcome was CIMT safety. Furthermore, we assessed CIMT effects through clinical outcomes (hand grip strength, HGS, and 9 Hole Peg Test, 9HPT) and 3D kinematic analysis (normalized jerk, number of movement units, going phase duration, mean velocity, endpoint error). All evaluations were performed at baseline (T0) and after 2 weeks of treatment (T1) for both arms in both groups. Results Ten MS patients, mean aged 51.0±7.7 years, were randomly allocated in the 2 groups. After treatment, no differences were found in the blocked arm. Furthermore, CIMT group showed significant improvements in clinical and kinematic parameters. Conclusions CIMT might be considered a safe and effective technique in MS patients.

People with Multiple Sclerosis (PwMS) show low levels of physical activity (PA), however there has been limited research on PA in early diagnosed and no/minimally impaired (5 years, EDSS≤ 2.5) PwMS. The aims of the study were to objectively quantify PA levels in non-disabled PwMS, to compare the time spent daily at different PA levels (No activity (NPA), Light PA (LPA), Moderate PA (MPA), and Vigorous PA (VPA)) with healthy subjects (HS), and to examine the association of PA with disability, and clinical measures in PwMS.We assessed 58 PwMS (mean age±standard deviation, SD 39.1 ± 10.6years) and 20 HS (mean age±SD 39.3 ± 8.9 years). Demographic and clinical data were recorded at the hospital during the baseline assessment. Subjects wore the wrist GENEActiv accelerometer for 7-days. Data were collected at 100 Hz and summarized into a motor activity (MA) index using 60 s epochs with the following thresholds: MAPwMS show higher NPA and lower VPA compared to matched healthy subjects (NPA: Mean±SD, HS: 7.2 ± 0.9 h/day; PwMS: 8.1 ± 1.2 h/day, p0.01; VPA: HS: 0.78± 0.42 h/day; PwMS: 0.50± 0.40 h/day, p = 0.01), while no between group differences were observed for LPA and MPA (p0.05). Bivariate analysis showed that higher NPA was associated with fatigue (Fatigue Severity Scale, FSS score) in PwMS with EDSS 0-1.5 (r = 0.34, p = 0.05). In PwMS with EDSS 2-2.5, NPA was correlated with Six Minute Walk Test (6MWT, r=-0.45, p = 0.02) and CIQ (r=-0.41, p = 0.04), while VPA was more associated with FSS (R= -0.38, p = 0.06).The PA level of PwMS differs from that of healthy subjects even in early diagnosed subjects. In PwMS with EDSS 0-1.5 only, fatigue is associated to prolonged inactive behavior. Conversely, in PwMS with EDSS 2-2.5 both inactivity and vigorous activities are modulated by fatigue, endurance and associated with different level of social participation.

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.

BACKGROUND Older people affected by severe osteoarthritis could need to undergo total joint replacement, with a consequent hospitalization and rehabilitation. In this postacute phase, they might suffer from other symptoms, including dysphagia, defined as a dysfunction of the digestive system, characterized by an objective difficulty or a sensation of difficulty in swallowing. It is considered as a very challenging problem in older people and early detection is fundamental for a prompt and effective management. However, up to date, there is a lack of data on dysphagia risk screening in orthopedic rehabilitation inpatients. AIM The aim of this study was to evaluate dysphagia risk through Eating Assessment Tool (EAT-10) in older people undergoing rehabilitation after total hip or knee arthroplasty. DESIGN Cross-sectional study. SETTING Rehabilitation Unit. POPULATION All consecutive patients undergone total hip or knee arthroplasty, aged ≥65 years, referring to Orthopedics Rehabilitation Unit "Mons. Luigi Novarese" Hospital, Moncrivello, Italy, for a 24-month period (from 1st January 2018 to 31st December 2019). We excluded patients with: 1) diagnosis of neurological diseases; 2) pharyngeal or esophageal cancer; 3) maxillofacial cancer; 4) tracheotomy. METHODS Dysphagia risk was assessed through EAT-10. The cohort was divided into two groups, according to water swallowing test (WST), in order to evaluate differences in terms of different EAT-10 scores. Furthermore, based on pathological WST, we have stratified study participants by the American Speech-Language-Hearing Association (ASHA)'s National Outcomes Measurement System (NOMS) swallowing scale in order to evaluate differences in terms of the different EAT-10 scores. RESULTS We included 534 participants (180 men, 357 women), mean aged 74.8±5.6 years. Thirty-one patients (5.8%) had pathological WST and 34 (6.4%) reported EAT-10 ≥3. There were significant differences (P

Background: Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening. Methods: By re-analyzing original published results from MSBase, France, and Denmark using uniform meth-odologies, we aimed at identifying the effects of differences in methodology, in the MS-populations, and at re-evaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/ exclusion criteria and statistical methods with Inverse Probability Treatment Weighting. Results: The pooled analyses comprised 968 natalizumab-and 1479 fingolimod treated patients. The on-treatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod. Conclusion: The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed. BiogenBiogen; NovartisNovartis; MerckMerck & Company; RocheRoche Holding; Teva; Sanofi GenzymeSanofi-AventisGenzyme Corporation; NHMRCNational Health and Medical Research Council of Australia [1140766,1129789, 1157717]; French State; Agence Nationale de la Recherche-French National Research Agency (ANR)European Commission [ANR-10-COHO-002]; Eugene Devic EDMUS Foundation; ARSEP Foundation