Search

Introduction: CD20-depleting therapies are a real milestone in the treatment of multiple sclerosis (MS). This study examined the ocrelizumab (OCR) use in patients with primary progressive (PP) and relapsing remitting (RR) MS, also evaluating the predictors of treatment response., Methods: Patients with MS treated with OCR between 2017 and 2022 were included, and OCR use trends examined. The patients' characteristics were assessed at baseline and after 24 months of OCR to assess the NEDA-3 status., Results: This study included 421 patients: 33 (7.9%) with PP and 388 (92.1%) with RR MS. Among these, 67 (17.3%) were naïve, while switchers from first- and second-line disease-modifying therapies (DMTs) were 199 (51.3%) and 122 (31.4%), respectively. An increasing trend in OCR use was reported. For six patients treated with rituximab, OCR was chosen to improve tolerability; for 390 switcher patients, the choice was due to ineffectiveness; and for 25, as an exit strategy from natalizumab due to JC virus positivity. NEDA-3 status was calculated for subjects exposed to 24 months of OCR and was achieved by 163/192 (84.9%) RR patients and 9/16 (56%) PP patients, with younger age (p = 0.048) and annualized relapse rate in the year previous to OCR (p = 0.005) emerging as determinants. For the 25 patients who switched to OCR after natalizumab, no clinical or MRI activity after 12 months was reported., Conclusion: OCR has been confirmed to be a highly efficacious option for patients with PP and RR MS, even proving to be a valid exit strategy for natalizumab., (© 2024. Fondazione Società Italiana di Neurologia.)

Background: in the early stages of Multiple Sclerosis (MS), initiating high-efficacy disease-modifying therapy (HE DMTs) may represent an optimal strategy for delaying neurological damage and long-term disease progression, especially in highly active MS patients (HAMS). Natalizumab (NAT) and Ocrelizumab (OCR) are recognized as HE DMTs with significant anti-inflammatory effects. This study investigates NEDA-3 achievement in treatment-naïve HAMS patients receiving NAT or OCR over three years., Methods: we retrospectively enrolled treatment-naïve HAMS patients undergoing NAT or OCR, collecting demographic, clinical, and instrumental data before and after treatment initiation to compare with propensity score analysis disease activity, time to disability worsening, and NEDA-3 achievement., Results: we recruited 281 HAMS patients with a mean age of 32.7 years (SD 10.33), treated with NAT (157) or OCR (124). After three years, the Kaplan-Meier probability of achieving NEDA-3 was 66.0 % (95 % CI: 57.3 % - 76.0 %) with OCR and 68.2 % (95 % CI: 59.9 % - 77.7 %) with NAT without significant differences between the two groups (p = 0.27) DISCUSSION AND CONCLUSION: starting HE DMT with monoclonal antibodies for HAMS could achieve NEDA-3 in a high percentage of patients without differences between NAT or OCR., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Irene Schiavetti reports a relationship with Roche, Biogen, Horizon, Novartis, Hoya, Hippocrates Research, D.M.G Italia, Eyepharma, DreamsLab that includes: consulting or advisory. Livia Pasquali reports a relationship with Alexion, Biogen, Sanofi, Merck, Novartis, Roche that includes: consulting or advisory and travel reimbursement. Elisabetta Signoriello reports a relationship with Almirall, Biogen, Genzyme, Novartis, Teva that includes: board membership and travel reimbursement. Maria Pia Sormani reports a relationship with Biogen Idec, Merck Serono, Teva, Genzyme, Roche, Novartis, GeNeuro, Medday that includes: consulting or advisory. Jessica Frau reports a relationship with Biogen, Bristol, Novartis, Genzyme, Merck, Teva, Alexion that includes: board membership, consulting or advisory, and speaking and lecture fees. Daniele Caliendo reports a relationship with Merck that includes: funding grants. Alessio Signori reports a relationship with Roche, Horizon, Novartis that includes: speaking and lecture fees. Andrea Surcinelli reports a relationship with Roche, Merck, Biogen, Sanofi, Novartis that includes: travel reimbursement. Simona Bonavita reports a relationship with Novartis, Merck-Serono, Alexion, BMS, Biogen, Roche, Janssen-Cilag, Horizon that includes: speaking and lecture fees and travel reimbursement. Roberta Fantozzi reports a relationship with Novartis, Roche, Merck Serono, Bristol-Myers Squibb that includes: board membership and consulting or advisory. Antonio Carotenuto reports a relationship with Almirall, ECTRIMS- MAGNIMS, Biogen, Roche, Sanofi-Genzyme, Merck, Ipsen, Novartis that includes: funding grants. Doriana Landi reports a relationship with Biogen, Merck Serono, Teva, Bristol Myers Squibb, Mylan, Novartis, Roche, Horizon, Alexion, Sanofi-Genzyme, Novartis, Bayer-Schering that includes: speaking and lecture fees and travel reimbursement. Giacomo Lus reports a relationship with Biogen Idec, Merck Serono, Novartis, Sanofi- Aventis Pharmaceuticals, Teva neuroscience that includes: funding grants. Eleonora Cocco reports a relationship with Biogen, Merck, Novartis, Roche, Genzyme that includes: consulting or advisory and funding grants. Matteo Lucchini reports a relationship with Biogen, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Almirall, Horizon, Bayer that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Girolama Alessandra Marfia reports a relationship with Almirall, Bayer-Schering, Biogen, Sanofi Genzyme, Merck Serono, Novartis, Teva, Mylan, Bristol Mayers Squibb, Roche, Biogen that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Matteo Foschi reports a relationship with Merck, Biogen, Sanofi, Roche, Novartis that includes: consulting or advisory and travel reimbursement. Massimiliano Mirabella reports a relationship with Bayer Schering, Biogen, Sanofi-Genzyme, Merck, Novartis, Teva, Mylan, Almirall, CSL Behring, Roche, Ultragenix that includes: board membership, consulting or advisory, speaking and lecture fees, and travel reimbursement. Diego Centonze reports a relationship with Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Protagon, Sandoz, Bristol-Myers Squibb, Alexion, Mitsubishi, Teva, Celgene that includes: board membership, funding grants, and non-financial support. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To analyse the course of multiple sclerosis (MS) after fingolimod withdrawal in a multicentre cohort., Methods: Patients who discontinued fingolimod were included. Relapses, Expanded Disability Status Scale (EDSS), and new/gadolinium-enhancing lesions on magnetic resonance imaging (MRI) were assessed during the last year on fingolimod, and in the year after discontinuation. Wilcoxon test was used to analyse the difference in EDSS and relapses between the two periods, and to compare lymphocyte counts at discontinuation and 3 months later. Demographic and clinical variables were evaluated using univariable and multivariable logistic regression analyses., Results: Patients were 230 (females 66.1%; mean age 38 years; median EDSS 3). Fingolimod was discontinued due to inefficacy in 57%, and 87.4% started another treatment. Relapse was observed in 33% of the patients in the year after discontinuation. Severe reactivation was observed in 15%. During the first 6 months after discontinuation, new/enhancing lesions were seen in 62/116 patients. Higher age at the fingolimod discontinuation was found to be associated with a lower probability of inflammatory activity (p = 0.001) and severe reactivation (p = 0.007) during the year after discontinuation. Lower lymphocyte count was a risk factor for clinical, radiological, and severe activity (p = 0.02, p = 0.002, p = 0.01, respectively)., Conclusions: The main reason for the discontinuation of fingolimod was inefficacy. One-third of the patients had a relapse during the year after discontinuation, 15% experienced a severe reactivation, and approximately 50% of patients with available MRI scan had new/enhancing lesions. The risk factors for disease activity after discontinuation were low lymphocyte count and younger age., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Purpose: Real-world data on alemtuzumab are limited and do not provide evidence of its effectiveness after various disease-modifying therapies (DMTs). Our aim was to provide real-world data on the impact of clinical variables and previous DMTs on clinical response to alemtuzumab., Methods: Sixteen Italian multiple sclerosis centers retrospectively included patients who started alemtuzumab from January 2015 to December 2018, and recorded demographics, previous therapies, washout duration, relapses, Expanded Disability Status Scale (EDSS) score, and magnetic resonance imaging data. Negative binomial regression models were used to assess the effect of factors on annualized relapse (ARR) after alemtuzumab initiation., Results: We studied 322 patients (mean age 36.8 years, median EDSS score 3, median follow-up 1.94 years). Previous treatments were: fingolimod (106), natalizumab (80), first-line oral agents (56), first-line injectables (interferon/glatiramer acetate; 30), and other drugs (15). Thirty-five patients were treatment-naïve. The pre-alemtuzumab ARR was 0.99 and decreased to 0.13 during alemtuzumab treatment (p < 0.001). The number of previous-year relapses was associated with alemtuzumab ARR (adjusted risk ratio [RR] 1.38, p = 0.009). Progression-free survival was 94.5% after 1 year, and 89.2% after 2 years of alemtuzumab treatment. EDSS score improvement occurred in 13.5% after 1 year, and 20.6% after 2 years. Re-baselining patients after 6 months of alemtuzumab treatment, led to no evidence of disease activity status in 71.6% after 1 year and 58.9% after 2 years., Conclusions: Alemtuzumab decreases ARR independent of previous therapy, including patients with disease activity during natalizumab treatment. Overall, 90% of patients showed no disease progression, and 20% an improvement after 2 years of alemtuzumab., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objectives: Switching between treatments is an opportunity for patients with multiple sclerosis (MS) to ameliorate disease control or safety. The aim of this study was to investigate the impact of switching from fingolimod (FTY) or natalizumab (NTZ) to ocrelizumab (OCR) on disease activity., Methods: We retrospectively enrolled 165 patients treated with OCR from 11 MS centres. We assessed the association of demographic and clinical characteristics on relapse rate (RR) and activity on magnetic resonance imaging (MRI) during wash-out and after 6 months of treatment with OCR through univariable and multivariable negative binomial regression models., Results: We registered a total of 35 relapses during the wash-out period. Previous treatment with FTY, relapses in the previous year, and relapsing-remitting course were associated with higher RR. In the first 6 months of OCR, 12 patients had clinical or MRI disease activity. Higher Expanded Disability Status Scale (EDSS) and higher lymphocyte count at OCR start were associated with a reduced probability of relapse., Discussion and Conclusion: This study confirms that withdrawal from sequestering agents as FTY increases the risk of relapses in the wash-out period. Nevertheless, starting OCR before achieving complete immune reconstitution could limit its effectiveness in the first 6 months probably because trapped lymphocytes escape the CD20-mediated depletion.

Multiple sclerosis (MS) is a complex disease of the central nervous system that can cause permanent disability in young adults. A large armamentarium is available for its management and is increasing over time. Ozanimod is an oral drug belonging to the sphingosine-1-phosphate receptor (S1PR) modulator family recently approved in different countries for MS with active disease. It selectively modulates S1PR1 and S1PR5 to prevent autoreactive lymphocytes from entering the central nervous system (CNS), where they can determine inflammation and neurodegeneration. Ozanimod was tested in one Phase II and two Phase III pivotal trials and was shown to be effective and well tolerated. Moreover, further investigations, including comparative trials with other S1P modulators and MS disease-modifying drugs, are needed to better define placement in MS treatment. Furthermore, ozanimod is currently under evaluation for inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, in international phase III studies. This article retraces the itinerary leading to the approval of ozanimod for MS treatment and its peculiarities and potentiality inside the S1PR modulator family., Competing Interests: Nothing to declare related to the present article. MF has nothing to declare. LL serves on scientific advisory boards and received honoraria for speaking from Biogen, Merck, Novartis, Genzyme and Roche. JF serves on scientific advisory boards and received honoraria for speaking from Biogen, Merck, Novartis, Genzyme and Roche. EC serves on scientific advisory boards and received honoraria for speaking and scientific research support from Biogen, Merck, Novartis, Genzyme, Roche and Teva. The authors reported no other potential conflicts of interest for this work., (© 2021 Fronza et al.)

Background: Rituximab, an anti-CD20 monoclonal antibody leading to B lymphocyte depletion, is increasingly used as an off-label treatment option for multiple sclerosis (MS)., Objective: To investigate the effectiveness and safety of rituximab in relapsing-remitting (RR) and progressive MS., Methods: This is a multicenter, retrospective study on consecutive MS patients treated off-label with rituximab in 22 Italian and 1 Swiss MS centers. Relapse rate, time to first relapse, Expanded Disability Status Scale (EDSS) progression, incidence of adverse events, and radiological outcomes from 2009 to 2019 were analyzed., Results: A total of 355/451 enrolled subjects had at least one follow-up visit and were included in the outcome analysis. Annualized relapse rate significantly decreases after rituximab initiation versus the pre-rituximab start year in RRMS (from 0.86 to 0.09, p  < .0001) and in secondary-progressive (SP) MS (from 0.34 to 0.06, p  < .0001) and had a slight decrease in primary-progressive (PP) MS patients (from 0.12 to 0.07, p  = 0.45). After 3 years from rituximab start, the proportion of patients with a confirmed EDSS progression was 14.6% in the RRMS group, 24.7% in the SPMS group, and 41.5% in the PPMS group. No major safety concerns arose., Conclusion: Consistently with other observational studies, our data show effectiveness of rituximab in reducing disease activity in patients with MS.

Objective: Cladribine tablets were tested against placebo in randomized controlled trials (RCTs). In this study, the effectiveness of cladribine vs other approved drugs in patients with relapsing-remitting MS (RRMS) was compared by matching RCT to observational data., Methods: Data from the pivotal trial assessing cladribine tablets vs placebo (CLARITY) were propensity score matched to data from the Italian multicenter database i-MuST. This database included 3,150 patients diagnosed between 2010 and 2018 at 24 Italian MS centers who started a disease-modifying drug. The annualized relapse rate (ARR) over 2 years from treatment start and the 24-week confirmed disability progression were compared between patients treated with cladribine and other approved drugs (interferon, glatiramer acetate, fingolimod, natalizumab, and dimethyl fumarate), with comparisons with placebo as a reference. Treatment effects were estimated by the inverse probability weighting negative binomial regression model for ARR and Cox model for disability progression. The treatment effect has also been evaluated according to baseline disease activity., Results: All weighted baseline characteristics were well balanced between groups. All drugs tested had an effect vs placebo close to that detected in the RCT. Patients treated with cladribine had a significantly lower ARR compared with interferon (relapse ratio [RR] = 0.48; p < 0.001), glatiramer acetate (RR = 0.49; p < 0.001), and dimethyl fumarate (RR = 0.6; p = 0.001); a similar ARR to that with fingolimod (RR = 0.74; p = 0.24); and a significantly higher ARR than natalizumab (RR = 2.13; p = 0.014), confirming results obtained by indirect treatment comparisons from RCTs (network meta-analyses). The relative effect of cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years) was higher in patients with high disease activity vs all treatments except fingolimod and natalizumab. Effects on disability progression were largely nonsignificant, probably due to lack of power for such analysis., Conclusion: In patients with RRMS, cladribine tablets showed lower ARR compared with matched patients who started interferon, glatiramer acetate, or dimethyl fumarate; was similar to fingolimod; and was higher than natalizumab. The beneficial effect of cladribine tablets was generally amplified in the subgroup of patients with high disease activity., Classification of Evidence: This study provides Class III evidence that for patients with RRMS, cladribine-treated patients had lower ARR compared with interferon, glatiramer acetate, or dimethyl fumarate; similar ARR compared with fingolimod; and higher ARR compared with natalizumab., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: The approval of an increasing number of disease modifying drugs for the treatment of Multiple Sclerosis (MS) creates new challenges for patients and clinicians on the first treatment choice. The main aim of this study was to assess factors impacting first therapy choice in a large Italian MS cohort., Methods: Newly diagnosed relapsing-remitting (RR) MS patients (2010-2018) followed in 24 Italian MS centres were included in the study. We evaluated the association of baseline demographics, clinical and MRI characteristics to the first treatment choice by logistic regression models applied to pre-defined binary alternatives: dimethyl fumarate vs injectables (interferon and glatiramer acetate), teriflunomide vs injectables, fingolimod vs dimethyl fumarate and fingolimod vs natalizumab., Results: We enrolled 3025 patients in the period between January 2010 and June 2018. Relapses in the previous year (OR = 2.75; p = 0.001), presence of spinal cord lesions (OR = 1.80; p = 0.002) and higher number (>9) of T2 lesions on the baseline brain MRI scan (OR = 1.65; p = 0.022) were the factors associated to dimethyl fumarate choice as first therapy vs an injectable drug. Older age (OR = 1.06; p < 0.001), male sex (OR = 2.29; p = 0.001) and higher EDSS (OR = 1.36; p < 0.001) were the factors associated with the choice of teriflunomide vs injectables. In more recent years, dimethyl fumarate (OR = 3.23; p < 0.001) and teriflunomide (OR = 2.53; p < 0.001) were chosen more frequently than injectables therapies. The main determinant for the choice of fingolimod as compared with dimethyl fumarate was a higher EDSS (OR = 1.56; p = 0.001), while there was a weak association with a longer disease duration (p = 0.068) and a longer time from onset to diagnosis (p = 0.085). Compared to fingolimod, natalizumab was preferred in patients with a younger age (OR = 0.95; p = 0.003) and higher EDSS (OR = 1.45; p = 0.007) and a shorter disease duration (OR = 0.52; p = 0.076)., Conclusion: Many factors guided therapeutic decision for our Italian cohort of MS patients; they are mainly related to MS disease activity, baseline EDSS, disease duration and age., Competing Interests: Deckaration of Competing Interest None, (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: A high reactivation of multiple sclerosis (MS) was reported in patients treated with alemtuzumab after fingolimod. We aimed to understand whether this shift enhanced the risk for reactivation in a real-life cohort., Methods: Subjects with relapsing MS, shifting from fingolimod to alemtuzumab were enrolled. We collected the following data: age, sex, disease duration, relapses after fingolimod withdrawal, new T2/gadolinium (Gd)-enhancing lesions in the last magnetic resonance imaging (MRI) during fingolimod and in the first, while on alemtuzumab, lymphocyte counts at alemtuzumab start, and Expanded Disability Status Scale (EDSS) before and after alemtuzumab., Results: We enrolled 77 patients (women 61 (79%); mean age 36.2 years (SD 9.6), and disease duration 12.3 years (SD 6.8) at fingolimod discontinuation; median washout 1.8 months). The annualised relapse rate was 0.89 during fingolimod, 1.32 during washout, and 0.15 after alemtuzumab (p = 0.001). The EDSS changed from a median of 3 (IQR 2-4) at the end of fingolimod to 2.5 after alemtuzumab (IQR 1.5-4) (p = 0.013). The washout length and the lymphocyte count before alemtuzumab were not associated with EDSS change after alemtuzumab (p = 0.59 and p = 0.33, respectively). MRI activity decreased after alemtuzumab compared to that during fingolimod (p = 0.001). At alemtuzumab start, lymphocyte counts were < 0.8 × 10 3 /mL in 21 patients., Conclusions: In our cohort, alemtuzumab reduced relapse, new T2/Gd-enhancing lesions, and EDSS score, as compared to the previous periods (fingolimod/washout). These results were not related to washout length or lymphocyte counts. Therefore, a rapid initiation of alemtuzumab after fingolimod does not seem to be a risk factor for MS reactivation.

Background: With many options now available, first therapy choice is challenging in multiple sclerosis (MS) and depends mainly on neurologist and patient preferences., Objectives: To identify prognostic factors for early switch after first therapy choice., Methods: Newly diagnosed relapsing-remitting MS patients from 24 Italian centers were included. We evaluated the association of baseline demographics, clinical, and magnetic resonance imaging (MRI) data to the switch probability for lack of efficacy or intolerance/safety with a multivariate Cox analysis and estimated switch rates by competing risks models., Results: We enrolled 3025 patients. The overall switch frequency was 48% after 3 years. Switch risk for lack of efficacy was lower with fingolimod (hazard ratio (HR) = 0.50; p  = 0.009), natalizumab (HR = 0.13; p  < 0.001), dimethyl-fumarate (HR = 0.60; p  = 0.037), teriflunomide (HR = 0.21; p  = 0.031) as compared to interferons. Younger age (HR = 0.96; p  < 0.001), diagnosis delay (HR = 1.23; p  = 0.021), higher baseline Expanded Disability Status Scale (HR = 1.17; p  = 0.001), and spinal cord lesions (HR = 1.46; p  = 0.001) were independently associated with higher inefficacy switch rates. We found lower switch for intolerance/safety with glatiramer acetate (HR = 0.61; p  = 0.001), fingolimod (HR = 0.35; p  = 0.002), and dimethyl-fumarate (HR = 0.57; p  = 0.022) as compared to interferons, while it increased with natalizumab (HR = 1.43; p  = 0.022). Comorbidities were associated with intolerance switch (HR = 1.28; p  = 0.047)., Conclusion: Several factors are associated with higher switch risk in patients starting a first-line therapy and could be integrated in the decision-making process of first treatment choice.

Background: No postmarketing randomised clinical trials are available about alemtuzumab, and real-world data are limited. We aimed to analyse the efficacy and safety of alemtuzumab in a single-centre cohort of patients with relapsing-remitting MS., Methods: Patients who took alemtuzumab were enrolled. We collected the following data: age, sex, MS history, expanded disability status scale (EDSS), relapses, magnetic resonance imaging (MRI) parameters after alemtuzumab, and adverse events. EDSS scores before alemtuzumab and at the last follow-up were compared by Wilcoxon test. Time to first relapse was analysed after dividing the cohort on the basis of previous treatment., Results: Ninety patients were enrolled [women 74.4%; naïve 7; mean follow-up 27 months (SD 23)]. The EDSS was reduced from a median of 2.5 (IQR 1.5-4) before alemtuzumab to 2.0 (IQR 1.5-3.5) after (p = 0.025). The time to first relapse was shorter in patients shifting from a second-line therapy (p = 0.011). Over 2 years, 43.7% had no evidence of disease activity. We observed infusion-related reactions in 95.5% patients, including 11.1% with pneumonitis, thyroiditis in 11%, and thrombocytopenia in 3.3%., Conclusions: We confirmed the clinical and MRI efficacy of alemtuzumab in the clinical setting and the frequency of infusion-related reactions. Compared with that in clinical trials, higher number of patients developed pneumonitis during infusion.

Objective: Cognitive impairment concerns a significant percentage of patients with multiple sclerosis (MS). A transient impairment of cognition with a simultaneous presence of non-symptomatic gadolinium (Gd)-enhancing lesions in patients with MS was previously described. Our study aimed to evaluate modifications in cognitive function before and after the occurrence of asymptomatic MRI gadolinium (Gd)-enhancing lesions in relapsing MS patients., Patients and Methods: All patients underwent a neuropsychological evaluation before (30-60 days) and after (30-60 days) brain MRI with Gd administration. Patients were classified as Gd positive (presence of enhancing-lesions) and Gd negative (absence of enhancing-lesions). We also recruited a healthy controls group underwent to the same neuropsychological assessment for two times with the same timing of MS patients., Results: We included 84 relapsing-remitting patients and 40 healthy controls. Brain MRI results showed that 14/84 (16.7%) patients had asymptomatic Gd-enhancing-lesion. No significant variation in cognitive performance between baseline and follow-up was observed in patients with or without MRI-enhancing lesions. However, an increase between baseline and follow-up was observed in the mean scores of the Symbol Digit Modality Test (41.9 at baseline versus 46.7 at follow-up, p :< 0.001). This increase was significantly lower in Gd positive patients compared to Gd negative patients (mean increase 1.1 in Gd positive versus 4.9 in Gd negative, p: < 0.001) and to healthy controls groups (mean increase 7.2; p < 0.001) CONCLUSIONS: In our study, the absence of a practice effect in Gd positive compared to Gd negative patients and to healthy controls suggests a possible role of focal inflammation on cognitive function of MS patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Few studies have evaluated the impact of physical activity (PA) on cognition and fatigue, and none have considered the effects of PA on the relationship between cognition and fatigue., Objectives: We evaluated the effect of PA in people with multiple sclerosis (pwMS) in a 6-month-long single-blind randomized controlled trial. We focused on the impact of exercise on cognition, fatigue, and the relationship between cognition and fatigue., Methods: We recruited pwMS, who were then randomly assigned 1:1 to either a PA protocol group or a control group (CG). All patients underwent assessments using the Brief International Cognitive Assessment for Multiple Sclerosis including symbol digit modality test (SDMT), Berg Balance Scale (BBS), gait analysis, 6-Minute Walk Test, Timed Up and Go (TUG) test, and the Modified Fatigue Impact Scale (MFIS) at the beginning of the study (T0), at the end of the study (EOS) 24 weeks after T0, and at 24 weeks following the EOS (FU)., Results: A Wilcoxon test revealed a significant effect of exercise in the PA group, but not in the CG. Significant differences between T0 and EOS were found in the spatiotemporal parameters of gait, and performance on the SDMT, TUG, BBS, and MFIS. These differences were also present during the FU period. A regression model revealed that the baseline MFIS score predicted processing speed improvement (R 2  = 0.65, p < 0.01), as the SDMT T score increased by 0.3 for each one-unit increase in the MFIS score at T0., Conclusion: PA affects multiple aspects of the pathology in pwMS. Patients with greater fatigue must not be discouraged from exercise, as they may greatly benefit from PA. Specifically, PA was shown to improve information processing speed.

Background: The principal biomarker of neurodegeneration in multiple sclerosis (MS) is believed to be brain volume, which is associated with cognitive functions and retinal nerve fibre layer (RNFL). A cross-sectional and longitudinal assessment of the relationship between RNFL, cognitive functions and brain volume., Methods: At baseline, relapsing patients and healthy controls underwent 1.5 T MRI to estimate the normalized volume of brain (NBV), grey (NGV), white (NWV) and peripheral grey (pNGV) matter. Cognitive functions were evaluated by BICAMS, RNFL by Spectral-Domain OCT. Patients were re-evaluated after 12 months., Results: Cognitive functions, brain volume, and RNFL differed between the group of 66 patients and that of 16 healthy controls. In the MS group, at baseline, an association was found between: p-NGV and symbol-digit (SDMT) (p = 0.022); temporal-RNFL and NBV (p = 0.007), NWV (p = 0.012), NGV (p = 0.048), and p-NGV (p = 0.021); papillo-macular bundle-RNFL and NBV (p = 0.013), NWV (p = 0.02), NGV (p = 0.049), and p-NGV (p = 0.032). Over the observational period, we found a reduction of brain volume (p < 0.001), average-RNFL (p = 0.001), temporal-RNFL (p = 0.006), and papillo-macular bundle-RNFL (p = 0.009). No association was found between OCT, MRI, and cognitive changes., Conclusions: Brain volume, cognitive functions, and RNFL are continuous measures of different neurodegenerative aspects. BICAMS and OCT have low costs and can be easily used in clinical practice to monitor neurodegeneration.

Background: The dual task paradigm (the simultaneous performance of motor and cognitive task) is used in a laboratory setting to evaluate walking impairments that affect patients' daily lives. Although promising, it is poorly standardized and neither the cognitive task nor the motor task have been validated in a matched healthy control group (HC) for multiple sclerosis (MS)., Objective: Our aim was to set up a standardized instrument to evaluate cognitive motor interference in MS using the interference test par excellence: the stroop colour word test (SCWT)., Methods: Patients with MS and HC underwent 3D gait analysis with a dual task protocol, using the SCWT as a cognitive task. Gait performance impairment during the dual task was evaluated by dual task cost (DTC). A MANOVA was used to verify the effect of status (MS, HC) on DTC, calculated for the spatiotemporal parameter of the gait., Results: In MS, the DTC was higher for the following gait parameters: speed (p = .013), cadence (p = .004), stride time (p = .005) stance phase (p < .001), and swing phase duration (p = .032)., Conclusion: DTC is present in MS and HC, but the motor cost in MS is higher. The present work provides a useful and validated basis for future studies about cognitive motor interference in MS., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Autologous hematopoietic stem cell transplantation (aHSCT) is used in aggressive relapsing and progressive multiple sclerosis (MS). The multicentre studies and case series reported have relatively short follow-up., Aim: To evaluate long-term effect and safety of HSCT in MS., Materials and Methods: Patients referred to the MS centre of Cagliari and undergoing HSCT were included. Variations in relapses and EDSS before and after HSCT were evaluated by Wilcoxon test. A descriptive analysis was made for other clinical data., Results: Nine patients (female 6, males 3; 5 relapsing-remitting, 2 secondary progressive, 1 primary progressive, and 1 progressive relapsing) performed HSCT (1999-2006). The median follow-up was 11 years (11-18). Eight patients underwent aHSCT, seven using a low intensity conditioning regimen, and one an intermediate intensity. The primary progressive underwent allogeneic HSCT, due to onco hematological disease. The relapses number decreased in the 2 years following the procedure compared to the two preceding years (p = 0.041). New relapses or disease progressions were observed after a range of 7 (low intensity regimen)-118 (intermediate intensity) months. At last follow-up, the EDSS was stable in two patients, improved in two, and worse in five (maximum 2 EDSS in one patient). Six patients showed new lesions, and seven gadolinium-enhancing on brain MRI after a mean of 23.3 and 19.8 months, respectively. Two serious adverse events were reported: melanoma, and progressive multifocal leukoencephalopathy., Conclusions and Discussion: Our results confirm in a long follow-up the efficacy of HSCT in reducing relapses and disability progression. The risk/benefit profile is better for intermediate intensity regimens.

Background: Several reports suggest a higher risk of psychiatric disorders after high-dose corticosteroids (HDC), routinely used to treat clinical relapses in multiple sclerosis (MS). The present study aimed to examine the possible effect of HDC on mood in patients with MS and to determine the specific factors that influence mood changes., Methods: The study included MS patients prior to receive HDC. The presence of depressive and bipolar symptoms was determined with the Beck Depression Inventory-Second Edition (BDI-II) and the Mood Disorder Questionnaire (MDQ). These assessments were made at three time points: prior to HDC initiation, after HDC completion, and 1 month after HDC., Results: The study included 101 MS patients. At baseline, 32 (31.7%) patients had depressive symptoms (BDI-II scores ≥ 14) and 20 (19.8%) patients had bipolar symptoms (MDQ scores ≥ 7). While it was observed a reduction of BDI-II scores after HDC, an increase in MDQ score was found in patients with MDQ positivity at baseline, resulting associated with a higher number of HDC infusions (p 0.018)., Conclusions: Our results emphasize the importance of accurate screening for mood disorders in patients with MS prior to HDC initiation, and indicate that HDC should be used with caution in patients with MDQ positivity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We report the case of a 42-year-old female patient who developed peculiar skin lesions due to subcutaneous polyethylene glycol (PEG) interferon beta-1a. The dermatological examination showed hypochromic macules that had coalesced into a 10-cm-diameter patch. On the abdomen injection sites, there was a greyish diffuse hyperpigmentation arranged irregularly in annular macules. Fungal infection, vitiligo and pityriasis alba were excluded. After 6 months, the lesions had worsened. This is the first case of localized pigmentation disorder reported with interferon beta, and while the clinical findings are not ascribable to vitiligo or interferon-related facial/mucosal hyperpigmentation, they may partially share the underlining mechanisms.

Background and Objective: A critical aspect of multiple sclerosis (MS) treatments is understanding the effect of disease-modifying drugs (DMDs) on the long-term risk of disability and whether the effect is related to disability at start of treatment., Methods: We performed an observational study on 3060 MS patients. The effect of therapy on progression to Expanded Disability Status Scale (EDSS) 3.0 and 6.0 from onset was analysed in treated vs untreated (UTP) patients using Cox regression analysis adjusted for propensity score and immortal time bias., Results: Compared to UTP, the risks of EDSS 3.0 were 94% and 73% lower in immunomodulant (IMTP-) and immunosuppressant (ISTP-) treated patients, respectively, while the risk of EDSS 6.0 was 86% lower in IMTP. The risk of EDSS 6.0 was, respectively, 91% and 75% lower in 1275 IMTP before and 114 after EDSS 3.0 than in 539 UTP; the risk was higher in IMTP starting therapy after EDSS 3.0 than before (HR = 4.42)., Conclusions: DMDs delayed long-term disability in MS patients treated either in the early or, to a lesser extent, in the later phase of the disease. Thus, the window of therapeutic opportunity is relatively extended, assuming that early is better than late treatment, but late is better than never., (© The Author(s), 2014.)