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Background: Neurofilament light chain (NFL) is a neuroaxonal cytoskeletal protein released into cerebrospinal fluid (CSF) and eventually into blood upon neuronal injury. Its detection in serum (sNFL) makes it a promising marker in multiple sclerosis (MS)., Objective: To evaluate the usefulness of a single dosage of sNFL in clinical practice., Methods: 626 consecutive relapsing-remitting (RR) MS patients treated with disease modifying treatments (DMTs) for at least 12 months underwent a single sNFL dosage. 553 patients had NEDA-3 status (no relapses, no disability progression, no new/enlarging or contrast-enhancing lesions on brain magnetic resonance imaging) in the 12 months prior blood sampling. sNFL levels were measured by single molecule array (Simoa™). Association between sNFL levels and NEDA-3 status at 12, 24, and 36 months was evaluated with logistic regression models adjusted for sex, EDSS, disease duration, and type of DMTs., Results: 469 out of the 553 NEDA-3 patients had normal sNFL level, whereas 42 had elevated level. The two groups did not differ regarding baseline characteristics. A very strong association between elevated sNFL levels and loss of NEDA-3 status within 12 months was found, with an odds ratio [OR] of 10.74 (95% CI 4.34-26.57); 15 and 10 patients with normal and elevated sNFL, respectively lost NEDA-3 (p < 0.001). The effect was not detected during the subsequent 13-24 and 25-36 months., Conclusions: A single elevated sNFL is strongly associated with NEDA-3 loss within 1 year. Elevated sNFL in apparently stable patients suggests an ongoing disease activity below the detection threshold of standard parameters., Competing Interests: Declarations. Conflicts of interest: Malucchi Simona received compensation for speaking and consulting from Biogen, Merck, Novartis, Roche. Valentino Paola received speaker honoraria from Roche, research support from Merck, grant support from Quanterix. Bava Cecilia Irene: nothing to discose. Martire Serena: nothing to disclose. Di Sapio Alessia received compensation for speaking and consulting by Biogen, Novartis, Roche, Sanofi, Alexion, Sandoz and reimbursement by Merck, Biogen, Genzyme and Roche for attending conferences. Lo Re Marianna received compensation for consulting by Novartis. Bertolotto Antonio served on the scientific advisory board of Almirall, Bayer, Biogen, Genzyme; received speaker honoraria from Biogen, Novartis, Sanofi, grant support from Almiral, Biogen, Associazione San Luigi Gonzaga ONLUS, Fondazione per la Ricerca Biomedica ONLUS, Mylan, Novartis and the Italian Multiple sclerosis Society. Ethical approval: The study was approved by the ethical committee of San Luigi Gonzaga University Hospital (approvals number 7262/2019 and 18,390/2019). All participants provided informed consent., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: In the field of research for new validated surrogate biomarkers of treatment efficacy, disease activity and progression in Multiple Sclerosis (MS), serum neurofilament light-chain (sNFL) are actually the best candidate for MS patient monitoring. However, before they can be implemented in clinical practice, their usefulness as additional red flag routine measure must be demonstrated. To tackle the problem, this real-life cross-sectional study at the Regional Referring Center for Multiple Sclerosis (CRESM) aims to characterize sNFL levels and prevalence of elevated sNFL, according to our age-dependent cut-off values, in a large group of patients with different types of MS and treatment conditions., Methods: 908 serum samples from as many MS patients being admitted at CRESM for diagnostic definition and/or during routinary treatment monitoring were consecutively collected between January 2019 and January 2020. sNFL levels were measured by single molecule array (Simoa™) technology on SR-X instrument using NF-light assays (Quanterix); results were interpreted using previously published cut-off values., Results: Primary and Secondary Progressive MS (PPMS, SPMS) forms demonstrate higher levels and prevalence of elevated sNFL (PPMS= 32 %, SPMS= 21 %) compared to the Relapse and Remitting one (RRMS = 12 %). Besides, naïve samples of RRMS and PPMS subtypes showed higher prevalence of elevated sNFL (RRMS naïve= 31 %, PPMS naïve=67 %) compared to samples from patients treated for more than 12 months (RRMS treat>12m= 9 %, PPMS treat>12m= 19 %); treated SPMS patients demonstrated higher sNFL levels and a prevalence (22 %) of elevated sNFL compared to RRMS treated patients. Focusing on RRMS, no statistical difference was found between groups of patients treated for whatever time (up to or more than 60 months) and with either DMT type (high or low-efficacy DMT). Finally, RRMS patients treated with all DMTs for more than 12 months, with the exception of teriflunomide and alemtuzumab showed a prevalence of elevated sNFL in the range of 5-10 %., Conclusion: in a real-world setting comprising about 1000 MS patients, sNFL quantification was elevated in 5-to-67 % of patients, in different MS forms and treatment conditions. Elevated levels of sNFL must be considered a red-flag suggesting the need of a further clinical monitoring in any circumstance, as it can be indicative of new inflammation, ongoing degeneration or co-morbidities. This study supports the introduction of sNFL quantification in everyday patient management., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Antonio Bertolotto reports financial support was provided by Roche SpA. Antonio Bertolotto reports financial support was provided by Italian Multiple Sclerosis Association. Paola Valentino reports a relationship with Biogen that includes: speaking and lecture fees and travel reimbursement. Paola Valentino reports a relationship with Novartis that includes: speaking and lecture fees and travel reimbursement. Paola Valentino reports a relationship with Roche SpA that includes: speaking and lecture fees and travel reimbursement. Paola Valentino reports a relationship with Merck & Co Inc that includes: funding grants. Paola Valentino reports a relationship with Quanterix Corp that includes: funding grants. Simona Malucchi reports a relationship with Biogen that includes: speaking and lecture fees and travel reimbursement. Simona Malucchi reports a relationship with Merck & Co Inc that includes: speaking and lecture fees and travel reimbursement. Simona Malucchi reports a relationship with Novartis that includes: speaking and lecture fees and travel reimbursement. Simona Malucchi reports a relationship with Roche SpA that includes: speaking and lecture fees and travel reimbursement. Serena Martire reports a relationship with Biogen that includes: board membership, consulting or advisory, speaking and lecture fees, and travel reimbursement. Serena Martire reports a relationship with Novartis that includes: board membership, consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Bertolotto reports a relationship with Almirall that includes: board membership, consulting or advisory, and funding grants. Antonio Bertolotto reports a relationship with Bayer that includes: board membership and consulting or advisory. Antonio Bertolotto reports a relationship with Biogen that includes: board membership, consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Antonio Bertolotto reports a relationship with Genzyme Corporation that includes: board membership and consulting or advisory. Antonio Bertolotto reports a relationship with Novartis that includes: funding grants, speaking and lecture fees, and travel reimbursement. Antonio Bertolotto reports a relationship with Sanofi that includes: speaking and lecture fees and travel reimbursement. Antonio Bertolotto reports a relationship with Associazione San Luigi Gonzaga ONLUS that includes: funding grants. Antonio Bertolotto reports a relationship with Fondazione per la Ricerca Biomedica ONLUS that includes: funding grants. Antonio Bertolotto reports a relationship with Mylan Pharmaceuticals Inc that includes: funding grants. Antonio Bertolotto reports a relationship with Italian Multiple Sclerosis Association that includes: funding grants. Rugiada Bottero reports a relationship with Novartis that includes: consulting or advisory. Rugiada Bottero reports a relationship with Sanofi that includes: consulting or advisory. Rugiada Bottero reports a relationship with Merck that includes: consulting or advisory. Alessia Di Sapio reports a relationship with Biogen that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Alessia Di Sapio reports a relationship with Novartis that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Alessia Di Sapio reports a relationship with Roche that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Alessia Di Sapio reports a relationship with Sanofi that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Alessia Di Sapio reports a relationship with Alexion that includes: speaking and lecture fees and travel reimbursement. Alessia Di Sapio reports a relationship with Merck that includes: travel reimbursement. Alessia Di Sapio reports a relationship with Genzyme Corporation that includes: travel reimbursement. 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 Elsevier B.V. All rights reserved.)

Background: Neurofilament light chains (NfL) are cytoskeletal biomarkers of axonal damage, about 40-fold higher in cerebrospinal fluid (CSF) compared to serum, and requiring ultrasensitive techniques to be measured in this latter fluid., Objectives: To compare CSF and serum NfL levels in multiple sclerosis (MS) patients using different platforms., Methods: 60 newly diagnosed relapsing-remitting MS patients (38 females; median age: 36.5 years, range: 15-60) were enrolled before steroid or disease-modifying treatments. CSF and serum NfL were measured with: the commercial Ella™ microfluidic platform (Bio-Techne), the Lumipulse™ Chemiluminescent Enzyme ImmunoAssay (Fujirebio), and the SIMOA™ on the SR-X instrument using NF-light assays (Quanterix)., Results: CSF and serum NfL absolute levels strongly correlated between assays, although being more elevated with Ella™. Passing-Bablok regression showed high agreement in measuring CSF NfL between assays (with greater proportional difference using Ella™), and very high agreement for serum comparing SIMOA™ and Lumipulse™. Similarly, the Bland-Altman comparison evidenced lower biases for Lumipulse™ for both fluids., Conclusions: CSF and serum NfL in naïve MS patients are reliably measured with all assays. Although not interchangeable, SIMOA™ and Lumipulse™ showed high agreement for serum and CSF values., Competing Interests: Declaration of competing interest Conflicts of interest/Competing interests: none for all authors for this work; Ethics approval: local Ethical Committee approvals (Comitato Etico Interaziendale AOU "Maggiore della Carità" di Novara, ASL BI, ASL NO, ASL VCO): CE 060/2022 and 260/2022). Consent to participate/consent for publication: written consent obtained from all participants; Availability of data and material: data available on request., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: EASIER is a multicenter, observational, cross-sectional study investigating the consumption of healthcare resources, including healthcare professional (HCP) active working time, the costs associated with the current natalizumab intravenous (IV) administration, and the potential impact of the adoption of subcutaneous (SC) route., Methods: The EASIER study has three parts: (1) time and motion study to measure healthcare resources and working time needed for natalizumab IV administration using a digital data collection tool operated directly by HCPs; (2) HCP structured questionnaire-based estimation of the potential impact of natalizumab SC vs. IV administration; and (3) patient survey on the burden of natalizumab administration., Results: Nine Italian multiple sclerosis (MS) centers measured 404 IV natalizumab administration procedures and administered 26 HCP questionnaires and 297 patient questionnaires. Patients had a mean of 52 (range 1-176) previous IV administrations and spent a mean (median, IQR) of 152 (130, 94-184) minutes in the center per each IV procedure, with IV infusion covering 50% of the total. Including patient travel time, an average of 5 h was dedicated to each IV administration. Active working time by HCP amounted to 29 min per IV administration procedure, 70% of which by nursing staff. With adoption of the SC route, HCPs estimated a 50% reduction in patient procedure time and 55% lower HCP active working time. This translated into a 63% cost reduction for the MS center per natalizumab administration procedure., Conclusions: SC natalizumab administration will consistently reduce consumption of patient and HCP times per procedure and associated costs., (© 2023. The Author(s).)

Background: COVID-19 vaccines have been recommended to people with multiple sclerosis (pwMS) and, to ensure durable immunity, a third booster dose has been administered in several countries. Data about potential risks associated with the third booster dose in pwMS, such as vaccine-triggered disease exacerbations, are still scarce., Objective: To investigate whether the administration of a third booster dose of mRNA COVID-19 vaccines was associated with an increased risk of short-term disease reactivation in a large cohort of pwMS., Methods: We retrospectively selected 1265 pwMS who received a third booster dose of an mRNA COVID-19 vaccine. Demographic and clinical data were collected, including the presence, number and characteristics of relapses in the 60 days prior to and after the third booster dose., Results: In the selected cohort, the relapse rate in the two months after administration of the third booster dose of mRNA COVID-19 vaccines did not increase when compared with the prior two months. Indeed, the percentage of pwMS experiencing relapses in the 60 days following the administration of the third booster dose was 2.1%, similar to the percentage recorded in 60 days prior to vaccination, which was 1.9%., Conclusions: The third booster dose of mRNA COVID-19 vaccines appeared to be safe for pwMS., (© 2023. The Author(s).)

Background: Cognitive impairment (CI) is a prevalent and debilitating manifestation of multiple sclerosis (MS); however, it is not included in the widely used concept of No Evidence of Disease Activity (NEDA-3). We expanded the NEDA-3 concept to NEDA-3 + by encompassing CI assessed through the Symbol Digit Modality Test (SDMT) and evaluated the effect of teriflunomide on NEDA3 + in patients treated in a real-world setting. The value of NEDA-3 + in predicting disability progression was also assessed., Methods: This 96-weeks observational study enrolled patients already on treatment with teriflunomide for ≥ 24 weeks. The predictiveness of NEDA-3 and NEDA-3 + at 48 weeks on the change in motor disability at 96 weeks was compared through a two-sided McNemar test., Results: The full analysis set (n = 128; 38% treatment naïve) featured relatively low level of disability (baseline EDSS = 1.97 ± 1.33). NEDA-3 and NEDA-3 + statuses were achieved by 82.8% and 64.8% of patients, respectively at 48 weeks vs. baseline, and by 57.0% and 49.2% of patients, respectively at 96 weeks vs. baseline. All patients except one were free of disability progression at Week 96, and NEDA-3 and NEDA-3 + were equally predictive. Most patients were free of relapse (87.5%), disability progression (94.5%) and new MRI activity (67.2%) comparing 96 weeks with baseline. SDMT scores were stable in patients with baseline score ˃35 and improved significantly in those with baseline score ≤ 35. Treatment persistence was high (81.0% at Week 96)., Conclusion: Teriflunomide confirmed its real-world efficacy and was found to have a potentially beneficial effect on cognition., (© 2023. The Author(s).)

Background: The earliest detection of progressive multifocal leukoencephalopathy (PML) is crucial in Natalizumab (NTZ)-treated Multiple Sclerosis (MS) patients. This study aims to assess serum Neurofilaments (sNFL) ability to early detect PML in longitudinal patients' follow-up., Methods: NFL were retrospectively measured in four PML cases occurred at the Regional Referring Center for MS (CRESM, Italy), in samples collected since one year before PML diagnosis, at PML diagnosis, during PML and in post-PML follow-up. sNFL levels were interpreted according to previously defined reference values. Clinical examination and EDSS were performed at each NTZ infusion. Routinary MRI was undertaken every six months; after PML diagnosis, MRI was performed according to clinical evaluation. sNFL were also measured in 45 NTZ-treated patients experiencing NEDA-3 status for at least 12 months., Results: Patients showed different PML onsets and manifestations: in 3 patients routinary brain MRI revealed radiological signs of PML preceding different clinical manifestations, while in one patient brain MRI was performed after the clinical onset. PML diagnosis was defined at the time of the first detection of JCV DNA in cerebrospinal fluid. The following different PML phases were considered: 1. Basal (up to 4 months before PML diagnosis): sNFL values were in the normal range in all patients' samples, except for one (median 9.1 pg/ml, range 6.2-15.1 pg/ml) 2. Pre-PML (within 3 months before PML diagnosis): sNFL were elevated in all available samples (median 19.50 pg/ml, range 15.50-33.80 pg/ml). 3. PML diagnosis: sNFL were elevated in all patients (median 59.20 pg/ml, range 11.1-101.50 pg/ml). 4. PML/IRIS: during this phase, sNFL levels reached their peak (median 96.35 pg/ml, range 20.5-272.9) in all patients. 5. Post-PML (recovery phase, starting from the first MRI without enhancement, up to the end of follow-up): sNFL levels showed a decrease (median 12.80 pg/ml, range 9.30-30.60); however, based on reference values, sNFL were still elevated in 2 out of 4 patients at the end of their follow-up (622 and 887 days after PML diagnosis). sNFL were always elevated when MRI scan suggested a suspicious of PML. In NEDA-3 patients, sNFL levels were in the normal range in all patients' samples (median 4.7 pg/ml, range 1.4-8.6 pg/ml)., Conclusion: Elevated sNFL were observed not only at PML diagnosis, but also in pre-PML phase. At PML recovery, sNFL weren't normalized in all patients' samples, suggesting ongoing neuronal degeneration. sNFL represent a reliable biomarker and should be introduced in clinical practice as an additional/alternative parameter to MRI to early detect and monitor PML., Competing Interests: Declaration of Competing Interest Valentino Paola received speaker honoraria from Roche, research support from Merck and grant support from Quanterix. Malucchi Simona received speaker honoraria from Biogen and Roche. Bava Cecilia Irene: nothing to discose Martire Serena: nothing to discose Capobianco Marco served on the scientific advisory board of Biogen, Sanofi Genzyme, Novartis, Roche, Becton-Dickinson, Alexion and Horizon and received speaker honoraria from Almirall, Biogen, Novartis, Sanofi Genzyme. Malentacchi Maria: nothing to discose Sperli Francesca: nothing to discose Oggero Alessandra: nothing to discose Di Sapio Alessia received personal compensation for speaking and consulting by Biogen, Novartis, Roche, Sanofi and Alexion and has been reimbursed by Merck, Biogen, Genzyme and Roche for attending several conferences. Bertolotto Antonio served on the scientific advisory board of Almirall, Bayer, Biogen, and Genzyme; received speaker honoraria from Biogen, Novartis and Sanofi and grant support from Almiral, Biogen, Associazione San Luigi Gonzaga ONLUS, Fondazione per la Ricerca Biomedica ONLUS, Mylan, Novartis and the Italian Multiple sclerosis Society., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: B-cell-depleting agents have been widely used for neuromyelitis optica spectrum disorder (NMOSD) and MOG-associated diseases (MOGAD), but no consensus exists on the optimal dose and frequency of treatment administration. The aim of our study was to evaluate the effect of a Rituximab (RTX) personalized treatment approach based on CD27-positive B-cell monitoring on efficacy, safety, and infusion rates., Methods: This is a retrospective, uncontrolled, single-center study including patients with NMOSD and MOGAD treated with RTX at a tertiary multiple sclerosis center at the San Luigi University Hospital, Orbassano, Italy. All the patients were treated with RTX induction, followed by maintenance infusion at the dosage of 1000 mg according to cell repopulation: initially according to total CD19-positive B-cell monitoring (> 0.1% of lymphocytes), and subsequently according to CD27-positive B-cell repopulation (> 0.05% of lymphocytes for the first 2 years, and subsequently > 0.1%). NMOSD and MOGAD activity was assessed as clinical or MRI activity. All patients were screened of the occurrence of severe adverse events (AEs)., Results: A total of 19 patients were included in the analysis. Median follow-up was 7.64 years (range 3.09-16.25). The annualized relapse rate (ARR) 1 year before RTX start was 2.37 [Standard deviation (SD), 1.34] and decreased to 0.08 (SD 0.11) in the subsequent years after RTX initiation. ARR did not differ before and after start of CD27 monitoring. Median inter-dose time was 8.80 (range 5.78-14.23) before CD27 monitoring and 15.93 months (range 8.56-35.37) after CD27 monitoring (p < 0.001). We observed no AEs., Conclusion: Our findings suggest that in our cohort CD27-positive B-cell-based RTX reinfusion regimen was able to reduce the number of RTX reinfusions relative to CD19-positive B-cell monitoring, with comparable efficacy and safety profile. In order to achieve an even more individualized and effective treatment, the FCGR3A genetic polymorphisms could be evaluated when assessing RTX efficacy., (© 2023. The Author(s).)

Background: Clinicians are increasingly recognizing the importance of shared decision-making in complex treatment choices, highlighting the importance of the patient's rationale and motivation for switching therapies. This study aimed to evaluate the association between different modalities of changing multiple sclerosis (MS) treatments, cognitive profile and attitude and preferences of patients concerning treatment choice., Methods: This multicenter cross-sectional study was conducted at 28 Italian MS centers in the period between June 2016 and June 2017. We screened all MS patients treated with any DMT, with a treatment compliance of at least 80% of therapy administered during the 3 last months who needed to modify MS therapy because of efficacy, safety or other reasons during a follow-up visit. At the time of switching the symbol digit modalities test (SDMT) and the Control Preference Scale (CPS) were evaluated. According to the CPS, patients were classified as "active" (i.e. who prefer making the medical decision themselves), "collaborative" (i.e. who prefer decisions be made jointly with the physician), or "passive" (i.e. who prefer the physician make the decision)., Results: Out of 13,657 patients recorded in the log, 409 (3%) changed therapy. Of these, 336 (2.5%) patients, 69.6% were female and with mean age 40.6 ± 10.5 years, were enrolled. According to the CPS score evaluation, a significant high percentage of patients (51.1%) were considered collaborative, 74 patients (22.5%) were passive, and 60 (18.2%) patients were active. Stratifying according to CPS results, we found a higher SDMT score among collaborative patients compared to active and passive ones (45.8 ± 12.3 versus 41.0 ± 13.2 versus 41.7 ± 12.8, p < 0.05)., Conclusion: In this study, the CPS evaluation showed that more than 50% of patients who needed to change therapy chose a "collaborative" role in making treatment decision. Cognitive profile with SDMT seems to correlate with patients' preference on treatment decision, showing better scores in collaborative patients., Competing Interests: Declaration of Competing Interest Francesco Patti 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. Clara G. Chisari has received grants for congress participation from Almirall, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. Simona Toscano declares no conflict of interest. Pietro Annovazzi has received honoraria for lecturing and participation in advisory boards, and/or travel expenses for attending congresses and meetings from Almirall, Biogen Idec, Merck Serono, Mylan, Novartis, Roche, Sanofi Genzyme, and TEVA. Paola Banfi has received support for attendance to scientific meetings from Biogen Idec, Merck Serono, Novartis, and Sanofi Genzyme. Roberto Bergamaschi has received honoraria for lectures, travel and registration coverage for attending several national or international congresses or symposia from Almirall, Bayer Shering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Aventis, Sanofi Genzyme, and TEVA. Raffaella Clerici has received speaker's honoraria, consulting fees, honoraria in advisory boards, support for attendance of scientific meetings from Meck Serono, Novartis, and Sanofi Genzyme. Marta Zaffira Conti declares there is no conflict of interest. Antonio Cortese has received speaker honoraria, travel grants, advisory boards member honoraria from Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, and TEVA. Roberta Fantozzi has received consulting fees and honoraria for advisory boards from Biogen Idec, Merck Serono, Novartis, Roche, and TEVA Diana Ferraro declares there is no conflict of interest. Mariano Fischetti declares there is no conflict of interest. Maura Frigo declares there is no conflict of interest. Maurizia Gatto declares there is no conflict of interest. Paolo Immovilli has received speaking honoraria, consulting fees, advisory board honoraria from Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. Stefania Leoni declares there is no conflict of interest. Simona Malucchi has received speaker's honoraria and consulting fees, honoraria in advisory boards from Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, and TEVA Giorgia Maniscalco has received honoraria for public speaking and advisory boards from Biogen, Novartis, and Merck Serono. Girolama Alessandra Marfia is an Advisory Board member of Biogen Idec, Sanofi Genzyme, Merck-Serono, Novartis, and TEVA, and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme, and TEVA. She is the principal investigator in clinical trials for Actelion, Biogen Idec, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, and TEVA Damiano Paolicelli has received honoraria for consultancy and/or speaking from Almirall, Bayer Shering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. Paola Perini has received speaker honoraria and consulting fees from Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. Carlo Serrati declares no conflict of interest. Rocco Totaro has received speaker's honoraria, consulting fee, honoraria for advisory boards, support for attendance of scientific meetings from Alfa Wasserman, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi genzyme, and TEVA. Gabriella Turano has received support for attendance to scientific meetings from Almirall, Biogen Idec, Merck Serono, Novartis, and Sanofi Genzyme. Paola Valentino has received speaker's honoraria and consulting fee, honoraria for advisory boards from Biogen Idec, Novartis, Merck Serono, Sanofi Genzyme, and TEVA. Mauro Zaffaroni has received honoraria for lecturing or participating for advisory boards or travel funding from Almirall, Biogen, Merck Serono, Novartis, Sanofi Genzyme, and TEVA. Cristina Zuliani has received speaker's honoraria and consulting fees, honoraria for advisory boards, support for attendance of scientific meetings from Almirall, Bayer Shering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. Diego Centonze is an Advisory Board member of Almirall, Bayer Schering, Biogen Idec, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA, and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and TEVA. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi Genzyme, and TEVA. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi Genzyme and TEVA., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: Extended interval dosing (EID) of Natalizumab (NAT) has been proposed to reduce progressive multifocal leukoencephalopathy (PML) risk associated with standard interval dosing (SID) in people with multiple sclerosis (MS). Previous studies have suggested that NAT effectiveness is maintained in the great majority of patients who switch from SID to EID; monitoring of disease activity is currently based exclusively on clinical and MRI parameters. Frequent MRI are expensive and not always applicable, underlining the need for biological markers able to detect central nervous system lesions. Serum Neurofilament-light chain (sNFL) currently represents the most promising biomarker of disease activity, prognosis and treatment response in MS, and their clinical suitability is increasingly evident. The objective of the present study is to assess the applicability of sNFL as additional/alternative measure of treatment efficacy during EID regimen., Methods: We measured sNFL by Simoa technology in longitudinal samples from 63 Relapsing Remitting (RR) MS patients switched from SID to EID., Inclusion Criteria: diagnosis of RRMS, age 18-60 years; NAT SID for at least 12 months; NEDA-3 (no evidence of disease activity) for at least 12 months; availability of at least 2 serum samples collected 6 months apart. Patients' follow-up time during EID was at least 12 months and 2 blood samples were collected after at least 6 and 12 months. Clinical examination was performed before each infusion, while MRI 6 and 12 months after NAT initiation and according to PML risk during the whole study., Results: No patients showed clinical or MRI activity during the whole follow-up. sNFL levels measured during SID and EID were comparable, without significant difference between groups. The effect of EID on NFL levels did not show significant effects (LMM, p> 0.05) and sNFL levels did not vary with time during SID or EID protocols (LMM, p> 0.05). Intra-individual sNFL levels demonstrated overall stability during SID and EID (median CV=11% between SID and EID samples). According to our previously published reference values, sNFL levels were in the normal range in all samples, both during SID and EID., Conclusions: Our results suggest that sNFL quantification can be used as an alternative/additional approach to MRI in managing individual patients. The present work provides a new clinical application of sNFL to monitor NAT efficacy., Competing Interests: Declaration of Competing Interest Valentino Paola received speaker honoraria from Biogen, Novartis and Roche, research support from Merck and grant support from Quanterix. Malucchi Simona received speaker honoraria from Biogen. Martire Serena received speaker honoraria from Biogen and Novartis and served on the advisory boards of Biogen and Novartis Bava Cecilia Irene: nothing to discose Capobianco Marco served on the scientific advisory board of Biogen, Sanofi Genzyme, Novartis, and Bayer Schering and received speaker honoraria from Almirall, Biogen, Novartis, Sanofi Genzyme, and Teva. Bertolotto Antonio served on the scientific advisory board of Almirall, Bayer, Biogen, and Genzyme; received speaker honoraria from Biogen, Novartis and Sanofi and grant support from Almiral, Biogen, Associazione San Luigi Gonzaga ONLUS, Fondazione per la Ricerca Biomedica ONLUS, Mylan, Novartis and the Italian Multiple sclerosis Society., (Copyright © 2022. Published by Elsevier B.V.)

Objective: Assessing the risk of clinical and radiological reactivation during pregnancy and post partum in women with multiple sclerosis (MS) treated with natalizumab (NTZ) throughout pregnancy (LONG&#95;EXP) compared with women interrupting treatment before (NO&#95;EXP) and within >-30 days and ≤90 days from conception (SHORT&#95;EXP), and describing newborns' outcomes., Methods: Maternal clinical and radiological outcomes and obstetric and fetal outcomes were retrospectively collected and compared among groups (NO&#95;EXP, SHORT&#95;EXP, LONG&#95;EXP). Predictors of clinical and radiological reactivation were investigated through univariable and multivariable analysis., Results: 170 eligible pregnancies from 163 women referring to 29 Italian MS centres were included. Annualised relapse rate (ARR) was significantly lower in LONG&#95;EXP (n=66, 0.02 (0.001-0.09)) compared with NO&#95;EXP (n=31, 0.43 (0.21-0.75), p=0.002) and SHORT&#95;EXP (n=73, 0.46 (0.30-0.66), p=0.0004) during pregnancy, and in LONG&#95;EXP (0.12 (0.05-0.24)) compared with SHORT&#95;EXP (0.30 (0.17-0.50), p=0.008) during post partum. Gadolinium-enhancing (Gd+) lesions were less frequent in LONG&#95;EXP (n=6/50, 2.00%) compared with NO&#95;EXP (n=9/21, 42.86%) and SHORT&#95;EXP after delivery (n=17/49, 34.69%, p=0.010).Delaying NTZ resumption after delivery significantly increased the risk of relapses (OR=1.29 (95% CI 1.07 to 1.57), p=0.009) and Gd+ lesions (OR=1.49 (95% CI 1.17 to 1.89, p=0.001). Newborns' weight, length, head circumference and gestational age did not differ among groups after adjusting for confounders. Anaemia was tracked in 4/69 LONG&#95;EXP newborns. Congenital anomaly rate was within the expected range for the untreated MS population., Conclusions: Our findings indicate that in women with MS treated with NTZ before conception, continuation of NTZ throughout pregnancy and its early resumption after delivery mitigate the risk of clinical and radiological reactivation. This approach has no major impact on newborns' outcomes., Competing Interests: Competing interests: DL received travel funding from Biogen, Merck-Serono, Sanofi-Genzyme, Teva, speaking or consultations fees from Sanofi-Genzyme, Merck-Serono, Teva, Biogen, Roche; FB received teaching honoraria from Novartis; AGr reports no disclosures relevant to the manuscript; PA received travel support, compensation for serving on scientific advisory boards and speaker's fees from Almirall, Biogen, Celgene, Merck-Serono, Mylan, Novartis, Sanofi-Genzyme and Teva; ABe reports no disclosures relevant to the manuscript; ABi reports no disclosures relevant to the manuscript; GB received honoraria for speaking or consultation fee from Almirall, Biogen, Merck, Novartis, Sanofi, Teva, Roche; VB received fees for consultancies or public speaking from Merck, Novartis, Biogen, Roche, Genzyme and Biogen; SB has been founded for advisory board, academic purposes and speech honoraria by Genzyme, Roche, Biogen, Merck-Serono, Novartis and Almirall; MCB has advisory board membership and honoraria for speaking from Teva, Novartis, Sanofi, Merck-Serono and Biogen; FC received honoraria for advisory board and/or for public speaking, and/or travel grant, from Biogen, Merck, Teva, Sanofi-Genzyme, Roche; RCa received lecture fees and/or travel grants from Novartis, Biogen, Roche, Celgene and Merck; DC is an Advisory Board member of Almirall, Bayer-Schering, Biogen, GW Pharmaceutical, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva and received honoraria for speaking or consultation fee from Almirall, Bayer-Schering, Biogen, GW Pharmaceuticals, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva. He is also the principal investigator in clinical trials for Bayer-Schering, Biogen, Merck-Serono, Novartis, Roche, Sanofi-Genzyme; RCe has received funding for travel and/or speaker honoraria from Sanofy, Biogen Idec, Merck-Serono and Roche; CGC received grants for congress participation from Almirall, Biogen, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva; MCa received personal compensation for speaking/advising/consulting from Merck, Sanofi-Genzyme, Biogen, Novartis, Roche, Teva, EMF Serono; was supported in travelling expenses for congresses from Merck, Sanofi-Genzyme, Biogen, Novartis, Roche, Teva, Almirall; received research grants from Italian MS Foundation (FISM), Italian Ministry of Research, Merck, Sanofi-Genzyme, Biogen, Novartis; ECo received travel grant, speaker fee and consultancy from Biogen Idec, Teva, Genzyme, Merck-Serono, Novartis, Roche and Admirall; CC received personal compensation for advisory board and speaking from: Biogen, Roche, Novartis, Almirall, Merck-Serono; ECu received fees for advisory boards and speaking honoraria from Merck-Serono, Novartis and Biogen, travel funding from Biogen, Sanofi-Genzyme, Merck-Serono, Roche, Novartis and Teva; AD reports no disclosures relevant to the manuscript; EDA received speaking honoraria from Biogen, Merck-Serono, Novartis, Sanofi-Genzyme, Bayer-Schering; GDL served on scientific advisory boards for Merck, Sanofi-Genzyme and Roche, and has received travel and/or speaker honoraria from Merck, Roche, Teva, Biogen, Novartis and Sanofi-Genzyme; MDF participated on advisory boards for and received speaker or writing honoraria and funding for travelling from Bayer, Biogen Idec, Genzyme, Merck, Mylan, Novartis, Roche and Teva; DF has received travel grants, speaker honoraria and/or research support to her institution by Merck-Serono, Biogen, Roche, Genzyme, Novartis, Teva and Binding Site; AGa received speaker and consulting fees from Actelion, Biogen, Coloplast, Merck-Serono, Mylan, Roche, Sanofi-Genzyme, Teva; CG received fee as speaker or advisory board from Merck, Biogen, Teva, Bayer, Roche, Sanofi, Almirall; FG received research funding from Sanofi-Genzyme and Biogen, fees for advisory boards and speaking honoraria from Biogen, Novartis, Sanofi-Genzyme, Merck-Serono and Roche, travel funding from Biogen, Sanofi-Genzyme, Merck-Serono and Roche; MI received grants from NIH, NMSS, FISM; received fees for consultation from Roche, Genzyme, Merck, Biogen and Novartis; RL received fees for consultancies or public speaking from Merck, Novartis, Biogen, Roche, Genzyme and Biogen; LL received travel grant, speaker fee and consultancy from Biogen Idec, Teva, Genzyme, Merck-Serono, Novartis, Roche and Admirall; GL received speaker honoraria and/or consultancy from Biogen, Teva, Genzyme, Merck, Novartis, Almirall, Roche; MM received personal fees from Sanofi-Genzyme, Merck-Serono, Novartis and Almirall; MM has scientific advisory board membership of Bayer-Schering, Biogen, Sanofi-Genzyme, Merck, Novartis, Teva; consulting and/or speaking fees, research support or travel grants from Almirall, Bayer-Schering, Biogen, CSL, Sanofi-Genzyme, Merck, Novartis, Teva, Roche, Ultragenix; principal investigator in clinical trials for Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, Teva, Ultragenix, CSL Behring; LM received honoraria for speaking activity at scientific meetings and/or advisory boards from Biogen Idec, Merck-Serono, Sanofi-Genzyme, Novartis, Roche; CGN received travel funding from Almirall, Biogen, Novartis and Sanofi-Genzyme, Merck-Serono; VN has received consulting fees from Novartis, Roche, Mylan, Biogen Idec, Merk and Bayer; speaker and writing honoraria from Mylan, Teva, Biogen Idec, Bayer, Sanofi-Genzyme and Merk; travel grants from Teva, Biogen Idec, Sanofi-Genzyme, Roche and Novartis; FPa 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; EP received compensation for travel grants, participation in advisory board and/or speaking activities from Biogen, Merck-Serono, Sanofi, Teva and Novartis; serves on the editorial board of Frontiers in Neurology and Brain Sciences; CP received honoraria for speaking or consultation fee from Almirall, Biogen, Merck, Novartis, Sanofi, Teva, Roche; PR received travel expenses or honoraria for speaking or participating to advisory board by: Biogen, Merck, Sanofi-Genzyme, Novartis, Teva, Roche; GS received travel expenses or honoraria for speaking or participating to advisory board by: Biogen idec, Sanofi-Genzyme, Novartis, Roche; ESi received speaker honoraria and/or consultancy from Biogen, Teva, Genzyme, Merck, Novartis, Almirall, Roche; FV has received travel grants and/or speaker honoraria by Merck-Serono, Biogen, Roche, Genzyme, Novartis and Teva; RT has served on advisory boards and/or received honoraria for speaking or consultation fees from Almirall, Biogen, Laborest, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva; MPS received personal fees from Biogen, Merck, Teva, Novartis, Sanofi-Genzyme, Roche, GeNeuro and Medday, outside the submitted work; MPA received research grants and honoraria as a speaker and member of advisory boards by: Bayer, Biogen, Merck, Novartis, Sanofi-Genzyme, Teva, Almirall, Celgene and Roche; GAM received speaking or consultation fees from Almirall, Bayer-Schering, Biogen, Genzyme, Merck-Serono, Novartis, Teva, Sanofi-Genzyme., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Fingolimod (FTY) induces sequestration of lymphocytes in secondary lymphoid organs and the average lymphocyte recovery following discontinuation takes 1-2 months. It has been hypothesized that the therapeutic effects of subsequent cell-depleting agents may be compromised if initiated before lymphocyte recovery has occurred., Objective: To assess the risk of relapses following FTY discontinuation and the initiation of a B/T cell-depleting agent in relation to washout duration using data from the Italian MS Register., Methods: The risk of relapses was assessed in relation to different washout durations (< 6, 6-11, 12-17 and > / = 18 weeks) in patients starting alemtuzumab, rituximab, ocrelizumab or cladribine following FTY discontinuation., Results: We included 329 patients in the analysis (226F, 103 M; mean age 41 ± 10 years). During the cell-depleting treatment, the incidence rate ratio for a relapse was significantly greater in patients with a washout period of 12-17 and > / = 18 weeks compared to the reference period (< 6 weeks). The risk of a relapse was significantly influenced by the occurrence of relapses during FTY treatment and by washout length, with hazard ratios markedly increasing with the washout duration., Conclusion: The risk of relapses increases with the washout duration when switching from FTY to lymphocyte-depleting agents., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Objectives: Several studies have assessed risk factors associated with the severity of COVID-19 outcomes in people with multiple sclerosis (PwMS). The potential role of disease-modifying therapies (DMTs) and demographic and clinical factors on the risk of acquiring SARS-CoV-2 infection has not been evaluated so far. The objective of this study was to assess risk factors of contracting SARS-CoV-2 infection in PwMS by using data collected in the Italian MS Register (IMSR)., Methods: A case-control (1:2) study was set up. Cases included PwMS with a confirmed diagnosis of COVID-19, and controls included PwMS without a confirmed diagnosis of COVID-19. Both groups were propensity score-matched by the date of COVID-19 diagnosis, the date of last visit, and the region of residence. No healthy controls were included in this study. COVID-19 risk was estimated by multivariable logistic regression models including demographic and clinical covariates. The impact of DMTs was assessed in 3 independent logistic regression models including one of the following covariates: last administered DMT, previous DMT sequences, or the place where the last treatment was administered., Results: A total of 779 PwMS with confirmed COVID-19 (cases) were matched to 1,558 PwMS without COVID-19 (controls). In all 3 models, comorbidities, female sex, and a younger age were significantly associated ( p < 0.02) with a higher risk of contracting COVID-19. Patients receiving natalizumab as last DMT (OR [95% CI]: 2.38 [1.66-3.42], p < 0.0001) and those who underwent an escalation treatment strategy (1.57 [1.16-2.13], p = 0.003) were at significantly higher COVID-19 risk. Moreover, PwMS receiving their last DMT requiring hospital access (1.65 [1.34-2.04], p < 0.0001) showed a significant higher risk than those taking self-administered DMTs at home., Discussion: This case-control study embedded in the IMSR showed that PwMS at higher COVID-19 risk are younger, more frequently female individuals, and with comorbidities. Long-lasting escalation approach and last therapies that expose patients to the hospital environment seem to significantly increase the risk of SARS-CoV2 infection in PwMS., Classification of Evidence: This study provides Class III evidence that among patients with MS, younger age, being female individuals, having more comorbidities, receiving natalizumab, undergoing an escalating treatment strategy, or receiving treatment at a hospital were associated with being infected with COVID-19. Among patients with MS who were infected with COVID-19, a severe course was associated with increasing age and having a progressive form of MS, whereas not being on treatment or receiving an interferon beta agent was protective., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Serum Neurofilament Light (sNFL) is the most promising marker for patient's monitoring in Multiple Sclerosis (MS). However, operating reference values for use in clinical practice are still lacking. Here, we defined sNFL reference cut-off values in a cohort of healthy controls (HC) and assessed their performance in Multiple Sclerosis (MS) patients, as well as the intra-individual sNFL variability., Methods: We measured sNFL by single molecule array (Simoa) assay in 79 HC assessing their correlation with age. Changes of sNFL levels were evaluated during a short-term follow-up (median 67 days between consecutive samples) in a subgroup of 27 participants. sNFL were tested in 23 untreated MS patients, at both diagnostic time and start of therapy (median 80 days after), considering disease activity., Results: Findings confirmed a correlation between sNFL levels and age in HC, thus cut-off values specific for age decades were calculated. sNFL did not vary significantly with time during short-term follow-up (median CV 13%). sNFL levels in MS patients were higher and demonstrated a higher variability between diagnostic time and treatment start (median CV 39%). According to cut-off values, "pathologic" sNFL levels were found in 57% of MS patients at diagnostic time, and in 30% of samples at treatment start. In particular, "pathologic" sNFL levels were found in 80% of samples (16/20) obtained during a phase of disease activity, while a total of 85% of samples (22/26) associated with inactive disease showed sNFL in the normal range., Conclusion: This study demonstrates an overall intra-individual stability of sNFL values in the short-term in HC and suggests age-dependent reference cut-off values that could be beneficial for sNFL implementation in clinical practice., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Pediatric-onset multiple sclerosis (MS) has a highly active and aggressive course, which can have a devastating effect on the physical and cognitive functioning of a child if not treated appropriately with effective disease-modifying drugs. The optimal treatment strategy of pediatric MS is currently unknown and debate continues as to whether treatment escalation or initiation of a highly active therapy provides a better outcome. Here, we present the case of a 16-year-old female diagnosed with highly active relapsing-remitting MS (age at onset: 14 years) who received first-line treatment with fingolimod within 1 year of the first recorded symptom. Since starting fingolimod, the course of the disease has essentially been stable. No new or active lesions were observed in magnetic resonance imaging scans performed at 3 and 12 months after starting fingolimod, and treatment was well tolerated. These data suggest that, in this case, early treatment with first-line fingolimod was able to slow disease progression.

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.

In the last years, change in multiple sclerosis (MS) therapeutic scenario has highlighted the need for an improved doctor-patient communication in advance of treatment initiation in order to allow patient's empowerment in the decision-making process. AIMS: The aims of our project were to review the strategies used by Italian MS specialists to inform patients about treatment options and to design a multicentre shared document that homogenizes the information about disease-modifying treatment (DMTs) and the procedure of taking informed consent in clinical practice. RESULTS: The new resource, obtained by consensus among 31 neurologists from 27 MS Centres in Italy with the supervision of a medico-legal advisor, received the aegis of Italian Neurological Society (SIN) and constitutes a step toward a standardized decision process around DMTs in MS.

Background: clinical factors and frequency of disease-modifying therapy (DMT) changes/interruptions in relapsing-remitting multiple sclerosis (RRMS) patients have not been well defined. The aim of this study was to describe reasons of MS treatment modifications in a large cohort of Italian MS patients., Methods: this multicenter, cross-sectional non interventional study (SWITCH) conducted at 28 Italian MS centers, screened, by visit/telephone contact between June 2016 and June 2017, all RRMS patients receiving stable DMT treatment and enrolled patients with change in DMT treatment., Results: out of 13,657 recorded in the log, 409 (3%) changed therapy. Of these, 336 (2.5%), met the study criteria and were considered eligible. Among 303 (90.2% of 336) patients switching, the most common reason was "lack of efficacy" (58.4% of 303). Among 30 (8.9%) patients who interrupted treatment temporarily, the most common reason was pregnancy (40.0% of 30). Out of 3 (0.9%) patients who discontinued treatment permanently, 2 (66.7%) had as first reason as "patient decision". Multivariate analysis showed that EDSS was the only variable with statistically significant effect on changing treatments (r = 8.33; p-value of Type III Sum of Squares = 0.016)., Conclusion: in our study, 303 (90.2% of eligible patients) switched treatment, 30 (8.9%) interrupted treatment temporarily, and 3 (0.9%) discontinued treatment permanently. Efficacy remains the main driving force behind switching behavior, as the primary aim of treatment is to be disease free or reduce disease activity., Competing Interests: Declaration of Competing Interest The authors declare the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: F.P. 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. C.G.C. has received grants for congress participation from Almirall, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. E.D'A. has received grants for speaking activities from Bayer Schering, Biogen Idec, Merck Serono, Novartis, TEVA and grants for congress participation from Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. P.A. has received honoraria for lecturing and participation in advisory boards, and/or travel expenses for attending congresses and meetings from Almirall, Biogen Idec, Merck Serono, Mylan, Novartis, Roche, Sanofi Genzyme, and TEVA. P.B. has received support for attendance to scientific meetings from Biogen Idec, Merck Serono, Novartis, and Sanofi Genzyme. R.B: has received honoraria for lectures, travel and registration coverage for attending several national or international congresses or symposia from Almirall, Bayer Shering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Aventis, Sanofi Genzyme, and TEVA. R.C. has received speaker's honoraria, consulting fees, honoraria in advisory boards, support for attendance of scientific meetings from Meck Serono, Novartis, and Sanofi Genzyme. M.C. Author declares there is no conflict of interest. A.C. has received speaker honoraria, travel grants, advisory boards member honoraria from Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, and TEVA. R.F. has received consulting fees and honoraria for advisory boards from Biogen Idec, Merck Serono, Novartis, Roche, and TEVA. M.Fi. Author declares there is no conflict of interest. M.Fr. has received speaker's honoraria and consulting fees, honoraria for advisory boards, support for attendance of scientific meetings from Biogen Idec, Merck Serono, Novartis, TEVA, and Sanofi Genzyme. M.G. Author declares there is no conflict of interest. P.I. has received speaking honoraria, consulting fees, advisory board honoraria from Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA S.L. Author declares there is no conflict of interest. S.M. has received speaker's honoraria and consulting fees, honoraria in advisory boards from Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, and TEVA. G.M. has received honoraria for public speaking and advisory boards from Biogen, Novartis, and Merck Serono. G.A.M. is an Advisory Board member of Biogen Idec, Sanofi Genzyme, Merck-Serono, Novartis, and TEVA, and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme, and TEVA. She is the principal investigator in clinical trials for Actelion, Biogen Idec, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, and TEVA. D.P. has received honoraria for consultancy and/or speaking from Almirall, Bayer Shering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. C.S. Author declares there is no conflict of interest. P.P. has received speaker honoraria and consulting fees from Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. P.S. has received speaker's honoraria and consulting fees, honoraria for advisory boards, and travel grants from Biogen Idec, Merck Serono, Novartis, Sanofi genzyme, and TEVA. R.T. has received speaker's honoraria, consulting fee, honoraria for advisory boards, support for attendance of scientific meetings from Alfa Wasserman, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi genzyme, and TEVA. G.T. has received support for attendance to scientific meetings from Almirall, Biogen Idec, Merck Serono, Novartis, and Sanofi Genzyme. P.V. has received speaker's honoraria and consulting fee, honoraria for advisory boards from Biogen Idec, Novartis, Merck Serono, Sanofi Genzyme, and TEVA. M.Z. has received honoraria for lecturing or participating for advisory boards or travel funding from Almirall, Biogen, Merck Serono, Novartis, Sanofi Genzyme, and TEVA. C.Z. has received speaker's honoraria and consulting fees, honoraria for advisory boards, support for attendance of scientific meetings from Almirall, Bayer Shering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. D.C. is an Advisory Board member of Almirall, Bayer Schering, Biogen Idec, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA, and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and TEVA. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi Genzyme, and TEVA. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi Genzyme and TEVA., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate disease activity according to rituximab (RTX) induction and maintenance regimens in a multicenter real-life dataset of NMOSD patients., Methods: This is an observational-retrospective multicentre study including patients with NMOSD treated with RTX in 21 Italian and 1 Swiss centers. Demographics, relapse rate and adverse events over the follow-up were summarized taking into account induction strategy (two-1 g infusions at a 15-day interval (IND-A) vs. 375 mg/m2/week infusions for one month (IND-B)) and maintenance therapy (regimen A (M-A) with fixed time-points infusions vs. regimen B (M-B) based on cytofluorimetric driven reinfusion regimens, the least further subdivided according to CD19+ B cells (M-B1) or CD27+ memory B cells (M-B2) monitoring)., Results: 131 subjects were enrolled, 127 patients completed the induction regimen and 119 patients had at least one follow-up visit and were included in the outcome analysis. Median follow-up was 1.7 years (range 0.1-11.6). Annualized relapse rate (ARR) was 1.7 in the year before RTX start and decreased to 0.19 during the follow-up. Both ARR and Time to first relapse (TTFR) analysis showed a trend toward an increased disease activity for IND-B and M-A. No patients with MT-B2 experienced relapses during the follow-up. Number of relapses in the year before RTX initiation and having received a previous treatment were significantly associated with higher ARR and reduced TTFR in the multivariate analysis., Interpretation: We confirm RTX efficacy in NMOSD patients. Use of specific induction and maintenance protocols is warranted in order to foster RTX efficacy and to reduce costs and side effects., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The 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., Methods: A 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., Findings: A 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., Interpretation: This 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., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

In this independent, multicenter, retrospective study, we investigated the short-term persistence to treatment with first-line self-injectable or oral disease-modifying treatments (DMTs) in patients with relapsing-remitting multiple sclerosis. Data of patients regularly attending 21 Italian MS Centres who started a self-injectable or an oral DMT in 2015 were collected to: (1) estimate the proportion of patients discontinuing the treatment; (3) explore reasons for discontinuation; (3) identify baseline predictors of treatment discontinuation over a follow-up period of 12 months. We analyzed data of 1832 consecutive patients (1289 women, 543 men); 374 (20.4%) of them discontinued the prescribed DMT after a median time of 6 months (range 3 days to 11.5 months) due to poor tolerability (n = 163; 43.6%), disease activity (n = 95; 25.4%), adverse events (n = 64; 17.1%), convenience (i.e. availability of new drug formulations) and pregnancy planning (n = 21; 1.1%). Although the proportion of discontinuers was higher with self-injectable (n = 107; 22.9%) than with oral DMT (n = 215; 16.4%), the Cox regression model revealed no significant between-group difference (p = 0.12). Female sex [hazard ratio (HR) = 1.39, p = 0.01] and previous exposure to ≥ 3 DMTs (HR = 1.71, p = 0.009) were two independent risk factors for treatment discontinuation, regardless of prescribed DMTs. Our study confirms that persistence to treatment represents a clinical challenge, irrespective of the route of administration.

Purpose: Mindfulness interventions have been shown to treat depressive symptoms and improve quality of life in patients with several chronic diseases, including multiple sclerosis, but to date most evaluation of the effectiveness of mindfulness interventions in multiple sclerosis have used patients receiving standard care as the control group. Hence we decided to evaluate the effectiveness of a group-based body-affective mindfulness intervention by comparing it with a psycho-educational intervention, by means of a randomized controlled clinical trial. The outcome variables (i.e., depression, anxiety, perceived stress, illness perception, fatigue and quality of life) were evaluated at the end of the interventions (T1) and after a further 6 months (T2). Methods: Of 90 multiple sclerosis patients with depressive symptoms (Beck Depression Inventory-II score greater than 13) who were randomized, 71 completed the intervention (mindfulness group n = 36; psycho-educational group n = 35). The data were analyzed with GLM repeated-measures ANOVA followed by pairwise comparisons. Results: Per-protocol analysis revealed a time by group interaction on Beck Depression Inventory-II score, with the mindfulness intervention producing a greater reduction in score than the psycho-educational intervention, both at T1 and at T2. Furthermore, the mindfulness intervention improved patients' quality of life and illness perception at T1 relative to the baseline and these improvements were maintained at the follow-up assessment (T2). Lastly, both interventions were similarly effective in reducing anxiety and perceived stress; these reductions were maintained at T2. A whole-sample intention-to-treat (ITT) analysis broadly confirmed the effectiveness of the mindfulness intervention. Conclusion: In conclusion, these results provide methodologically robust evidence that in multiple sclerosis patients with depressive symptoms mindfulness interventions improve symptoms of depression and anxiety and perceived stress, modulate illness representation and enhance quality of life and that the benefits are maintained for at least 6 months. Trial registration: the study was registered in the ClinicalTrials.gov registry (NCT02611401).

Besides the impact of disease per se, the use of immunomodulatory therapies in adolescents with relapsing-remitting multiple sclerosis (RRMS) may have an effect on quality of life (QL). The FUTURE (Quality of liFe in adolescent sUbjecTs affected by mUltiple sclerosis treated with immunomodulatoRy agEnt using self-injecting device) study was designed to evaluate the changes in QL of Italian adolescents with RRMS receiving treatment with IFN-β1a (Rebif; 22 μg), administered subcutaneously three times weekly using the RebiSmart™ electronic autoinjection device over a 52-week period. Fifty adolescents with RRMS were enrolled and 40 completed the study. Changes from baseline to end of treatment (EoT) in adolescent self-reported and parent-reported QL were assessed using the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (PedsQL), which has been validated for use in pediatric MS and for which an Italian version is available. The adolescent self-reported total PedsQL4.0 score and all of its subscales tended to increase from baseline to EoT, the only exception being "Emotional functioning." In parent-reported measures, the total PedsQL4.0 score increased significantly from baseline to EoT (+ 5.27 points, p = 0.041). Significant increases were also evident for parent-reported "Psychosocial health summary score" (+ 5.90 points; p = 0.015) and "School functioning" (+ 7.84 points; p = 0.029). Our results indicate that adolescents with RRMS using the electronic injection device RebiSmart™ for self-administration of Rebif® can experience long-term improvements in QL.

Glatiramer acetate (GA) is a widely used treatment for multiple sclerosis (MS), with incompletely defined mechanism of action. Short-term studies suggested its involvement in the modulation of anti-inflammatory cytokines and regulatory T cells (Treg), while long-term effect is still unknown. To investigate this aspect, we analyzed by flow-cytometry peripheral-blood Treg, natural killer (NK), CD4 and CD8 T-cells and anti-inflammatory CD14 + CD163 + monocytes from 37 healthy donor and 90 RRMS patients divided in untreated, treated with GA for 12months and from 34 to 192months. While NK, CD4 and CD8 T-cells did not show any significant differences among groups over time, we demonstrated that GA increased the anti-inflammatory monocytes and restored the Treg level in both GA-treated groups. Both these effects are a characteristic of responder patients and are observed not just in short-term but even after as long as a decade of GA treatment., (Copyright © 2017. Published by Elsevier Inc.)

Introduction: The choice of therapy in patients withdrawing from natalizumab treatment is still an open question and neurologists need strategies to manage this group of patients. The aim of this study is to evaluate if alemtuzumab is able to control the disease when used in patient who have stopped natalizumab., Methods: 16 patients stopped natalizumab treatment after a median number of 20 infusions (range 12-114); all the patients were responders to natalizumab (neither clinical nor radiological activity during natalizumab therapy) and the reason for stopping was the risk of PML for all of them. Patients were switched to alemtuzumab after a median wash-out period of 70 days (range 41-99 days); patients underwent brain MRI every three months during natalizumab treatment and then just before starting alemtuzumab in order to exclude signs suggestive of PML; then, contrast-enhanced brain MRI was planned 6 and 12 months after alemtuzumab infusion., Results: At present, 8 out of 16 patients have a follow-up >6 months and 2 out of 8 reached 1-year follow-up; 5 have a follow-up of 3-6 months and 3 have a follow-up <3 months. Brain MRI at 6 months after alemtuzumab is available for 8 out of 16 patients and in all of them, neither signs of disease activity nor new lesions are present; in 2 out of 8 patients, brain MRI at 12 months is also available, showing no sign of disease activity. Clinical evaluation performed at 6 and at 12 months (when available) showed stability, in particular neither relapses nor increase in EDSS were observed., Conclusions: Alemtuzumab was able to control the disease course in patients who stopped natalizumab; of course, as this is a single-centre study and the number of patients is small, these findings are very preliminary and need further confirmation.

Objective: In this longitudinal study, we monitored two large groups of multiple sclerosis (MS) patients and healthy controls (HC) for 2 years, with the aim of comparing their neuropsychological profile over time., Method: Three hundred and twenty-two patients with MS and 303 HC were administered the Brief Repeatable Battery of Neuropsychological tests (BRB-N); neuropsychiatric measures were also administered. Two follow-ups were scheduled at 1 and 2 years, respectively., Results: A linear mixed model (LMM) with random intercept was run by considering participants' performance on each test of the BRB-N at the three assessment points (baseline and follow-ups) as the within-subjects variable, and group (patients and controls) as the between-subjects factor. The interaction term was statistically significant for the tests: Symbol Digit Modalities test (SDMT) (p = 0.044), Paced Auditory Serial Addition test (PASAT) (p = 0.011) and Word List Generation (WLG) (p < 0.001), whereas for the PASAT-3 approached statistical significance (p = 0.05). In addition, a LMM with random intercept was also run by identifying three groups (controls, relapsing-remitting course of MS (i.e. RR-MS), and prog-MS). The interaction term was statistically significant for: PASAT-3 (p = 0.017), PASAT-2 (p = 0.0026), and WLG (p = 0.0022)., Conclusions: Our results corroborate on a very large scale evidence that the abilities tapped by the tasks SDMT, PASAT and WLG are particularly sensitive to MS, and further extend this issue by showing that these abilities are likely to be more sensitive than others to the progression of the disease, as compared to HC.

Objective: The TRACER multicenter retrospective study aimed to collect data on treatment adherence in a real-life setting, in order to identify predictors of adherence at baseline., Methods: We recruited 384 relapsing-remitting (RR) multiple sclerosis patients with at least 12 months of use of RebiSmart®. This electronic device records the performed injections and assesses adherence as the percentage of 'not missing doses', through the connection to the iMed database. Subjects with at least 80% of completed doses at the 12 month of therapy were defined 'treatment adherents'., Results: After 12 months, 89.3% of patients were adherent; 93.2% of patients aged 26-40 years at baseline were adherent (vs 79% of the ≤25 and 87.5% of the ≥41 year olds; p = 0.006). Furthermore, 90.5% of patients with a baseline Expanded Disability Status Scale (EDSS) score <4 showed ≥80% adherence (vs 71.4% in those with EDSS score ≥4; p = 0.016). Fifty-four percent of the patients who were not adherent after 3 months were also not adherent after 12 months (OR 16.8; CI 95%:7.1-39.8)., Conclusions: Patients aged 26-40 years and with an EDSS score <4 at baseline were the most adherent. The status of 'treatment adherent' in the first 3 months was predictive of higher adherence in the long term.

Objective: Intertrial variability (ITV) of motor responses to peripheral (CMAP) and transcranial (MEP) stimulation prevents their use in follow-up studies. Our purpose was to develop strategies to reduce and measure CMAP and MEP ITV to guide long-term monitoring of conduction slowing and conduction failure of peripheral and central motor pathway in the individual patient., Methods: Maximal compound muscle action potentials to High Voltage Electrical Stimulation (HVES) of lumbo-sacral nerve roots (r-CMAP) and activated, averaged motor evoked potentials (MEPs) to Transcranial Magnetic Stimulation (TMS) using double cone coil were recorded from 10 proximal and distal muscle districts of lower limbs. The procedure was repeated twice, 1-2 days apart, in 30 subjects, including healthy volunteers and clinically stable multiple sclerosis patients, using constant stimulating and recording sites and adopting a standardized procedure of voluntary activation. ITV for latency and area indexes and for the ratio between MEP and r-CMAP areas (a-Ratio) was expressed as Relative Intertrial Variation (RIV, 5th-95th percentile). As an inverse correlation between the size of area and ITV was found, raw ITV values were normalized as a function of area to make them comparable with one another., Results: All RIV values for latencies were significantly below the optimum threshold of ± 10%, with the exception of r-CMAP latencies recorded from Vastus Lateralis muscle. RIVs for a-Ratio, the most important index of central conduction failure, ranged from a maximum of -25.3% to +32.2% (Vastus Medialis) to a minimum of -15.0% to + 17.4% (Flexor Hallucis Brevis)., Conclusions: The described procedure represents an effort to lower as much as possible variability of motor responses in serial recording; the reported ITV normative values are the necessary premise to detect significant changes of motor conduction slowing and failure in the individual patient in follow-up studies.

Objective: Multiple Sclerosis (MS) is a demyelinating autoimmune disease that imposes a significant emotional burden with heavy psychosocial consequences. Several studies have investigated the association between MS and mental disorders such as depression and anxiety, and recently researchers have focused also on Post-traumatic Stress Disorder (PTSD). This is the first study that investigates the usefulness of proposing a treatment for PTSD to patients with MS., Methods: A randomized controlled trial with patients with MS diagnosed with PTSD comparing Eye Movement Desensitization and Reprocessing (EMDR; n = 20) and Relaxation Therapy (RT; n = 22). The primary outcome measure was the proportion of participants that no longer meet PTSD diagnosis as measured with Clinician Administered PTSD Scale 6-months after the treatment., Results: The majority of patients were able to overcome their PTSD diagnosis after only 10 therapy sessions. EMDR treatment appears to be more effective than RT in reducing the proportion of patients with MS suffering from PTSD. Both treatments are effective in reducing PTSD severity, anxiety and depression symptoms, and to improve Quality of Life., Conclusion: Although our results can only be considered preliminary, this study suggests that it is essential that PTSD symptoms are detected and that brief and cost-effective interventions to reduce PTSD and associated psychological symptoms are offered to patients, in order to help them to reduce the psychological burden associated with their neurological condition., Trial Registration: NCT01743664, https://clinicaltrials.gov/ct2/show/NCT01743664.

Objectives: The objectives of this article are to test the feasibility of lumbar puncture (LP) using 25-gauge (G) needles in daily neurological practice and to compare the risk of post-dural puncture headache (PDPH) with four types of needles., Methods: In a prospective rater-blind study, pros and cons of four different LP needles, the 20G Quincke (20Q), 22G Sprotte (22S), 25G Whitacre (25W) and 25G Sprotte (25S), were evaluated in 394 LPs performed by seven neurologists. The neurologist performing the LP recorded the type and size of needle, intensity of pain, safety, time of the procedure and failure or success. Between five and 15 days later another neurologist, blind to the type of needle used, completed an ad-hoc questionnaire for PDPH., Results: PDPH developed in 35.9% patients when using a 20Q needle, and in 12.9%, 6.8% and 1.6%, respectively, when using a 22S, 25W or 25S needle. The difference in incidence of PDPH following LP performed with the 20Q needle and the 25S or 22S was statistically significant (p < 0.001 and p = 0.008, respectively) and it approached significance when comparing the 25S and 25W (p = 0.06). As 25W and 25S needles need CSF aspiration, LP requires more time and skill. Pain caused by LP was similar with the four needles., Conclusion: The use of the 25S needle in diagnostic LP reduces the frequency and severity of PDPH., (© International Headache Society 2015.)

Objective: To evaluate serum cytokine profiles for their utility to determine the heterogeneous responses to interferon (IFN)-β treatment in patients with multiple sclerosis (MS)., Methods: Patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome receiving de novo IFN-β treatment were included in this prospective, observational study. Number of relapses and changes in disability were assessed 2 years prior to and 2 years after initiation of treatment. Sera were collected at baseline and after 3 months on therapy. Cytokine levels in sera were assessed by Luminex multiplex assays. Baseline cytokine profiles were grouped by hierarchical clustering analysis. Demographic features, changes in cytokines, and clinical outcome were then assessed in the clustered patient groups., Results: A total of 157 patients were included in the study and clustered into 6 distinct subsets by baseline cytokine profiles. These subsets differed significantly in their clinical and biological response to IFN-β therapy. Two subsets were associated with patients who responded poorly to therapy. Two other subsets, associated with a good response to therapy, showed a significant reduction in relapse rates and no worsening of disability. Each subset also had differential changes in cytokine levels after 3 months of IFN-β treatment., Conclusions: There is heterogeneity in the immunologic pathways of the RRMS population, which correlates with IFN-β response.

Background: Multiple Sclerosis has a great impact on psychological functioning of patients and can be associated with various mental health disorders and symptoms. The most prevalent one is depression, which ranges from 15 to 47%. Mindfulness Based Interventions are a relatively brief and cost-effective program that has been studied in patients with several chronic diseases and recently also in patients with Multiple Sclerosis. Mindfulness Based Interventions are based on the assumption that a non-judgmental awareness and acceptance of one's moment-to-moment experience can have a positive effect on the adaptation to the disease, reducing the psychological burden and improving patients' quality of life. Several studies concluded that Mindfulness Based Interventions can be beneficial in terms of improving both psychological and psychical aspects of Multiple Sclerosis, but none of them compared the intervention with an active control group. The primary objective of the study is to evaluate the efficacy of a group-based Mindfulness Based Intervention on depressive symptoms in patients with Multiple Sclerosis, as compared with an active control group., Methods: The study design is a randomized controlled clinical trial. Eighty-eight patients with Multiple Sclerosis and depressive symptoms will be recruited and randomized to either Mindfulness Based Intervention or an active control group. The latter is designed to control for non-specific elements of the intervention and it comprises psycho-education and relaxation techniques. The primary outcome is the reduction of depressive symptoms as measured via the Beck Depressive Inventory-II. Secondary outcome measures are level of quality of life, anxiety, perceived stress, illness perception, fatigue and quality of interpersonal relationship. Outcomes will be assessed at baseline, after treatment and 6 months after the end of the treatment. Caregivers will participate in groups together with patients., Discussion: As far as we know this trial will be the first randomized controlled trial testing the efficacy of group-based Mindfulness Based Intervention for patients with Multiple Sclerosis with a comparison with an active control group with a specific focus on depressive symptoms., Trial Registration: NCT02611401.

Introduction: Natalizumab (NTZ) discontinuation can be followed by multiple sclerosis (MS) disease reactivation. Currently no disease-modifying drug (DMD) has been shown to be able to abolish disease reactivation. The aims of the current study were: (1) to determine the frequency of MS reactivation after NTZ discontinuation; (2) to evaluate predictors of reactivation risk, and (3) to compare the effect of different treatments in reducing this risk., Methods: Data from 132 patients with MS followed-up for 2 years before NTZ treatment and 1 year after interruption were collected from two Italian MS centers and retrospectively evaluated., Results: Overall, 72 of 132 patients (54.5%) had relapses after NTZ discontinuation and 60 of 125 patients (48%), who had magnetic resonance imaging, had radiological reactivation. Rebound was observed in 28 of 132 patients (21.2%). A higher number of relapses in the 2 years before NTZ treatment, a longer washout period, and a lower number NTZ infusions correlated with reactivation and rebound. Untreated patients (n = 37) had higher clinical and radiological activity and rebound in comparison to patients receiving DMDs. Moreover, a lower risk of relapses was found in patients treated with second-line therapies (NTZ and fingolimod) than in those treated with first-line therapies (interferon beta, glatiramer acetate, teriflunomide, azathioprine). Interestingly, no disease reactivation in off-label treatment (rituximab, autologous hematopoietic stem cell transplantation) was observed., Conclusion: NTZ discontinuation is a risk for MS reactivation and rebound. An alternative treatment should be promptly resumed mainly in patients with a previous very active disease course and with a shorter NTZ therapy. Second-line therapies demonstrate superiority in preventing relapses after NTZ discontinuation.

Introduction: Tumor necrosis factor-α (TNF-α) blocking agents may be associated with neurological adverse events, including demyelinating syndromes, that can be difficult to differentiate from multiple sclerosis (MS) and clinically isolated syndrome (CIS) as neither the clinical nor laboratory distinctive features have been reported. Usually clinicians mainly examine the diagnostic value of immunoglobulin G oligoclonal bands underestimating the value of other cerebrospinal fluid (CSF) parameters (such as CSF cytology)., Case Report: We present a case of a patient who acutely developed mild pyramidal and sensory impairment of lower limbs and urinary hesitancy during treatment with adalimumab, a monoclonal antibody to TNF-α, for psoriatic arthritis. Magnetic resonance imaging demonstrated a widespread area of hyperintense signal extending from C5 to D8 level in T2-weighted images. Two consecutive CSF examinations showed an intense activation of monocyte/macrophage lineage (88% and 90%, respectively) with some giant and binucleated cells that notably decreased five months after TNF-α blocker cessation. We compared the results of CSF examinations of our patient with CSF results of 20 patients with MS and 20 patients with CIS that demonstrated activation of both lymphocytic and monocytic lineage (MS: 48% and 52%, respectively, CIS: 54.5% and 43.5%, respectively) that were very different from the findings in adalimumab-related encephalomyelitis in acute phase (11% and 89%, respectively). CSF cytology in two patients with neuromyelitis optica during the relapse (n = 3) showed minor monocyte/macrophage activation (9%) and an increased number of granulocytes (77%)., Conclusion: Prominent activation of monocyte/macrophage lineage with some binucleated giant cells in CSF could be induced by anti-TNF-α treatment. The peculiar CSF pattern, never found in MS, CIS, and NMO, can help in differential diagnosis and stresses the importance of careful CSF cytology evaluation in the course of demyelinating diseases.

Multiple Sclerosis (MS) is a heterogeneous disease and a variable percentage of patients are non-responders to common treatment. Early diagnosis of non-responders allows change to a more useful therapy for the patient and better allocates a large amount of financial resources. Quantification of Neutralizing antibodies (Nabs) and of biological activity of IFN-β are recognized approaches to identify immuno-pharmacological non-responders. A consistent number of studies have demonstrated that quantification of Myxovirus-induced protein A (MxA) is a valid biomarker to detect immune-pharmacological non responders after one year of treatment. Persistent high titre of Nabs and absence of biological activity predict abolition of IFN-β effects in disease activity measured through MRI, number of relapses and disability. Guidelines and flow-charts including both Nabs and MxA quantification are presented., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background and Purpose: Natalizumab discontinuation induces the recurrence of multiple sclerosis disease activity: currently no therapeutic approach has been found able to abolish disease reactivation., Methods: The recurrence of disease activity after natalizumab discontinuation was retrospectively evaluated in 79 patients who had been treated with immunomodulating agents, other first-line therapies, fingolimod or not treated., Results: No differences have been found in clinical or magnetic resonance imaging recurrence of disease activity amongst the groups. Interestingly, no disease reactivation was observed only in one patient treated for 6 months with monthly pulses of cyclophosphamide., Conclusion: Disease modifying treatment or 'no treatment' is unable to abolish disease activity reactivation after natalizumab discontinuation., (© 2014 The Author(s) European Journal of Neurology © 2014 EAN.)

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system caused by a complex interaction between multiple genes and environmental factors. HLA region is the strongest susceptibility locus, but recent huge genome-wide association studies identified new susceptibility genes. Among these, BACH2, PTGER4, RGS1 and ZFP36L1 were highlighted. Here, a gene expression analysis revealed that three of them, namely BACH2, PTGER4 and ZFP36L1, are down-regulated in MS patients' blood cells compared to healthy subjects. Interestingly, all these genes are involved in the immune system regulation with predominant anti-inflammatory role and their reduction could predispose to MS development., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Few long-term follow-up data are available on thyroid dysfunction (TD) in multiple sclerosis (MS) patients treated with glatiramer acetate (GA) or with interferon-beta (IFNb). In a cohort of 787 relapsing-remitting MS (RRMS) patients whom were followed up for 8 years, we observed an increased prevalence of TD and thyroid autoimmunity (TA) within the first year of IFNb treatment, regardless of the dose or frequency of administration, while no change was observed with GA treatment. The increased prevalence of TD and TA within the first year of IFNb treatment suggested the need for close monitoring of thyroid function and autoimmunity, though only during the first year of IFNb treatment., (© The Author(s) 2014.)

We recently found a gene signature for multiple sclerosis (MS) that reverted to normal during pregnancy in MS patients and included NR4A2 and TNFAIP3, key molecules in anti-inflammatory processes. Here we focus on the expression levels of these two genes in monocytes and CD4+ T cells from healthy controls and treatment-naïve RRMS patients. Our findings show that monocytes play a key role in the dysregulated anti-inflammatory response, being the expression of both genes down-regulated in these cells in RRMS patients with respect to healthy individuals. CD4+ T cells seem to have only a marginal part, because we can observe only a slight down-regulation in NR4A2., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Neutralizing antibodies (NAb) affect efficacy of interferon-beta (IFN-b) treatment in multiple sclerosis (MS) patients. NAbs evolve in up to 44% of treated patients, usually between 6-18 months on therapy., Objectives: To investigate whether early binding antibody (BAb) titers or different IFN-b biomarkers predict NAb evolution., Methods: We included patients with MS or clinically isolated syndrome (CIS) receiving de novo IFN-b treatment in this prospective European multicenter study. Blood samples were collected at baseline, before and after the first IFN-b administration, and again after 3, 12 and 24 months on that therapy; for determination of NAbs, BAbs, gene expression of MxA and protein concentrations of MMP-9, TIMP-1, sTRAIL, CXCL-10 and CCL-2., Results: We found that 22 of 164 (13.4%) patients developed NAbs during a median time of 23.8 months on IFN-b treatment. Of these patients, 78.9% were BAb-positive after 3 months. BAb titers ≥ 1:2400 predicted NAb evolution with a sensitivity of 74.7% and a specificity of 98.5%. Cross-sectionally, MxA levels were significantly diminished in the BAb/NAb-positive samples; similarly, CXCL-10 and sTRAIL concentrations in BAb/NAb-positive and BAb-positive/NAb-negative samples, respectively, were also diminished compared to BAb/NAb-negative samples., Conclusions: BAb titers reliably predict NAbs. CXCL-10 is a promising sensitive biomarker for IFN-b response and its abrogation by anti-IFN-b antibodies.

Interferon beta (IFNβ) was the first specific disease-modifying treatment licensed for relapsing-remitting multiple sclerosis, and is still one of the most commonly prescribed treatments. A strong body of evidence supports the effectiveness of IFNβ preparations in reducing the annual relapse rate, magnetic resonance (MRI) disease activity and disease progression. However, the development of binding/neutralizing antibodies (BAbs/NAbs) during treatment negatively affects clinical and MRI outcomes. Therefore, guidelines for the clinical use for the detection of NAbs in MS may result in better treatment of these patients. In October 2012, a panel of Italian neurologists from 17 MS clinics convened in Milan to review and discuss data on NAbs and their clinical relevance in the treatment of MS. In this paper, we report the panel's recommendations for the use of IFNβ Nabs detection in the early identification of IFNβ non-responsiveness and the management of patients on IFNβ treatment in Italy, according to a model of therapeutically appropriate care.

Objective: To develop a neurophysiological method to explore central motor pathways to proximal and distal muscles of lower limbs., Methods: MEPs to transcranial magnetic stimulation using the double cone coil were bilaterally and simultaneously recorded from vastus medialis, tibialis anterior and flexor hallucis brevis. Voluntary facilitation was controlled using a predefined sequence of movements of constant amplitude. Compound motor action potentials elicited by maximal high voltage electrical stimulation of lumbosacral roots (root-CMAPs) were recorded from the same muscles to obtain the corresponding peripheral conduction times. We studied 28 healthy subjects and 28 multiple sclerosis (MS) patients with no or mild motor impairment., Results: The described facilitation procedure and the averaging of 5 MEPs reduced area variability to about 10%. In MS patients conduction slowing and/or MEP area reduction in at least one muscle was found in 91.7% of cases, with significant correlation with individual motor impairment., Conclusions: Combined use of stable MEPs and maximal root-CMAPs was able to detect both conduction slowing and conduction failure in central motor pathways to proximal and distal districts of lower limbs in MS patients., Significance: The proposed method provides an extensive electrophysiological mapping of central motor impairment of lower limbs in clinical application., (Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Although it is still debated whether chronic cerebro-spinal venous insufficiency (CCSVI) plays a role in multiple sclerosis (MS) development, many patients underwent endovascular treatment (ET) of CCSVI. The objective of the study is to evaluate the outcome and safety of ET in Italian MS patients. Italian MS centers that are part of the Italian MS Study Group were all invited to participate to this retrospective study. A structured questionnaire was used to collect detailed clinical data before and after the ET. Data from 462 patients were collected in 33 centers. ET consisted of balloon dilatation (93 % of cases) or stent application. The mean follow-up duration after ET was 31 weeks. Mean EDSS remained unchanged after ET (5.2 vs. 4.9), 144 relapses occurred in 98/462 cases (21 %), mainly in RR-MS patients. Fifteen severe adverse events were recorded in 3.2 % of cases. Given the risk of severe adverse events and the lack of objective beneficial effects, our findings confirm that at present ET should not be recommended to patients with MS.

Objectives: To investigate the presence and the nature of cognitive impairment in a large sample of patients with Multiple Sclerosis (MS), and to identify clinical and demographic determinants of cognitive impairment in MS., Methods: 303 patients with MS and 279 healthy controls were administered the Brief Repeatable Battery of Neuropsychological tests (BRB-N); measures of pre-morbid verbal competence and neuropsychiatric measures were also administered., Results: Patients and healthy controls were matched for age, gender, education and pre-morbid verbal Intelligence Quotient. Patients presenting with cognitive impairment were 108/303 (35.6%). In the overall group of participants, the significant predictors of the most sensitive BRB-N scores were: presence of MS, age, education, and Vocabulary. The significant predictors when considering MS patients only were: course of MS, age, education, vocabulary, and depression. Using logistic regression analyses, significant determinants of the presence of cognitive impairment in relapsing-remitting MS patients were: duration of illness (OR = 1.053, 95% CI = 1.010-1.097, p = 0.015), Expanded Disability Status Scale score (OR = 1.247, 95% CI = 1.024-1.517, p = 0.028), and vocabulary (OR = 0.960, 95% CI = 0.936-0.984, p = 0.001), while in the smaller group of progressive MS patients these predictors did not play a significant role in determining the cognitive outcome., Conclusions: Our results corroborate the evidence about the presence and the nature of cognitive impairment in a large sample of patients with MS. Furthermore, our findings identify significant clinical and demographic determinants of cognitive impairment in a large sample of MS patients for the first time. Implications for further research and clinical practice were discussed.

Chronic and life-threatening neurodegenerative diseases may be associated with post-traumatic stress disorder (PTSD). Therefore, the current study was an investigation of the prevalence of PTSD in multiple sclerosis (MS) patients, and identification of significant determinants of PTSD. Two hundred thirty-two MS patients were consecutively recruited and screened for the presence of PTSD with the Impact of Event Scale-Revised, corroborated by the Structured Clinical Interview for DSM-IV. Furthermore, participants were administered the Hospital Anxiety and Depression Scale and the Fatigue Severity Scale. Twelve patients (12/232, i.e. 5.17 %) were diagnosed as suffering from PTSD. Levels of education, anxiety and depression were significant determinants of the presence of PTSD. The role played by the levels of education, anxiety and depression in determining the presence of PTSD has been discussed. Further research on the psychological features of neurodegenerative diseases is urgently needed in order to plan appropriate treatments and improve patients' quality of life.

Despite the existence of therapeutic guidelines, management of multiple sclerosis relapse remains heterogeneous. Optimisation of relapse outcome demands an improved understanding of the neurologist's therapeutic attitude towards relapse management, which is the aim of this study. Neurologists from 13 multiple sclerosis centres completed a questionnaire every time they assessed multiple sclerosis relapses. The questionnaire requested a guided description of the relapse's clinical characteristics and an indication of the prescribed therapy, supported with up to 3 out of 20 suggested reasons. Over 3 months, 368 questionnaires were collected. Median percentage (%) of 21 relapses resulting in a prescription was 88.9%. Corticosteroids represented the most frequent prescription. A short-course of high-dose intravenous methylprednisolone was the most used corticosteroid (73.7%). Treatment was administrated mainly in day case unit (80.0%) and at home (13.6%). A tapered therapy was prescribed to 28.8% of patients. Neurologists' therapeutic decisions were driven mainly by relapse severity (45.3%) and symptom evolution (24.2%). Our study confirms the therapeutic attitude of multiple sclerosis specialists in treating relapses with high-dose intravenous corticosteroids in a day hospital setting, with a tapering in a proportion of cases. The main reasons for prescription are relapse severity and symptom evolution.

Background: Glatiramer acetate (GA) in multiple sclerosis acts through the induction of GA-specific T-helper 2 cells. Nevertheless, the phenomenon is not universal in patients, explaining individual differences in clinical response., Objective: The objective of this article was to categorize GA-treated patients., Method: An enhanced quantitative PCR assay was used for measuring ex-vivo GA-induced IFNγ and IL4 mRNA responses in mononuclear cells from 23 healthy donors, 27 untreated patients, 33 short-term (≤6 months) and 77 long-term (>6 months) GA-treated patients. Thresholds for IFNγ and IL4 transcriptional response were calculated by ROC analysis and long-term treated patients were compared in terms of prognostic stratification., Results: Thresholds for IFNγ and IL4 transcriptional response were calculated at 5.36 and 1.41 relative expression (RE). Finally, 67% of long-term treated patients scored above both response thresholds. These patients had a higher proportion of relapse-free subjects (74% vs 40% when compare to patients who scored below both thresholds) and a significantly better relapse-free survival rate (p=0.006; CI 0.29-0.75). The negative predictive value to predict adverse clinical outcome was 79% (CI 0.63-0.90), meaning that by a positive response, there is a 79% chance that the patient will not experience a negative outcome at 3 years., Conclusions: Our enhanced quantitative PCR assay produced clinically significant results for GA-treated patients. As such, if patients have a positive response, it means they have less chance of a relapse, while patients with a negative response have a greater probability of a worse outcome.

Background: In a recent genome-wide transcriptional analysis, we identified a gene signature for multiple sclerosis (MS), which reverted back to normal during pregnancy. Reversion was particularly evident for 7 genes: SOCS2, TNFAIP3, NR4A2, CXCR4, POLR2J, FAM49B, and STAG3L1, most of which encode negative regulators of inflammation., Objectives: To corroborate dysregulation of genes, to evaluate the prognostic value of genes, and to study modulation of genes during different treatments., Design: Comparison study., Setting: Italian referral center for MS., Patients: Quantitative polymerase chain reaction measurements were performed for 274 patients with MS and 60 healthy controls. Of the 274 patients with MS, 113 were treatment-naive patients in the initial stages of their disorder who were followed up in real-world clinical settings and categorized on the basis of disease course. The remaining 161 patients with MS received disease-modifying therapies (55 patients were treated with interferon beta, 52 with glatiramer acetate, and 54 with natalizumab) for a mean (SD) of 12 (2) months., Main Outcome Measures: Gene expression levels, relapse rate, and change in Expanded Disability Status Scale., Results: We found a dysregulated gene pathway (P ≤ .006), with a downregulation of genes encoding negative regulators. The SOCS2, NR4A2, and TNFAIP3 genes were inversely correlated with both relapse rate (P ≤ .002) and change in Expanded Disability Status Scale (P ≤ .005). SOCS2 was modulated by both interferon beta and glatiramer acetate, TNFAIP3 was modulated by glatiramer acetate, and NR4A2 was not altered at all. No changes were induced by natalizumab., Conclusions: We demonstrate that there is a new molecular pathogenic mechanism that underlies the initiation and progression of MS. Defects in negative-feedback loops of inflammation lead to an overactivation of the immune system so as to predispose the brain to inflammation-sensitive MS.

MxA is an antiviral protein induced by type I interferons (IFN) and some viruses; MxA gene expression is an appropriate marker for measuring biologic activity of exogenous IFNβ, as its induction indicates IFNAR receptor stimulation. A recent study has shown that measurement of MxA mRNA, after 1 year of treatment, predicts clinical responsiveness to IFNβ therapy. Loss of IFNβ bioactivity is mostly due to anti-IFNβ antibodies (both neutralizing and binding), non-compliance and receptor saturation. The aim of this study was to evaluate all possible causes of loss of IFNβ bioactivity after 1 year in treated patients. One hundred sixty-seven multiple sclerosis (MS) patients were included. One year after beginning IFNβ therapy, each patient underwent a blood test; MxA gene expression was measured by real time PCR, antiviral CPE assay to detect neutralizing antibodies (NAbs), and capture-ELISA (cELISA) to measure binding antibodies (BAbs). For MxA an upper normal threshold of 87 (RE) was considered, 20 TRU/mL was the threshold for NAbs, and 1 U for BAbs positivity. Thirty-seven out of 167 patients (22%) were MxA-negative; of these, 22 were both BAbs and NAbs+, whereas 12 were BAbs+ but Nabs-, and three were both BAbs and NAbs-. The following conclusions were drawn from the study: (1) MxA mRNA should be measured after 1 year of IFNβ therapy; (2) after 1 year of IFNβ treatment, absence of IFNβ bioactivity was detected in 22% of the patients; (3) different biological phenomena and reduced compliance explain this absence; (4) identification of the reason for absence of IFN bioactivity improves patients' management.