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Cerebrospinal fluid (CSF) core biomarkers of Alzheimer's disease (AD), including amyloid peptide beta-42 (Aβ42), Aβ42/40 ratio, and phosphorylated tau (pTau), are precious tools for supporting AD diagnosis. However, their use in clinical practice is limited due to the invasiveness of CSF collection. Thus, there is intensive research to find alternative, noninvasive, and widely accessible biological matrices to measure AD core biomarkers. In this study, we measured AD core biomarkers in saliva and plasma by a fully automated platform. We enrolled all consecutive patients with cognitive decline. For each patient, we measured Aβ42, Aβ40, and pTau levels in CSF, saliva, and plasma by Lumipulse G1200 (Fujirebio). We included forty-two patients, of whom 27 had AD. Levels of all biomarkers significantly differed in the three biofluids, with saliva having the lowest and CSF the highest levels of Aβ42, Aβ40, and pTau. A positive correlation of pTau, Aβ42/40 ratio, and pTau/Aβ42 ratio levels in CSF and plasma was detected, while no correlation between any biomarker in CSF and saliva was found. Our findings suggest that plasma but not saliva could represent a surrogate biofluid for measuring core AD biomarkers. Specifically, plasma Aβ42/40 ratio, pTau/Aβ42 ratio, and pTau could serve as surrogates of the corresponding CSF biomarkers., (© 2024. The Author(s).)

Background: Therapeutic plasma exchange (TPE) is a highly effective rescue treatment for patients with acute exacerbation of neuroimmunological disease that removes circulating autoantibodies and inflammatory components from the bloodstream. The aims of this study are to explore the safety and the effectiveness of TPE in patients with autoimmune neurological disorders., Methods: We retrospectively evaluated the frequency of adverse events (AEs) and the effectiveness of TPE using the modified Ranking Scale (mRS) in patients with acute neurological flares who underwent TPE at the University Hospital of Palermo., Results: Of 59 patients, the majority underwent TPE due to multiple sclerosis (MS) relapse. In 23.7% of cases, TPE was performed before obtaining a definite diagnosis due to the severity of the clinical presentation. After TPE, the mRS score was globally reduced ( p < 0.0001), and this effect was marked in patients with MS, Guillain-Barré syndrome, and myasthenia gravis crisis but not in those with paraneoplastic syndromes. Circulating pathogenetic antibodies, younger age, and the early use of TPE were factors strongly associated with TPE effectiveness. The overall safety profile of TPE was satisfactory with an AE frequency of 15%., Conclusions: These results highlight the early use of TPE in patients with circulating pathogenetic antibodies as well as its favorable safety profile.

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

Background: High-efficacy disease-modifying therapies have been proven to slow disability accrual in adults with relapsing-remitting multiple sclerosis. However, their impact on disability worsening in paediatric-onset multiple sclerosis, particularly during the early phases, is not well understood. We evaluated how high-efficacy therapies influence transitions across five disability states, ranging from minimal disability to gait impairment and secondary progressive multiple sclerosis, in people with paediatric-onset multiple sclerosis., Methods: Longitudinal data were obtained from the international MSBase registry, containing data from people with multiple sclerosis from 151 centres across 41 countries, and the Italian Multiple Sclerosis and Related Disorders Register, containing data from people with multiple sclerosis from 178 Italian multiple sclerosis centres. People younger than 18 years at the onset of multiple sclerosis symptoms were included, provided they had a confirmed diagnosis of relapsing-remitting multiple sclerosis and at least four Expanded Disability Status Scale (EDSS) scores recorded within 12-month intervals. The primary outcome was the time to change in disability state: minimal disability (EDSS scores 0, 1·0, and 1·5), mild disability (EDSS scores 2·0 and 2·5), moderate disability (EDSS scores 3·0 and 3·5), gait impairment (EDSS scores ≥4·0), and clinician diagnosed secondary progressive multiple sclerosis. A multi-state model was constructed to simulate the natural course of multiple sclerosis, modelling the probabilities of both disability worsening and improvement simultaneously. The impact of high-efficacy disease-modifying therapies (alemtuzumab, cladribine, daclizumab, fingolimod, mitoxantrone, natalizumab, ocrelizumab, rituximab, or autologous haematopoietic stem cell transplantation) and low-efficacy disease-modifying therapies (dimethyl fumarate, glatiramer acetate, interferon beta, or teriflunomide), compared with no treatment, on the course of disability was assessed. Apart from recruitment, individuals with lived experience of multiple sclerosis were not involved in the design and conduct of this study., Findings: A total of 5224 people (3686 [70·6%] female and 1538 [29·4%] male) with mean age at onset of multiple sclerosis 15·24 years (SD 2·52) were included. High-efficacy therapies reduced the hazard of disability worsening across the disability states. The largest reduction (hazard ratio 0·41 [95% CI 0·31-0·53]) was observed in participants who were treated with high-efficacy therapies while in the minimal disability state, compared with those remained untreated. The benefit of high-efficacy therapies declined with increasing disability. Young people with minimal disability who received low-efficacy therapy also experienced a reduced hazard (hazard ratio 0·65 [95% CI 0·54-0·77]) of transitioning to mild disability, in contrast to those who remained untreated., Interpretation: Treatment of paediatric-onset relapsing-remitting multiple sclerosis with high-efficacy therapy substantially reduces the risk of reaching key disability milestones. This reduction in risk is most pronounced among young people with minimal or mild disability when treatment began. Children with relapsing-remitting multiple sclerosis should be treated early with high-efficacy therapy, before developing significant neurological impairments, to better preserve their neurological capacity., Funding: National Health and Medical Research Council, Australia; MSBase Foundation Fellowship; MS Australia Postdoctoral Fellowship., Competing Interests: Declaration of interests SS has received research support from the MSBase Foundation and MS Australia. IR served on scientific advisory boards and received conference travel support or speaker honoraria from Roche, Novartis, Merck, and Biogen. CBM has received conference travel support from Merck, Novartis, and Biogen, and research support from the National Health and Medical Research Council Australia, MS Australia, The University of Melbourne, The Royal Melbourne Hospital Neuroscience Foundation, and Dementia Australia. PI has served on scientific advisory boards for Biogen Idec, Bayer, Bristol Myers Squibb (BMS), Teva, Roche, Merck Serono, Novartis, and Genzyme, and has received funding for travel or speaker honoraria from Sanofi Aventis, Genzyme, Roche, Biogen Idec, Teva, Merck Serono, Alexion, BMS, and Novartis. MF received compensation for consulting services or speaking activities from Almiral, Alexion, Bayer, Biogen, Celgene, Eli Lilly, Genzyme, Merck-Serono, Novartis, Roche, Sanofi, Takeda, and Teva Pharmaceutical Industries, and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). EKH received honoraria or research support from Biogen, Merck Serono, Novartis, Roche, and Teva; has been member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novartis, and Sanofi Genzyme; and has been supported by the Czech Ministry of Education (project Cooperatio LF1) and the National Institute for Neurological Research of the Czech Republic (programme EXCELES, project number LX22NPO5107) funded by the Next Generation EU. VBM received compensation for public speaking or consultancy from Merck, Novartis, Biogen, Genzyme, Teva, and Alrmirall. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche, and Sanofi-Genzyme. MZ received travel support and fees for lecturing or participating in advisory boards from Almirall, Biogen, Merck, Novartis, and Sanofi-Genzyme. FP received personal compensation for serving on advisory boards by Almirall, Alexion, Biogen, BMS, Janssen, Merck, Novartis, and Roche, and research grants from Alexion, Almirall, Biogen, BMS, Merck, Novartis, Roche, Fondazione Italiana Sclerosi Multipla, Reload Association (Onlus), Italian Health Minister, and University of Catania. SE received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche, and Teva. GS received grants and honoraria from Roche, Sanofi, Merck, Biogen, and Novartis. ADS received speaker honoraria and consultant fees from Biogen, Novartis, Merck, Roche, Alexion, and Sanofi. EP received compensation for travel grants, participation in advisory boards, or speaking activities from Biogen, Merck Serono, Sanofi, Teva, and Novartis, and serves on the editorial boards of Frontiers in Neurology and Brain Sciences. MT has served on scientific advisory boards for Biogen, Novartis, Roche, Merck, and Genzyme; received speaker honoraria from Biogen, Roche, Sanofi, Merck, Genzyme, and Novartis; and received research grants for her institution from Biogen, Merck, and Novartis. MPA served on scientific advisory boards for and has received speaker honoraria and research support from Biogen Idec, Merck Serono, Bayer Schering Pharma, Novartis, Roche, BMS Celgene, and Sanofi Aventis, and is Editor of Multiple Sclerosis Journal. TK served on scientific advisory boards for MS International Federation and WHO, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck, and Biogen, and the steering committee for Brain Atrophy Initiative by Sanofi Genzyme; received conference travel support or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi-Genzyme, Teva, BioCSL, and Merck; and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene, and Merck. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Multiple sclerosis (MS) is a complex disorder in which environmental and genetic factors interact modifying disease risk and course. This multicentre, case-control study involving 18 Italian MS Centres investigated MS course by ethnicity and native-country economic status in foreign-born patients living in Italy., Methods: We identified 457 MS patients who migrated to Italy and 893 age- and sex-matched native-born Italian patients. In our population, 1225 (93.2%) subjects were White Europeans and White Northern Americans (WENA) and 89 (6.8%) patients were from other ethnical groups (OEG); 1109 (82.1%) patients were born in a high-income (HI) Country and 241 (17.9%) in a low-middle-income (LMI) Country. Medical records and patients interviews were used to collect demographic and disease data., Results: We included 1350 individuals (973 women and 377 men); mean (SD) age was 45.0 (11.7) years. At onset, 25.45% OEG patients vs 12.47% WENA (p = 0.039) had > 3 STIR spine lesions. At recruitment, the same group featured mean (SD) EDSS score of 2.85 (2.23) vs 2.64 (2.28) (p = 0.044) reached in 8.9 (9.0) vs 12.0 (9.0) years (p = 0.018) and underwent 1.10 (4.44) vs. 0.99 (0.40) annual MRI examinations (p = 0.035). At disease onset, patients from LMI countries had higher EDSS score than HI patients (2.40 (1.43) vs 1.99 (1.17); p = 0.032)., Discussion: Our results suggested that both ethnicity and socio-economic status of native country shape MS presentation and course and should be considered for an appropriate management of patients. To the best of our knowledge, this is the first study reporting on the impact of ethnicity in MS at an individual level and beyond an ecological population-perspective., (© 2024. The Author(s).)

Background: Generally infrequent, multiple sclerosis (MS) with late onset (LOMS) is characterized by an onset over the age of 50 and a mainly progressive course, while relapsing-remitting (RR) forms are less frequently observed and explored. This study aimed to characterize a large cohort of MS patients with RRMS at onset to assess the baseline factors related to the worst disability trajectories and explore the role of LOMS., Methods: The data were extracted from the Italian MS Register (IMSR). Disability trajectories, defined using at least two and up to twenty expanded disability status scale (EDSS) assessments annually performed, were implemented using group-based trajectory models (GBTMs) to identify different groups with the same trajectories over time. MS profiles were explored using multinomial logistic regression., Results: A total of 16,159 RR patients [1012 (6.26%) presented with LOMS] were analyzed. The GBTM identified four disability trajectories. The group with the most severe EDSS trend included 12.3% of the patients with a mean EDSS score > 4, which increased over time and exceeded 6 score. The group with medium severity EDSS trend comprised 21.9% of the patients and showed a change in EDSS > 3 scores over time. The largest group with 50.8% of patients reported a constant EDSS of 2 score. Finally, the benign group comprised 14.9% of the patients with a low and constant EDSS of 1 score over time. The probability of being in the worst groups increased if the patient was male; had LOMS or experienced brainstem, spinal, or supratentorial symptoms., Conclusions: Four MS severity profiles among RRMS patients in the IMSR have been reported, with LOMS being associated with a rapid worsening of EDSS scores. These findings have important implications for recognizing and managing how older age, aging, and age-related factors interact with MS and its evolution., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Despite its widespread use in clinical practice, the effectiveness of natalizumab extended interval dosing (EID) adopted from treatment start across different treatment intervals and individual modifiers (body mass index - BMI) is still under-investigated. Here, seven-hundred and forty-five multiple sclerosis (MS) patients, exposed to natalizumab for 3.30 ​± ​1.34 years, were retrospectively enrolled in an observational multicenter study. After stratifying patients in EID or standard interval dosing (SID), we assessed differences in time to relapse, MRI activity and Expanded Disability Status Scale (EDSS) progression. The primary analysis was conducted on patients exposed to EID interval from 5 weeks and 1 day to 7 weeks, while a secondary analysis included also EID periods up to 8 weeks. An additional analysis explored the impact of BMI. No differences in time to first relapse, time to radiological activity, time to EDSS progression or time to EDA (evidence of disease activity) were detected between SID and EID group (EID interval from 5 weeks to 1 day to 7 weeks). When including EID periods from 7 weeks and 1 day to 8 weeks, the EID group showed a trend towards higher risk of experience clinical relapses than the SID group. A higher EDA risk was also identified in EID patients with BMI above median. In conclusion, a higher risk of relapses seems to occur for EID above 7 weeks. Independently from the EID scheme adopted, higher BMI increases the risk of EDA in these patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Carlo Pozzilli reports financial support was provided by Biogen. Many authors (see manuscript) reports a relationship with Teva, Janssen, Merck, Biogen, Novartis, Eisai, Intercept, Bayer, Sanofi, Genzyme, Bristol, Almirall, GW, Roche, Mitsubishi, Celgene, Actelion, Serono Foundation, CSL, Behring, Ultragenix, Horizon, HEALTH&LIFE, AIM Education, FARECOMUNICAZIONE E20 that includes: board membership, consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Myelin oligodendrocyte glycoprotein-immunoglobulin G associated disease (MOGAD) is an autoimmune demyelinating disorder of the central nervous system (CNS) which usually occurs with recurrent optic neuritis, transverse myelitis, acute disseminating encephalomyelitis, or brainstem encephalitis. To date, the anti-CD 20 drug rituximab (RTX) is employed in MOGAD although some authors reported the efficacy of Tocilizumab (TCZ) in refractory patients. We present the case of a woman affected by refractory MOGAD who was treated with TCZ after therapy with RTX had failed to prevent relapses. We also conducted a current literature review on TCZ use in MOGAD. A 57-year-old Caucasian woman affected by MOGAD with severe motor impairment and cognitive dysfunction was treated from 2020 to February 2022 with RTX. However, she experienced progressive clinical and cognitive worsening associated with white matter lesions mimicking leukodystrophy. In February 2022, the patient started therapy with TCZ administered with improvement of cognitive performance, walking ability, and brainstem functions. During TCZ, our patient reached the condition of NEDA-3 (no relapse, no increase in disability, no MRI activity on neuroimaging follow-up performed in September 2023). Moreover, the patient experienced paucisymptomatic SARS-CoV-2 infection that did not modify TCZ schedule. To date, there are few evidence on the efficacy and safety of TCZ in MOGAD. However, all the reviewed cases showed that TCZ represents an effective therapy in drug-resistant MOGAD. Our case highlights the efficacy of TCZ in drug resistant MOGAD and strengthens previous reports of TCZ safety and efficacy in MOGAD., (© 2023. The Author(s).)

Background: Active relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS) are currently defined as "relapsing MS" (RMS). The aim of this cross-sectional study was to assess drivers of treatment switches due to clinical relapses in a population of RMS patients collected in the Italian MS and Related Disorders Register (I-MS&RD)., Methods: RRMS and SPMS patients with at least one relapse in a time window of 2 years before of data extraction were defined as RMS. Factors associated with disease-modifying therapy (DMT) switching due to clinical activity were assessed through multivariable logistic regression models in which treatment exposure was included as the last recorded DMT and the last DMT's class [moderate-efficacy (ME), high-efficacy (HE) DMTs and anti-CD20 drugs]., Results: A cohort of 4739 RMS patients (4161 RRMS, 578 SPMS) was extracted from the I-MS&RD. A total of 2694 patients switching DMTs due to relapses were identified. Switchers were significantly (p < 0.0001) younger, less disabled, more frequently affected by an RR disease course in comparison to non-switcher patients. The multivariable logistic regression models showed that Alemtuzumab (OR 0.08, 95% CI 0.02-0.37), Natalizumab (0.48, 0.30-0.76), Ocrelizumab (0.1, 0.02-0.45) and Rituximab (0.23, 0.06-0.82) exposure was a protective factor against treatment switch due to relapses. Moreover, the use of HE DMTs (0.43, 0.31-0.59), especially anti-CD20 drugs (0.14, 0.05-0.37), resulted to be a protective factor against treatment switch due to relapses in comparison with ME DMTs., Conclusions: More than 50% of RMS switched therapy due to disease activity. HE DMTs, especially anti-CD20 drugs, significantly reduce the risk of treatment switch., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Importance: Although up to 20% of patients with multiple sclerosis (MS) experience onset before 18 years of age, it has been suggested that people with pediatric-onset MS (POMS) are protected against disability because of greater capacity for repair., Objective: To assess the incidence of and factors associated with progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) in POMS compared with typical adult-onset MS (AOMS) and late-onset MS (LOMS)., Design, Setting, and Participants: This cohort study on prospectively acquired data from the Italian MS Register was performed from June 1, 2000, to September 30, 2021. At the time of data extraction, longitudinal data from 73 564 patients from 120 MS centers were available in the register., Main Outcomes and Measures: The main outcomes included age-related cumulative incidence and adjusted hazard ratios (HRs) for PIRA and RAW and associated factors., Exposures: Clinical and magnetic resonance imaging features, time receiving disease-modifying therapy (DMT), and time to first DMT., Results: After applying the inclusion and exclusion criteria, the study assessed 16 130 patients with MS (median [IQR] age at onset, 28.7 [22.8-36.2 years]; 68.3% female). Compared with AOMS and LOMS, patients with POMS had less disability, exhibited more active disease, and were exposed to DMT for a longer period. A first 48-week-confirmed PIRA occurred in 7176 patients (44.5%): 558 patients with POMS (40.4%), 6258 patients with AOMS (44.3%), and 360 patients with LOMS (56.8%) (P < .001). Factors associated with PIRA were older age at onset (AOMS vs POMS HR, 1.42; 95% CI, 1.30-1.55; LOMS vs POMS HR, 2.98; 95% CI, 2.60-3.41; P < .001), longer disease duration (HR, 1.04; 95% CI, 1.04-1.05; P < .001), and shorter DMT exposure (HR, 0.69; 95% CI, 0.64-0.74; P < .001). The incidence of PIRA was 1.3% at 20 years of age, but it rapidly increased approximately 7 times between 21 and 30 years of age (9.0%) and nearly doubled for each age decade from 40 to 70 years (21.6% at 40 years, 39.0% at 50 years, 61.0% at 60 years, and 78.7% at 70 years). The cumulative incidence of RAW events followed a similar trend from 20 to 60 years (0.5% at 20 years, 3.5% at 30 years, 7.8% at 40 years, 14.4% at 50 years, and 24.1% at 60 years); no further increase was found at 70 years (27.7%). Delayed DMT initiation was associated with higher risk of PIRA (HR, 1.16; 95% CI, 1.00-1.34; P = .04) and RAW (HR, 1.75; 95% CI, 1.28-2.39; P = .001)., Conclusions and Relevance: PIRA can occur at any age, and although pediatric onset is not fully protective against progression, this study's findings suggest that patients with pediatric onset are less likely to exhibit PIRA over a decade of follow-up. However, these data also reinforce the benefit for DMT initiation in patients with POMS, as treatment was associated with reduced occurrence of both PIRA and RAW regardless of age at onset.

Background : Orofacial pain syndromes (OFPs) are a heterogeneous group of syndromes mainly characterized by painful attacks localized in facial and oral structures. According to the International Classification of Orofacial Pain (ICOP), the last three groups (non-dental facial pain, NDFP) are cranial neuralgias, facial pain syndromes resembling primary headache syndromes, and idiopathic orofacial pain. These are often clinical challenges because the symptoms may be similar or common among different disorders. The diagnostic efforts often induce a complex diagnostic algorithm and lead to several imaging studies or specialized tests, which are not always necessary. The aim of this study was to describe the encountered difficulties by these patients during the diagnostic-therapeutic course. Methods : This study was based on the responses to a survey questionnaire, administered to an Italian Facebook Orofacial Patient Group, searching for pain characteristics and diagnostic-therapeutic care courses. The questionnaire was filled out by patients affected by orofacial pain, who were 18 years and older, using a free online tool available on tablets, smartphones, and computers. Results : The sample was composed of 320 subjects (244F/76M), subdivided by age range (18-35 ys: 17.2%; 36-55 ys: 55.0%; >55 ys 27.8%). Most of the patients were affected by OFP for more than 3 years The sample presented one OFP diagnosis in 60% of cases, more than one in 36.2% of cases, and 3.8% not classified. Trigeminal neuralgia is more represented, followed by cluster headaches and migraines. About 70% had no pain remission, showing persisting background pain (VAS median = 7); autonomic cranial signs during a pain attack ranged between 45 and 65%. About 70% of the subjects consulted at least two different specialists. Almost all received drug treatment, about 25% received four to nine drug treatments, 40% remained unsatisfied, and almost 50% received no pharmacological treatment, together with drug therapy. Conclusion : To the authors' knowledge, this is the first study on an OFP population not selected by a third-level specialized center. The authors believe this represents a realistic perspective of what orofacial pain subjects suffer during their diagnostic-therapeutic course and the medical approach often results in unsatisfactory outcomes.

Aims: Neuroinflammation might be involved in the degeneration and progression of Amyotrophic Lateral Sclerosis (ALS). Here, we studied the role of the circulating lymphocytes in ALS, in particular the NK cells. We focused on the relationship between blood lymphocytes, ALS clinical subtype and disease severity., Subjects and Methods: Blood samples were collected from 92 patients with sporadic ALS, 21 patients with Primary Lateral Sclerosis (PLS) and 37 patients affected by primary progressive multiple sclerosis (PPMS) with inactive plaques. Blood was taken from ALS and controls at the time of diagnosis/referral. Circulating lymphocytes were analyzed by flow cytometry with specific antibodies. Values were expressed as absolute number (n°/µl) of viable lymphocytes subpopulations in ALS were compared with controls. Multivariable analysis was made using site of onset, gender changes in ALSFRS-R and disease progression rate (calculated as ΔFS score)., Results: Age at onset was 65y (58-71) in ALS (spinal 67.4%; bulbar, 32.6%), 57y (48-78) in PLS and 56y (44-68) PPMS. Absolute blood levels of the lymphocytes in the different cohorts were within normal range. Furthermore, while levels of lymphocytes T and B were not different between disease groups, NK cells were increased in the ALS cohort (ALS = 236 [158-360] vs. Controls = 174[113-240], p < 0.001). In ALS, blood levels of NK cells were not related with the main clinical-demographic variables, including the rate of disease progression. Multivariable analysis suggested that male gender and bulbar onset were independently associated with a risk of high blood NK cells levels., Conclusions: We show that blood NK cells are selectively increased in ALS, though their level appear unaffected in patients with an estimated rapidly progressing disease. Being of a male gender and with a bulbar onset seems to confer higher susceptibility to have increased NK lymphocytes levels at diagnosis/referral. Our experiments provides a further clear-cut evidence of the role of the NK lymphocytes as a significant player in ALS pathogenesis., (© 2023. The Author(s).)

Objective: Vaccines are a major achievement of science, and new vaccines against SARS-CoV-2 are protecting the entire population from a life-threatening infection. Although several neurological complications or worsening of pre-existing neurological conditions after vaccination have been observed, whether a biological plausibility exist between new vaccines against-SARS-CoV-2 and neurological consequences is unclear. The aim of this study is to evaluate whether vaccines against SARS-CoV-2 induce systemic or cerebrospinal fluid alterations in patients with neurological disorders., Methods: Patients who underwent lumbar puncture (LP) between February 2021 and October 2022 were enrolled. Serum C-reactive protein (CRP), neutrophil to lymphocyte ratio (NLR), cerebrospinal fluid total protein content (CSF-TPc), glucose CSF/serum ratio, number of CSF cells per cubic millimeter, and CSF neurofilament light chain (CSF-NfL) were compared between unvaccinated and vaccinated patients., Results: A total of 110 patients were included and fitted into three groups according firstly to vaccination status (vaccinated and unvaccinated) and then to time from last dose of vaccine to LP (within or after 3 months). TPc, CSF/S Glu ratio, number of cells per cubic millimeter, CSF-NfL, CRP, and NLR were not different between groups (all p > 0.05), and also, they did not differ neither according to age nor diagnosis. No relevant differences between groups were also noticed when the at-risk time window was set to 6 weeks., Interpretation: No signs of neuroinflammation, axonal loss and systemic inflammation were found in patients with neurological disorders after anti-SARS-CoV-2 vaccination compared with unvaccinated ones., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Objectives: Uncontrolled evidence suggests that autologous hematopoietic stem cell transplantation (AHSCT) can be effective in people with active secondary progressive multiple sclerosis (SPMS). In this study, we compared the effect of AHSCT with that of other anti-inflammatory disease-modifying therapies (DMTs) on long-term disability worsening in active SPMS., Methods: We collected data from the Italian Bone Marrow Transplantation Study Group and the Italian Multiple Sclerosis Register. Patients were considered eligible if treatment had been started after the diagnosis of SPMS. Disability worsening was assessed by the cumulative proportion of patients with a 6-month confirmed disability progression (CDP) according to the Expanded Disability Status Scale (EDSS) score. Key secondary endpoints were the EDSS time trend after treatment start and the prevalence of disability improvement over time. Time to first CDP was assessed by means of proportional hazard Cox regression models. A linear mixed model with a time × treatment group interaction was used to assess the longitudinal EDSS time trends. Prevalence of improvement was estimated using a modified Kaplan-Meier estimator and compared between groups by bootstrapping the area under the curve., Results: Seventy-nine AHSCT-treated patients and 1975 patients treated with other DMTs (beta interferons, azathioprine, glatiramer-acetate, mitoxantrone, fingolimod, natalizumab, methotrexate, teriflunomide, cyclophosphamide, dimethyl fumarate, and alemtuzumab) were matched to reduce treatment selection bias using propensity score and overlap weighting approaches. Time to first CDP was significantly longer in transplanted patients (hazard ratio [HR] = 0.50; 95% CI = 0.31-0.81; p = 0.005), with 61.7% of transplanted patients free from CPD at 5 years. Accordingly, EDSS time trend over 10 years was higher in patients treated with other DMTs than in AHSCT-treated patients (+0.157 EDSS points per year compared with -0.013 EDSS points per year; interaction p < 0.001). Patients who underwent AHSCT were more likely to experience a sustained disability improvement: 34.7% of patients maintained an improvement (a lower EDSS than baseline) 3 years after transplant vs 4.6% of patients treated by other DMTs ( p < 0.001)., Discussion: The use of AHSCT in people with active SPMS is associated with a slowing of disability progression and a higher likelihood of disability improvement compared with standard immunotherapy., Classification of Evidence: This study provides Class III evidence that autologous hematopoietic stem cell transplants prolonged the time to CDP compared with other DMTs., (© 2022 American Academy of Neurology.)

Background: Sleep disorders are common in patients with multiple sclerosis and have a bidirectional interplay with fatigue and depression., Objective: To evaluate the effect of treatment with oral dimethyl fumarate on the quality of sleep in relapsing-remitting multiple sclerosis., Methods: This was a multicentre observational study with 223 relapsing-remitting multiple sclerosis subjects starting treatment with dimethyl fumarate ( n =177) or beta interferon ( n =46). All patients underwent subjective (Pittsburgh Sleep Quality Index) and objective (wearable tracker) measurements of quality of sleep. Fatigue, depression, and quality of life were also investigated and physical activity was monitored., Results: Patients treated with dimethyl fumarate had significant improvement in the quality of sleep as measured with the Pittsburgh Sleep Quality Index ( p <0.001). At all-time points, no significant changes in Pittsburgh Sleep Quality Index score were observed in the interferon group. Total and deep sleep measured by wearable tracker decreased at week 12 with both treatments, then remained stable for the total study duration. Depression significantly improved in patients treated with dimethyl fumarate. No significant changes were observed in mobility, fatigue and quality of life., Conclusion: In patients with relapsing-remitting multiple sclerosis, the treatment with dimethyl fumarate was associated with improvements in patient-reported quality of sleep. Further randomised clinical trials are needed to confirm the benefits of long-term treatment with dimethyl fumarate., (© The Author(s), 2023.)

Aims: During pregnancy, fetal cells can migrate to the mother via blood circulation. A percentage of these cells survive in maternal tissues for decades generating a population of fetal microchimeric cells (fMCs), whose biological role is unclear. The aim of this study was to investigate the association between the sex of offspring, an indirect marker of fMCs, and magnetic resonance imaging (MRI) features in women with multiple sclerosis (MS)., Methods: We recruited 26 nulliparous MS patients (NPp), 20 patients with at least one male son (XYp), and 8 patients with only daughters (XXp). Each patient underwent brain MR scan to acquire 3D-T2w FLAIR FatSat and 3D-T1w FSPGR/TFE. Lesion Segmentation Tool (LST) and FreeSurfer were used to obtain quantitative data from MRI. Additional data were collected using medical records. Multiple regression models were applied to evaluate the association between sex of offspring and MS data., Results: Comparing NPp and XXp, we found that NPp had larger 4th ventricle volume (2.02 ± 0.59 vs. 1.70 ± 0.41; p = 0.022), smaller left entorhinal volume (0.55 ± 0.17 vs. 0.68 ± 0.25; p = 0.028), and lower thickness in the following cortical areas: left paracentral (2.34 ± 0.16 vs. 2.39 ± 0.17; p = 0.043), left precuneus (2.27 ± 0.11 vs. 2.34 ± 0.16; p = 0.046), right lateral occipital (2.14 ± 0.11 vs. 2.25 ± 0.08; p = 0.006). NPp also had lower thickness in left paracentral cortex (2.34 ± 0.16 vs. 2.46 ± 0.17; p = 0.004), left precalcarine cortex (1.64 ± 0.14 vs. 1.72 ± 0.12; p = 0.041), and right paracentral cortex (2.34 ± 0.17 vs. 2.42 ± 0.14; p = 0.015) when compared to XYp. Comparing XYp and XXp, we found that XYp had higher thickness in left cuneus (1.80 ± 0.14 vs. 1.93 ± 0.10; p = 0.042) and left pericalcarine areas (1.59 ± 0.19 vs. 1.72 ± 0.12; p = 0.032) and lower thickness in right lateral occipital cortex (2.25 ± 0.08 vs. 2.18 ± 0.13; p = 0.027)., Discussion: Our findings suggested an association between the sex of offspring and brain atrophy. Considering the sex of offspring as an indirect marker of fMCs, we speculated that fMCs could accumulate in different brain areas modulating MS neuropathological processes., Competing Interests: GSa received grants outside of this study, for speaking or consultancies from: Almirall, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme. PR received grants outside of this study for speaking or consultancies from: Biogen, Bristoll-Myers-Squibb, Merck, Novartis, Roche, and Sanofi Genzyme. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bianchi, Aprile, Schirò, Gasparro, Iacono, Andolina, Marrale, Gattuso, La Tona, Midiri, Gagliardo, Salemi and Ragonese.)

Objective: Multiple sclerosis (MS) is a chronic disease with different clinical courses and a tendency to worsening. The relapsing-remitting MS presents acute onset and relapses of neurological symptoms, followed by their remission. This form can convert to secondary progressive MS (SPMS) with irreversible neurological worsening and disability. The identification of signs, symptoms, markers of progression, and strategies to manage MS patients is mandatory to allow early identification of those at higher risk of conversion to SPMS, for prompt intervention to cope with the progression of the disease., Methods: A panel of Italian experts from Southern Italy have reviewed the current knowledge on MS and its management and identified the crucial tools for SPMS recognition., Results: More effective communication between patients and clinicians should be established, with the support of digital tools. Moreover, the improvement in the clinical use of biomarkers for progression (cellular structures and tissue organization, such as neurofilaments and chitinase 3-like 1, axonal and neurons density) and of instrumental analyses for recognition of whole-brain atrophy, chronic active lesions, spinal cord lesions and atrophy, and the improvement the combination of the Expanded Disability Status Scale and the evaluation of cognitive dysfunction are discussed., Conclusion: Given the availability of a pharmacological option, adequate education both for patients, regarding the evolution of the disease and the specific treatment, and for professionals, to allow more effective and sensitive communication and the best use of diagnostic and management tools, could represent a strategy to improve patient management and their quality of life., (© 2022. The Author(s).)

Background: Definitions for reliable identification of transition from relapsing-remitting multiple sclerosis (MS) to secondary progressive (SP)MS in clinical cohorts are not available., Objectives: To compare diagnostic performances of two different data-driven SPMS definitions., Methods: Data-driven SPMS definitions based on a version of Lorscheider's algorithm (DDA) and on the EXPAND trial inclusion criteria were compared, using the neurologist's definition (ND) as gold standard, in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), Akaike information criterion (AIC) and area under the curve (AUC)., Results: A cohort of 10,240 MS patients with ⩾5 years of follow-up was extracted from the Italian MS Registry; 880 (8.5%) patients were classified as SPMS according to the neurologist definition, 1806 (17.6%) applying the DDA and 1134 (11.0%) with the EXPAND definition. The DDA showed greater discrimination power (AUC: 0.8 vs 0.6) and a higher sensitivity (77.1% vs 38.0%) than the EXPAND definition, with similar specificity (88.0% vs 91.5%). PPV and NPV were higher using the DDA than considering EXPAND definition (37.5% vs 29.5%; 97.6% vs 94.0%)., Conclusion: Data-driven definitions demonstrated greater ability to capture SP transition than neurologist's definition and the global accuracy of DDA seems to be higher than the EXPAND definition.

Aims: To evaluate how improved treatment adherence with a lower-frequency regimen/treatment of intramuscular (IM) IFNβ-1a impacts therapeutic effectiveness in relapsing-remitting multiple sclerosis (MS) patients switching from a higher-frequency injectable regimen/treatment. Patients & methods: Italian patients with relapsing-remitting MS and prior poor adherence to high-frequency injectable treatments (n = 181) were followed for 24 months after starting IM IFNβ-1a. Results: During the study, 97.4% of patients were treatment adherent; 22.1% of patients reported a relapse. The estimated probability of remaining relapse-free after 2 years was 78%. A high dropout rate (52.5%) led to small sample size and reduced statistical power. Conclusion: Intramuscular IFNβ-1a treatment was associated with high adherence and a low relapse rate. Unfortunately, low patient retention limited the generalizability of these findings.

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: Multiple sclerosis (MS) is characterized by phenotypical heterogeneity, partly resulting from demographic and environmental risk factors. Socio-economic factors and the characteristics of local MS facilities might also play a part., Methods: This study included patients with a confirmed MS diagnosis enrolled in the Italian MS and Related Disorders Register in 2000-2021. Patients at first visit were classified as having a clinically isolated syndrome (CIS), relapsing-remitting (RR), primary progressive (PP), progressive-relapsing (PR), or secondary progressive MS (SP). Demographic and clinical characteristics were analyzed, with centers' characteristics, geographic macro-areas, and Deprivation Index. We computed the odds ratios (OR) for CIS, PP/PR, and SP phenotypes, compared to the RR, using multivariate, multinomial, mixed effects logistic regression models., Results: In all 35,243 patients from 106 centers were included. The OR of presenting more advanced MS phenotypes than the RR phenotype at first visit significantly diminished in relation to calendar period. Females were at a significantly lower risk of a PP/PR or SP phenotype. Older age was associated with CIS, PP/PR, and SP. The risk of a longer interval between disease onset and first visit was lower for the CIS phenotype, but higher for PP/PR and SP. The probability of SP at first visit was greater in the South of Italy., Discussion: Differences in the phenotype of MS patients first seen in Italian centers can be only partly explained by differences in the centers' characteristics. The demographic and socio-economic characteristics of MS patients seem to be the main determinants of the phenotypes at first referral., (© 2022. The Author(s).)

Disability accrual in multiple sclerosis may occur as relapse-associated worsening or progression independent of relapse activity. The role of progression independent of relapse activity in early multiple sclerosis is yet to be established. The objective of this multicentre, observational, retrospective cohort study was to investigate the contribution of relapse-associated worsening and progression independent of relapse activity to confirmed disability accumulation in patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, assessed within one year from onset and with follow-up ≥5 years (n = 5169). Data were extracted from the Italian Multiple Sclerosis Register. Confirmed disability accumulation was defined by an increase in Expanded Disability Status Scale score confirmed at 6 months, and classified per temporal association with relapses. Factors associated with progression independent of relapse activity and relapse-associated worsening were assessed using multivariable Cox regression models. Over a follow-up period of 11.5 ± 5.5 years, progression independent of relapse activity occurred in 1427 (27.6%) and relapse-associated worsening in 922 (17.8%) patients. Progression independent of relapse activity was associated with older age at baseline [hazard ratio (HR) = 1.19; 95% confidence interval (CI) 1.13-1.25, P < 0.001], having a relapsing-remitting course at baseline (HR = 1.44; 95% CI 1.28-1.61, P < 0.001), longer disease duration at baseline (HR = 1.56; 95% CI 1.28-1.90, P < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.92; 95% CI 0.88-0.96, P < 0.001) and lower number of relapses before the event (HR = 0.76; 95% CI 0.73-0.80, P < 0.001). Relapse-associated worsening was associated with younger age at baseline (HR = 0.87; 95% CI 0.81-0.93, P < 0.001), having a relapsing-remitting course at baseline (HR = 1.55; 95% CI 1.35-1.79, P < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.94; 95% CI 0.89-0.99, P = 0.017) and a higher number of relapses before the event (HR = 1.04; 95% CI 1.01-1.07, P < 0.001). Longer exposure to disease-modifying drugs was associated with a lower risk of both progression independent of relapse activity and relapse-associated worsening (P < 0.001). This study provides evidence that in an early relapsing-onset multiple sclerosis cohort, progression independent of relapse activity was an important contributor to confirmed disability accumulation. Our findings indicate that insidious progression appears even in the earliest phases of the disease, suggesting that inflammation and neurodegeneration can represent a single disease continuum, in which age is one of the main determinants of disease phenomenology., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Multiple Sclerosis (MS) is a multifactorial disease whose pathogenesis is the result of interaction among genetic, epigenetic, and environmental factors. Among these, a role for vitamin D hypovitaminosis has emerged in recent decades. Vitamin D levels are influenced by both environmental and genetic factors. Single nucleotide polymorphisms (SNPs) in genes codifying for molecules involved in vitamin D metabolism have been associated with an increased risk of developing MS. However, few studies assessed the association of such SNPs with the severity of the disease. The aim of this observational study was to evaluate the potential association among vitamin D status, MS severity, and vitamin D-related SNPs, alone or in combination., Methods: In a cohort of 100 MS patients, we genotyped 18 SNPs in the following genes: NAD synthetase 1, CYP2R1, vitamin D binding protein, vitamin D receptor, Retinoid X Receptor-α, KLOTHO, CYP24A1, and CYP27A1. Serum 25(OH)D3 levels were measured by high-performance liquid chromatography. Genotyping was performed by real-time polymerase chain reaction or PCR-RFLP., Results: We did not find any association between SNPs, alone or in combination, and MS severity., Conclusion: In this study, we make an initial evaluation of the possible influence of several SNPs in vitamin D-related genes on MS severity., Competing Interests: The authors declare no conflict of interest.

The growing incidence of neurodegenerative disorders in our populations is leading the research to identify potential biomarkers and targets for facilitating their early management and treatments. Biomarkers represent the crucial indicators of both physiological and pathological processes. Specific changes in molecular and cellular mechanisms of physiological processes result in biochemical alterations at systemic level, which can give us comprehensive information regarding the nature of any disease. In addition, any disease biomarker should be specific and reliable, able to consent of distinguishing the physiological condition of a tissue, organ, or system from disease, and be diverse among the various diseases, or subgroups or phenotypes of them. Accordingly, biomarkers can predict chances for diseases, facilitate their early diagnosis, and set guidelines for the development of new therapies for treating diseases and disease-making process. Here, we focus our attention on brain neurotrophic factor (BDNF)-tropomyosin receptor kinase (Trk) pathway, describing its multiple roles in the maintenance of central nervous system (CNS) health, as well as its implication in the pathogenesis of multiple sclerosis (MS). In addition, we also evidence the features of such pathway, which make of it a potential MS biomarker and therapeutic target., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schirò, Iacono, Ragonese, Aridon, Salemi and Balistreri.)

Objective: This study was undertaken to describe and compare disease course and prognosis of early (ie, disease onset before age 11 years) and late (ie, disease onset after age 11 years) onset pediatric multiple sclerosis., Methods: Prospectively collected clinical information from Italian Multiple Sclerosis Register of 1993 pediatric multiple sclerosis patients, of whom 172 had early onset, was analyzed. Cox models adjusted for sex, baseline Expanded Disability Status Scale score, and disease-modifying treatments and stratified for diagnostic criteria adopted (Poser vs McDonald) were used to assess the risk of reaching irreversible Expanded Disability Status Scale scores of 3, 4, and 6, and conversion to secondary progressive phenotype in early versus late onset pediatric patients. Prognostic factors were also evaluated., Results: A greater proportion of males, isolated brainstem involvement, and longer time interval between first and second clinical episode were observed in early versus late onset pediatric patients. Compared to late onset, early onset pediatric patients took longer from disease onset to convert to secondary progressive phenotype and to reach all disability milestones. Recovery from first demyelinating event, time to first relapse, annualized relapse rate during the first 3 years of disease, and disease-modifying treatment exposure were independent predictors for long-term disability in early onset pediatric patients. In late onset pediatric patients, isolated optic neuritis, multifocal symptoms, and progressive course at disease onset were additional predictors for long-term disability., Interpretation: These findings point toward the existence of a different natural history in early versus late onset pediatric multiple sclerosis patients. ANN NEUROL 2022;91:483-495., (© 2022 American Neurological Association.)

Background: Natalizumab (NTZ) is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). However, patients and physicians may consider discontinuing NTZ therapy due to safety or efficacy issues. The aim of our study was to evaluate the NTZ discontinuation rate and reasons of discontinuation in a large Italian population of RRMS patients., Materials and Methods: The data were extracted from the Italian MS registry in May 2018 and were collected from 51,845 patients in 69 Italian multiple sclerosis centers. MS patients with at least one NTZ infusion in the period between June 1st 2012 to May 15th 2018 were included. Discontinuation rates at each time point were calculated. Reasons for NTZ discontinuation were classified as "lack of efficacy", "progressive multifocal leukoencephalopathy (PML) risk" or "other"., Results: Out of 51,845, 5151 patients, 3019 (58.6%) females, with a mean age of 43.6 ± 10.1 years (median 40), were analyzed. Out of 2037 (39.5%) who discontinued NTZ, a significantly higher percentage suspended NTZ because of PML risk compared to lack of efficacy [1682 (32.7% of 5151) vs 221 (4.3%), p < 0.001]; other reasons were identified for 99 (1.9%) patients. Patients discontinuing treatment were older, had longer disease duration and worse EDSS at the time of NTZ initiation and at last follow-up on NTZ treatment. The JCV index and EDSS at baseline were predictors for stopping therapy (HR 2.94, 95% CI 1.22-4.75; p = 0.02; HR 1.36, 95% CI 1.18-5.41; p = 0.04)., Conclusions: Roughly 60% of MS patients stayed on NTZ treatment during the observation period. For those patients in whom NTZ discontinuation was required, it was mainly due to PML concerns., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Physical activity could play a key role in improving the quality of life, particularly in patients with nervous system diseases such as multiple sclerosis (MS). Through lactacid anaerobic training, this study aims to investigate the effects at a bio-psycho-physical level to counteract the chronic fatigue associated with the pathology, and to improve mental health at a psychological and neurotrophic level. Eight subjects (age: 34.88 ± 4.45 years) affected by multiple sclerosis were involved. A lactate threshold training program was administered biweekly for 12 weeks at the beginning of the study (T0), at the end of the study (T1) and at 9 months after the end of the study (T2), with physical, psychological and hematochemicals parameters, and dietary habits being tested. The results obtained confirmed that lactacid exercise can influence brain-derived neurotrophic factor (BDNF) levels as well as dehydroepiandrosterone sulfate (DHEAS) levels. In addition, levels of baseline lactate, which could be best used as an energy substrate, showed a decrease after the protocol training. Self-efficacy regarding worries and concerns management significantly increased from T0 to T1. The eating attitudes test (EAT-26) did not highlight any eating disease in the patients with a normal diet enrolled in our study. Physical exercise also greatly influenced the patients psychologically and emotionally, increasing their self-esteem. Lactate threshold training, together with dietary habits, appears to exert synergic positive effects on inflammation, neural plasticity and neuroprotection, producing preventive effects on MS symptoms and progression.

Multiple factors combined are currently recognized as contributors to cognitive decline. The main independent risk factor for cognitive impairment and dementia is advanced age followed by other determinants such as genetic, socioeconomic, and environmental factors, including nutrition and physical activity. In the next decades, a rise in dementia cases is expected due largely to the aging of the world population. There are no hitherto effective pharmaceutical therapies to treat age-associated cognitive impairment and dementia, which underscores the crucial role of prevention. A relationship among diet, physical activity, and other lifestyle factors with cognitive function has been intensively studied with mounting evidence supporting the role of these determinants in the development of cognitive decline and dementia, which is a chief cause of disability globally. Several dietary patterns, foods, and nutrients have been investigated in this regard, with some encouraging and other disappointing results. This review presents the current evidence for the effects of dietary patterns, dietary components, some supplements, physical activity, sleep patterns, and social engagement on the prevention or delay of the onset of age-related cognitive decline and dementia.

Studies on the role of nutritional factors and physical activity (PA) in the pathogenesis of multiple sclerosis (MS) go back a long time. Despite the intrinsic difficulty of studying their positive or negative role in MS, the interest of researchers on these topics increased during the last few decades, since the role of diet has been investigated with the perspective of the association with disease-modifying drugs (DMD). The association of DMD, diets, and PA might have an additive effect in modifying disease severity. Among the various diets investigated (low-carbohydrate, gluten-free, Mediterranean, low-fat, fasting-mimicking, and Western diets) only low-carbohydrate, Mediterranean, and fast-mimicking diets have shown both in animal models and in humans a positive effect on MS course and in patient-reported outcomes (PROs). However, the Mediterranean diet is easier to be maintained compared to fast-mimicking and low-carbohydrate diets, which may lead to detrimental side effects requiring careful clinical monitoring. Conversely, the Western diet, which is characterized by a high intake of highly saturated fats and carbohydrates, may lead to the activation of pro-inflammatory immune pathways and is therefore not recommended. PA showed a positive effect both in animal models as well as on disease course and PROs in humans. Training with combined exercises is considered the more effective approach.

Background: The incidence of stroke in high-income countries has been on the decline; however, few epidemiological surveys have been conducted in recent years to specifically estimate the incidence along with outcome of stroke, in Italy. This study aimed to examine the incidence and case fatality rates of stroke in an elderly Italian population., Methods: A cohort of 2200 people > 65 years was randomly stratified from the total elderly population of Bagheria, Italy. A 9-year prospective population-based study was performed (19,800 person/years)., Results: We identified 112 first-ever strokes, 53 females and 59 males: 82 (73.1%) ischemic, 13(11.6%) intracerebral haemorrhages, 6 (5.35%) subarachnoid haemorrhages, while 11(9.8%) were classified as undetermined strokes. The crude overall annual incidence was 5.65 per 1000 (95%CI: 4.61 to 6.70) for first-ever stroke. The overall crude incidence rates were 4.74 per 1000 (5.08 for males and 4.46 for females) for ischemic stroke, 0.65 (0.99 for males and 0.37 for females) for intracerebral haemorrhage, and 0.03 for subarachnoid haemorrhage. The incidence rate for first-ever stroke was 5.4 per 1000 (95% CI: 5.36 to 5.45) after adjustment for the 2015 World population and 5.56 (95% CI: 5.52 to 5.61), compared to the 2015 European population. Overall case fatality rates for first-ever stroke was 8.19% at 28 days and 24.1% at 1 year., Conclusion: Our study shows that in the elderly population investigated, stroke incidence and case fatality rates resulted being lower, compared to those from Italian and most European populations. Similar to previous studies, these rates increased linearly with age and were higher in males.

Importance: Availability of new disease-modifying therapies (DMTs) and changes of therapeutic paradigms have led to a general improvement of multiple sclerosis (MS) prognosis in adults. It is still unclear whether this improvement also involves patients with pediatric-onset MS (POMS), whose early management is more challenging., Objective: To evaluate changes in the prognosis of POMS over time in association with changes in therapeutic and managing standards., Design, Setting, and Participants: Retrospective, multicenter, observational study. Data were extracted and collected in May 2019 from the Italian MS Registry, a digital database including more than 59 000 patients. Inclusion criteria were MS onset before age 18 years, diagnosis before January 2014, and disease duration of at least 3 years. Exclusion criteria were primary progressive MS, Expanded Disability Status Scale (EDSS) score of at least 8 one year after onset, unavailability of diagnosis date, and less than 2 EDSS score evaluations. Eligible patients were 4704 patients with POMS. According to these criteria, we enrolled 3198 patients, excluding 1506., Exposures: We compared time to reach disability milestones by epoch of MS diagnosis (<1993, 1993-1999, 2000-2006, and 2007-2013), adjusting for possible confounders linked to EDSS evaluations and clinical disease activity. We then analyzed the difference among the 4 diagnosis epochs regarding demographic characteristics, clinical disease activity at onset, and DMTs management., Main Outcomes and Measures: Disability milestones were EDSS score 4.0 and 6.0, confirmed in the following clinical evaluation and in the last available visit., Results: We enrolled 3198 patients with POMS (mean age at onset, 15.2 years; 69% female; median time to diagnosis, 3.2 years; annualized relapse rate in first 1 and 3 years, 1.3 and 0.6, respectively), with a mean (SD) follow-up of 21.8 (11.7) years. Median survival times to reach EDSS score of 4.0 and 6.0 were 31.7 and 40.5 years. The cumulative risk of reaching disability milestones gradually decreased over time, both for EDSS score of 4.0 (hazard ratio [HR], 0.70; 95% CI, 0.58-0.83 in 1993-1999; HR, 0.48; 95% CI, 0.38-0.60 in 2000-2006; and HR, 0.44; 95% CI, 0.32-0.59 in 2007-2013) and 6.0 (HR, 0.72; 95% CI, 0.57-0.90; HR, 0.44; 95% CI, 0.33-0.60; and HR, 0.30; 0.20-0.46). In later diagnosis epochs, a greater number of patients with POMS were treated with DMTs, especially high-potency drugs, that were given earlier and for a longer period. Demographic characteristics and clinical disease activity at onset did not change significantly over time., Conclusions and Relevance: In POMS, the risk of persistent disability has been reduced by 50% to 70% in recent diagnosis epochs, probably owing to improvement in therapeutic and managing standards.

Background and Aims: No consensus exists on how aggressively to treat relapsing-remitting multiple sclerosis (RRMS) nor on the timing of the treatment. The objective of this study was to evaluate disability trajectories in RRMS patients treated with an early intensive treatment (EIT) or with a moderate-efficacy treatment followed by escalation to higher-efficacy disease modifying therapy (ESC)., Methods: RRMS patients with ⩾5-year follow-up and ⩾3 visits after disease modifying therapy (DMT) start were selected from the Italian MS Registry. EIT group included patients who received as first DMT fingolimod, natalizumab, mitoxantrone, alemtuzumab, ocrelizumab, cladribine. ESC group patients received the high efficacy DMT after ⩾1 year of glatiramer acetate, interferons, azathioprine, teriflunomide or dimethylfumarate treatment. Patients were 1:1 propensity score (PS) matched for characteristics at the first DMT. The disability trajectories were evaluated by applying a longitudinal model for repeated measures. The effect of early versus late start of high-efficacy DMT was assessed by the mean annual Expanded Disability Status Scale (EDSS) changes compared with baseline values (delta-EDSS) in EIT and ESC groups., Results: The study cohort included 2702 RRMS patients. The PS matching procedure produced 363 pairs, followed for a median (interquartile range) of 8.5 (6.5-11.7) years. Mean annual delta-EDSS values were all significantly ( p  < 0.02) higher in the ESC group compared with the EIT group. In particular, the mean delta-EDSS differences between the two groups tended to increase from 0.1 (0.01-0.19, p  = 0.03) at 1 year to 0.30 (0.07-0.53, p  = 0.009) at 5 years and to 0.67 (0.31-1.03, p  = 0.0003) at 10 years., Conclusion: Our results indicate that EIT strategy is more effective than ESC strategy in controlling disability progression over time., Competing Interests: Conflict of interest statement: All the authors report no competing interest related to this specific project. The authors report no conflicts of interest with respect to the contents of the current study, but note that the patients in the study were treated with a number of disease modifying drugs and that authors Pietro Iaffaldano, Giuseppe Lucisano, Francesca Caputo, Damiano Paolicelli, Francesco Patti, Mauro Zaffaroni, Vincenzo Brescia Morra, Carlo Pozzilli, Giovanna De Luca, Matilde Inglese, Giuseppe Salemi, Giorgia Teresa Maniscalco, Eleonora Cocco, Patrizia Sola, Giacomo Lus, Antonella Conte, Maria Pia Amato, Franco Granella, Claudio Gasperini, Paolo Bellantonio, Rocco Totaro, Marco Rovaris, Marco Salvetti, Valentina Liliana Adriana Torri Clerici, Roberto Bergamaschi, Davide Maimone, Elio Scarpini, Marco Capobianco, Giancarlo Comi, Massimo Filippi and Maria Trojano report having received advisory board membership, speaker’s honoraria, travel support, research grants, consulting fees, or clinical trial support from the manufacturers of those drugs, including Actelion, Allergan, Almirall, Bayer Schering, Biogen, Celgene, Excemed, Genzyme, Forward Pharma, Ipsen, Medday, Merck, Merz, Mylan, Novartis, Sanofi, Roche, Teva, and their local affiliates., (© The Author(s), 2021.)

The current study aims to compare injectable and oral first-line disease-modifying therapies (DMTs) for time to first relapse, time to confirmed disability progression (CDP), and time to discontinuation using a cohort of relapsing remitting multiple sclerosis (RRMS) patients, with data extracted from the Italian MS Register. This multicenter, observational, retrospectively acquired, and propensity-adjusted cohort study utilized RRMS-naïve patients from the Italian MS Register who started either injectable or oral first-line DMTs between January 1, 2010, and December 31, 2017, to evaluate the impact on disability outcomes in patients. Enrolled patients were divided into two groups, namely the injectable group (IG) and the oral group (OG). Of a cohort of 11,416 patients, 4602 were enrolled (3919 in the IG and 683 in the OG). The IG had a higher rate of women (67.3% vs 63.4%, p < 0.05) and a lower mean age (36.1 ± 10.9 vs 38.9 ± 11.8, p < 0.001). The event time to first relapse demonstrated a lower risk in the OG (HR = 0.58; CI 95% 0.48-0.72, p < 0.001). However, no differences were found between the two groups with respect to the risk of CDP (HR = 0.94; CI 95% 0.76-1.29, p = 0.941), while a lower risk of DMT was found in the OG (HR = 0.72; CI 95% 0.58-0.88, p = 0.002) for the event time to discontinuation. Real-world data from the Italian MS Register suggests that first-line oral DMTs are associated with a lower risk of experiencing a new relapse and of therapy discontinuation compared to injectable DMTs., (© 2021. The Author(s).)

Background: Regulatory T cells (Tregs) alterations have been implicated in the pathogenesis of Multiple Sclerosis (MS). Recently, a crucial role of the X-Linked Forkhead Box P3 (FoxP3) for the development and the stability of Tregs has emerged, and FOXP3 gene polymorphisms have been associated with the susceptibility to autoimmune diseases. The expression of Foxp3 in Tregs is regulated by the transcription factor GATA binding-protein 3 (GATA3) and vitamin D 3 . The aim of this retrospective case-control study was to investigate the potential association between FOXP3 and GATA3 genetic variants, Vitamin D 3 , and MS risk., Methods: We analyzed two polymorphisms in the FOXP3 gene (rs3761547 and rs3761548) and a polymorphism in the GATA3 gene (rs3824662) in 106 MS patients and 113 healthy controls. Serum 25(OH)D3 was also measured in all participants., Results: No statistically significant genotypic and allelic differences were found in the distribution of FOXP3 rs3761547 and rs3761548, or GATA3 rs3824662 in the MS patients, compared with controls. Patients that were homozygous for rs3761547 had lower 25(OH)D3 levels., Conclusions: Our findings did not show any association among FOXP3 and GATA3 SNPs, vitamin D 3 , and MS susceptibility.

Transcranial magnetic resonance-guided focused ultrasound is a recently introduced incisionless treating option for essential tremor and tremor-dominant idiopathic Parkinson disease. There is preliminary evidence that it may result in a promising effective treatment option for other movement disorders too. Here, we report on two patients with multiple sclerosis with medication refractory debilitating essential tremor comorbidity who successfully underwent unilateral Vim tcMRgFUS thalamotomy for tremor control. Patients' clinical condition and expanded disability status scale scores showed no changes during the 1-year follow-up period with no evidence of multiple sclerosis activity or progression.

Background: No uniform criteria for a sensitive identification of the transition from relapsing-remitting multiple sclerosis (MS) to secondary-progressive multiple sclerosis (SPMS) are available., Objective: To compare risk factors of SPMS using two definitions: one based on the neurologist judgment (ND) and an objective data-driven algorithm (DDA)., Methods: Relapsing-onset MS patients ( n  = 19,318) were extracted from the Italian MS Registry. Risk factors for SPMS and for reaching irreversible Expanded Disability Status Scale (EDSS) 6.0, after SP transition, were estimated using multivariable Cox regression models., Results: SPMS identified by the DDA ( n  = 2343, 12.1%) were older, more disabled and with a faster progression to severe disability ( p  < 0.0001), than those identified by the ND ( n  = 3868, 20.0%). In both groups, the most consistent risk factors ( p  < 0.05) for SPMS were a multifocal onset, an age at onset >40 years, higher baseline EDSS score and a higher number of relapses; the most consistent protective factor was the disease-modifying therapy (DMT) exposure. DMT exposure during SP did not impact the risk of reaching irreversible EDSS 6.0., Conclusion: A DDA definition of SPMS identifies more aggressive progressive patients. DMT exposure reduces the risk of SPMS conversion, but it does not prevent the disability accumulation after the SP transition.

Objective: In this study, we explored the relationship between migraine and sport in a physically active population of students, analyzing the risk of migraine among sporty students., Background: The relationship between sport and migraine is controversial; moreover, several studies report on sport as a migraine trigger, but there is evidence that physical activity could have a relevant role in migraine prevention., Methods: A cross-sectional survey was conducted using the validated ID-migraine questionnaire including specific demo-anthropometric (gender, age, weight, height) and sports variables on a potentially active student population of the University of Palermo. Evaluation in putative migraine subjects of clinical features and disability was explored through the administration of the Italian version of the Migraine Disability Assessment Scale. Statistical analyses were performed using univariate and logistic regression analyses., Results: Three hundred and ninety-three out of 520 students (210 F, mean age: 23.5 ± 0.7 years; 183 M; mean age: 20.5 ± 0.7 years) participated in this study. Migraine screened positive in 102 subjects (26.0%) and its prevalence was significantly higher among females (P < .001). An increased risk of migraine was found in females, and a protective effect of sport on the risk of migraine among females, but not among males., Conclusions: The role of exercise in migraine is still unclear. This study supports a protective role of sport in migraine reporting a protective effect in females. Further studies are needed to deepen the association between sport and migraine., (© 2020 American Headache Society.)

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.

An ever-expanding number of disease-modifying drugs for multiple sclerosis have become available in recent years, after demonstrating efficacy in clinical trials. In the real-world setting, however, disease-modifying drugs are prescribed in patient populations that differ from those included in pivotal studies, where extreme age patients are usually excluded or under-represented. In this multicentre, observational, retrospective Italian cohort study, we evaluated treatment exposure in three cohorts of patients with relapsing-remitting multiple sclerosis defined by age at onset: paediatric-onset (≤18 years), adult-onset (18-49 years) and late-onset multiple sclerosis (≥50 years). We included patients with a relapsing-remitting phenotype, ≥5 years follow-up, ≥3 Expanded Disability Status Scale (EDSS) evaluations and a first neurological evaluation within 3 years from the first demyelinating event. Multivariate Cox regression models (adjusted hazard ratio with 95% confidence intervals) were used to assess the risk of reaching a first 12-month confirmed disability worsening and the risk of reaching a sustained EDSS of 4.0. The effect of disease-modifying drugs was assessed as quartiles of time exposure. We found that disease-modifying drugs reduced the risk of 12-month confirmed disability worsening, with a progressive risk reduction in different quartiles of exposure in paediatric-onset and adult-onset patients [adjusted hazard ratios in non-exposed versus exposed >62% of the follow-up time: 8.0 (3.5-17.9) for paediatric-onset and 6.3 (4.9-8.0) for adult-onset, P < 0.0001] showing a trend in late-onset patients [adjusted hazard ratio = 1.9 (0.9-4.1), P = 0.07]. These results were confirmed for a sustained EDSS score of 4.0. We also found that relapses were a risk factor for 12-month confirmed disability worsening in all three cohorts, and female sex exerted a protective role in the late-onset cohort. This study provides evidence that sustained exposure to disease-modifying drugs decreases the risk of disability accumulation, seemingly in a dose-dependent manner. It confirms that the effectiveness of disease-modifying drugs is lower in late-onset patients, although still detectable., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To assess the usefulness of the κ free light chain index (κFLCi) as a screening test to identify patients with suspected MS., Methods: The study included 56 patients with a request to test for oligoclonal bands (OCBs). OCBs were detected by isoelectric focusing, followed by immunofixation. Cerebrospinal fluid (CSF) and serum κFLC were measured by a turbidimetric assay. Also, the κFLC index (κFLCi) was calculated., Results: CSF κFLC levels and κFLCi were significantly higher in patients with multiple sclerosis (MS) than in patients with other neurological diseases (NDs; P < .001 and P < .001, respectively). At the cutoff value of 2.9, the κFLCi detected MS with sensitivity of 97% and specificity of 65%. Overall, 92% patients with κFLCi of 2.9 or greater and who had tested positive for OCBs were diagnosed as having MS., Conclusion: Our findings support the use of κFLCi as a screening test when MS is suspected, followed by OCB detection as a confirmatory test for the diagnosis of MS., (© American Society for Clinical Pathology 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Multiple sclerosis (MS) is an autoimmune and degenerative disorder of the central nervous system (CNS) that causes a progressive loss of motor and cognitive performances. Moreover, since the earlier phases, axonal loss as well as neuronal degeneration and a failure of oligodendrocytes to promote myelin repair have been demonstrated. In previous studies, it has been shown that the treatment of rat neuronal primary cultures with serum from MS patients can be toxic for neurons. Here we report a pilot investigation showing that CSF from patients contains extracellular vesicles (EVs) able to induce cell death in rat cultured astrocytes. Although these data are still preliminary, they suggest at least two notable considerations: i) EVs can be instrumental to pathology, and their concentration in CSF might be proportional to MS severity; ii) astrocytes can be part of the degenerative process. As a consequence, we propose that cultured astrocytes can be used as a model to study the toxicity of EVs from patients affected by MS at different stages. In addition, we suggest that EVs and their cargoes might be used as biomarkers of MS severity.

We evaluated the combined use of transcranial random noise stimulation (tRNS) with the Graded Repetitive Arm Supplementary Program (GRASP) in sub-acute ischemic stroke patients suffering from arm impairment. Eighteen ischemic stroke patients with upper limb disability were randomly assigned to either the GRASP + tRNS or GRASP + Sham stimulation group. Fugl-Meyer Assessment-Upper extremity (FMA-UE) was performed to evaluate upper limb impairment before treatment (T0), after the last stimulation (T1) and after 30 days (T2). At T1 and T2, beneficial effects in the tRNS group correlated with better FMA-UE score than sham stimulation group (p < 0.001) and these results did not correlate to stroke severity, because no associations were observed between National Institute of Health Stroke Scale and FMA UE T1 and T2. This study displayed a good feasibility and was the first to evaluate the use of tRNS in association with Grasp in sub-acute stroke survivors having arm impairment to improve arm motor recovery.

Background: The increase in disease-modifying drugs (DMDs) allows individualization of treatment in relapsing multiple sclerosis (RMS); however, the long-term impact of different treatment sequences is not well established. This is particularly relevant for MS patients who may need to postpone more aggressive DMD strategies., Objective: To evaluate different therapeutic strategies and their long-term outcomes, measured as relapses and confirmed disability progression (CDP), in MS 'real-world' settings., Methods: Multicentre, observational, retrospectively acquired cohort study evaluating the long-term impact of different treatment strategies on disability outcomes in patients with RMS in the Italian MS Register., Results: We evaluated 1152 RMS-naïve patients after propensity-score adjustment. Patients included were receiving: interferon beta-1a (IFN-β1a) 44 µg switching to fingolimod (FTY; IFN-switchers; n = 97); FTY only (FTY-stayers; n = 157); IFN-β1a only (IFN-stayers; n = 849). CDP and relapses did not differ between FTY-stayers and IFN-switchers [HR (95% CI) 0.99 (0.48-2.04), p = 0.98 and 0.81 (0.42-1.58), p = 0.55, respectively]. However, IFN-stayers showed increased risk of relapses compared with FTY-stayers [HR (95% CI) 1.46 (1.00-2.12), p = 0.05]., Conclusion: The ideal treatment option for MS is becoming increasingly complex, with the need to balance benefit and risks. Our results suggest that starting with FTY affects the long-term disease outcome similarly to escalating from IFN-β1a to FTY.

Introduction: Low vitamin D levels have been recognised as an important risk factor for autoimmune diseases, including multiple sclerosis (MS). MS is a multifactorial disease, the pathogenesis of which contributes both to genetic and environmental factors. Polymorphisms in genes codifying molecules involved in vitamin D homeostasis have been associated with hypovitaminosis D. However, the influence of polymorphisms of Klotho, which codify a protein with a pivotal role in vitamin D metabolism, have never been investigated. The aim of this study was to evaluate the association among genetic variants of Klotho, namely rs1207568 and rs9536314, serum 25(OH)D 3 levels, and multiple sclerosis (both risk and disease progression)., Material and Methods: 107 patients with MS and 133 healthy controls were enrolled in this study. Serum 25(OH)D 3 levels and genotyping of Klotho SNPs were evaluated in all participants by high-performance liquid chromatography and real-time polymerase chain reaction, respectively., Results: Allelic and genotypic frequencies did not differ between patients and controls. Concerning rs1207568, we found a trend toward lower serum 25(OH)D 3 levels in MS patients with A allele (mutant), both in heterozygosis (AG) and in homozygosis (AA), in comparison to MS patients with G allele in homozygosis (GG) (AG + AA 20.5 ±6.3 µg/l; GG 22.5 ±7.5 µg/l, p = 0.07)., Conclusions: Our findings did not identify a role of Klotho in the genetic susceptibility to MS., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 Termedia & Banach.)

Migraine is a highly disabling disease characterized by recurrent pain. Despite an intensive effort, mechanisms of migraine pathophysiology still represent an unsolved issue. Evidence from both animal and human studies suggests that migraine is characterized by hyperresponsivity or hyperexcitability of sensory cortices, especially the visual cortex. This phenomenon, in turn, may affect multisensory processing. Indeed, migraineurs present with an abnormal, reduced, perception of the Sound-induced Flash Illusion (SiFI), a crossmodal illusion that relies on optimal integration of visual and auditory stimuli by the occipital visual cortex. Decreasing visual cortical excitability with transcranial direct current stimulation (tDCS) can increase the SiFI in healthy subjects. Moving away from these issues, we applied cathodal tDCS over the visual cortex of migraineurs, with and without aura, in order to decrease cortical excitability and thus physiologically restoring the perception of a reliable SiFI. Differently from our expectations, tDCS was unable to reliably modulate SiFI in migraine. The chronic, relatively excessive, visual cortex hyperexcitability, featuring the migraineur brain, may render tDCS ineffective for restoring multisensory processing in this disease.

We evaluated the effects of transcranial random noise stimulation (tRNS) on fatigue in 17 subjects with relapsing-remitting multiple sclerosis with low physical disability. Two different patient groups underwent real or sham stimulation for 10 days, targeting the primary motor cortex of the dominant side or contralateral to the most compromised limb. In the 'real group', beneficial effects were observed using the Modified Fatigue Impact Scale (p = 0.04; physical subscale: p = 0.03), the subscales 'change in health' (p = 0.006) and 'role limitations due to physical problems' (p = 0.001) of the Multiple Sclerosis Quality of Life-54, and by assessing the patient impression of perceived fatigue (p = 0.005).

Objectives: Recent literature proved that social cognition impairments may characterize the neuropsychological profile of Multiple Sclerosis (MS) patients. However, little is still known about moral cognition in MS. In this study, we evaluated non-social, social, and moral cognitive performances in 45 relapsing-remitting MS patients., Methods: Patients underwent the Brief International Cognitive Assessment for Multiple Sclerosis battery, the Cognitive Estimation and Stroop tasks, the Ekman-60 Faces test, the Reading the Mind in the Eye and Story-based Empathy task. Additionally, a task of moral dilemmas including both "instrumental" and "incidental" conditions was administered to patients. Forty-five age-, gender- and education-matched healthy control subjects (HC) were enrolled for comparisons., Results: The majority of patients (i.e., 77.6%) showed deficits at non-social tasks, particularly in the executive domains. A subset of MS sample (i.e., 24%) presented with emotion recognition and socio-affective processing impairments. Overall, MS patients showed comparable levels of moral judgment with respect to HC. The rate of yes/no response in resolution of moral dilemmas and scores of attribution of emotional valence were comparable between groups. Nevertheless, lower moral permissibility and emotional arousal, particularly for the instrumental dilemmas, characterized the MS profile. Significant correlations between the attribution of emotional valence to moral actions and mentalizing scores emerged., Conclusions: Our findings expand current literature on MS supporting not only deficits in executive and socio-emotional domains but also low levels of permissibility of immoral actions and emotional detachment in the moral judgment process., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background The Quality of Life in Short Stature Youth (QoLISSY) questionnaire is a condition-specific instrument for measuring the health-related quality of life (HRQoL) in short statured children/adolescents from patients' and parents' perspectives. The aim of this study was to investigate the psychometric properties of the Greek version of the QoLISSY questionnaire. Methods The original European QoLISSY scales were translated into Greek following the guidelines for linguistic validation and applied to 184 dyads of children 8-18 years old and their parents, as well as to 14 parents of children 4-7 years old in Greece. The field testing responses to the Greek version of QoLISSY were analyzed. Results The qualitative analysis of the Greek data provided results consistent with the European sample. The subsequent field test showed acceptable internal consistency (Cronbach α between 0.67-0.93) and high test-retest reliability (intraclass correlation coefficients [ICC] ≥0.70). Correlations with the generic KIDSCREEN questionnaire indicated good convergent validity. Confirmatory factor analysis (CFA) also yielded acceptable results. Higher HRQoL for taller children suggests that QoLISSY was able to detect significant height-related differences. Conclusions The Greek version of the QoLISSY questionnaire is psychometrically sound and its use is recommended in further clinical research to ascertain the impact of short stature (SS) and treatments in Greek children/adolescents and families.