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Background: People with rare neurological diseases (RNDs) often experience symptoms related to movement disorders, requiring a multidisciplinary approach, including rehabilitation. Telemedicine applied to rehabilitation and symptom monitoring may be suitable to ensure treatment consistency and personalized intervention. The objective of this scoping review aimed to emphasize the potential role of telerehabilitation and teleassessment in managing movement disorders within RNDs. By providing a systematic overview of the available literature, we sought to highlight potential interventions, outcomes, and critical issues. Methods: A literature search was conducted on PubMed, Google Scholar, IEEE, and Scopus up to March 2024. Two inclusion criteria were followed: (1) papers focusing on telerehabilitation and teleassessment and (2) papers dealing with movement disorders in RNDs. Results: Eighteen papers fulfilled the inclusion criteria. The main interventions were home-based software and training programs, exergames, wearable sensors, smartphone applications, virtual reality and digital music players for telerehabilitation; wearable sensors, mobile applications, and patient home video for teleassessment. Key findings revealed positive outcomes in gait, balance, limb disability, and in remote monitoring. Limitations include small sample sizes, short intervention durations, and the lack of standardized protocols. Conclusion: This review highlighted the potential of telerehabilitation and teleassessment in addressing movement disorders within RNDs. Data indicate that these modalities may play a major role in supporting conventional programs. Addressing limitations through multicenter studies, longer-term follow-ups, and standardized protocols is essential. These measures are essential for improving remote rehabilitation and assessment, contributing to an improved quality of life for people with RNDs.

Background: ChatGPT is an open-source natural language processing software that replies to users' queries. We conducted a cross-sectional study to assess people living with Multiple Sclerosis' (PwMS) preferences, satisfaction, and empathy toward two alternate responses to four frequently-asked questions, one authored by a group of neurologists, the other by ChatGPT., Methods: An online form was sent through digital communication platforms. PwMS were blind to the author of each response and were asked to express their preference for each alternate response to the four questions. The overall satisfaction was assessed using a Likert scale (1-5); the Consultation and Relational Empathy scale was employed to assess perceived empathy., Results: We included 1133 PwMS (age, 45.26 ± 11.50 years; females, 68.49%). ChatGPT's responses showed significantly higher empathy scores (Coeff = 1.38; 95% CI = 0.65, 2.11; p > z < 0.01), when compared with neurologists' responses. No association was found between ChatGPT' responses and mean satisfaction (Coeff = 0.03; 95% CI = - 0.01, 0.07; p = 0.157). College graduate, when compared with high school education responder, had significantly lower likelihood to prefer ChatGPT response (IRR = 0.87; 95% CI = 0.79, 0.95; p < 0.01)., Conclusions: ChatGPT-authored responses provided higher empathy than neurologists. Although AI holds potential, physicians should prepare to interact with increasingly digitized patients and guide them on responsible AI use. Future development should consider tailoring AIs' responses to individual characteristics. Within the progressive digitalization of the population, ChatGPT could emerge as a helpful support in healthcare management rather than an alternative., (© 2024. The Author(s).)

Background: The management of Multiple Sclerosis (MS) has undergone transformative evolution with the introduction of high-efficacy disease-modifying therapies (DMTs), specifically anti-CD20 monoclonal antibodies, such as ocrelizumab (OCR) and ofatumumab (OFA)., Materials and Methods: This is an independent retrospective cohort study in Relapsing MS (RMS) patients followed at eight Italian MS centers who initiated treatment with OCR or OFA in the participating centers and with at least 12 months on therapy. A generalized linear regression model inverse probability of treatment weight (IPTW) PS-adjusted was performed to evaluate the relationship between annualized relapse rate (ARR) and treatment groups. No evidence of disease activity-NEDA-3 at 12-month score was also collected. Safety profile of the investigated DMTs was recorded., Results: A total cohort of 396 RMS patients fulfilled the required criteria and were enrolled in the study. Out of them, 216 had a prescription of OCR and 180 of OFA. The mean follow-up was 13.2 ± 1.9 months. The estimated means for ARR did not show differences between the two groups, 0.059 for patients on OCR and 0.038 for patients on OFA (p = 0.185). The generalized regression model IPTW PS-adjusted did not reveal differences between patients on OCR and OFA (ExpB OFA 0.974, 95%CI 934-1.015, p = 0.207). NEDA-3 at 12 months was experienced by 199(92.1%) patients on OCR and 170(94.4%) patients on OFA (p = 0.368). Generally, both therapies exhibit good tolerability., Conclusions: The treatment with OCR and OFA resulted in comparable control of disease activity with good safety profile. Our results need further validation in larger multicentre studies with long-term follow-up., (© 2024. The Author(s).)

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

Background and Objectives: The role of B cells in the pathogenic events leading to relapsing multiple sclerosis (R-MS) has only been recently elucidated. A pivotal step in defining this role has been provided by therapeutic efficacy of anti-CD20 monoclonal antibodies. Indeed, treatment with anti-CD20 can also alter number and function of other immune cells not directly expressing CD20 on their cell surface, whose activities can contribute to unknown aspects influencing therapeutic efficacy. We examined the phenotype and function of cytotoxic lymphocytes and Epstein-Barr virus (EBV)-specific immune responses in people with R-MS before and after ocrelizumab treatment., Methods: In this prospective study, we collected blood samples from people with R-MS (n = 41) before and 6 and 12 months after initiating ocrelizumab to assess the immune phenotype and the indirect impact on cytotoxic functions of CD8 + T and NK cells. In addition, we evaluated the specific anti-EBV proliferative responses of both CD8 + T and NK lymphocytes as surrogate markers of anti-EBV activity., Results: We observed that while ocrelizumab depleted circulating B cells, it also reduced the expression of activation and migratory markers on both CD8 + T and NK cells as well as their in vitro cytotoxic activity. A comparable pattern in the modulation of immune molecules by ocrelizumab was observed in cytotoxic cells even when patients with R-MS were divided into groups based on their prior disease-modifying treatment. These effects were accompanied by a significant and selective reduction of CD8 + T-cell proliferation in response to EBV antigenic peptides., Discussion: Taken together, our findings suggest that ocrelizumab-while depleting B cells-affects the cytotoxic function of CD8 + and NK cells, whose reduced cross-activity against myelin antigens might also contribute to its therapeutic efficacy during MS.

Introduction: People with multiple sclerosis (PwMS) exhibit a spectrum of needs that extend beyond solely disease-related determinants. Investigating unmet needs from the patient perspective may address daily difficulties and optimize care. Our aim was to identify patterns of unmet needs among PwMS and their determinants., Methods: We conducted a cross-sectional multicentre study. Data were collected through an anonymous, self-administered online form. To cluster PwMS according to their main unmet needs, we performed agglomerative hierarchical clustering algorithm. Principal component analysis (PCA) was applied to visualize cluster distribution. Pairwise comparisons were used to evaluate demographics and clinical distribution among clusters., Results: Out of 1764 mailed questionnaires, we received 690 responses. Access to primary care was the main contributor to the overall unmet need burden. Four patterns were identified: cluster C1, 'information-seekers with few unmet needs'; cluster C2, 'high unmet needs'; cluster C3, 'socially and assistance-dependent'; cluster C4, 'self-sufficient with few unmet needs'. PCA identified two main components in determining the patterns: the 'public sphere' (access to information and care) and the 'private sphere' (need for assistance and social life). Older age, lower education, longer disease duration and higher disability characterized clusters with more unmet needs in the private sphere. However, demographic and clinical factors failed in explaining the four identified patterns., Conclusion: Our study identified four unmet need patterns among PwMS, emphasizing the importance of personalized care. While clinical and demographic factors provide some insight, additional variables warrant further investigation to fully understand unmet needs in PwMS., (© 2024. The Author(s).)

Background: Multiple sclerosis (MS) and psoriasis (PsO) are distinct chronic autoimmune conditions with varying impacts on patients' lives. While the co-occurrence of MS and PsO has been reported, the underlying pathogenic link remains unclear. This study aimed to investigate the prevalence of PsO in a MS outpatient clinic population and explore the potential interplay between these conditions., Methods: 316 MS patients who had at least one visit at our MS center in the last year, were selected from our outpatient MS Clinic electronic database and were e-mailed in August 2023 and inquired about a previous diagnosis of PsO. Demographic and MS history data were retrospectively gathered for two groups: MS patients without and with PsO. Information about MS phenotype, Expanded Disability Status Scale (EDSS) score at the diagnosis and at last follow-up, disease modifying therapy (DMT) were collected retrospectively from our MS data set. PsO diagnosis was confirmed by an experienced dermatologist and severity was assessed with the Psoriasis Area and Severity Index (PASI)., Results: Among 253 respondents, 5.85% reported a PsO diagnosis that was confirmed after the dermatological evaluation Among patients with psoriasis 66.67% had progressive course of MS (p = 0.032) and the onset of PsO typically occurred after MS diagnosis. 9 out 15 patients had a PASI score of 0 and 6 are currently undergoing treatment with an anti-CD20 therapy. Notably, a subset of our patients were on anti-CD20 therapy and did not experience a worsening of dermatological symptoms., Discussion and Conclusion: The prevalence of PsO in our outpatient MS population aligns with previous studies. Treatment approaches should be tailored to individual patient needs, emphasizing collaboration between neurologists and dermatologists. Medications like dimethyl fumarate, effective in both conditions, could be considered. The data from our study also suggest that anti-CD20 therapy may be a viable option for some patients with concurrent MS and mild PsO, without a significant worsening of dermatological symptoms. Further research is needed to elucidate the complex relationship between MS and PsO and to develop more effective therapeutic strategies for patients with both conditions., (© 2024. The Author(s).)

Background and Purpose: Cladribine tablets, a purine analogue antimetabolite, offer a unique treatment regimen, involving short courses at the start of the first and second year, with no further treatment needed in years 3 and 4. However, comprehensive evidence regarding patient outcomes beyond the initial 24 months of cladribine treatment is limited., Methods: This retrospective, multicenter study enrolled 204 patients with multiple sclerosis who had completed the 2-year course of cladribine treatment. The primary outcomes were therapeutic choices and clinical disease activity assessed by annualized relapse rate after the 2-year treatment course., Results: A total of 204 patients were enrolled; most patients (75.4%) did not initiate new treatments in the 12 months postcladribine. The study found a significant reduction in annualized relapse rate at the 12-month follow-up after cladribine completion compared to the year prior to starting therapy (0.07 ± 0.25 vs. 0.82 ± 0.80, p < 0.001). Furthermore, patients with relapses during cladribine treatment were more likely to start new therapies, whereas older patients were less likely. The safety profile of cladribine was favorable, with lymphopenia being the primary registered adverse event., Conclusions: This study provides insights into therapeutic choices and disease activity following cladribine treatment. It highlights cladribine's effectiveness in reducing relapse rates and disability progression, reaffirming its favorable safety profile. Real-world data, aligned with previous reports, draw attention to ocrelizumab and natalizumab as common choices after cladribine. However, larger, prospective studies for validation and a more comprehensive understanding of cladribine's long-term impact are necessary., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

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: In the general population, maternal COVID-19 is associated with worse maternal and fetal outcomes. Two previous studies have assessed COVID-19 clinical outcomes in pregnant women with multiple sclerosis (MS), but there are no data about maternal and fetal outcomes., Objectives: In this multicenter study, we aimed to assess maternal and fetal outcomes in pregnant women with MS and COVID-19 infection., Methods: We recruited pregnant patients with MS who contracted COVID-19 and were followed up in Italian and Turkish Centers, during 2020-2022. A control group was extracted from a previous Italian cohort. Associations between group (COVID-19 or healthy patients) and clinical outcomes (maternal complications, fetal malformations, and spontaneous abortion) were investigated with a weighted logistic regression where propensity score-based inverse probability of treatment weighting (IPTW) approach was applied for adjusting for difference in baseline confounders., Results: In the multivariable analysis, COVID-19 during pregnancy was associated with a higher risk of maternal complications (odd ratio (OR) = 2.12; 95% confidence interval (CI) = 1.32-3.48; p = 0.002), while it was not associated with higher risk of spontaneous abortion and fetal malformations., Conclusion: Our data indicate that COVID-19 during pregnancy increases the risk of maternal complications, while it seems to have no significant impact on fetal outcomes., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S.S. has received honoraria or consultancy fees for participating to advisory boards, giving educational lectures and/or travel and registration coverage for attending scientific congresses or symposia from F. Hoffmann-La Roche Ltd, Sanofi-Genzyme, Merck Serono, Novartis, Teva, and Biogen Idec/Gen Pharma. R.K. has received honoraria for giving educational lectures, consultancy fees for participating advisory boards, and travel grants for attending scientific congresses or symposia from Roche, Sanofi-Genzyme, Merck Serono, Novartis, Teva, Biogen Idec/Gen Pharma of Turkey, Abdi İbrahim İlac, Deva, and ARIS. A.S. has received honoraria or consultancy fees for participating to advisory boards, giving educational lectures and/or travel and registration coverage for attending scientific congresses or symposia from F. Hoffmann-La Roche Ltd, Sanofi-Genzyme, Merck Serono, Novartis, Teva, Biogen Idec/Gen Pharma of Turkey, and Abdi İbrahim İlac. E.P. received compensation for travel grants, participation in advisory board and/or speaking activities from Biogen, Merck Serono, Sanofi, Teva, and Novartis and serves on the editorial board of Frontiers in Neurology and Brain Sciences. M.P.A. served on scientific advisory boards for and has received speaker honoraria and research support from Biogen Idec, Merck Serono, Bayer Schering Pharma, and Sanofi Aventis and serves on the editorial board of Multiple Sclerosis Journal and BMC Neurology. M.P.S. received consulting fees from Roche, Biogen, Merck, Novartis, Sanofi, Celgene, Immunic, Geneuro, GSK, and MedDay; received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Roche, Biogen Merck, Novartis, Sanofi, and Celgene; and participated on a Data Safety Monitoring Board or Advisory Board for Roche, Sanofi, Novartis, and Merck. I.S. received consulting fees from Hippocrates Research, NovaNeuro, Sakura Italia, ADL Farmaceutici, and Associazione Commissione Difesa Vista Onlus. C.C. received grants or contracts from Roche, Novartis, Merck Serono, Biogen, and Celgene and received consulting fees from Biogen. L.M. received compensation for consulting services, travel grants, and/or speaking activities from Biogen, Serono, Sanofi, Teva, Roche, and Novartis. E.S. received personal compensation from Almirall, Biogen, Sanofi, Novartis, Roche, Horizon, Alexion, Merck, Mylan, and Teva for traveling and advisory boards. S.D.B. received personal compensation from Alexion, Almirall, Biogen, Merck Novartis, Roche, and Sanofi for traveling and advisory boards. M.B. received honoraria for speaking, advisory board, consulting from Teva, Genzyme, Biogen, Bristol MS, Merck, and Novartis. M.C. received personal compensations from Novartis, Genzyme, and Teva and consulting fees from Zambon. R.F. received honoraria for advisory boards and consulting from Bristol MS, Roche, Merck, and Novartis. P.C. received honoraria as speaker or travel grants to attend national and international conferences or consultation for advisory boards from Alexion, Almirall, Bayer Schering, Biogen, Cellgene-BMS, Janssen, Merck Serono, Teva, Roche, Novartis, Sandoz, and Sanofi-Genzyme. S.T. received travel grants or personal compensations from Biogen, Novartis, Sanofi-Genzyme, Roche, Janssen, Teva, and Almirall. The remaining authors have nothing to report.

Large-scale brain activity has long been investigated under the erroneous assumption of stationarity. Nowadays, we know that resting-state functional connectivity is characterized by aperiodic, scale-free bursts of activity (i.e. neuronal avalanches) that intermittently recruit different brain regions. These different patterns of activity represent a measure of brain flexibility, whose reduction has been found to predict clinical impairment in multiple neurodegenerative diseases such as Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease. Brain flexibility has been recently found increased in multiple sclerosis, but its relationship with clinical disability remains elusive. Also, potential differences in brain dynamics according to the multiple sclerosis clinical phenotypes remain unexplored so far. We performed a brain dynamics study quantifying brain flexibility utilizing the 'functional repertoire' (i.e. the number of configurations of active brain areas) through source reconstruction of magnetoencephalography signals in a cohort of 25 multiple sclerosis patients (10 relapsing-remitting multiple sclerosis and 15 secondary progressive multiple sclerosis) and 25 healthy controls. Multiple sclerosis patients showed a greater number of unique reconfigurations at fast time scales as compared with healthy controls. This difference was mainly driven by the relapsing-remitting multiple sclerosis phenotype, whereas no significant differences in brain dynamics were found between secondary progressive multiple sclerosis and healthy controls. Brain flexibility also showed a different predictive power on clinical disability according to the multiple sclerosis type. For the first time, we investigated brain dynamics in multiple sclerosis patients through high temporal resolution techniques, unveiling differences in brain flexibility according to the multiple sclerosis phenotype and its relationship with clinical disability., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Vitamin D is known for its role in modulating calcium and phosphate homeostasis and is implicated both in bone mineralization and immune system regulation. The immune-modulatory role of vitamin D and its impact on multiple sclerosis (MS) courses are still debated. The aim of this review was to check the effect of vitamin D supplementation on cytokine profile regulation in people with MS. A significant increase in serum concentrations of interleukin (IL)-10 and Transforming growth factor (TGF)-β1 after vitamin D supplementation was demonstrated in most studies, with some of them reporting a reduction in disability scores after vitamin D supplementation and an inverse correlation between IL-10 levels and disability. The effect of vitamin D on the serum levels of IL-17 and IL-6 was controversial; different results across studies could be explained by a variability in the treatment duration, route, and frequency of administration, as well as the dosage of vitamin D supplementation, responses to vitamin D treatment and the serum levels reached with supplementation, including the methods used for cytokine analysis and the different cell types investigated, the MS phenotype, the disease phase (active vs. non-active) and duration, and concomitant treatment with disease-modifying therapies. Nevertheless, the significant increase in the serum concentrations of IL-10 and TGF-β1, demonstrated in most studies, suggests an anti-inflammatory effect of vitamin D supplementation.

Background: Telemedicine has proven successful in relieving the burden of chronic neurological disorders from the national health care systems by ensuring a highly customized and effective management plan. Although many studies focus on assessing telemedicine effectiveness, little is known about the economic implications of telemedicine applications in chronic neurological diseases (CNDs). This issue could account for a lack of widespread implementation. Objective: Our study attempted to fill this gap by systematically reviewing scientific literature on the economic evaluation of telemedicine compared with traditional care in the management of CNDs. Methods: We performed a literature search on PubMed, Google Scholar, Scopus, Embase, and Medline. The inclusion criteria were as follows: (1) studies with a full cost-analysis; (2) randomized controlled trials; (3) studies comparing telemedicine interventions with traditional care; (4) articles focusing only on CNDs. Conversely, the exclusion criteria were as follows: (1) studies focusing on acute neurological conditions or other diseases and (2) study protocols, case report, duplicate articles, abstract only, books, letters to editors, and review articles. Results: Ten articles met the inclusion criteria. Three different approaches of telemedicine intervention could be identified: digital cognitive-behavioral therapy (CBT), motor telerehabilitation, and home monitoring and assessment devices. Conclusion: Cost-analysis showed an overall benefit in terms of both cost and effectiveness from the application of telemedicine instead of in-presence management in CNDs. Among the identified interventions, digital CBT proved to be the most cost-saving. However, promising results were also found in monitoring and assessment devices and in telerehabilitation. Definitely, however, more thorough, comprehensive, and high-quality economic evaluation studies are needed.

Background: The DYSPHAGIA IN MULTIPLE SCLEROSIS (DYMUS) questionnaire is the only specific tool developed to screen for dysphagia in people with Multiple Sclerosis (pwMS). However, some limitations of DYMUS could potentially be addressed by the SWALLOWING DISTURBANCE QUESTIONNAIRE (SDQ), which has not yet been validated in pwMS. The objective of this study was to translate and validate the SDQ into the Italian language for use in pwMS to detect swallowing disturbances., Methods: We translated the SDQ into Italian and adapted it for use in Italian pwMS. PwMS aged > 18 years, assessed for disability using the Expanded Disability Status Scale (EDSS), completed the SDQ and DYMUS questionnaires and performed the 3-OUNCE WATER SWALLOW TEST (WST). Clinical and demographic data were collected for each patient. The Italian version of the SDQ was retested after 30 days., Results: A total of 84 pwMS were recruited for the study, consisting of 73.8 % women and 48.8 % with a relapsing-remitting form of MS. The mean age of participants was 44.5 years (SD: ±12.46), with a mean disease duration of 17 years (SD: ±10.27), and a median EDSS of 4 (range 1.5-7.5). The Cronbach's alpha for SDQ (to assess internal consistency) was 0.902, which increased to 0.908 after the elimination of item 15, resulting in the SDQ composed of 14 items. ROC analysis demonstrated good accuracy of the 14-item SDQ in pwMS (AUC: 0.811). By dividing the 14-item SDQ score into quartiles, three risk levels for dysphagia were identified: low (score 1-3), intermediate (score 4-8), and high (score ≥9). 14-item SDQ scores significantly correlated with DYMUS (r = 0.820; p<0.0001) and with EDSS (r = 0.541; p<0.0001). PwMS who reported dysphagia had a significantly higher mean 14-item SDQ score (8.27 ± SD 8.15) compared to those without swallowing problems (2.77 ± SD 4.25; p = 0.003). Additionally, pwMS with a positive WST had a significantly higher mean 14-item SDQ score (10.17 ± SD 8.96) than those with a negative WST (2.96 ± SD 3.93; p = 0.02). The Intraclass Correlation Coefficient for the retest, calculated on 48 pwMS in a stable phase of the disease, was 0.91 (95 % CI 0.84-0.95)., Conclusion: The 14-item SDQ has demonstrated high internal consistency, good accuracy, and reliability in pwMS, making it a readily applicable tool for investigating dysphagia in MS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The intervals between two courses of anti CD20 therapies in the COVID19 pandemic era provided the opportunity to individually delay therapy, known as extended interval dosing (EID)., Methods: We collect real-world data on patients with primary progressive MS (PPMS) treated with Ocrelizumab (OCR) during the COVID'19 pandemic. The observation period in which the standard interval dosing (SID) or EID occurred (always a maintenance cycle, 600 mg) was from January 2020 to June 2021. All patients had two infusions during the observation period. Our first aim was to compare confirmed disability progression (CDP) between SID and EID patients., Results: From a total cohort of 410 patients treated with OCR, 96 patients fulfilled the inclusion criteria. All patients received two infusions during the index window, 71 received only SID infusions whilst 25 received at least one EID infusion throughout the entire follow-up. During the entire available follow-up (median 10 months, IQR 7-11), CDP was recorded in 5 patients (3/71, 4.2% SID and 2/25, 8% EID, V-Cramer = 0.141, p-value = 0.167). EID regimen did not influence the risk of CDP during the investigated follow up., Conclusion: In our multicentre real-world cohort, the EID regimen in PPMS patients did not result in increased CDP during the available follow-up., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Mild cognitive impairment (MCI) is a transitional clinical stage prior to dementia. Patients with amnestic MCI have a high risk of progression toward Alzheimer's disease. Both amnestic mild cognitive impairment and sporadic Alzheimer's disease are multifactorial disorders consequential from a multifaceted cross-talk among molecular and biological processes. Non-coding RNAs play an important role in the regulation of gene expression, mainly long non-coding RNAs (lncRNAs), that regulate other RNA transcripts through binding microRNAs. Cross-talk between RNAs, including coding RNAs and non-coding RNAs, produces a significant regulatory network all through the transcriptome. The relationship of genes and non-coding RNAs could improve the knowledge of the genetic factors contributing to the predisposition and pathophysiology of MCI. The objective of this study was to identify the expression patterns and relevant lncRNA-associated miRNA regulatory axes in the blood of MCI patients, which includes lncRNA- SNHG16 , lncRNA- H19 , and lncRNA- NEAT1 . Microarray investigations have demonstrated modifications in the expression of long non-coding RNAs (lncRNA) in the blood of patients with MCI compared with control samples. This is the first study to explore lncRNA profiles in mild cognitive impairment blood. Our study proposes RNAs targets involved in molecular pathways connected to the pathogenesis of MCI.

Multiple sclerosis (MS) predominantly affects women of fertile age. Various aspects of MS could impact on fertility, such as sexual dysfunction, endocrine alterations, autoimmune imbalances, and disease-modifying therapies (DMTs). The proportion of women with MS (wMS) requesting infertility management and assisted reproductive technology (ART) is increasing over time. In this review, we report on data regarding ART in wMS and address safety issues. We also discuss the clinical aspects to consider when planning a course of treatment for infertility, and provide updated recommendations to guide neurologists in the management of wMS undergoing ART, with the goal of reducing the risk of disease activation after this procedure. According to most studies, there is an increase in relapse rate and magnetic resonance imaging activity after ART. Therefore, to reduce the risk of relapse, ART should be considered in wMS with stable disease. In wMS, especially those with high disease activity, fertility issues should be discussed early as the choice of DMT, and fertility preservation strategies might be proposed in selected cases to ensure both disease control and a safe pregnancy. For patients with stable disease taking DMTs compatible with pregnancy, treatment should not be interrupted before ART. If the ongoing therapy is contraindicated in pregnancy, then it should be switched to a compatible therapy. Prior to beginning fertility treatments in wMS, it would be reasonable to assess vitamin D serum levels, thyroid function and its antibody serum levels; start folic acid supplementation; and ensure smoking and alcohol cessation, adequate sleep, and food hygiene. Cervico-vaginal swabs for Ureaplasma urealyticum, Mycoplasma hominis, and Chlamydia trachomatis, as well as serology for viral hepatitis, HIV, syphilis, and cytomegalovirus, should be performed. Steroids could be administered under specific indications. Although the available data do not clearly show a definite raised relapse risk associated with a specific ART protocol, it seems reasonably safe to prefer the use of gonadotropin-releasing hormone (GnRH) antagonists for ovarian stimulation. Close clinical and radiological monitoring is reasonably recommended, particularly after hormonal stimulation and in case of pregnancy failure., (© 2023. The Author(s).)

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique also used as a non-pharmacological intervention against cognitive impairment. The purpose of the present review was to summarize what is currently known about the effectiveness of rTMS intervention on different cognitive domains in patients with mild cognitive impairment (MCI) and to address potential neuromodulation approaches in combination with electroencephalography (EEG) and neuroimaging, especially functional magnetic resonance imaging (fMRI). In this systematic review, we consulted three main databases (PubMed, Science Direct, and Scopus), and Google Scholar was selected for the gray literature search. The PRISMA flowchart drove the studies' inclusion. The selection process ensured that only high-quality studies were included; after removing duplicate papers, explicit ratings were given based on the quality classification as high (A), moderate (B), or low (C), considering factors such as risks of bias, inaccuracies, inconsistencies, lack of direction, and publication bias. Seven full-text articles fulfilled the stated inclusion, reporting five double-blind, randomized, sham-controlled studies, a case study, and a randomized crossover trial. The results of the reviewed studies suggested that rTMS in MCI patients is safe and effective for enhancing cognitive functions, thus making it a potential therapeutic approach for MCI patients. Changes in functional connectivity within the default mode network (DMN) after targeted rTMS could represent a valuable indicator of treatment response. Finally, high-frequency rTMS over the dorsolateral prefrontal cortex (DLPFC) has been shown to significantly enhance cognitive functions, such as executive performance, together with the increase of functional connectivity within frontoparietal networks. The main limitations were the number of included studies and the exclusion of studies using intermittent theta-burst stimulation, used in studies on Alzheimer's disease. Therefore, neuroimaging techniques in combination with rTMS have been shown to be useful for future network-based, fMRI-guided therapeutic approaches.

Ocrelizumab is a humanized monoclonal anti-CD20 antibody, approved for the treatment of relapsing and primary-progressive multiple sclerosis. We reported a case of pericarditis in an RRMS patient treated with ocrelizumab, who presented with chest pain, high body temperature and laboratory findings of systemic inflammation, with a favorable clinical outcome., (© 2023. Fondazione Società Italiana di Neurologia.)

Introduction: The diagnosis of the progression phase of Multiple Sclerosis (MS) is still retrospective and based on the objectivation of clinical disability accumulation., Objectives: To assess whether the Patient Reported Outcomes Measures (PROMs) scores predict the occurrence of disease progression within three years of follow-up., Methods: Observational prospective multicenter study. Stable Relapsing-Remitting MS (RRMS) patients were enrolled. At enrollment, patients completed the following PROMs: Beck Depression Inventory- II, The Treatment Satisfaction Questionnaire for Medications, Medical Outcomes Study Short Form 36- Item (SF36), Fatigue Severity Scale. EDSS was assessed at enrollment and three years later. The outcome measure was defined as the occurrence of confirmed disability progression (CDP) within three years of follow-up. Univariable and multivariable logistic regression models were performed to study the association between the final score of each test and the outcome., Results: SF36-Physical Functioning (SF36-PF) was the only independent variable associated with the outcome. The ROC curve analysis determined a score of 77.5 at SF36-PF as the cut-off point identifying patients experiencing CDP within three years of follow-up [AUC: 0.66 (95% CI: 0.56-0.75)]., Conclusions: RRMS patients scoring higher (>77.5) at SF36-PF subscale have a higher likelihood to experience CDP within the next three years., Competing Interests: Declaration of Competing Interest The authors declare no competing interests for this work., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) is the most widely used screening tool for cognitive impairment in Multiple Sclerosis (MS). However, the administration and scoring procedures of the paper version are time consuming and prone to errors. Aim of our study was to develop a tablet version of BICAMS (iBICAMS), and to assess its reliability compared to the paper version., Methods: We administered both BICAMS and iBICAMS to 139 MS patients in two different sessions. We compared scores on both versions using a paired t-test. We used a repeated measures ANOVA to test the impact of rater, order of administration and test-retest time on test-retest performances. We used the Intraclass Correlation Coefficient (ICC) to assess the reliability between BICAMS and iBICAMS., Results: All three sub-tests of the BICAMS (SDMT, CVLT-II and BVMT-R) were different between the paper and the tablet versions. Order of administration influenced test-retest performances at the SDMT (p<0.001), CVLT- II (p<0.001) and BVMT-R (p<0.001). Intraclass coefficient correlation (ICC) revealed a high level of agreement between the paper BICAMS and the iPad version for all three tests: SDMT (0.92), CVLT-II (0.83) and BVMT-R (0.82)., Conclusions: We found a high reliability between BICAMS and iBICAMS. Considering the inherent advantages of automated scoring, digital storage of data, standardized timing, the iBICAMS could become a standard in clinical practice., Competing Interests: Declaration of Competing Interest F.S. received public speaking honoraria from Alexion, Argenx, Biogen, Mylan, Novartis, Roche, Sanofi, Teva; he also received compensation for Advisory boards or consultation fees from Alexion, Almirall, Argenx, Avexis, Biogen, Forward Pharma, Lexeo Therapeutics, Merk, Novartis, Novatek, Roche, Sanofi, Takeda. The other authors report no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Ocrelizumab is a humanized monoclonal antibody designed to bind to the CD20 molecule, resulting in a rapid depletion of B-cells; however, it has been shown that lymphocyte subpopulations other than B-cells are affected by the drug. To review the effects of ocrelizumab on circulating lymphocytes and identify candidate biomarkers to predict and monitor treatment response. A literature search for the most relevant articles from 2006 to 2022 was conducted in PubMed and Scopus. The effect of ocrelizumab on the peripheral immune system goes beyond B-cells; it also depletes T CD20 + lymphocytes. Further, ocrelizumab reshapes the T-cell response toward a low inflammatory profile and induces an increase in T CD8 + regulatory cell percentage. A higher Body Mass Index and higher B-cell count at baseline have been associated with early B-cell reappearance. Serum neurofilament light chain reduction has been associated with treatment response. Ocrelizumab treatment exerts a broad immunomodulatory effect and may be tailored based on patients' clinical and biological profiles.

Background: Recently, concern has been raised about the influence of the previous disease-modifying treatments (DMTs) on the clinical efficacy of ocrelizumab (OCR). We aimed to evaluate whether the previous DMT affects the lymphocyte subset kinetics in people with Multiple Sclerosis (MS) switching to OCR., Methods: This is a multicenter, retrospective, real-world study on consecutive MS patients who started or switched to OCR. We grouped them by prior DMT in: (i) naïve-to-treatment (NTT), (ii) switching from fingolimod (SF) and (iii) switching from natalizumab (SN). Differences in absolute lymphocyte count and lymphocyte subset count changes, considering the period from baseline to 6 months, over all the three groups were assessed with an inverse-probability-weighted regression adjustment model., Results: Mean T CD4+ cell count reduction from baseline to the six-month follow-up was more pronounced in the SN group compared to the NTT (p = 0,026). Further, patients in the SF group experienced a less pronounced CD4 T cell number decrease than both NTT and SN groups (p = 0,04 and p < 0,001, respectively). Patients in the SF group experienced an increase in CD8 T cell absolute number, whereas those in the NTT and SN groups experienced a significant decrease (p = 0,015 and p < 0,001, respectively). Patients experiencing early inflammatory activity showed a lower CD8+ cell count at baseline than stable patients (p = 0,02)., Conclusions: Previous DMTs influence the lymphocyte kinetics in people with MS switching to OCR. Reassessment of these findings over a larger population may help optimize the switch., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) is a rare but potentially reversible autoimmune encephalopathy. The most frequent neuroimaging correlates are normal brain MRI or non-specific white matter hyperintensities., Methods: We present the first description of conus medullaris involvement, also providing an extensive review of MRI patterns described so far., Results: Our results show that in less than 30% of cases, it is possible to find focal SREAT neuroanatomical correlates. Among these, T2w/FLAIR temporal hyperintensities are the most frequent, followed by basal ganglia/thalamic and brainstem involvement, respectively., Conclusions: Unfortunately, spinal cord investigation is an uncommon practice in the diagnostic approach of encephalopathies, thus neglecting potential pathological lesions of the medulla spinalis. In our opinion, the extension of the MRI study to the cervical, thoracic, and lumbosacral regions may allow finding new, and hopefully specific, anatomical correlates., (© 2023. Fondazione Società Italiana di Neurologia.)

Despite being a common issue in people with multiple sclerosis (pwMS), sexual dysfunction is still underinvestigated. This work aims to assess the potential determinants of sexual dysfunction in pwMS by considering its relationship with disease severity (in terms of global disability), illness perception, and depressive symptoms. In this multicenter study, 1010 pwMS responded to an online survey. A serial mediation model considering negative illness perception and depressive symptoms as mediators of the relationship between disease severity and sexual dysfunction was conducted using the SPSS PROCESS Macro with bias-corrected bootstrapping (5000 samples). Disease severity exerts an indirect effect on sexual dysfunction via illness perception, both independently and through depressive symptoms. However, the results indicated that illness perception plays a more crucial role in sexual dysfunction in pwMS with mild disability than in pwMS with moderate-severe disability. This study suggests that higher disability increases its magnitude by enhancing negative illness perception, that, in turn, affects sexual dysfunction both directly and through depressive symptoms, especially in pwMS with mild disability. Modulating the effect of illness perception by favoring adaptive coping strategies might represent a valid approach to mitigate sexual dysfunction symptoms in MS.

Objective: To report for the first time an Italian epidemiological analysis of the prevalence of multiple sclerosis (MS) in patients with endometriosis (EMS), through the study of the endometriosis population of our referral center; to analyze the clinical profile and perform a laboratory analysis to examine the immune profile and the possible correlation to other autoimmune diseases of the enrolled patients., Methods: We evaluated 1652 women registered with EMS in the University of Naples Federico II and retrospectively searched patients with a co-diagnosis of MS. Clinical features of both conditions were recorded. Serum autoantibody and immune profiles were analyzed., Results: 9 out of 1652 patients presented a co-diagnosis of EMS and MS (9/1652 = 0.005%). Clinically, EMS and MS presented in mild forms. Hashimoto's thyroiditis was found in two patients (2/9). Even if not statistically significant, a trend of variation in CD4- CD8 T lymphocytes and of B cells were found., Conclusion: Our findings suggest an increased risk of MS in women with EMS. However, large-scale prospective studies are needed.

Background and Objectives: alemtuzumab is a monoclonal anti-CD52 antibody acting on B and T cells in highly active multiple sclerosis (MS). We analyzed changes in lymphocyte subsets after alemtuzumab administration in relation to disease activity and autoimmune adverse events., Methods: lymphocyte subset counts were assessed longitudinally using linear mixed models. Subset counts at baseline and during follow-up were correlated with relapse rate, adverse events, or magnetic resonance (MRI) activity., Results: we recruited 150 patients followed for a median of 2.7 years (IQR: 1.9-3.7). Total lymphocytes, CD4, CD8, and CD20 significantly decreased in all patients over 2 years ( p < 0.001). Previous treatment with fingolimod increased the risk of disease activity and adverse events ( p = 0.029). We found a higher probability of disease reactivation in males and in patients with over three active lesions at baseline. Higher EDSS scores at baseline and longer disease duration predicted the switch to other treatments after alemtuzumab., Discussion and Conclusions: Our real-world study supports data from clinical trials in which lymphocyte subsets were not useful for predicting disease activity or autoimmune disease during treatment. The early use of an induction therapy such as alemtuzumab in patients with a lower EDSS score and short history of disease could mitigate the risk of treatment failure.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that is used against cognitive impairment in mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, the neurobiological mechanisms underlying the rTMS therapeutic effects are still only partially investigated. Maladaptive plasticity, glial activation, and neuroinflammation, including metalloproteases (MMPs) activation, might represent new potential targets of the neurodegenerative process and progression from MCI to AD. In this study, we aimed to evaluate the effects of bilateral rTMS over the dorsolateral prefrontal cortex (DLPFC) on plasmatic levels of MMP1, -2, -9, and -10; MMPs-related tissue inhibitors TIMP1 and TIMP2; and cognitive performances in MCI patients. Patients received high-frequency (10 Hz) rTMS (MCI-TMS, n = 9) or sham stimulation (MCI-C, n = 9) daily for four weeks, and they were monitored for six months after TMS. The plasmatic levels of MMPs and TIMPs and the cognitive and behavioral scores, based on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Beck Depression Inventory II, Beck Anxiety Inventory, and Apathy Evaluation Scale, were assessed at baseline (T0) and after 1 month (T1) and 6 months (T2) since rTMS. In the MCI-TMS group, at T2, plasmatic levels of MMP1, -9, and -10 were reduced and paralleled by increased plasmatic levels of TIMP1 and TIMP2 and improvement of visuospatial performances. In conclusion, our findings suggest that targeting DLPFC by rTMS might result in the long-term modulation of the MMPs/TIMPs system in MCI patients and the neurobiological mechanisms associated with MCI progression to dementia.

Background: Many factors are believed to be positively associated with the incidence of relapses in people with multiple sclerosis (MS), including infections. However, their role is still controversial. We aimed to investigate whether symptomatic infections in people with MS increase the risk of relapse in the short, medium, or long term., Materials and Methods: We enrolled consecutive patients with relapsing MS (RMS) from October to December 2018. From enrolment up to September 2020, an online questionnaire investigating the occurrence of infections was sent via WhatsApp ® monthly to the enrolled patients, while in-person visits were performed every six months. When patients complained of symptoms compatible with relapses, they attended an extra in-person visit., Results: We enrolled 155 patients with RMS, and 88.38% of patients were treated with disease-modifying therapies. In the dataset, 126,381 total patient days, 78 relapses, and 1202 infections were recorded over a period of about 2 years. No increased risk of relapse after clinically manifest infections was found in the short-, medium-, or long-term period. No correlation was found between all infections and the number of relapses ( p = 0.212). The main analyses were repeated considering only those infections that had at least two of the following characteristics: duration of infection ≥ 4 days, body temperature > 37° Celsius, and the use of drugs (antibiotics and/or antivirals), and no significant associations were observed., Conclusions: No associations between infections and relapses were observed, likely suggesting that disease-modifying therapies may protect against the risk of relapse potentially triggered by infections.

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: Brain connectome fingerprinting is progressively gaining ground in the field of brain network analysis. It represents a valid approach in assessing the subject-specific connectivity and, according to recent studies, in predicting clinical impairment in some neurodegenerative diseases. Nevertheless, its performance, and clinical utility, in the Multiple Sclerosis (MS) field has not yet been investigated., Methods: We conducted the Clinical Connectome Fingerprint (CCF) analysis on source-reconstructed magnetoencephalography signals in a cohort of 50 subjects: twenty-five MS patients and twenty-five healthy controls., Results: All the parameters of identifiability, in the alpha band, were reduced in patients as compared to controls. These results implied a lower similarity between functional connectomes (FCs) of the same patient and a reduced homogeneity among FCs in the MS group. We also demonstrated that in MS patients, reduced identifiability was able to predict, fatigue level (assessed by the Fatigue Severity Scale)., Conclusion: These results confirm the clinical usefulness of the CCF in both identifying MS patients and predicting clinical impairment. We hope that the present study provides future prospects for treatment personalization on the basis of individual brain connectome., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background: Several observational studies have shown an association between low circulating levels of 25-hydroxy- vitamin D (25(OH)D) and an increase in inflammatory activity in Multiple Sclerosis (MS). Among its immunomodulatory functions, 25(OH)D suppresses proliferation and immunoglobulin production of B cells. 25(OH)D supplementation has been associated with better radiological outcomes in MS patients treated with interferon (IFN)-B, glatiramer acetate, fingolimod, natalizumab and rituximab. Our study is aimed at analyzing the association of 25(OH)D serum levels and supplementation with B cell kinetics and clinical-radiological outcomes of people with MS treated with ocrelizumab., Methods: We have retrospectively collected clinical and radiological data from 136 MS patients who have been treated with ocrelizumab, have undergone at least two treatment cycles and for whom data on serum 25(OH)D levels and intake were available. The patients were divided into three groups according to baseline 25(OH)D serum levels: deficient (≤19,9 ng/ml), insufficient (20-29,9 ng/ml), and normal range 25(OH)D (>30 ng/ml). According to 25(OH)D intake, we divided our population into users and non-users. To explore B cell kinetics at six- and twelve-month follow-ups, the patients were divided into two groups: with fast repopulation (FR) and slow repopulation rate (SR), based on the reappearance or non- appearance of CD19 at each time point., Results: When considering the entire population, the mean 25(OH)D serum level (sd) was 26.27 ng/ml (14.15). 43 (31,62%) patients were classified as deficient, 52 (38,24%) were classified as insufficient, and 41 (30,14%) showed 25(OH)D serum levels within the normal range. 60.29% (82/136) of the patients were classified as users, and 39.70% (54/136) as non-users. Over the eighteen-month treatment period, we observed a significant difference between the 25(OH)D users and the non-users as concerns the number of scans with at least one new/enlarging T2 lesion (2% vs 15.38%, respectively; p= 0.025). In the multinomial regression model, 25(OH)D deficiency (serum levels ≤19,9 ng/ml) was significantly associated with a higher likelihood of disease activity during a follow-up of eighteen months (p = 0.029, RRR = 4.84, Confidence Interval (CI) 1.17 - 20.01). After six months, there were 30/136 FR patients (22,05%), whereas only 22/136 (16,17%) showed early B cell reappearance at twelve month follow up. 86.66% of the patients in the FR group showed 25(OH)D levels lower than 30 ng/ml (25(OH)D deficiency or insufficiency), whereas only 65.09% of the SR patients presented vitamin D levels lower than 30 ng/ml (p= 0.024). In the logistic regression model, 25(OH)D serum levels below 30 ng/ml were associated with a higher likelihood of early B cell reappearance at six month follow up (p= 0.042)., Conclusions: 25(OH)D supplementation and serum levels might be associated with B cell kinetics and radiological activity of patients with MS treated with ocrelizumab., (Copyright © 2022. Published by Elsevier B.V.)

Background: Patients with multiple sclerosis (pwMS) treated with anti-CD20 or fingolimod showed a reduced humoral response to SARS-CoV-2 vaccines., Objective: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in pwMS on different disease-modifying therapies (DMTs)., Methods: Data on the number of vaccinated patients and the number of patients with a breakthrough infection were retrospectively collected in 27 Italian MS centers. We estimated the rate of breakthrough infections and of infection requiring hospitalization per DMT., Results: 19,641 vaccinated pwMS were included in the database. After a median follow-up of 8 months, we observed 137 breakthrough infections. Compared with other DMTs, the rate of breakthrough infections was significantly higher on ocrelizumab (0.57% vs 2.00%, risk ratio (RR) = 3.55, 95% CI = 2.74-4.58, p  < 0.001) and fingolimod (0.58% vs 1.62%, RR = 2.65, 95% CI = 1.75-4.00, p  < 0.001), while there were no significant differences in any other DMT group. In the ocrelizumab group the hospitalization rate was 16.7% versus 19.4% in the pre-vaccination era (RR = 0.86, p  = 0.74) and it was 3.9% in all the other DMT groups versus 11.9% in the pre-vaccination period (RR = 0.33, p  = 0.02)., Conclusions: The risk of breakthrough SARS-CoV-2 infections is higher in patients treated with ocrelizumab and fingolimod, and the rate of severe infections was significantly reduced in all the DMTs excluding ocrelizumab.

Background: A growing body of evidence has shed light on the role of the hemostatic pathway and its components in the pathogenesis of multiple sclerosis (MS), particularly in enhancing and sustaining neuroinflammation., Objective: To review the clinical, experimental, and neuroimaging evidence supporting the role of different components of the hemostatic pathway in the pathogenesis of neuroinflammation in MS and discuss their translational potential as disease biomarkers and therapeutic targets., Methods: A literature search for most relevant articles from 1956 to 2020 was conducted in PubMed and Scopus., Results: Hemostasis components appear to be involved in different key events of neuroinflammation in MS including mononuclear cell diapedesis, microglia activation, and neuronal damage., Conclusion: The findings on the interplay between hemostatic and thrombotic molecular pathways in the pathogenesis of neuroinflammation in MS open new opportunities for developing novel biomarkers for disease monitoring and prognosis, as well as novel therapeutic targets.

Introduction: Cladribine administration has been approved for the treatment of relapsing-remitting multiple sclerosis (MS) in 2017; thus, data on cladribine in a real-world setting are still emerging., Methods: We report on cladribine effectiveness, safety profile, and treatment response predictors in 243 patients with MS followed at eight tertiary MS centers. Study outcomes were: (1) No Evidence of Disease Activity-3 (NEDA-3) status and its components (absence of clinical relapses, MRI activity, and sustained disability worsening); (2) development of grade III/IV lymphopenia. The relationship between baseline features and the selected outcomes was tested via multivariate logistic models., Results: Of the 243 subjects included in the study (66.5% female, age 34.2 ± 10 years, disease duration 6.6 ± 9.6 years), 64% showed NEDA-3 at median follow-up (22 months). Patients with higher number of previous treatments had lower probability to retain NEDA-3 [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.41-0.98, p = 0.04] and were more prone to experience clinical relapses (OR 1.6, 95% CI 1-2.6, p = 0.04). The presence of active lesions at baseline was associated with follow-up magnetic resonance imaging (MRI) activity (OR 1.92, 95% CI 1.04-3.55, p = 0.04). Patients with higher rate of relapses in the year prior to cladribine start were at higher risk of developing sustained disability worsening (OR 2.95% CI 1-4.2, p = 0.04). Lymphopenia grade III/IV over the follow-up was associated with baseline lymphocyte count (OR 0.998, 95% CI 0.997-0.999, p = 0.01)., Conclusion: In this large cohort, we confirm previous data about cladribine effectiveness on disease activity and disability worsening and provide information on response predictors that might inform therapeutic choices., (© 2022. The Author(s).)

In the COVID-19 pandemic era, safety concerns have been raised regarding the risk of severe infection following administration of ocrelizumab (OCR), a B-cell-depleting therapy. We enrolled all relapsing remitting multiple sclerosis (RRMS) patients who received maintenance doses of OCR from January 2020 to June 2021. Data were extracted in December 2021. Standard interval dosing (SID) was defined as a regular maintenance interval of OCR infusion every 6 months, whereas extended interval dosing (EID) was defined as an OCR infusion delay of at least 4 weeks. Three infusions were considered in defining SID vs. EID (infusions A, B, and C). Infusion A was the last infusion before January 2020. The primary study outcome was a comparison of disease activity during the A-C interval, which was defined as either clinical (new relapses) or radiological (new lesions on T1-gadolinium or T2-weighted magnetic resonance imaging (MRI) sequences). Second, we aimed to assess confirmed disability progression (CDP). A total cohort of 278 patients (174 on SID and 104 on EID) was enrolled. Patients who received OCR on EID had a longer disease duration and a higher rate of vaccination against severe acute respiratory syndrome-coronavirus 2 (p &lt; 0.05). EID was associated with an increased risk of MRI activity during the A-C interval (OR 5.373, 95% CI 1.203-24.001, p = 0.028). Being on SID or EID did not influence CDP (V-Cramer 0.47, p = 0.342). EID seemed to be associated with a higher risk of MRI activity in our cohort. EID needs to be carefully considered for OCR-treated patients., (© 2022. The Author(s).)

Background: Patients with multiple sclerosis (MS) are considered at higher risk of COVID-19 infection due to treatment with immune modulators and immune-suppressive agents. The exact risk factors are not clear. So, we aimed to conduct a study to determine the predictors of catching COVID-19 infection during the pandemic stage in patients with multiple sclerosis (MS)., Methods: We conducted a multicenter screening study and developed an online questionnaire to collect patients' self-reported demographic features along with MS-related and COVID-19-related information. The online questionnaire link was released by the Iran Multiple Sclerosis Society (IMSS) social media channel, accessible for 4160 MS patients totally and also was sent by WhatsApp for nonmember cases., Results: Totally, 1448 MS patients participated in our study. Twenty-five (1.7%) patients were diagnosed with COVID-19, from which 4 were hospitalized, 4 were treated with medical therapy, and 17 patients had home-quarantine. The patients with COVID-19 diagnosis were more frequently treated with rituximab (28% vs 24%, P = 0.001) than others, and cardiovascular comorbidity was more frequent in this group (8% vs 1.6%, P = 0.01). Regression analysis showed that cardiovascular disease was a significant positive predictor of COVID-19 infection (OR = 5.2, 95% CI: 1.1-23.7)., Conclusions: Patients with MS who have cardiovascular disease should be more monitored for COVID-19 infection as they are at higher risk of infection., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 International Journal of Preventive Medicine.)

Introduction: Several studies have shown the efficacy of rituximab (RTX) in preventing relapses in patients suffering from Neuromyelitis Optica spectrum disorder (NMSOD) and have explored different therapeutic schemes. Given the extreme inter-individual variability of the disease course, there is the need to identify biomarkers to tailor the retreatment schedule and dosage. This review aimed to identify the most useful biomarker to guide reinfusion and, in turn, the optimal retreatment schedule of RTX for NMSOD., Methods: The literature search was conducted in the Web of Science, Scopus and Pubmed electronic databases. We limited document type to articles written in English and published up to 28 February 2022. Inclusion criteria were: (i) Patients affected by NMSOD and treated with RTX, (ii) followed up for at least one year and for whom Annualized Relapse rate (ARR) was collected over a period of at least 12 months before and after therapy initiation and (iii) induction protocols consisting of 375 mg / m2 / week for four weeks or 1000 mg infused once or twice two weeks apart. Collected information was: first authors' name, publication year, study design, sample size, sex, age, percentage of patients positive for antibodies to aquaporin 4 (AQP4-IgG), maintenance regimen, primary outcome, mean ARR pre-therapy and mean ARR post-therapy initiation, percentage of relapse-free patients. The primary outcome that we considered was the ARR reduction. Further, we considered the number of relapses that occurred when B cells and memory B cells were under the chosen threshold and the percentage of relapse-free patients when available., Results: Among 31 potentially eligible studies, 9 fulfilled the inclusion criteria. ARR reduction was not comparable between studies. The studies that monitored CD19+ and CD27+ cell kinetics showed a higher number of relapses when CD19+ lymphocyte count was below the threshold compared to the number of relapses that occurred when CD27+ cell count was below the threshold. Further, a higher percentage of patients achieved the relapse-free condition with a reinfusion schedule when CD27+ reached 0, 05% of peripheral blood mononuclear cells (PBMCs) compared to the reinfusion when CD19+ reached 0, 1% of PBMCs., Conclusions: To date, the optimal retreatment schedule for RTX in NMOSD has not yet been determined. However, the presented findings suggest that CD27+ B cells might be a reliable biomarker to guide retreatment in AQP4-IgG positive patients, at least in the first six months from the infusion. Further effort is needed to identify those factors influencing anti-CD20 therapy effectiveness to tailor dosage and treatment schedule to achieve the most favourable risk/benefit ratio., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background/objectives: The present cross-national study addressed the relationship among three pandemic-related variables and multiple sclerosis (MS) disability outcomes among people with MS in Italy and the United States (US)., Methods: This cross-sectional web-based study was administered to 708 patients with MS from the US and Italy in late Spring through mid-Summer of 2020. Pandemic-related variables assessed worry, self-protection, and post-traumatic growth. The Performance Scales© assessed MS disability. Multivariate multiple regression models addressed, separately by country, the relationship among worry, protection, and post-traumatic growth with MS disability, after covariate adjustment., Results: The Italian sample (n = 292) was younger and less disabled than the US group (n = 416). After covariate adjustment, all three pandemic-related variables were associated with MS disability outcomes in the US sample, but only worry and post-traumatic growth were associated in the Italian sample. Worse cognitive and depression symptoms were associated with worry, and lesser mobility disability was associated with endorsed growth in both countries. More disability variables were associated with worry and growth in the Italian sample., Conclusions: The pandemic's negative aspects were associated with worse disability in both countries, and reported post-traumatic growth was associated with lesser disability. These findings may suggest directions for clinical intervention., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Cognitive impairment (CI) occurs in about 40-65% of people with multiple sclerosis (MS) during the disease course. Cognitive rehabilitation has produced non-univocal results in MS patients., Objective: The present study aimed to evaluate whether an Integrated Cognitive Rehabilitation Program (ICRP) in MS patients might significantly improve CI., Methods: Forty patients with three phenotypes of MS were randomly assigned into two groups: the experimental group (EG, n = 20), which participated in the ICRP for 10 weeks of training; and the control group (CG, n = 20). All participants' cognitive functions were assessed at three timepoints (baseline, post-treatment, and 3-month follow-up) with the California Verbal Learning (CVLT), Brief Visuospatial Memory (BVMTR), Numerical Stroop, and Wisconsin tests., Results: When compared to CG patients, EG patients showed significant improvements in several measures of cognitive performance after ICRP, including verbal learning, visuospatial memory, attention, and executive functions., Conclusions: Home-based ICRP can improve cognitive functions and prevent the deterioration of patients' cognitive deficits. As an integrated cognitive rehabilitation program aimed at potentiation of restorative and compensatory mechanisms, this approach might suggest an effective role in preserving neuronal flexibility as well as limiting the progression of cognitive dysfunction in MS.

Posterior cortical atrophy (PCA) is a neurodegenerative disorder characterized by an early prominent deficit of visual functions associated with signs and symptoms that are the expression of dysfunction of posterior brain regions. Although PCA is commonly associated with Alzheimer's disease (AD), in recent years new pathological substrates have emerged. Among them, frontotemporal lobar degeneration (FTLD) is the most commonly reported but, to date, little is known about the clinical features of PCA due to FTLD. We conducted a systematic search in the main biomedical database MEDLINE. We searched for all clinical PCA reports that assessed the pathological basis of such syndrome with at least one of the following: (1) neuropathological examination, (2) cerebrospinal fluid biomarkers, (3) amyloid-PET imaging and (4) genetic testing. Of 369 potentially eligible studies, 40 fulfilled the inclusion criteria with an overall number of 144 patients (127 PCA-AD vs. 17 PCA-FTD/non-AD). We found that hallucinations/illusions were present in none of the probable PCA-FTD/non-AD subjects while were reported in 15 out of 97 PCA-AD individuals. Optic ataxia and Parkinsonism showed a significantly greater prevalence in probable PCA FTD/non-AD than in PCA-AD whereas myoclonus and disorientation in time and space were significantly more frequent in PCA-AD than in probable PCA FTD/non-AD. We also found a predominance of a left-side pattern of atrophy/hypometabolism in the probable PCA FTD/non-AD. Clinical features such as optic ataxia, Parkinsonism, myoclonus, hallucinations and disorientation in time and space suggest the underlying pathological basis of PCA and help in leading the diagnostic protocol consequently., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Migraine affects more than a billion people all over the world and requires critical employment of healthcare resources. Telemedicine could be a reasonable tool to manage people suffering from headaches, and it received a big push from the COVID-19 pandemic., Objective: This review aims to propose a practical approach for the virtual management of these patients., Methods: To do this, we conducted a literature search, including 32 articles relevant to the topic treated in this review., Results: The most challenging step in telemedicine applied to practical neurology remains the clinical assessment, but through a careful headache history and a recently proposed entirely virtual neurological assessment, this hitch can be easily overcome. Electronic diary compilations and virtual administration of disability-measuring scales, conversely, are the key features of effective long-term follow-up although we do not have apps that met the criteria of scientific reliability. Furthermore, tele-rehabilitation seems to be effective and has demonstrated to be a solution to alternatively treat chronic patients at home, and can be considered part of the remote management of headache patients. Moreover, virtual management of headaches finds an application in specific communities of patients, as pediatric patients and for rural communities of low- and middle-income countries suffer from health disparities, with inadequate resources and knowledge gaps., Conclusion: Telemedicine could be promising for patients with no regular or convenient access to headache specialists and seems to be a priority in managing migraine patients to avoid non-urgent hospitalizations., (© 2022. The Author(s).)

We have previously evidenced that Mindfulness Meditation (MM) in experienced meditators (EMs) is associated with long-lasting topological changes in resting state condition. However, what occurs during the meditative phase is still debated. Utilizing magnetoencephalography (MEG), the present study is aimed at comparing the topological features of the brain network in a group of EMs (n = 26) during the meditative phase with those of individuals who had no previous experience of any type of meditation (NM group, n = 29). A wide range of topological changes in the EM group as compared to the NM group has been shown. Specifically, in EMs, we have observed increased betweenness centrality in delta, alpha, and beta bands in both cortical (left medial orbital cortex, left postcentral area, and right visual primary cortex) and subcortical (left caudate nucleus and thalamus) areas. Furthermore, the degree of beta band in parietal and occipital areas of EMs was increased too. Our exploratory study suggests that the MM can change the functional brain network and provides an explanatory hypothesis on the brain circuits characterizing the meditative process., Competing Interests: Conflict of interest: The authors declare no conflict of interest., (© 2022 the Author(s), licensee AIMS Press.)

Background: Friedreich's ataxia (FRDA) is an untreatable disease that negatively impacts patients' and caregivers' quality of life., Objectives: The aims were to improve the quality of the information for FRDA patients and caregivers and suggest a possible tool to spread this information., Material and Methods: Thirty-four FRDA patients and 45 caregivers were interviewed separately using a structured self-administered survey about their information-seeking behavior, their level of expectation and satisfaction for the information received, and the need for further information., Results and Conclusion: For patients and caregivers, the main source of information was the FRDA specialist and the media. The most searched items were "general information"; patients and particularly caregivers desired to get more information on existing and experimental therapies. Adequate information supply is part of good medical care; therefore, a deeper insight of clinicians in information-seeking behavior of FRDA patients and caregivers would provide tailored information and improve therapeutic alliance., (© 2021. Fondazione Società Italiana di Neurologia.)