Background Optical coherence tomography (OCT) can assess optic nerve involvement and facilitate the diagnosis of multiple sclerosis (MS).Objective To evaluate the current use of OCT for MS care among neurologists in Switzerland.Methods Nationwide online survey with Swiss neurologists, comprising 11 questions on availability, use of OCT, and its role in diagnostic workup and monitoring.Results Thirty-four neurologists from all main Swiss regions responded (53% hospital-based, 47% private practice). Only 26.5% had access to OCT in their clinic/practice, all of whom were MS specialists, mainly hospital-based (66.7%). All respondents assess the visual pathway in first demyelinating event and optic neuritis (ON), primarily using magnetic resonance imaging (MRI: 88.2% and 91.2%, respectively), often in combination with visual evoked potentials (VEP). OCT use was reported by 32% (first demyelinating event) and 44% (ON) of respondents. OCT was infrequently used for monitoring (20.6%), the most frequent reasons being "lack of availability" or "insufficient evidence."Conclusions Despite the scientific evidence, OCT availability and routine use by neurologists is limited in Switzerland. Awareness, education and guidelines on its clinical use in MS care are needed, while ongoing real-world research should shed more light into its role for personalized disease monitoring in people with MS.

BackgroundAlthough cognitive impairment (CI) is common in multiple sclerosis (MS), conventional cognitive rehabilitation is often limited by accessibility and adherence challenges. Telerehabilitation offers an accessible alternative, but its efficacy across different CI severity levels remains unclear. The present prospective, single-center, single-arm interventional study with repeated measures aimed to identify changes in cognitive and psychosocial outcomes following a home-based cognitive telerehabilitation program with weekly synchronous coaching in MS patients with mild versus moderate CI, and to explore whether baseline impairment severity was associated with differences in change over time.MethodsSixty-six MS patients (34 mild CI; 32 moderate CI) completed a 12-week home-based cognitive telerehabilitation program (five sessions/week), supported by weekly Skype coaching. Outcomes were assessed at baseline (T0), post-intervention (T1), and 3-month follow-up (T2). Cognitive and emotional-behavioral functioning were investigated using standardized, validated instruments in the MS population. Changes over time and between-group differences were analyzed using linear models.ResultsAt T1, both groups improved in attention, verbal memory, and subjective cognitive perception (all p < 0.05). Processing speed improved only in mild CI (p < 0.001), whereas executive function improved only in moderate CI (p = 0.007). At T2, mild CI further improved in attention and verbal memory (p = 0.003–0.035), while moderate CI improved only in processing speed (p = 0.006). Emotional-behavioral outcomes improved in both groups at T1 (anxiety p = 0.002; depression p = 0.023; fatigue p < 0.001) and were largely maintained at T2, with no statistically significant between group differences. Mental quality of life improved over time, whereas physical quality of life remained unchanged.ConclusionFollowing the intervention, both groups showed improvements in cognitive and emotional-behavioral outcomes, with larger and more sustained changes in mild CI. These findings should be confirmed in randomized controlled studies.

Background and objectiveCalcitonin gene–related peptide (CGRP) is a key mediator in migraine and a target of recent preventive therapies. Since CGRP is also expressed in bone and involved in skeletal regulation, concerns have been raised regarding potential bone effects of CGRP pathway inhibition. We report a prespecified 6-month analysis of a prospective, observational controlled, cohort study evaluating early bone outcomes during anti-CGRP monoclonal antibody (mAb) therapy.MethodsAdults with migraine initiating anti-CGRP mAb monotherapy (treated, n = 27) and age- and sex-matched migraine controls not receiving preventive therapy (controls, n = 14) underwent dual-energy X-ray absorptiometry [bone mineral density (BMD) at lumbar spine, total hip, and femoral neck], lumbar trabecular bone score (TBS), and bone turnover marker assessment (serum CTX and P1NP) at baseline and 6 months. The primary endpoint was the within-treated change from baseline to month 6 in BDM and TBS. Secondary endpoint included within-patient changes in bone turnover markers and between-group change from baseline to month 6, which were assessed using linear mixed-effects models.ResultsAt baseline, BMD, TBS, CTX and P1NP were within the expected age-specific range in both groups. After 6 months of anti-CGRP mAb exposure all values remained within normal ranges and no clinically meaningful changes in BMD, TBS, CTX or P1NP were observed. In adjusted models, no significant group×time interactions were detected for BMD, CTX or P1NP (all p > 0.05). Lumbar spine TBS showed a small between-group difference in change over time (group×time interaction), with a greater decrease in treated patients than in controls (β = −0.052, 95% CI − 0.095 to −0.008; p = 0.023), with values remaining within the normal range. Anti-CGRP treatment was clinically effective, with ≥50% and ≥75% reductions in monthly migraine days achieved by 80.8 and 42.3% of patients, respectively.DiscussionThis prospective, observational, controlled, cohort study suggests that anti-CGRP mAb therapy is not associated with early adverse effects on bone density, structure, or turnover, while providing substantial migraine improvement. Ongoing follow-up will determine longer-term skeletal safety.Clinical trial registrationClinicalTrials.gov, NCT06035458.

Background:Spinal cord cross-sectional area (CSA) is a biomarker of disability in multiple sclerosis (MS). Vertebral-based CSA suffers from anatomical variability and positional bias. Objectives:To evaluate a fully automated PMJ-referenced approach, as implemented in the open-source Spinal Cord Toolbox, to assess cervical cord CSA at a fixed distance from the pontomedullary junction (PMJ) in MS. Methods:Retrospective study performed at the MS center of Lugano (Switzerland). Inclusion criteria were treatment with natalizumab or ocrelizumab and absence of clinical/radiological disease activity over ≥2 years. CSA at 64 mm caudal to the PMJ (CSA PMJ) and at C2-C3 vertebral level (CSA C2-C3) were calculated using the Spinal Cord Toolbox. Results:Seventy-five MS patients [females = 44 (58.7%), age = 45.1 (36.7-53.8) years, natalizumab = 36 (48%), ocrelizumab = 39 (52%)] were included. Median CSA PMJ and CSA C2-C3 were 57.7 (53.1-62.1) and 58.1 (53.2-62.6) mm2, respectively. The two measures were highly correlated (rho = 0.95, p < 0.001), with some exceptions related to errors in vertebral labelling in CSA C2-C3 assessments. PMJ was correctly identified in all subjects. CSA PMJ measures were negatively associated with disability (β = -0.08, p = 0.002), independent of age and sex. Conclusion:Automated measurement of spinal cord CSA at fixed distance from the PMJ is applicable in MS, performs better than vertebral-based CSA, and correlates with neurological disability.

Background/Objectives: Multiple sclerosis (MS) is often associated with comorbidities that affect clinical outcomes. Data on comorbidities can be sourced from self-reports, medical records, and administrative databases. The gold standard for collecting such data is prospective clinical collection, as in clinical trials, but this is not feasible in large epidemiological studies. This study aimed to assess the agreement between two data sources, clinical interviews and administrative records, identifying major comorbidities in people with MS (pwMS). Methods: We evaluated the agreement between clinical interview data and administrative records in pwMS enrolled at two sites (2021-2022). Seven comorbidities were investigated: depression, anxiety, diabetes, hypertension, autoimmune disease, chronic lung disease, and hyperlipidemia. We used kappa (κ), sensitivity, specificity, and predictive values to assess agreement. Results: The frequency of comorbidities varied between the sources. Administrative data often underestimated hypertension, autoimmune diseases, hyperlipidemia, and anxiety, but over-reported depression. It had high sensitivity for diabetes (80%) and moderate sensitivity for hypertension (62%). The agreement for diabetes (κ = 98.9%, PABAK = 0.98, positive agreement = 83.3%) and hypertension (κ = 89.8%, PABAK = 0.80, positive agreement = 70.8%) was high. Conclusions: The agreement between administrative data and clinical interviews was excellent for diabetes and hypertension. For other conditions, such as psychiatric, hyperlipidemia, and autoimmune comorbidities, administrative data had lower sensitivity, and often under-reported or misclassified the data.

OBJECTIVE:Extended interval dosing protocols of B-cell-depleting therapies in multiple sclerosis (MS) are being developed, but intervals between infusions are often arbitrary. We describe total and memory B-cell repopulation dynamics in MS patients on a memory B-cell-guided extended interval dosing ocrelizumab (OCR) protocol. METHODS:OCR was administered on peripheral CD19+ CD27+ memory B-cell repopulation (≥1 cell/μL), monitored using fluorescence-activated cell sorting. Associations with CD19+ B cells and CD19+ CD27+ memory B cells were tested using mixed-effect hurdle models, with rate ratios (RR) predicting cell counts and odds ratios (OR) predicting cell depletion. RESULTS:We collected 1,369 samples from 101 patients, 61.4% women, aged 42.2 years (IQR 32.3-51.1 years) and follow up 4.1 years (IQR 2.9-5.2 years). The median time between samples and previous OCR infusion was 6.6 months (IQR 4.7-8.8 months). Time since previous OCR infusion was positively associated with CD19+ B cells (RR = 1.11, 95% CI 1.10-1.11, p < 0.001) and CD19+ CD27+ memory B-cell counts (RR = 1.11, 95% CI 1.09-1.13, p < 0.001). A greater cumulative OCR dose was associated with persistent CD19+ CD27+ memory B-cell depletion (OR 1.90, 1.57-2.31, p < 0.001). CD19+ B-cell repopulation was inversely associated with age (RR = 0.82, 95% CI 0.71-0.95, p = 0.010). Female patients showed a lower ratio of CD19+ CD27+ memory B cells/total CD19+ B cells (RR = 0.42, 95% CI 0.26-0.69, p = 0.001). Disease activity was low, with most radiological activity observed within the first year of OCR treatment. INTERPRETATION:Memory B-cell repopulation becomes slower with increasing cumulative OCR dose. Age- and sex-related mechanisms probably influence repopulation dynamics. Given the evidence for a pathogenic role of memory B cells, these observations could be considered when planning extended interval dosing strategies of OCR treatment. ANN NEUROL 2025;98:603-615.

Background: Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, such as erenumab (ERE), are effective migraine-preventive therapies for many patients. Identifying clinical and genetic factors associated with treatment failure is crucial for optimizing patient management. Methods: This multicenter, prospective observational study included patients with episodic or chronic migraine treated with ERE for 12 months. Demographics, migraine history, comorbidities, treatment outcomes, and genetic variants in CGRP receptor-related genes (CALCRL and RAMP1) were evaluated for associations with non-response to ERE, defined as a <50% reduction in monthly migraine days. Results: Of the 140 patients starting ERE, 11 were lost to follow up, 12 stopped ERE due to side effects; 18 patients were non-responders and were compared to 99 responders. Arterial hypertension [adjusted OR (aOR): 7.77, p = 0.007], smoking (aOR: 4.98, p = 0.014), and insomnia requiring medication (aOR: 4.51, p = 0.027) were associated with non-responder status. Genetic analysis revealed a nominal association between the RAMP1 rs6431564 polymorphism and non-responder status (nominal p = 0.025), which did not survive Bonferroni correction. The G allele was linked to a reduced risk (aOR per G allele: 0.28, p = 0.025) and caused the increased expression of RAMP1 in an allele-dose manner. Conclusions: Hypertension, smoking, insomnia requiring medication, and, nominally, the RAMP1 rs6431564 polymorphism were associated with non-responder status to ERE in migraine patients. Further validation of the present results in larger cohorts is needed.

Background:Recent studies support the need for early and intensive disease-modifying treatment (DMT) for patients with multiple sclerosis (PWMS). Abrupt DMT withdrawal may risk disease reactivation. Recent studies showed that MS disease activity was not rare after DMT withdrawal for PWMS aged >45/55 y. Immune reconstitution therapy (IRT) with cladribine tablets (CladT), may be an option for older PWMS who wish to stop DMT. Objective:We retrospectively analysed PWMS aged >45 y who initiated CladT in 6 MS centers in Europe. Results:One hundred and twenty nine PWMS (95 women/34 men, mean age 55.0 +/-7.5y initiated CladT; 83 (64.3%) previously received platform DMT, 35 (27.2%) previously received high efficacy DMT and 11 (8.5%) received CladT as a 1st DMT due to a late onset of MS or to a delayed therapy decision. Mean follow-up was 2.4 y (1-5) on CladT. Only three patient experienced 4 relapses. The first one had 2 relapses after switching from fingolimod with a 2-month interval between treatments. The 2 remaining were naïve patients that had a relapse between the 2 courses of CladT. Conclusion:Last/exit therapy with CladT seems to avoid MS disease reactivation in older PWMS and may be an interesting alternative solution to continue immunosuppression/immunomodulation.

BACKGROUND:Neurostatus-Expanded Disability Status Scale (EDSS) is the standard measure used to assess impairment and disability in multiple sclerosis (MS) trials but requires trained expert neurologists. OBJECTIVES:This study aims to evaluate the concordance of Neurostatus-EDSS assessments from specially trained health care professionals (HCPs) and standardized trained neurologists. METHODS:A Swiss multicenter, randomized, cross-over study with 100 people with MS. HCPs were trained to assess the Neurostatus-EDSS based on the newly developed SMARTCARE-EDSS training method. RESULTS:The concordance rate between HCPs and neurologists was 0.87 (95% confidence interval (CI) = 0.815-0.925). CONCLUSION:Trained HCPs can reliably perform Neurostatus-EDSS assessments, supporting broader implementation and improved trial access.

BACKGROUND:Multiple sclerosis (MS) is frequently accompanied by comorbid conditions. OBJECTIVES:This study aimed to determine the prevalence of key comorbid conditions in people with multiple sclerosis (pwMS) and assess their impact on quality of life and work-related activities. METHODS:A cross-sectional study involving 755 pwMS from two third-level Italian MS centers was conducted. Comorbidities were identified from medical records, and quality of life was assessed using the EQ-5D-3L questionnaire. Work-related challenges were evaluated using the Multiple Sclerosis Questionnaire for Job Difficulties (MSQ-Job). RESULTS:53.8% of pwMS had at least one comorbidity. Hypertension, depression, and anxiety were the most prevalent. Comorbidity presence was associated with reduced quality of life scores in almost all EQ-5D-3L domains and greater job difficulties in all but one MSQ-Job domain. CONCLUSION:Comorbidities in pwMS are prevalent and have a profound influence on quality of life and work-related activities. This comprehensive study offers new insights into the role of comorbidities in MS within the Italian context, emphasizing the need for a multidisciplinary approach in MS management. Further research is crucial to deepen our understanding of these findings in the broader Italian MS community.

Few data are available regarding vaccine induced SARS-CoV-2 specific T cell responses over time and after booster doses in multiple sclerosis (MS) patients on different disease modifying treatments. We measured SARS-CoV-2 specific CD4+ T cell responses in 72 samples collected from 36 MS patients. The percentage of CD4+ CTVlow CD25+ ICOS+ T cells after stimulation with Spike Recombinant Protein was 29.9 (17.0-43.6) on teriflunomide, 32.4 (11.9-42.5) on ocrelizumab, but much lower (0.6 [0.3-5.9]) on sphingosine-1-phospate receptor modulators (β = -26.35, p = 0.003). SARS-CoV-2 specific T cells were mainly of Th1 type and stable over time and after booster vaccine doses. mRNA vaccines elicit strong and persistent CD4+ T cell responses against SARS-CoV-2 in MS patients on anti-CD20 and teriflunomide, but not in those on sphingosine-1-phospate receptor modulators.

Predicting disease progression in patients with the first clinical episode suggestive of multiple sclerosis (MS) is crucial for personalized therapeutic approaches. This study aimed to develop the EUMUS score for accurately estimating the risk of early evidence of disease activity and progression (EDA). Retrospective analysis was conducted on data from 221 patients with a first clinical MS episode collected from four Italian MS centers. Various variables including socio-demographics, clinical features, cerebrospinal fluid analysis, evoked potentials, and brain MRI were considered. A prognostic multivariate regression model was identified to develop the EUMUS score. The optimal cutoff for predicting the transition from no evidence of disease activity (NEDA3) to EDA was determined. The accuracy of the prognostic model and score were tested in a separate UK MS cohort. After 12 months, 61.54

Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody approved for both Relapsing and Primary Progressive forms of Multiple Sclerosis (MS) treatment. OCR is postulated to act via rapid B cell depletion; however, by analogy with other anti-CD20 agents, additional effects can be envisaged, such as on Protein Kinase C (PKC). Hence, this work aims to explore novel potential mechanisms of action of OCR in peripheral blood mononuclear cells from MS patients before and after 12 months of OCR treatment. We first assessed, up-stream, PKCβII and subsequently explored two down-stream pathways: hypoxia-inducible factor 1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF), and human antigen R (HuR)/manganese-dependent superoxide dismutase (MnSOD) and heat shock proteins 70 (HSP70). At baseline, higher levels of PKCβII, HIF-1α, and VEGF were found in MS patients compared to healthy controls (HC); interestingly, the overexpression of this inflammatory cascade was counteracted by OCR treatment. Conversely, at baseline, the content of HuR, MnSOD, and HSP70 was significantly lower in MS patients compared to HC, while OCR administration induced the up-regulation of these neuroprotective pathways. These results enable us to disclose the dual positive action of OCR: anti-inflammatory and neuroprotective. Therefore, in addition to B cell depletion, the effect of OCR on these molecular cascades can contribute to counteracting disease progression.

Calcitonin gene-related peptide (CGRP), implicated in migraine pain, also possesses bone anabolic properties, which leads to the possibility that monoclonal antibodies targeting CGRP (anti-CGRPs) might increase the risk of bone density abnormalities. The objective of this study was to explore bone mineral density abnormalities in a cohort of migraine patients treated with anti-CGRPs. This was a single-center, cross-sectional, cohort study including migraine patients who underwent a densitometry assessment during anti-CGRP treatment. We assessed the frequency of osteopenia or osteoporosis (OSTEO+ status), defined as a bone mineral density T-score of −1 to −2.5, and <−2.5 standard deviations from the young female adult mean, respectively. Additionally, the association of OSTEO+ status with anti-CGRP treatment duration and primary osteoporosis’ risk factors was investigated using logistic regression models. Data from 51 patients (43 female, mean age 46 ± 13.9 years) were evaluated. The mean duration of anti-CGRP treatment was 15.7 (±11.8) months. Twenty-seven patients (53

Background: The costs of disease-modifying therapies (DMTs) for multiple sclerosis (MS) have increased interest in generic alternatives. Methods: This prospective and observational study aims to investigate the safety, tolerability, and acceptance of switching from brand glatiramer acetate (GA) 40 mg/mL three times per week (Copaxone®) to generic GA 40 mg/mL three times per week (Glatiramyl®). Conducted at the Neurocenter of Southern Switzerland from September 2020 to September 2021, the study enrolled 27 patients; 21 completed the study. Participants reported on local and systemic side effects three months before and after the switch, and on switch acceptance by means of visual analogue scales (from 0 to 10). Results: Results indicated that those on generic GA experienced fewer local (81.0% vs. 96.3%) and systemic (33.3% vs. 59.3%) adverse events than with the brand drug. The median intensity of local adverse events was 8 (4–20) on generic GA vs. 16 (9–22) on brand GA, while the median intensity of systemic adverse events was similar between generic and brand GA [0 (0–27) vs. 0 (0–21.5), respectively]. Seventy-one percent of participants rated their acceptance of generic GA as 7/10 or higher. Conclusions: The results suggest that switching from brand to generic GA 40 mg/mL is safe, well-tolerated, and accepted by patients with MS.

Prolonged treatment with anti-CD20 antibodies can lead to hypogammaglobulinemia and increased infection risk in multiple sclerosis (MS). We investigated switch from anti-CD20 to cladribine as a strategy to prevent immunoglobulin reduction while preserving efficacy. We prospectively analysed serum IgG, IgM, neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in 44 patients, 14 who were switched from anti-CD20 to cladribine and 30 continuing anti-CD20. Over 1 year, serum IgG, IgM, NfL and GFAP remained stable after switch and similar to patients continuing anti-CD20. More than 90 % of patients remained free of disease activity. Cladribine should be further explored as de-escalating agent from anti-CD20 in MS.

Background Comorbid conditions are common in people with multiple sclerosis (pwMS). They can delay diagnosis and negatively impact the disease course, progression of disability, therapeutic management, and adherence to treatment. Objective To quantify the economic impact of comorbidity in multiple sclerosis (MS), based on cost-of-illness estimates made using a bottom-up approach. Methods A retrospective study was carried out in two northern Italian areas. The socio-demographic and clinical information, including comorbidities data, were collected through ad hoc anonymous self-assessment questionnaire while disease costs (direct and indirect costs of disease and loss of productivity) were estimated using a bottom-up approach. Costs were compared between pwMS with and without comorbidity. Adjusted incremental costs associated with comorbidity were reported using generalized linear models with log-link and gamma distributions or two-part models. Results 51.0% of pwMS had at least one comorbid condition. Hypertension (21.0%), depression (15.7%), and anxiety (11.7%) were the most prevalent. PwMS with comorbidity were more likely to use healthcare resources, such as hospitalizations (OR = 1.21, p < 0.001), tests (OR = 1.59, p < 0.001), and symptomatic drugs and supplements (OR = 1.89, p = 0.012), and to incur non-healthcare costs related to investment (OR = 1.32, p < 0.001), transportation (OR = 1.33, p < 0.001), services (OR = 1.33, p < 0.001), and informal care (OR = 1.43, p = 0.16). Finally, they experienced greater productivity losses (OR = 1.34, p < 0.001) than pwMS without comorbidity. The adjusted incremental annual cost per patient due to comorbidity was €3,106.9 (13% of the overall costs) with MS disability found to exponentially affect annual costs. Conclusion Comorbidity has health, social, and economic consequences for pwMS.