Abstract

Ocrelizumab is a recombinant humanized monoclonal antibody selectively targeting CD20-expressing B cells. The effect of ocrelizumab on primary progressive multiple sclerosis (PPMS) has been evaluated during phase 3 trials that enrolled patients under 55 years with a maximum Expanded Disability Status Scale (EDSS) of 6.5. However, little is known on older disabled patients with longer disease duration. We aimed to assess the clinical effectiveness of ocrelizumab in PPMS patients out of the ORATORIO eligibility criteria. This multicenter retrospective study collected data about the effectiveness of ocrelizumab in PPMS patients who received treatment between May 2017 and June 2022 in the Italian MS centers contributing to the Italian MS Registry who adhered to the Compassionate Use Program. The confirmed EDSS worsening (CEW) (defined as either a ≥ 1-point or ≥ 2-point increase in EDSS score from baseline that was confirmed at T12 and T24) was calculated. At the date of data extraction, out of 887 PPMS patients who had received ocrelizumab, 589 (mean age 49.7 ± 10.7 years, 242 (41.1%) females) were enrolled. The mean follow-up period was 41.3 ± 12.3 months. A total of 149 (25.3%) received ocrelizumab according to the ORATORIO criteria (ORATORIO group) and 440 (74.7%) outside the ORATORIO criteria (non-ORATORIO group). No differences in terms of cumulative probabilities of 12 and 24 months of CEW of ≤ 1 point were found between ORATORIO and non-ORATORIO groups. Cox regression analyses showed that age older than 65 years (HR 2.51, 25% CI 1.07-3.65; p = 0.01) was associated with higher risk of CEW at 24 months. Patients not responding to ORATORIO criteria for reimbursability may benefit from ocrelizumab treatment, as disease activity, disease duration, and EDSS seem to not impact the disability outcome. Our results may suggest to extend the possible use of this powerful agent in selected patients under the age of 65 years.

Keywords: Efficacy; Multiple sclerosis; Ocrelizumab; Primary progressive multiple sclerosis.

Abstract

Importance: Availability of new disease-modifying therapies (DMTs) and changes of therapeutic paradigms have led to a general improvement of multiple sclerosis (MS) prognosis in adults. It is still unclear whether this improvement also involves patients with pediatric-onset MS (POMS), whose early management is more challenging.

Objective: To evaluate changes in the prognosis of POMS over time in association with changes in therapeutic and managing standards.

Design, setting, and participants: Retrospective, multicenter, observational study. Data were extracted and collected in May 2019 from the Italian MS Registry, a digital database including more than 59 000 patients. Inclusion criteria were MS onset before age 18 years, diagnosis before January 2014, and disease duration of at least 3 years. Exclusion criteria were primary progressive MS, Expanded Disability Status Scale (EDSS) score of at least 8 one year after onset, unavailability of diagnosis date, and less than 2 EDSS score evaluations. Eligible patients were 4704 patients with POMS. According to these criteria, we enrolled 3198 patients, excluding 1506.

Exposures: We compared time to reach disability milestones by epoch of MS diagnosis (<1993, 1993-1999, 2000-2006, and 2007-2013), adjusting for possible confounders linked to EDSS evaluations and clinical disease activity. We then analyzed the difference among the 4 diagnosis epochs regarding demographic characteristics, clinical disease activity at onset, and DMTs management.

Main outcomes and measures: Disability milestones were EDSS score 4.0 and 6.0, confirmed in the following clinical evaluation and in the last available visit.

Results: We enrolled 3198 patients with POMS (mean age at onset, 15.2 years; 69% female; median time to diagnosis, 3.2 years; annualized relapse rate in first 1 and 3 years, 1.3 and 0.6, respectively), with a mean (SD) follow-up of 21.8 (11.7) years. Median survival times to reach EDSS score of 4.0 and 6.0 were 31.7 and 40.5 years. The cumulative risk of reaching disability milestones gradually decreased over time, both for EDSS score of 4.0 (hazard ratio [HR], 0.70; 95% CI, 0.58-0.83 in 1993-1999; HR, 0.48; 95% CI, 0.38-0.60 in 2000-2006; and HR, 0.44; 95% CI, 0.32-0.59 in 2007-2013) and 6.0 (HR, 0.72; 95% CI, 0.57-0.90; HR, 0.44; 95% CI, 0.33-0.60; and HR, 0.30; 0.20-0.46). In later diagnosis epochs, a greater number of patients with POMS were treated with DMTs, especially high-potency drugs, that were given earlier and for a longer period. Demographic characteristics and clinical disease activity at onset did not change significantly over time.

Conclusions and relevance: In POMS, the risk of persistent disability has been reduced by 50% to 70% in recent diagnosis epochs, probably owing to improvement in therapeutic and managing standards.

Abstract

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.

Keywords: COVID’19 pandemic.; Ocrelizumab; anti CD20 therapies; confirmed disability progression; extended interval dose; primary progressive multiple sclerosis.

Abstract

Background: Cognitive impairment (CI) is a prevalent and debilitating manifestation of multiple sclerosis (MS); however, it is not included in the widely used concept of No Evidence of Disease Activity (NEDA-3). We expanded the NEDA-3 concept to NEDA-3 + by encompassing CI assessed through the Symbol Digit Modality Test (SDMT) and evaluated the effect of teriflunomide on NEDA3 + in patients treated in a real-world setting. The value of NEDA-3 + in predicting disability progression was also assessed.

Methods: This 96-weeks observational study enrolled patients already on treatment with teriflunomide for ≥ 24 weeks. The predictiveness of NEDA-3 and NEDA-3 + at 48 weeks on the change in motor disability at 96 weeks was compared through a two-sided McNemar test.

Results: The full analysis set (n = 128; 38% treatment naïve) featured relatively low level of disability (baseline EDSS = 1.97 ± 1.33). NEDA-3 and NEDA-3 + statuses were achieved by 82.8% and 64.8% of patients, respectively at 48 weeks vs. baseline, and by 57.0% and 49.2% of patients, respectively at 96 weeks vs. baseline. All patients except one were free of disability progression at Week 96, and NEDA-3 and NEDA-3 + were equally predictive. Most patients were free of relapse (87.5%), disability progression (94.5%) and new MRI activity (67.2%) comparing 96 weeks with baseline. SDMT scores were stable in patients with baseline score ˃35 and improved significantly in those with baseline score ≤ 35. Treatment persistence was high (81.0% at Week 96).

Conclusion: Teriflunomide confirmed its real-world efficacy and was found to have a potentially beneficial effect on cognition.

Keywords: Cognition; Multiple sclerosis; No Evidence of Disease Activity; Observational; Teriflunomide.

Abstract

Background: The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) is the most widely used in clinical practice and the least time-consuming battery to estimate cognitive function in adults with Multiple Sclerosis (MS), while it has been included in few studies on young MS, also because of the absence of normative values.

Objective: The aim of this study is to evaluate the impact of age, sex and education on BICAMS scores in a young adolescent population.

Methods: We administered the BICAMS to 169, 11-to-18-year-old, healthy subjects. Linear regression models were used to assess the impact of age, sex, and education on sub-test scores. When statistically significant (p < 0.05), we used the regression coefficient to correct the raw scores.

Results: younger age was associated with worse performance on SDMT (β = 1.76; p < 0.05), CVLT-II (β = 3.33; p < 0.05) and BVMT-R (β = 0.62; p < 0.05). Female sex was associated SDMT (β = 2.75 (p < 0.05) and CVLT-II (β = 2.51 (p < 0.05). Educational attainment was associated with better performance on SDMT (β = 1.79 (p = < 0.05) and BVMT-R (β = 0.61; p < 0.05). Cut-off points were suggested at the 5th lowest percentile.

Conclusion: Age, sex, and education must be accounted for when applying the BICAMS to young population. Its use in everyday assessment of patients with Pediatric Onset Multiple Sclerosis (POMS) could help to compare and combine data across centers, identifying patients requiring a comprehensive evaluation and ad hoc cognitive stimulation programs.

Keywords: BICAMS; Cognition; Cognitive; Multiple sclerosis; Pediatric.

Abstract

Fatigue is a common and disabling nonmotor manifestation in patients with Parkinson's disease (PD), and the supplementary motor area (SMA) has been implicated in its pathophysiology. SMA is usually divided in its rostro-caudal axis, with the rostral (pre-) SMA playing a major role in motor planning, and the caudal (proper) SMA related to movement execution. To investigate brain functional connectivity of SMA subregions in de novo, drug-naïve PD patients affected by fatigue, 17 patients with fatigue, 18 without fatigue, and 16 matched healthy controls were recruited. All the participants were not depressed and did not suffer from daytime sleepiness. Parkinson Fatigue Scale (PFS) was used for fatigue screening (cut-off > 3.3 points) and severity rating. Seed-based resting-state functional MRI was used to compare the functional connectivity from bilateral SMA subregions to the whole brain. Voxel-based morphometry analysis was employed to test whether functional connectivity results were related to brain structural differences. PD-related fatigue was associated with an increased connectivity between the left pre-SMA and the left postcentral gyrus as well as a decreased connectivity between the left SMA proper and the left middle frontal gyrus (ps < 0.01). These patterns of functional connectivity were tightly correlated with PFS scores (Pearson's rs < 0.01). No structural brain changes were observed. In early PD, altered functional connectivity of both SMA subregions might play a crucial role in fatigue pathophysiology. These results offer new insights into the mechanisms responsible for fatigue in PD, suggesting possible targets for neuromodulation strategies oriented to modulate the SMA activity.

Keywords: De novo; Fatigue; Nonmotor symptoms; Parkinson; Supplementary motor area.

Abstract

Background: As a consequence of the coronavirus disease 2019 (COVID-19) pandemic, a large amount of consultations will be delivered through tele-medicine, especially for diseases causing chronic disability and requiring immunomodulatory treatments, such as multiple sclerosis (MS).

Methods: We have hereby reviewed available tools for tele-neurology examination in MS, including components of neurological examination that can be assessed through video, patient-reported outcome measures (PROMs), and digital technology.

Results: Overall, we have suggested a battery for assessing MS disability and relapses on tele-medicine, which brings together conventional examination, PROMs (e.g., Patient Determined Disease Steps, MS Impact Scale), and cognitive tests (Symbol Digit Modalities Test) that can be delivered remotely and in multiple languages.

Discussion: The use of common tools for neurological examination could improve tele-neurology practice for both general neurologists and MS specialists, and quality of care for people with MS.

Keywords: COVID; Multiple sclerosis; Tele-medicine; Tele-neurology.

Abstract

Objective: Despite the availability of effective therapies for Multiple Sclerosis (MS), the unpredictable nature of disease progression and the variability in individual treatment outcomes call for reliable biomarkers. This pilot study aims to investigate the potential of plasma circulating microRNAs (miRNAs) as predictive biomarkers for clinical responses to dimethyl fumarate (DMF), a widely used oral treatment for MS.

Methods: Peripheral blood samples were collected from nineteen treatment-naïve people with relapsing-remitting MS (pwRRMS) before and after 3, 6, 12, and 24 months of DMF administration, as well as from nineteen healthy individuals. MiRNAs were quantified by RT-qPCR after plasma RNA extraction, and peripheral blood immune cells were analyzed by flow cytometry. Pathway enrichment and protein-protein interaction analyses were performed to identify the biological processes and molecular networks associated with mRNAs targeted by the specific DMF-modulated miRNAs.

Results: We identified a DMF-modulated miRNA signature with significant changes occurring at early treatment stages. Notably, specific miRNAs were correlated with both clinical and immunological outcomes upon DMF treatment, including lymphocyte count reduction (let-7b-5p and miR-223-3p) and disease progression over 2 years (miR-223-3p, miR-23a-3p, miR-23b-3p, miR-27a-3p, and miR-27b-3p), suggesting their potential as predictive biomarkers for treatment response. Moreover, the validated mRNA targets of DMF-modulated miRNAs were enriched for IL-6 signaling and NRF2-dependent antioxidant pathways, highlighting the potential molecular mechanisms underpinning DMF efficacy.

Interpretation: This small exploratory study underscores the potential of plasma circulating miRNAs as candidate biomarkers for predicting therapeutic outcomes in MS and it calls for validation in larger studies, which may enhance our understanding of disease pathophysiology and offer a promising tool for personalized treatment strategies.

Keywords: circulating microRNA; dimethyl fumarate (DMF); multiple sclerosis.

Abstract

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.

Keywords: Artificial intelligence; Large language model; Machine learning; Multiple sclerosis.

Abstract

White matter changes are one of the several aging brain alterations. Actually, magnetic resonance imaging is the best diagnostic tool in investigation and monitoring these lesions that determine some common clinical manifestations in the elderly population.