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High-efficacy therapies in multiple sclerosis are traditionally used after unsuccessful treatment with first-line disease modifying therapies. We hypothesised that early commencement of high-efficacy therapy would be associated with reduced long-term disability. We therefore aimed to compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with those who started 4–6 years after disease onset. In this retrospective international observational study, we obtained data from the MSBase registry and the Swedish MS registry, which prospectively collect patient data that are specific to multiple sclerosis as part of routine clinical care. We identified adult patients (aged ≥18 years) with relapsing-remitting multiple sclerosis, with at least 6 years of follow-up since disease onset, and who started the high-efficacy therapy (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0–2 years (early) or 4–6 years (late) after clinical disease onset. We matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. The primary outcome was disability, measured with the Expanded Disability Status Score (EDSS; an ordinal scale of 0–10, with higher scores indicating increased disability), at 6–10 years after disease onset, assessed with a linear mixed-effects model. We identified 6149 patients in the MSBase registry who had been given high-efficacy therapy, with data collected between Jan 1, 1975, and April 13, 2017, and 2626 patients in the Swedish MS Registry, with data collected between Dec 10, 1997, and Sept 16, 2019. Of whom, 308 in the MSBase registry and 236 in the Swedish MS registry were eligible for inclusion. 277 (51%) of 544 patients commenced therapy early and 267 (49%) commenced therapy late. For the primary analysis, we matched 213 patients in the early treatment group with 253 in the late treatment group. At baseline, the mean EDSS score was 2·2 (SD 1·2) in the early group and 2·1 (SD 1·2) in the late group. Median follow-up time for matched patients was 7·8 years (IQR 6·7–8·9). In the sixth year after disease onset, the mean EDSS score was 2·2 (SD 1·6) in the early group compared with 2·9 (SD 1·8) in the late group (p<0·0001). This difference persisted throughout each year of follow-up until the tenth year after disease onset (mean EDSS score 2·3 [SD 1·8] vs 3·5 [SD 2·1]; p<0·0001), with a difference between groups of −0·98 (95% CI −1·51 to −0·45; p<0·0001, adjusted for proportion of time on any disease-modifying therapy) across the 6–10 year follow-up period. High-efficacy therapy commenced within 2 years of disease onset is associated with less disability after 6–10 years than when commenced later in the disease course. This finding can inform decisions regarding optimal sequence and timing of multiple sclerosis therapy. National Health and Medical Research Council Australia and MS Society UK.

Caregivers of people with Multiple Sclerosis are required to provide ongoing assistance especially during the advanced stages of the disease. They have to manage interventions and assume responsibilities which significantly impact both their personal quality of life and family's dynamics. A qualitative phenomenological study was carried out to understand the experience of burden in caregivers and their resources to manage it. The study also explores how healthcare services involved in the Multiple Sclerosis Clinical Pathway respond to the needs of well-being of patients and family members. 17 caregivers were involved in focus groups and in semi-structured individual interviews. Fatigue is experienced by all respondents and it starts when physical disabilities increase or when people become aware of them. Many caregivers declare that they refer to intrinsic (love towards their relatives, patience and dedication) or extrinsic (family members, hobbies) resources to cope with the burden of assistance. Patient associations and the Multiple Sclerosis Clinical Pathway play a significant role in supporting caregivers. Fatigue, loneliness, and isolation are experienced by caregivers and strongly affect their quality of life and health status. The study highlights caregivers' need to reconcile working times with care times, to give more space to self-care and to have moments to share their experiences with someone else. These needs should be at the core of health policies in order to avoid physical and emotional breakdowns which could lead to the rupture of the relational balance on which home care is based.

Multiple Sclerosis (MS) is an autoimmune demyelinating disease characterised by changes in iron and myelin content. These biomarkers are detectable by Quantitative Susceptibility Mapping (QSM), an advanced Magnetic Resonance Imaging technique detecting magnetic properties. When analysed with radiomic techniques that exploit its intrinsic quantitative nature, QSM may furnish biomarkers to facilitate early diagnosis of MS and timely assessment of progression. In this work, we explore the robustness of QSM radiomic features by varying the number of grey levels (GLs) and echo times (TEs), in a sample of healthy controls and patients with MS. We analysed the white matter in total and within six clinically relevant tracts, including the cortico-spinal tract and the optic radiation. After optimising the number of GLs (n = 64), at least 65% of features were robust for each Volume of Interest (VOI), with no difference ( p  > .05) between left and right hemispheres. Different outcomes in feature robustness among the VOIs depend on their characteristics, such as volume and variance of susceptibility values. This study validated the processing pipeline for robustness analysis and established the reliability of QSM-based radiomics features against GLs and TEs. Our results provide important insights for future radiomics studies using QSM in clinical applications.

Advance care planning (ACP) is increasingly acknowledged as a key step to enable patients to define their goals/preferences for future medical care, together with their carers and health professionals. We aimed to map the evidence on ACP in neurodegenerative disorders. We conducted a scoping review by searching PubMed (inception-December 28, 2020) in addition to trial, review, and dissertation registers. From 9367 records, we included 53 studies, mostly conducted in Europe (45%) and US-Canada (41%), within the last five years. Twenty-six percent of studies were qualitative, followed by observational (21%), reviews (19%), randomized controlled trials (RCTs, 19%), quasi-experimental (11%), and mixed-methods (4%). Two-thirds of studies addressed dementia, followed by amyotrophic lateral sclerosis (13%), and brain tumors (9%). The RCT interventions (all in dementia) consisted of educational programs, facilitated discussions, or videos for patients and/or carers. In conclusion, more research is needed to investigate barriers and facilitators of ACP uptake, as well as to develop/test interventions in almost all the neurodegenerative disorders. A common set of outcome measures targeting each discrete ACP behavior, and validated across the different diseases and cultures is also needed.

BackgroundDiscontinuation of injectable disease-modifying therapy (DMT) for multiple sclerosis (MS) after a long period of relapse freedom is frequently considered, but data on post-cessation disease course are lacking.Objectives(1) To compare time to first relapse and disability progression among ‘DMT stoppers’ and propensity-score matched ‘DMT stayers’ in the MSBase Registry; (2) To identify predictors of time to first relapse and disability progression in DMT stoppers.MethodsInclusion criteria for DMT stoppers were: age ≥18 years; no relapses for ≥5 years at DMT discontinuation; follow-up for ≥3 years after stopping DMT; not restarting DMT for ≥3 months after discontinuation. DMT stayers were required to have no relapses for ≥5 years at baseline, and were propensity-score matched to stoppers for age, sex, disability (Expanded Disability Status Score), disease duration and time on treatment. Relapse and disability progression events in matched stoppers and stayers were compared using a marginal Cox model. Predictors of first relapse and disability progression among DMT stoppers were investigated using a Cox proportional hazards model.ResultsTime to first relapse among 485 DMT stoppers and 854 stayers was similar (adjusted HR, aHR=1.07, 95% CI 0.84 to 1.37; p=0.584), while time to confirmed disability progression was significantly shorter among DMT stoppers than stayers (aHR=1.47, 95% CI 1.18 to 1.84, p=0.001). The difference in hazards of progression was due mainly to patients who had not experienced disability progression in the prebaseline treatment period.ConclusionsPatients with MS who discontinued injectable DMT after a long period of relapse freedom had a similar relapse rate as propensity score-matched patients who continued on DMT, but higher hazard for disability progression.

The ConCure-SM intervention [ISRCTN48527663] consists of an advance care planning (ACP) training program for neurologists/other professionals caring for people with progressive multiple sclerosis (PwPMS). We assessed the communication competences of ACP-trained neurologists who participated in the trial. Eighteen ACP conversations were audio-recorded. After each conversation, participants (PwPMS, significant others [SOs], and neurologists) rated the neurologist's communication skills using dedicated versions of the Quality of Communication questionnaire (QOC). Independent observers assessed the conversations using the Observing Patient Involvement in Shared Decision Making (SDM; OPTION), and the Verona Coding Definitions of Emotional Sequences (VR-CoDES). Mean duration of the ACP conversations was 62.7 minutes. Neurologists (5/7 women) were 30-62-year-old. PwPMS mean age was 61.8 years, 39% were women. Mean QOC scores (distinguished in general communication and end-of-life communication; 0-100 scale) were 92.4, 90.1 respectively, according to PwPMS; 95.2, 94.3 according to SOs. Mean neurologists' self-reported QOC score (0-100 scale) was 69.5. Mean OPTION score (0-100 scale) was 48.4. PwPMS expressed a median of 8.5 cues (hints to emotion) and 3.0 concerns (explicit expressions of emotion) per conversation. Neurologists provided space to 59% of cues and 73% of concerns. A quarter of cues/concerns contained figurative expressions or metaphors to express concerns or as signals of emotional distress. Moreover, 12% of expressions were coded as positive emotional statements (i.e., expressions indicating hope, confidence, and positive wishes). Neurologists' communication skills during ACP conversations were rated as high using the QOC by both PwPMS and SOs, while neurologists rated their own skills more critically. Neurologists' SDM competences were moderate, but higher compared to two published studies on MS consultations. Qualitative and quantitative analysis of ACP conversation transcripts indicate that ACP can evoke many emotions. In most instances neurologists provided space for the PwPMS to elaborate on affective expressions. ISRCTN48527663.

Advance care planning (ACP) practice in people with progressive multiple sclerosis (PwPMS) remains limited. ConCure-SM project aims to assess the effectiveness of a structured ACP intervention (clinician's training programme and use of a booklet during ACP conversations) using a multi-phased design. Single-arm pilot/feasibility trial involving PwPMS, their significant others (SOs), and clinicians from six Italian centers. Primary study outcome was completion of an advance care plan document (ACP-Doc). Other outcomes included safety, feasibility of enrollment and assessment, and (analyzed using mixed-methods approach) Hospital Anxiety and Depression Scale (HADS), quality of communication, quality of life (MSQOL-29), and caregiver burden. Participants were interviewed to identify factors influencing the ACP implementation process. Seventy-five PwPMS were eligible out of 164 screened; 56/75 (75%) refused participation and 19 were included. Of these, 11 (58% vs 30% hypothesized) completed the ACP-Doc. A total of 25 adverse events (increase in anxiety) occurred, three possibly related to the intervention, and we found a worsening of HADS-Anxiety score (p = 0.02) and MSQOL-29 mental health composite score (p = 0.04) during follow-up. PwPMS/SO interviews revealed four themes: significance of the ACP process (on the individual, on relation with clinicians), its impact (on emotions, on family relations), preparedness as key, and challenges (practicability, SO commitment). Barriers and facilitators for ACP were identified in two clinician focus groups. The intervention supported neurologists in guiding PwPMS in their ACP. However, trial findings and the high proportion of refusals point to the need to enrich the intervention with a new component targeting PwPMS and SOs. ISRCTN48527663.

Multiple Sclerosis is more common in women than men and females have more relapses than men. In a large international cohort we have evaluated the effect of gender on disability accumulation and disease progression to determine if male MS patients have a worse clinical outcome than females. Using the MSBase Registry, data from 15,826 MS patients from 25 countries was analysed. Changes in the severity of MS (EDSS) were compared between sexes using a repeated measures analysis in generalised linear mixed models. Kaplan-Meier analysis was used to test for sex difference in the time to reach EDSS milestones 3 and 6 and the secondary progressive MS. In relapse onset MS patients (n = 14,453), males progressed significantly faster in their EDSS than females (0.133 vs 0.112 per year, P<0.001,). Females had a reduced risk of secondary progressive MS (HR (95% CI) = 0.77 (0.67 to 0.90) P = 0.001). In primary progressive MS (n = 1,373), there was a significant increase in EDSS over time in males and females (P<0.001) but there was no significant sex effect on the annualized rate of EDSS change. Among registrants of MSBase, male relapse-onset patients accumulate disability faster than female patients. In contrast, the rate of disability accumulation between male and female patients with primary progressive MS is similar.

Multiple sclerosis (MS) is a progressive demyelinating disease impacting the central nervous system. Conventional Magnetic Resonance Imaging (MRI) techniques (e.g., T 2 w images) help diagnose MS, although they sometimes reveal non-specific lesions. Quantitative MRI techniques are capable of quantifying imaging biomarkers in vivo , offering the potential to identify specific signs related to pre-clinical inflammation. Among those techniques, Quantitative Susceptibility Mapping (QSM) is particularly useful for studying processes that influence the magnetic properties of brain tissue, such as alterations in myelin concentration. Because of its intrinsic quantitative nature, it is particularly well-suited to be analyzed through radiomics, including techniques that extract a high number of complex and multi-dimensional features from radiological images. The dataset presented in this work provides information about normal-appearing white matter (NAWM) in a cohort of MS patients and healthy controls. It includes QSM-based radiomic features from NAWM and its tracts, and MR sequences necessary to implement the pipeline: T 1 w, T 2 w, QSM, DWI. The workflow is outlined in this article, along with an application showing feature reliability assessment.

Background: Sex differences in multiple sclerosis (MS) progression are poorly characterized, especially for disability worsening independent of relapses. Objectives: To assess sex-specific risks of progression independent of relapse activity (PIRA), relapse and magnetic resonance imaging (MRI) activity (PIRMA), and relapse-associated worsening (RAW) in a real-world MS cohort, quantify each event’s contribution to disability accumulation, and explore variation across clinical subgroups. Design: Inverse probability-weighted analysis of adults with relapsing-remitting MS ambispectively enrolled in a local registry who had their first recorded neurological evaluation within 12 months of MS onset. Methods: We used weighted conditional proportional hazard models for recurrent events, adjusted for visit/MRI frequency, to compare risks between sexes. We also tested the homogeneity of sex effects across prespecified subgroups: age at MS onset, symptom location at onset, presence of ⩾10 T2-hyperintense brain lesions, ⩾1 spinal T2 lesion, ⩾1 Gadolinium-enhancing brain lesion at baseline, initial MS treatment type, and percentage of follow-up time on disease-modifying therapy (DMT). Results: We included 492 people with MS (median age 44.0 years, interquartile range (IQR) 35.0–53.6; 68.9% women), followed for a median of 5.1 years (IQR 3.1–7.2). In the weighted cohort, women had higher hazards of PIRA (hazard ratio (HR) 2.44, 95% confidence interval (CI) 1.56–3.70; p < 0.001) and PIRMA (HR 2.13, 95% CI 1.25–3.70; p < 0.001), mainly postmenopausal (56.6% and 52.4%). RAW risk was similar (HR 1.07, 95% CI 0.54–2.11; p = 0.843), despite higher relapse rates in women (0.13 ± 0.18 vs 0.06 ± 0.16; p < 0.001). Men had greater Expanded Disability Status Scale worsening per PIRA (+0.29 ± 0.71 vs +0.16 ± 0.53; p = 0.023) and PIRMA (+0.25 ± 0.71 vs +0.09 ± 0.38; p = 0.001). Age ⩾50 at onset increased PIRA/PIRMA risk without sex interaction. Significant sex interaction was seen for onset symptom location (p < 0.001 for both outcomes) and initial DMT (p = 0.013 for PIRA; p = 0.022 for PIRMA). Conclusion: Women, especially postmenopausal, had higher PIRA/PIRMA risk, but disability worsening per event was greater in men, associations varied by onset phenotype and initial DMT strategy.