Search

Background: Whether genetic factors influence the long-term course of multiple sclerosis (MS) is unresolved. Objective: To determine the influence of HLA-DRB1*1501 on long-term disease course in a homogeneous cohort of clinically isolated syndrome (CIS) patients. Methods: One hundred seven patients underwent clinical and MRI assessment at the time of CIS and after 1, 3, 5 and 15 years. HLA-DRB1*1501 status was determined using Sanger sequencing and tagging of the rs3135388 polymorphism. Linear/Poisson mixed-effects models were used to investigate rates of change in EDSS and MRI measures based on HLA-DRB1*1501 status. Results: HLA-DRB1*1501 -positive ( n = 52) patients showed a faster rate of disability worsening compared with the HLA-DRB1*1501 -negative ( n = 55) patients (annualised change in EDSS 0.14/year vs. 0.08/year, p 2/year, p Interpretation: These findings provide evidence that the HLA-DRB1*1501 allele plays a role in MS severity, as measured by long-term disability worsening and a greater extent of inflammatory disease activity and tissue loss. HLA-DRB1*1501 may provide useful information when considering prognosis and treatment decisions in early relapse-onset MS.

Background: Clinical studies in multiple sclerosis (MS) often require accurate measurement of walking distance. Utilisation of electronic devices could theoretically improve this. Mobile devices have the potential to continuously monitor health by collecting movement data. Popular fitness trackers record steps taken and distance travelled, typically using a fixed-stride length. However, applications using fixed-stride length may be less accurate in those with altered gait patterns. While useful for everyday purposes, medical monitoring requires greater accuracy. Objective: Our aim was to determine the agreement and reliability of using a smartphone application to measure distance walked. Method: A phone application (mSteps) was developed and tested in a pilot study and then a validation study, looking at an indoor and outdoor setting with people with multiple sclerosis (PwMS) and a control cohort. Results: In the pilot study, the 95% limits of agreement (LOA) for outdoor tracking in control cohort lay within the a priori defined limit; however, the indoor tracking in both cohorts did not meet the defined limit. The app was then successfully validated outdoors in PwMS. Conclusion: mSteps could be used to accurately measure distance outdoors in PwMS. There is still a need for solutions to accurately and reliably measure distance walked indoors.

Background: As patents for multiple sclerosis (MS) therapies expire, follow-on disease-modifying treatments (FO-DMTs) become available at reduced cost. Concerns exist that cheaper FO-DMTs are used simply to reduce healthcare costs. However, the well-being of people with MS should take priority. Objectives: To identify best practices for FO-DMT development and use by agreeing on principles and consensus statements through appraisal of published evidence. Methods: Following a systematic review, we formulated five overarching principles and 13 consensus statements. Principles and statements were voted on by a multidisciplinary panel from 17 European countries, Argentina, Canada and the United States. Results: All principles and statements were endorsed by >80% of panellists. In brief, FO-DMTs approved within highly regulated areas can be considered effective and safe as their reference products; FO-DMTs can be evaluated case by case and do not always require Phase III trials; long-term pharmacovigilance and transparency are needed; there is lack of evidence for multiple- and cross-switching among FO-DMTs; and education is needed to address remaining concerns. Conclusion: Published data support the use of FO-DMTs in MS. The consensus may aid shared decision-making. While our consensus focused on Europe, the results may contribute to enhanced quality standards for FO-DMTs use elsewhere.

Magnetic resonance imaging; Neurofilament light; Secondary progressive multiple sclerosis Imatge per ressonància magnètica; Llum del neurofilament; Esclerosi múltiple secundària progressiva Imagen por resonancia magnética; Luz de neurofilamento; Esclerosis múltiple secundaria progresiva Background: Cognitive impairment affects 50%–75% of people with secondary progressive multiple sclerosis (PwSPMS). Improving our ability to predict cognitive decline may facilitate earlier intervention. Objective: The main aim of this study was to assess the relationship between longitudinal changes in cognition and baseline serum neurofilament light chain (sNfL) in PwSPMS. In a multi-modal analysis, MRI variables were additionally included to determine if sNfL has predictive utility beyond that already established through MRI. Methods: Participants from the MS-STAT trial underwent a detailed neuropsychological test battery at baseline, 12 and 24 months. Linear mixed models were used to assess the relationships between cognition, sNfL, T2 lesion volume (T2LV) and normalised regional brain volumes. Results: Median age and Expanded Disability Status Score (EDSS) were 51 and 6.0. Each doubling of baseline sNfL was associated with a 0.010 [0.003–0.017] point per month faster decline in WASI Full Scale IQ Z-score (p = 0.008), independent of T2LV and normalised regional volumes. In contrast, lower baseline volume of the transverse temporal gyrus was associated with poorer current cognitive performance (0.362 [0.026–0.698] point reduction per mL, p = 0.035), but not change in cognition. The results were supported by secondary analyses on individual cognitive components. Conclusion: Elevated sNfL is associated with faster cognitive decline, independent of T2LV and regional normalised volumes. The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: No specific funding was received for this research. T.W. is currently funded by the MS-STAT2 trial grant (NCT03387670). This is funded by the NIHR Health Technology Assessment (HTA) Programme, Multiple Sclerosis Society (UK) and the National Multiple Sclerosis Society (US).

Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research.

New clinical activity in multiple sclerosis (MS) is often accompanied by acute inflammation which subsides. However, there is growing evidence that a substantial proportion of lesions remain active well beyond the acute phase. Chronic active lesions are most frequently found in progressive MS and are characterised by a border of inflammation associated with iron-enriched cells, leading to ongoing tissue injury. Identifying imaging markers for chronic active lesions in vivo are thus a major research goal. We reviewed the literature on imaging of chronic active lesion in MS, focussing on ‘slowly expanding lesions’ (SELs), detected by volumetric longitudinal magnetic resonance imaging (MRI) and ‘rim-positive’ lesions, identified by susceptibility iron-sensitive MRI. Both SELs and rim-positive lesions have been found to be prognostically relevant to future disability. Little is known about the co-occurrence of rims around SELs and their inter-relationship with other emerging techniques such as dynamic contrast enhancement (DCE) and positron emission tomography (PET).

Up to very recently, no treatments had proved effective in progressive multiple sclerosis (MS). In 2016, four drugs, two tested in phase 3 and two in phase 2 trials, showed a beneficial effect in primary or secondary progressive MS. Although this could indicate a turning point in progressive MS treatment, most of these successes have been modest and mainly restricted to patients with active inflammation, in the context of trials with powerful anti-inflammatory agents. This paper summarises these reasons, particularly focusing on the main lessons learned for the design of future trials. First, a drug’s mechanism of action should tackle the specific pathogenic mechanisms that characterise progressive MS. Second, trial populations where new drugs are to be tested should be carefully chosen, possibly including younger patients with shorter disease durations, which have greater chances of showing active deterioration during the trial, therefore increasing the power to detect treatment effects. Third, outcome measures used in future phase 2 and phase 3 trials should be highly sensitive and be accompanied by smart trial designs.

Background: The usefulness of performing a spinal cord (SC) magnetic resonance imaging (MRI) in all clinically isolated syndromes (CIS) is controversial. Objective: To assess the value of SC lesions for predicting multiple sclerosis (MS) diagnosis and disability accrual in CIS. Methods: Concerning SC lesions and MS diagnosis (2010 McDonald), adjusted Cox regression analyses were performed in increasingly specific CIS groups: all cases ( n = 207), non-SC CIS ( n = 143), non-SC CIS with abnormal brain MRI ( n = 90) and non-SC CIS with abnormal brain MRI not fulfilling 2010 MS ( n = 67). For the outcome Expanded Disability Status Scale (EDSS) ≥3.0, similar analyses were performed in all cases ( n = 207), non-SC CIS ( n = 143) and SC CIS ( n = 64). Performance at 2 years was assessed for all outcomes. Results: The presence of SC lesions increased MS risk 2.0–2.6 times independently of factors like brain lesions. If considering lesion number, the risk ranged from 1.6 to 2.1 for one lesion to 2.4–3.3 for ≥2. SC lesions increased the short-term disability risk around fivefold, better demonstrated in non-SC CIS. SC lesions were very specific for evolution to MS and showed very high sensitivity for EDSS ≥3.0. Conclusion: SC lesions are independent predictors of MS in all CIS and contribute to short-term disability accrual. SC MRIs in CIS could be useful to estimate their prognosis.

Objective: To investigate the association between activity during interferon-beta (IFNβ) therapy and disability outcomes in patients with relapsing–remitting multiple sclerosis (RRMS). Methods: A longitudinal study based on two previously described cohorts of IFNβ-treated RRMS patients was conducted. Patients were classified according to clinical activity after 2 years (clinical cohort) or to clinical and radiological activity after 1 year (magnetic resonance imaging (MRI) cohort). Multivariate Cox models were calculated for early disease activity predicting long-term disability. Results: A total of 516 patients from two different cohorts were included in the analyses. Persistent clinical disease activity during the first 2 years of therapy predicted severe long-term disability (clinical cohort). In the MRI cohort, modified Rio score and no or minimal evidence of disease activity (NEDA/MEDA) did not identify patients with risk of Expanded Disability Status Scale (EDSS) worsening. However, a Rio score ≥ 2 (hazard ratio (HR): 3.3, 95% confidence interval (CI): 1.7–6.4); ≥3 new T2 lesions (HR: 2.9, 95% CI: 1.5–5.6); or ≥2 Gd-enhancing lesions (HR: 2.1, 95% CI: 1.1–4) were able to identify patients with EDSS worsening. Conclusion: Although early activity during IFNβ therapy is associated with poor long-term outcomes, minimal degree of activity does not seem to be predictive of EDSS worsening over 6.7-year mean follow-up.

Background: Structural cortical networks (SCNs) reflect the covariance between the cortical thickness of different brain regions, which may share common functions and a common developmental evolution. SCNs appear abnormal in neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases, but have never been assessed in primary progressive multiple sclerosis (PPMS). Objective: The aim of this study was to test whether SCNs are abnormal in early PPMS and change over 5 years, and correlate with disability worsening. Methods: A total of 29 PPMS patients and 13 healthy controls underwent clinical and brain magnetic resonance imaging (MRI) assessments for 5 years. Baseline and 5-year follow-up cortical thickness values were obtained and used to build correlation matrices, considered as weighted graphs to obtain network metrics. Bootstrap-based statistics assessed SCN differences between patients and controls and between patients with fast and slow progression. Results: At baseline, patients showed features of lower connectivity ( p = 0.02) and efficiency ( p Conclusion: SCNs are abnormal in early PPMS. Longitudinal SCN changes demonstrated a switch from low- to high-efficiency networks especially among fast progressors, indicating their clinical relevance.

Background: Brain volume loss (BVL) is a key outcome in multiple sclerosis (MS) trials. Natalizumab is highly effective on inflammation with moderate impact on atrophy. Objective: To explore BVL in patients receiving natalizumab with an emphasis on grey matter (GM). Methods: We performed a retrospective post hoc analysis of BVL in 38 patients receiving natalizumab for 3 years using longitudinal voxel-based morphometry (VBM) and FreeSurfer. Results: Significant BVL was observed during first year: brain parenchymal fraction (BPF): −1.12% ( p right fronto-parietal cortex, right > left hippocampus and left caudate. FreeSurfer showed significant volume losses in subcortical GM, brainstem and cerebellum, and cortical thinning in the left insula. In the second year, only WMF decrease (−0.6%; p = 0.015) was observed with no VBM changes, although FreeSurfer detected significant volume loss in thalamus, hippocampus and cerebellum. Baseline gadolinium enhancement influenced WMF and BPF changes during the first year, but not GMF. Patients with confirmed Expanded Disability Status Scale (EDSS) worsening at 3 years had lower baseline GMF and left thalamus volume and greater BVL over follow-up. Conclusion: BVL develops mainly during the first year of natalizumab therapy. GM changes are independent of baseline inflammation and correlate with disability.

Background: Investigation of atrophy data from a pivotal natalizumab trial has demonstrated an increased rate of volume loss, compared to placebo, after the first year of therapy. It was considered to be probably due to a pseudoatrophy effect. Objective: To assess grey and white matter volume changes and their relation to global brain volume changes and to baseline inflammation, for patients under natalizumab therapy. Methods: We selected 45 patients on natalizumab therapy for at least 24 months, with magnetic resonance imaging (MRI) scans at baseline, 12 and 24 months. We calculated the percentage brain volume change (PBVC) for the first and second year, using SIENA software. Grey and white matter fractions (GMF and WMF, respectively) for the first year were calculated with SPM5, using lesion masks. After quality checks, six patients were excluded. We studied the predictive variables of change in brain volumes. Results: The PBVC decrease was faster during the first year (−1.10% ± 1.43%), as compared to the second (−0.51% ± 0.96%) ( p = 0.037). These differences were more marked in patients with baseline gadolinium-enhancing lesions ( p = 0.005). Mean GMF and WMF changes during the first year of treatment were +1.15% (n.s.) and −1.72% ( p = 0.017), respectively. The presence of active lesions at baseline MRI predicted PBVC ( p = 0.022) and WMF change ( p = 0.026) during the first year of treatment, after adjusting for age and corticosteroid treatment. No predictors were found for GMF volume changes. Conclusion: Early brain volume loss during natalizumab therapy is mainly due to WMF volume loss and it is related to the inflammatory activity present at the onset of therapy. We found that the pseudoatrophy effect is mostly due to white matter volume changes.

Multifocal progressive leukoencephalopathy (PML) is associated with JC virus (JCV) seropositivity, past immunosuppression, and natalizumab treatment for two years or more. The aim of our study was to investigate the rate of treatment discontinuation after stratifying for the three risk factors in a group of 104 natalizumab-treated patients with relapsing–remitting multiple sclerosis. We investigated JCV serological status in our population. We then divided patients into groups according to their PML risk. Treatment indication was reassessed. Of the patients, 64 (61.5%) were JCV seropositive. Amongst seropositive patients on natalizumab for 2 years or more, 10 had received immunosuppression (group A), and 38 had not (group B). After an informed and shared decision-making process, 6/10 (60%) from group A compared with 9/38 (23.7%) from group B discontinued treatment ( p=0.027). In groups A and B, discontinuation also depended upon doctors’ views ( p=0.019, group A; p=0.010, group B) and clinical outcomes ( p=0.021, group A). No-one from low–intermediate risk groups discontinued. The decision to discontinue natalizumab treatment is complex, even when clear PML risk rates are described. Clinical outcomes and doctors’ idiosyncrasies play a crucial part in patients’ final choice.

The diagnostic criteria used in primary progressive (PP) and relapsing—remitting (RR) multiple sclerosis (MS) show substantial differences. This introduces complexity in the diagnosis of MS which could be resolved if these criteria could be unified in terms of the requirements for dissemination in space (DIS). The aim of this study was to assess whether a single algorithm may be used to demonstrate DIS in all forms of MS. Five sets of RRMS criteria for DIS were applied to a cohort of 145 patients with established PPMS (mean disease duration: 11 years — PPMS-1): C1: Barkhof—Tintoré (as in 2005 McDonald’s criteria); C2: Swanton et al. (as in JNNP 2006); C3: presence of oligoclonal bands plus two lesions (as in McDonald’s criteria); C4 and C5: a two-step approach was also followed (patients not fulfilling C1 or C2 were then assessed for C3). Two sets of PPMS criteria for DIS were applied: C6: Thompson et al. (as in 2001 McDonald’s criteria); C7: 2005 McDonald criteria. A second sample of 55 patients with less than 5 years of disease duration (PPMS-2) was also analysed using an identical approach. For PPMS-1/PPMS-2, fulfilment was: C1:73.8%/66.7%; C2:72.1%/59.3%; C3:89%/79.2%; C4:96%/92.3%; C5:96%/85.7%; C6:85.8%/78.7%; C7:91%/80.4%. Levels of fulfilment suggest that the use of a single set of criteria for DIS in RRMS and PPMS might be feasible, and reinforce the added value of cerebrospinal fluid (CSF) findings to increase fulfilment in PPMS. Unification of the DIS criteria for both RRMS and PPMS could be considered in further revisions of the MS diagnostic criteria.

Objective Our objective in this study is to evaluate whether brain magnetic resonance imaging (MRI) performed at interferon-beta (IFN-β) onset and after 12 months allow us to identify relapsing–remitting multiple sclerosis (RRMS) patients with a disability increase in the first 2 years of therapy. Methods This is a prospective and longitudinal study of patients with RRMS treated with IFN-β. All patients included underwent brain MRI before the onset of therapy with IFN-β and 12 months after. MRI measures (T2, unenhanced T1-weighted and gadolinium-enhancing T1-weighted brain lesion load, brain parenchymal fraction) were undertaken at baseline and after 12 months. The number of active lesions (new or enlarging T2 plus gadolinium-enhancing brain lesions) was also assessed on the 12 months MRI scan. Expanded Disability Status Scale (EDSS) was scored every 3 months. We defined an increase in disability as an increase of at least 1 EDSS point confirmed and sustained during the first 2 years of therapy with IFN-β. Regression analysis was performed in order to identify MRI variables of response. Results We included 152 patients who were followed-up for at least 2 years. After 2 years of therapy, 24 patients (16%) had an increase in disability. The logistic regression model showed that active lesions in the scan performed at 12 months were the most important factor related with the increase of disability after 2 years of therapy (odds ratio 8.3, 95% confidence interval 3.1–21.9; p < 0.0001). Conclusions In RRMS patients treated with IFN-β the MRI changes occurring during the first year may have a prognostic value for identifying patients with a confirmed increase of disability after 2 years of therapy.

Objectives: To identify associations between cognitive impairment and imaging measures in a cross-sectional study of patients with primary progressive multiple sclerosis (PPMS). Methods: Neuropsychological tests were administered to 27 patients with PPMS and 31 controls. Patients underwent brain conventional magnetic resonance imaging (MRI) sequences, volumetric scans and magnetization transfer (MT) imaging; MT ratio (MTR) parameters, grey matter (GM) and normal-appearing white matter (NAWM) volumes, and WM T2 lesion load (T2LL) were obtained. In patients, multiple linear regression models identified the imaging measure associated with the abnormal cognitive tests independently from the other imaging variables. Partial correlation coefficients (PCC) were reported. Results: Patients performed worse on tests of attention/speed of visual information processing, delayed verbal memory, and executive function, and had a worse overall cognitive performance index, when compared with controls. In patients, a lower GM peak location MTR was associated with worse overall cognitive performance ( p Conclusions: The finding of strong associations between GM MTR, NAWM volume and T2LL and specific cognitive impairments suggests that models that predict cognitive impairment in PPMS should include comprehensive MRI assessments of both GM and WM. However, GM MTR appears to be the main correlate of overall cognitive dysfunction, underlining the role of abnormal GM integrity in determining cognitive impairment in PPMS.