Multiple Sclerosis Journal

The understanding of disease pathophysiology is pivotal for tailored treatments. The spatial distribution of brain damage relies on the regional antigen expression and the local balance of susceptibility and protective elements.

As proof-of-concept, we investigated the spatial association between brain damage and gene expression in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4 + NMOSD).

In this multicenter cross-sectional study, 90 AQP4 + NMOSD patients and 94 age-matched healthy controls underwent a brain magnetic resonance imaging (MRI). We used T2-hyperintense lesion probability maps and white/gray matter atrophy as proxies of inflammation and neurodegeneration. The association with the expression of 266 candidate genes was obtained with the Multimodal Environment for Neuroimaging and Genomic Analysis platform. A functional-enrichment analysis investigated overrepresented biological processes.

In AQP4 + NMOSD, T2-hyperintense lesions were mainly periventricular; atrophy mostly involved the visual pathway. The expression of AQP4 and complement (C4a and C5) was associated with both inflammation and neurodegeneration. Complement activation and regulation/uptake of the insulin-like growth factor were the most relevant enriched pathways. Nonspecific pathways related to DNA synthesis and repair were associated with brain atrophy.

Quantitative MRI and gene expression atlas identified the key elements of AQP4 + NMOSD pathophysiology. This analysis could help in understanding the pathophysiology of antibody-mediated autoimmune disorders.

In the DISCOMS (DISCOntinuation of disease-modifying therapies (DMTs) in multiple sclerosis (MS)) randomized clinical trial, we could not demonstrate that discontinuing MS DMTs in older, stable adults was not inferior to continuing DMTs. Relapses were rare in both groups, and most new disease activity was one to two new brain magnetic resonance imaging (MRI) lesions unassociated with clinical changes.

Describe results of the DISCOMS extension study.

Among 10/19 of the original sites, we enrolled patients who completed DISCOMS; did not reach the primary endpoint during the original trial; and retained original randomized assignment. Participants completed one study visit and brain MRI at least 30 months after original enrollment in DISCOMS. Primary endpoint was time from entry into the primary study to relapse or new brain MRI activity.

Mean (SD) total follow-up was 40 (11.7) months. There were no relapses, and new brain MRI lesions (1/30 continuer, 2/44 discontinuers) were uncommon during the extension. Time from primary trial entry to disease event was significantly shorter for subjects in the discontinue group (p = 0.043 from log-rank test).

From entry into DISCOMS extension study, time to new MS activity remained shorter in discontinuers, but relapses were absent and new brain MRI lesions were rare.

Exercise is a safe and effective way to improve physical function in people with multiple sclerosis (PWMS).

This study aimed to perform a head-to-head study of the effects of aerobic and resistance training on physical capacity and physical function.

A multicentre randomized controlled trial with 150 participants was conducted. Participants were randomized into 12 weeks of either aerobic training (AT; n = 62), resistance training (RT; n = 57), or usual care (UC; n = 31). The primary outcome was physical function (measured as a composite score of the 6-minute walk test and five-time sit-to-stand). Secondary outcomes were aerobic capacity (VO₂peak), maximal muscle strength (MVC), and self-reported walking ability.

Participants had a mean age of 45.5 (8.8), an expanded disability status scale (EDSS) of 2.8 (1.5), and 75% were female. Physical function did not increase in AT versus UC 0.08 [−0.16; 0.33] (mean (95% CI)) nor in RT versus UC 0.09 [−0.15; 0.34].VO₂peak increased in AT versus UC by 4.1 [2.0; 6.3] mL O₂/min/kg and in AT versus RT by 2.7 [1.1; 4.3], but not in RT versus UC 1.4 [−0.6; 3.5]. MVC increased in RT versus UC by 0.25 [0.01; 0.48] Nm/kg, but not in RT versus AT 0.17 [−0.02; 0.36] or AT versus UC 0.08 [−0.16; 0.31]).

AT and RT elicited improvements in physical capacity in PWMS. However, these improvements only moderately translated into improvements in physical function.

Clinicaltrials.gov (NCT04913012)

https://clinicaltrials.gov/study/NCT04913012

Previous studies have shown that people with multiple sclerosis (MS) had frequent healthcare visits up to 10 years before being diagnosed but with no information from magnetic resonance imaging (MRI) scans of the connection with the radiologically isolated syndrome (RIS).

To analyze healthcare use 3 years before the RIS diagnosis.

We examined healthcare usage before the first scan in RIS cases from 2010 to 2019. RIS subjects were identified from the French National MS observatory and compared to the general population (matched 10:1) and MS patients (matched 4:1).

Among 482 RIS individuals, 223 (46.3%) were not linked to the healthcare resources database. The remaining RIS individuals (53.7%) had higher healthcare usage before their RIS diagnosis for issues related to neurology visits, headaches (odds ratio (OR): 3.34, confidence interval (CI): [2.00–5.57], p < 0.0001), and the use of anti-migraine drugs (OR: 2.61, CI: [1.37–4.99], p = 0.004) compared to MS.

Only about half of RIS patients had MS-selected healthcare resources, which allowed for data linkage. Those who did seek care before their RIS diagnosis were most commonly known for other neurological comorbidities. These findings do not support the idea of a systemic prodrome before RIS diagnosis.

Little is known about how multiple sclerosis (MS) presents in Hispanic/Latinx (HL) people with MS (pwMS).

Compare age at onset (AAO) and onset severity between HL versus non-Hispanic White (NHW) pwMS.

A cross-sectional study leveraged the MS PATHS registry spanning seven US tertiary care institutions. HL was subcategorized as HL White (HLW) and HL Other (HLO; all other races). Multivariable models examined relationships between ethnoracial variables and AAO and self-reported presenting disease course. Models were repeated restricting to those born ⩾1970.

The study population included 8231 pwMS, including 540 HL (200 HLW, 340 HLO). The sex distribution did not differ across ethnoracial subgroups. From the statistical models (1) HLO pwMS had an earlier AAO and a higher prevalence of initial progressive disease course than NHW pwMS; (2) among all HL pwMS, irrespective of race, AAO did not differ by sex or between relapsing and progressive MS at onset. In younger HLO adults (born ⩾1970), those with progressive MS at onset had an earlier AAO than those with relapsing MS; and (3) in HL pwMS there was no sex-bias in presenting disease course.

Distinct differences in the presentation of MS in HL compared with NHW individuals were observed.

Memory decline is common in multiple sclerosis (MS), although pathophysiological mechanisms are not fully understood.

The objective was to investigate the relationship of changes in structural and functional neuroimaging markers to memory decline over 3-year follow-up.

Participants with MS underwent cognitive evaluation and structural, diffusion, and functional 3T magnetic resonance imaging (MRI) scans at baseline and 3-year follow-up. Changes in neuroimaging metrics from baseline to follow-up were compared between memory stable and memory decline groups. Our hypothesis that structural and functional connectivity changes mediate the association of atrophy to memory decline was tested.

A total of 249 MS patients completed baseline visit; 169 (67.8%) returned at 3-year follow-up. Based on ⩾10% decline, memory decline was observed in 44.4% (n = 75). Those with memory decline showed marginally greater whole-brain volume loss over time compared with those with stable memory performance (p = 0.08). In those with memory decline, changes in white matter tract integrity were related to regional cortical thinning (p < 0.01). Exploratory mediation analysis revealed structural and functional connectivity to mediate the relationship of atrophy to verbal and visual memory decline.

Further work is needed to characterize complex interrelationships of atrophy and structural/functional connectivity changes to memory decline in MS.

Cognitive decline in multiple sclerosis (MS) is associated with neuro-axonal loss, quantifiable by optical coherence tomography (OCT). Associations between OCT measures and cognition in relapsing-remitting MS (RRMS) remain incompletely investigated, particularly the added value of OCT when combined with magnetic resonance imaging (MRI). We investigated the contributions of OCT and MRI while applying stringent criteria to control for subclinical optic neuropathy.

In this cross-sectional study, 137 RRMS patients underwent OCT, Brief International Cognitive Assessment for MS (BICAMS), Expanded Disability Status Scale (EDSS) and brain MRI (lesion load, grey and white matter volume); associations were explored using linear regression models.

RRMS patients (aged 40.88 ± 10.6 years; disease duration 7.95 ± 7.39 years; EDSS 2; 0–6.5) were studied. Of BICAMS, 50.36% showed impaired Symbol Digit Modalities Test (SDMT), 37.23% impaired Brief Visuospatial Memory Test and 5.11% impaired California Verbal Learning and Memory Test; better SDMT performance was associated with thicker ganglion cell-inner plexiform (GCIPL) layers for eyes unaffected by optic neuritis (B = 0.23, 95% CI = (0.01–0.44), p = 0.03), but not when MRI measures were included (B = 0.18, CI = (−0.03 to 0.38), p = 0.09).

GCIPL thinning correlates with SDMT, supporting OCT as a biomarker of cognitive dysfunction. However, GCIPL did not uniquely predict SDMT performance when including MRI measures, suggesting limited utility of OCT in predicting cognitive performance over MRI in RRMS.

Fatigue is a major “invisible” symptom in people with multiple sclerosis (PwMS), which may affect speech. Automated speech analysis is an objective, rapid tool to capture digital speech biomarkers linked to functional outcomes.

To use automated speech analysis to assess multiple sclerosis (MS) fatigue metrics.

Eighty-four PwMS completed scripted and spontaneous speech tasks; fatigue was assessed with Modified Fatigue Impact Scale (MFIS). Speech was processed using an automated speech analysis pipeline (ki elements: SIGMA speech processing library) to transcribe speech and extract features. Regression models assessed associations between speech features and fatigue and validated in a separate set of 30 participants.

Cohort characteristics were as follows: mean age 49.8 (standard deviation (SD) = 13.6), 71.4% female, 85% relapsing-onset, median Expanded Disability Status Scale (EDSS) 2.5 (range: 0–6.5), mean MFIS 27.6 (SD = 19.4), and 30% with MFIS > 38. MFIS moderately correlated with pitch (R = 0.32, p = 0.005), pause duration (R = 0.33, p = 0.007), and utterance duration (R = 0.31, p = 0.0111). A logistic model using speech features from multiple tasks accurately classified MFIS in training (area under the curve (AUC) = 0.95, R² = 0.59, p < 0.001) and test sets (AUC = 0.93, R² = 0.54, p = 0.0222). Adjusting for EDSS, processing speed, and depression in sensitivity analyses did not impact model accuracy.

Fatigue may be assessed using simple, low-burden speech tasks that correlate with gold-standard subjective fatigue measures.

Colitis has been reported with some anti-CD20 therapies in multiple sclerosis (MS), but not previously with ofatumumab.

To report the first case of ofatumumab-associated colitis in MS and discuss its implications.

Case report.

A 56-year-old female with relapsing-remitting multiple sclerosis (RRMS) developed severe colitis 3 months after initiating ofatumumab, requiring hospitalization and treatment discontinuation.

This case suggests a potential class effect of anti-CD20 therapies, including ofatumumab, in relation to colitis in MS. Clinicians should monitor for gastrointestinal symptoms in MS patients receiving any anti-CD20 therapy.