Multiple Sclerosis Journal

Ecological comparisons suggest that neuromyelitis optic spectrum disorder (NMOSD) is more common in African Caribbean and Asian compared to White people.

The aim is to rigorously assess susceptibility across multiple racial and ethnic groups from the same cohort.

We conducted a retrospective cohort study of > 39 million person-years of observation from members of Kaiser Permanente Southern California. The electronic health records of individuals with at least one International Classification of Diseases (ICD) code for NMOSD were reviewed to identify persons who met 2015 diagnostic criteria for NMOSD.

We identified 153 NMOSD cases, 105 incident and 105 prevalent. The age- and sex-standardized incidence (2013–2022) and prevalence (2019) according to the 2020 US Census per 100,000 person-years was significantly higher in Black persons (incidence = 0.90, 95% confidence interval (CI) = 0.59–1.21; prevalence = 8.44, 95% CI = 5.52–11.36) compared to all other racial and ethnic groups. The incidence was similar among Asian/Pacific Islander (0.32, 95% CI = 0.16–0.48) compared to Hispanic people (0.19, 95% CI = 0.13–0.25) and lowest in White people (incidence = 0.13, 95% CI = 0.07–0.19).

NMOSD susceptibility is highest in Black people, followed by Asian/Pacific Islands, then Hispanic people, and lowest in White people. Studies in diverse groups of minoritized people are needed to determine whether this increased susceptibility is due to shared genetic ancestry, the ill-health consequences of racism, or both.

Smoking and vascular risk factors (VRFs) are reported to have adverse effects in multiple sclerosis but data are limited in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD). This study aimed to measure their impact on disability.

Smoking status was defined as never, past or current smokers and VRF comprised of ⩾1: hypertension, dyslipidemia, high body mass index or diabetes. Logistic regression models were fitted to predict their influence on recovery from onset attack and first optic neuritis (ON) attack.

A total of 442 patients were included. Current MOGAD smokers had a higher risk of disability from onset attack and first ON attack than never smokers (odds ratio (OR) 2.9, 95% confidence interval (CI) 1.3–6.9; OR 3.3, 95% CI 1.4–7.8). VRF in MOGAD was not predictive of disability. Current AQP4-NMOSD smokers and VRFs had a higher risk of residual disability from onset attacks (OR 7.5, 95% CI 2.1–27.7; OR 1.9, 95% CI 1.0–3.4). VRF was associated with higher risk of visual disability (OR 2.6, 95% CI 1.08–6.46) while smoking status was not.

Current smoking status detrimentally influenced onset attack recovery in AQP4-NMOSD and MOGAD patients, including visual recovery in MOGAD. Non-smoking VRFs influenced clinical and visual outcomes in AQP4-NMOSD.

Seizures are associated with reduced cognition in the general population and worse outcomes in people with multiple sclerosis (pwMS). Yet, it remains unclear whether seizures are linked to cognitive dysfunction in pwMS.

To evaluate the connection between seizure history and poorer cognition in pwMS.

A consecutive sample of 803 pwMS reported any prior seizures. Covariates included age, sex, Wechsler Test of Adult Reading scores, educational years, Expanded Disability Status Scale (EDSS) scores, disease duration, disease subtype, high-efficacy disease-modifying therapy use, Hospital Anxiety and Depression Scale scores for anxiety and depression and Modified Fatigue Impact Scale scores. Linear regression analyses, controlling for covariates, were undertaken to predict Minimal Assessment of Cognitive Function in MS scores from seizure history.

Mean age was 44.01 years (SD = 11.58), 76.84% were female, and median EDSS was 2.0 (interquartile range (IQR) = 1.5–3.5). Accounting for covariates, people with seizures (n = 43, 5.35%) performed worse than those without (n = 760) on Judgement of Line Orientation (β = −0.09, p < 0.01), California Verbal Learning Test-II learning (β = −0.08, p < 0.01) and memory (β = −0.10, p < 0.01), Brief Visuospatial Memory Test-Revised learning (β = −0.08, p = 0.01) and memory (β = −0.07, p = 0.05), Symbol Digit Modalities Test (β = −0.06, p = 0.04), Paced Auditory Serial Addition Test (β = −0.10, p < 0.01) and Delis-Kaplan Executive Function System (β = −0.07, p = 0.02).

A seizure history independently predicts reduced cognition in pwMS.

The Neurostatus-Expanded Disability Status Scale (EDSS) is the most frequently used measure of disability in multiple sclerosis (MS) trials. However, EDSS scores ⩾4.5 are mainly based on ambulation and may fail to capture relevant disability patterns in other functional domains.

The objective was to determine how assessments categorized with the same EDSS score may reflect distinct disability patterns.

We analysed 13,103 assessments from 1636 people with secondary progressive MS, from the EXPAND trial. The data set is composed of Functional System scores (FSS) and their corresponding subscores, Ambulation scores and EDSS scores. We performed a descriptive analysis to define the relevant Functional Systems (FS). The subscores were then binarized based on the Neurostatus definition and grouped by respective EDSS scores. Finally, we applied two consecutive machine learning algorithms, to cluster the data. New subscore patterns were then created by aggregating clusters based on their dominant features.

The clustering algorithm yielded numerous clusters, grouping assessments with similar patterns. In patients with EDSS ⩾4.0, our approach allowed differentiation into four subscore patterns within the same EDSS score.

Applying Artificial Intelligence (AI) to large data sets of high-quality clinical assessments allows for distinguishing among different subscore patterns within identical EDSS scores.

Measuring brain volume changes over time is an objective and dependable surrogate marker for the pathological processes that damage the brain in relapsing-remitting multiple sclerosis (RRMS). These measures are particularly valuable for monitoring the long-term impact of immunomodulatory treatments such as cladribine.

To evaluate the long-term impact of oral cladribine treatment on brain volume loss in patients with RRMS.

This real-world study processed magnetic resonance imaging (MRI) scans using FreeSurfer’s recon-all-clinical pipeline leveraging SynthSeg for brain segmentation. Piecewise linear regression was used to analyze brain atrophy changes over 4.5 years before and after cladribine treatment and estimate the time breakpoint of atrophy rate change.

A total of 448 MRI exams from 102 RRMS patients were analyzed. Before the initiation of cladribine treatment, brain atrophy rates were significantly steep with an α1 slope between −1.27 and −0.62 for the Thalamus, DGM, Subcortical GM, Cerebral WM, and BP. Over 2 years after treatment, breakpoints marked a shift in atrophy rates, with post-breakpoint slopes (α2) becoming non-significant, reflecting stabilization of brain atrophy.

Cladribine treatment in highly active RRMS patients protects the brain from atrophy, with stabilization occurring over 2 years after initiation. The extended observation period highlights its sustained benefits compared with shorter clinical trials.

Treatment with cladribine tablets (CladT) in relapsing–remitting multiple sclerosis (RRMS) reduced global grey matter (GM) atrophy, but the effects on regional GM are unknown.

This study aimed to investigate the effect of CladT compared with placebo on magnetic resonance imaging (MRI)-derived patterns of GM atrophy.

We used MRI and clinical data from the CLARITY study, including 393 people with RRMS (CladT (3.5 mg/kg), n = 200 or placebo, n = 193) at baseline, 24, 48 and 96 weeks after treatment initiation. SynthSeg-derived volume changes and GM atrophy patterns derived from source-based morphometry were analysed for group differences over time and associations with disability using mixed-effect models.

Deep GM (β = −0.03, p < 0.01), thalamus (β = −0.04, p < 0.01) and the brainstem–thalamus pattern (β = −0.03, p < 0.05) showed higher reduction in the placebo compared with treated group. These regions showed no effect during a predefined pseudo-atrophy period, where global volume loss was worse in the treatment group. Between W24 and W96, Expanded Disability Status Scale (EDSS) scores were associated with lower deep GM volume (β = −0.16, p = 0.001), thalamic volume (β = −0.16, p < 0.001), and the brainstem–thalamus pattern (β = −0.12, p < 0.05).

CladT are associated with clinically relevant and slower neurodegeneration in RRMS. Strongest effects were seen in deep GM, thalamus, and brainstem, underlining the importance of regional MRI measures for assessing treatment effects.

Siponimod, a sphingosine-1-phosphate (S1P) receptor modulator, reduces relapses and delays disability progression in patients with active progressive multiple sclerosis (MS).

EXCHANGE assessed the safety/tolerability of siponimod in patients with advancing relapsing MS (RMS) converting from other disease-modifying therapies (DMTs).

This 6-month, open-label, multicenter, single-arm, phase 3b study (NCT03623243) enrolled 185 patients with advancing RMS previously treated with other DMTs for ⩾3 months. Patients were converted to siponimod via a 6-day dose-titration regimen, or converted immediately, depending on prior DMT use.

Treatment-related adverse events (AEs) were reported by 31.9% (59/185) of patients, with headache (8.1%, n = 15), dizziness (3.8%, n = 7), and nausea (3.2%, n = 6) most commonly reported. Overall, an increase in heart rate (HR) 6 hours following the first dose of siponimod was observed (+2.47 bpm [0.66; 4.29]; p = 0.008). Patients switching from fingolimod without dose titration experienced no change in HR. Serious AEs were reported by 4.9% (9/185) of patients, and 8.6% (16/185) of patients discontinued the study treatment due to AEs.

Conversion to siponimod from other DMTs was found to be generally well tolerated. Patients switching from other S1P-receptor modulators may be able to immediately transition to the siponimod maintenance dose without effects on HR.

ClinicalTrials.gov: NCT03623243 (https://clinicaltrials.gov/study/NCT03623243)

Cognitive decline in multiple sclerosis (MS) is commonly assessed using the Symbol Digit Modalities Test (SDMT). However, the written (wSDMT), oral (oSDMT), and electronic (eSDMT) versions may display differing psychometric properties, despite often being used interchangeably.

The objective of the study is to compare the wSDMT, oSDMT, and eSDMT, including inter-test reliability, and to assess demographic and motor disability influences on test performance.

In this within-subjects study, 85 participants with MS completed all three SDMT versions. Statistical analyses included assessment of intraclass correlation coefficients (ICCs) and sequential multiple regression modeling.

The three SDMT versions demonstrated good inter-test reliability (ICC = 0.77) and similar mean scores (range: 53.5–56.2). Scores on all three test versions declined with age (p < 0.05), but the decline was significantly steeper in the eSDMT. Education correlated with eSDMT but not wSDMT or oSDMT scores. Paced Auditory Serial Addition Task (PASAT) scores predicted performance across all versions, while 9HPT times predicted only wSDMT and eSDMT scores (p < 0.01).

The wSDMT and eSDMT show signs of motor disability influence, while the eSDMT displays the greatest sensitivity to the influences of age and education. This differential construct validity necessitates SDMT version-specific normative data and motor-adjustments for accurate cognitive assessment in MS.

Multiple sclerosis (MS) often causes impairment in working memory (WM), information processing speed (IPS), and verbal memory (VM). These deficits are linked to disrupted neural oscillatory activity. Transcranial alternating current stimulation (tACS), which modulates cortical oscillations, may hold promise for treating cognitive impairment in MS.

To evaluate online and offline effects of gamma (γ)-tACS on WM, IPS, and VM while assessing changes in brain rhythms using electroencephalography (EEG).

Thirty-six MS patients with single-domain impairment in WM (12), IPS (13), or VM (11) underwent γ-tACS and sham-tACS over the left dorsolateral prefrontal cortex (DLPFC) (WM, IPS) or precuneus (VM). Cognitive performance was assessed pre-tACS (T0), during (T1), and post-tACS (T2) using the Digit Span Backward (DSBW) for WM, Symbol Digit Modalities Test (SDMT) for IPS, and Rey Auditory Verbal Learning Test (RAVLT) for VM. EEG was recorded at T0 and T2 to analyze local power spectral density and local-to-global connectivity.

DSBW, SDMT, and RAVLT scores transiently improved during γ-tACS and not during sham. IPS-impaired patients showed a reduction in spectral power across all frequency bands, at the stimulation site, post-DLPFC γ-tACS.

γ-tACS briefly improves WM, IPS, and VM in MS patients, warranting further trials of this non-invasive intervention.

Cryptogenic organizing pneumonia (COP) is an interstitial lung disease, with causes including anti-CD20 antibodies. Ocrelizumab is a humanized monoclonal antibody against CD20 approved for use in relapsing-remitting or primary progressive multiple sclerosis (MS), with no conclusive data regarding pulmonary toxicity.

We describe two cases of COP associated with ocrelizumab use in multiple sclerosis patients.

We suggest considering COP whenever respiratory symptoms arise in MS patients receiving ocrelizumab therapy. COP diagnosis requires clinical and radiological exclusion of alternative diagnoses such as opportunistic infections, autoimmunity, drugs, and neoplasms. Appropriate steroid therapy has an excellent clinical response rate.