BACKGROUND:Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a rare antibody-mediated inflammatory demyelinating disorder. In 2023, new international consensus diagnostic criteria were agreed. This study uses these criteria to describe epidemiological features of MOGAD in a population-based cohort of patients from south Wales, UK. METHODS:Retrospective review of case notes on all positive MOG-IgG results in South Wales between 01 January 2011 and 30 June 2024 was undertaken, 2023 diagnostic criteria applied and standardised clinical features recorded. Paediatric MOGAD was defined as age at onset < 16 years and adult MOGAD ≥ 16 years. The incidence period was between 01 January 2015 and 31 December 2023. RESULTS:Seventy-six prevalent cases were identified: 53 adults and 23 children. Minimum estimated prevalence of MOGAD in south Wales on 30 June 2024 was 76/1,974,110 population (3.85/100,000 population; 95% CI 3.03-4.82). Paediatric prevalence was 6.59/100,000 population (95% CI 4.18-9.89) and adult prevalence 3.26/100,000 population (95% CI 2.44-4.27). Sex ratio was almost equal in males and females. The most frequent presentations were optic neuritis in adults (62.3%) and ADEM in children (34.8%); 64.5% had a monophasic disease course over a median follow-up of 38 months (IQR 13-63). Mean annual incidence was 3.39 (95% CI 2.58-4.39) per million population. CONCLUSIONS:This regional study provides updated prevalence and incidence rates for MOGAD since the introduction of 2023 diagnostic criteria in a stable south Wales, UK population.

The genetic architecture of Multiple Sclerosis (MS) susceptibility has been extensively assessed in populations of European ancestry. Greater ancestral diversity in genetic analyses of MS susceptibility is needed to improve the utility of Multiple Sclerosis genetic risk scores, fine map causal variants underlying established associations, and thereby enhance the identification of drug targets. Here we report findings from a genetic study of Multiple Sclerosis susceptibility in an ancestrally-diverse United Kingdom-based cohort. Participants with Multiple Sclerosis were recruited via clinical sites, an online platform, and through the United Kingdom Multiple Sclerosis Register. Phenotype data were gathered using a standardised questionnaire. DNA was extracted from saliva samples obtained remotely or in person, and participants were genotyped using a commercial genotyping array. Following imputation, cases were combined with controls from the United Kingdom Biobank and subjected to stringent quality control and genetic ancestry inference. We defined two broad ancestral groups of South Asian and African ancestry. We performed within-ancestry case-control genome-wide association studies of Multiple Sclerosis susceptibility using logistic models accounting for population structure and sex. We examined both single nucleotide variants and imputed classical Human Leukocyte Antigen alleles. We curated two ancestrally-matched case-control genetic datasets (South Asian ancestry: NCase=175, NControl=6744; African ancestry: NCase=113, NControl=5177). In both ancestries, we found genetic variants within the Major Histocompatibility Complex associated with Multiple Sclerosis susceptibility (South Asian ancestry: lead variant chr6:32600515:G:A on hg38 co-ordinates, Odds Ratio=1.84, nearest gene HLA-DRB1, P=4.6x10-6; African ancestry: lead variant chr6:29919337:A:G, Odds Ratio=2.24, nearest gene HLA-A P=4.3x10-5). European-ancestry susceptibility alleles were over-represented in cases from both ancestries, with the degree of concordance stronger for the South Asian (ρ=0.31, P=8.1x10-6) than African (ρ=0.1, P=0.3) ancestry cohort. European-derived genetic risk scores performed better than chance but less well than in European ancestry cohorts, explaining 1.6% (South Asian, P=1.0x10-4) and 0.5% (African, P=0.08) of the liability to MS. The genetic architecture of MS susceptibility shows strong concordance across ancestral groups suggesting shared disease mechanisms. Larger studies in diverse populations are likely to enhance our understanding of how genetic variation contributes to MS susceptibility in people of all ancestral backgrounds. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by a Medical Research Council (MRC) Clinical Research Training Fellowship (CRTF) jointly funded by the UK MS Society (BMJ; grant reference: MR/V028766/1), by AIMS2CURE, and Barts Charity. BMJ is currently funded by a Guarantors of Brain post-doctoral fellowship. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The London South East Research Ethics Committee has approved this study and its amendments. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Code used to perform these analyses is provided on Github at https://github.com/benjacobs123456/ms\_geno\_diversity. Genetic association summary statistics will be made available via the GWAS catalogue on publication.

Background: Predicting response to treatment and risk of long-term disability in multiple sclerosis (MS) is challenging. In other disease areas, combining genetic risk variants enabled detection of relevant clinical endophenotypes associated with important outcomes, but this has never been applied to MS. Methods: We applied unsupervised hierarchical clustering to genomic risk scores of two cohorts (the prospective cohort study of 1455 Welsh MS patients was used as the discovery cohort and replication was performed in a multi-centre post-mortem Netherlands Brain Bank cohort of 272 MS patients) to predict relevant disease outcomes using survival analysis for time to disability milestones (expanded disability status scale, EDSS), and ANOVA to compare linear clinical outcomes. Results: Three genomic clusters were identified, in each cluster patients had similar genetic profiles. Baseline demographic characteristics were similar between clusters. Welsh patients in cluster 1 attained key disability milestones later, reaching EDSS6, 6 years later (p=0.003) and EDSS8, 13 years later (p=0.02) than those in clusters 2 and 3. Time to EDSS6 was also significantly longer for patients in cluster 1 versus cluster 2 in the NBB-MS cohort (6 years, p=0.04). Genomic clustering is an independent predictor for disease progression compared with well-validated risk factors (Hazard ratio for time to EDSS6 1.3-2.0, all p<0.05). Welsh patients in cluster 2 and 3 also had a significantly greater annual increase in T2 lesion load on serial MR imaging (p=0.04). In cluster 2, patients who had received MS disease modifying treatments (DMT) had a longer time to EDSS6 (p=0.003) compared to those that had received no DMTs, whereas no differences were observed in either cluster 1 or cluster 3. In the NBB-MS cohort, we also observed differences in symptomatology, including earlier development of swallowing problems (p=0.02) or muscle spasticity (p= 0.0008) in cluster 2 patients. Conclusion: This study demonstrates that unsupervised genetic clustering has utility to detect clinically relevant endophenotypes of MS, with genetic cluster 2 patients having a more severe phenotype and higher risk of disability. Moreover, genetic stratification is able to predict response to DMTs and could potentially be used for precision medicine in MS management. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: 1455 patients were recruited from the South Wales MS Registry established in 1985. This study was approved by the Wales Research Ethics Committee. The replication cohort consited of Caucasian donors with post-mortem confi rmed MS (n=272) from the Netherlands Brain Bank (NBB). The study was approved by the Free University Medical Center Medical Ethics Committee. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors and upon completion of a signed data transfer agreement.

A multiple sclerosis (MS) prodrome has recently been described and is characterised by increased rates of healthcare utilisation and an excess frequency of fatigue, bladder problems, sensory symptoms and pain, in the years leading up to clinical onset of disease. This important observation may have several potential applications including in the identification of risk factors for disease, the potential to delay or prevent disease onset and early opportunities to alter disease course. It may also offer possibilities for the use of risk stratification algorithms and effective population screening. If standardised, clearly defined and disease specific, an MS prodrome is also likely to have a profound influence on research and clinical trials directed at the earliest stages of disease. In order to achieve these goals, it is essential to consider experience already gleaned from other disorders. More specifically, in some chronic neurological disorders the understanding of disease pro-drome is now well advanced and has been successfully applied. However, understanding of the MS prodrome remains at an early stage with key questions including the length of the prodrome, symptom specificity and potential benefits of early intervention as yet unanswered. In this review we will explore the evidence available to date and suggest future research strategies to address unanswered questions. In addition, whilst current understanding of the MS prodrome is not yet sufficient to justify changes in public health policy or MS management, we will consider the practical utility and future application of the MS prodrome in a wider health care setting.

Objectives To model multiple sclerosis (MS) disease progression and compare disease trajectories by sex, age of onset, and year of diagnosis. Study Design and settings Longitudinal EDSS scores were collected since 1985 for relapse-onset MS patients at MS clinics in South Wales and modelled using a multilevel model (MLM). The MLM adjusted for baseline covariates (sex, age of onset, year of diagnosis, and disease modifying treatments (DMTs)), and included interactions between baseline covariates and time variables. Results The optimal model was truncated at 30 years after disease onset and excluded EDSS recorded within 3 months of relapse. As expected, older age of onset was associated with faster disease progression at 15 years (effect size (ES): 0.75; CI: 0.63, 0.86; P: <0.001) and female sex progressed more slowly at 15 years (ES: -0.43; CI: -0.68, -0.18; P: <0.001). Patients diagnosed more recently (defined as 2007-2011 and >2011) progressed more slowly than those diagnosed historically (<2006); (ES: -0.46; CI: -0.75, -0.16; P: 0.006) and (ES: -0.95; CI: -1.20, -0.70; P: <0.001), respectively. Conclusion We present a novel model of MS outcomes, accounting for the nonlinear trajectory of MS and effects of baseline covariates, validating well-known risk factors (sex and age of onset) associated with disease progression. Also, patients diagnosed more recently progressed more slowly than those diagnosed historically.

BACKGROUND AND PURPOSE:Treatment persistence is the continuation of therapy over time. It reflects a combination of treatment efficacy and tolerability. We aimed to describe real-world rates of persistence on disease-modifying therapies (DMTs) for people with multiple sclerosis (pwMS) and reasons for DMT discontinuation. METHODS:Treatment data on 4366 consecutive people with relapse-onset multiple sclerosis (MS) were pooled from 13 UK specialist centres during 2021. Inclusion criteria were exposure to at least one MS DMT and a complete history of DMT prescribing. PwMS in blinded clinical trials were excluded. Data collected included sex, age at MS onset, age at DMT initiation, DMT treatment dates, and reasons for stopping or switching DMT. For pwMS who had received immune reconstituting therapies (cladribine/alemtuzumab), discontinuation date was defined as starting an alternative DMT. Kaplan-Meier survival analyses were used to express DMT persistence. RESULTS:In 6997 treatment events (1.6 per person with MS), median time spent on any single maintenance DMT was 4.3 years (95% confidence interval = 4.1-4.5 years). The commonest overall reasons for DMT discontinuation were adverse events (35.0%) and lack of efficacy (30.3%). After 10 years, 20% of people treated with alemtuzumab had received another subsequent DMT, compared to 82% of people treated with interferon or glatiramer acetate. CONCLUSIONS:Immune reconstituting DMTs may have the highest potential to offer a single treatment for relapsing MS. Comparative data on DMT persistence and reasons for discontinuation are valuable to inform treatment decisions and in personalizing treatment in MS.

BackgroundAnnualized relapse rate (ARR) is used as an outcome measure in multiple sclerosis (MS) clinical trials. Previous studies demonstrated that ARR has reduced in placebo groups between 1990 and 2012. This study aimed to estimate real-world ARRs from contemporary MS clinics in the UK, in order to improve the feasibility estimations for clinical trials and facilitate MS service planning.MethodsA multicentre observational, retrospective study of patients with MS from 5 tertiary neuroscience centres in the UK. We included all adult patients with a diagnosis of MS that had a relapse between 01/04/2020 and 30/06/2020.ResultsOne hundred thirteen out of 8783 patients had a relapse during the 3-month study period. Seventy-nine percent of the patients with a relapse were female, the mean age was 39 years, and the median disease duration was 4.5 years; 36% of the patients that had a relapse were on disease-modifying treatment. The ARR from all study sites was estimated at 0.05. The ARR for relapsing remitting MS (RRMS) was estimated at 0.08, while the ARR for secondary progressive MS (SPMS) was 0.01.ConclusionsWe report a lower ARR compared to previously reported rates in MS.

Background: People with multiple sclerosis (pwMS) treated with certain disease-modifying therapies (DMTs) have attenuated IgG response following COVID-19 vaccination; however, the clinical consequences remain unclear. Objective: To report COVID-19 rates in pwMS according to vaccine serology. Methods: PwMS with available (1) serology 2–12 weeks following COVID-19 vaccine 2 and/or vaccine 3 and (2) clinical data on COVID-19 infection/hospitalisation were included. Logistic regression was performed to examine whether seroconversion following vaccination predicted risk of subsequent COVID-19 infection after adjusting for potential confounders. Rates of severe COVID-19 (requiring hospitalisation) were also calculated. Results: A total of 647 pwMS were included (mean age 48 years, 500 (77%) female, median Expanded Disability Status Scale (EDSS) 3.5% and 524 (81%) exposed to DMT at the time of vaccine 1). Overall, 472 out of 588 (73%) were seropositive after vaccines 1 and 2 and 222 out of 305 (73%) after vaccine 3. Seronegative status after vaccine 2 was associated with significantly higher odds of subsequent COVID-19 infection (odds ratio (OR): 2.35, 95% confidence interval (CI): 1.34–4.12, p = 0.0029), whereas seronegative status after vaccine 3 was not (OR: 1.05, 95% CI: 0.57–1.91). Five people (0.8%) experienced severe COVID-19, all of whom were seronegative after most recent vaccination. Conclusion: Attenuated humoral response to initial COVID-19 vaccination predicts increased risk of COVID-19 in pwMS, but overall low rates of severe COVID-19 were seen.

OBJECTIVE:Currently, 233 genetic loci are known to be associated with susceptibility to multiple sclerosis (MS). Two independent pivotal severity genome-wide association studies recently found the first genome-wide significant single-nucleotide variant (SNV; rs10191329A ) and several other suggestive loci associated with overall disability outcomes. It is now important to understand if these findings can influence individual patient management. METHODS:We assessed whether these progression SNVs are associated with detailed clinical phenotypes in a well-characterized prospective cohort of 1,455 MS patients. We used logistic regression, survival analysis, and propensity score matching to predict relevant long-term clinical outcomes. RESULTS:We were unable to detect any association between rs10191329A and a range of clinically relevant outcomes (eg, time to Expanded Disability Status Scale milestones, age-related MS severity score, anatomical localization at onset or during subsequent relapses, annualized relapse rate). In addition, an extremes of outcome case-control analysis using a propensity score matching for genotype detected no association between disease severity and rs10191329A . However, we were able to replicate the association of two suggestive SNVs (rs7289446G and rs868824C ) with the development of fixed disability, albeit with modest effect sizes, and the association of HLA-DRB1*1501 with age at onset. INTERPRETATION:Identification of rs10191329A and other suggestive SNVs are of considerable importance in understanding pathophysiological processes associated with MS severity. However, it is unlikely that individual genotyping can currently be used in a clinical setting to guide disease management. This study shows the importance of independent replication of genome-wide association studies associated with disease progression in neurodegenerative disorders. ANN NEUROL 2024;95:459-470.

RationaleRelapses remain a key outcome measure in multiple sclerosis (MS), are targeted by disease- modifying therapies (DMT), and guide treatment. As DMT prescribing continues to increase, it remains unclear what effect this has had on relapse frequency and phenotype over time.AimTo examine relapse patterns using 20 years of longitudinal data and correlate with DMT use.MethodProspectively collected relapse data from the South Wales MS registry was analysed from 2000- 2020. Relapse rate and phenotype according to DMT use were analysed across time epochs.ResultsOf 6,165 relapses in 1,460 patients; 76% were in females and 15% occurred on DMT. Annualised relapse rates (ARR) showed a decreasing trend from 2000 (ARR=0.23) to 2020 (ARR=0.08). Using cross- sectional analysis of data from years 2005 versus 2020, rates of DMT exposure increased from 6% to 31%, and ARR was significantly associated with DMT use (p<0.01). Polysymptomatic relapses and relapses associated with full recovery, were both more likely to occur in people on DMT.ConclusionIncreasing use of DMTs was associated with decreasing ARR in this population-based MS cohort over 20 years. We also demonstrate that relapses occurring on DMTs appear to be associated with more favourable recovery.

BACKGROUND:People with MS treated with anti-CD20 therapies and fingolimod often have attenuated responses to initial COVID-19 vaccination. However, uncertainties remain about the benefit of a 3rd (booster) COVID-19 vaccine in this group. METHODS:PwMS without a detectable IgG response following COVID-19 vaccines 1&2 were invited to participate. Participants provided a dried blood spot +/- venous blood sample 2-12 weeks following COVID-19 vaccine 3. Humoral and T cell responses to SARS-CoV-2 spike protein and nucleocapsid antigen were measured. RESULTS:Of 81 participants, 79 provided a dried blood spot sample, of whom 38 also provided a whole blood sample; 2 provided only whole blood. Anti-SARS-CoV-2-spike IgG seroconversion post-COVID-19 vaccine 3 occurred in 26/79 (33%) participants; 26/40 (65%) had positive T-cell responses. Overall, 31/40 (78%) demonstrated either humoral or cellular immune response post-COVID-19 vaccine 3. There was no association between laboratory evidence of prior COVID-19 and seroconversion following vaccine 3. CONCLUSIONS:Approximately one third of pwMS who were seronegative after initial COVID-19 vaccination seroconverted after booster (third) vaccination, supporting the use of boosters in this group. Almost 8 out of 10 had a measurable immune response following 3rd COVID-19 vaccine.

BackgroundAlthough most people with relapsing onset multiple sclerosis (R-MS) eventually transition to secondary progressive multiple sclerosis (SPMS), little is known about disability progression in SPMS.MethodsAll R-MS patients in the Cardiff MS registry were included. Cox proportional hazards regression was used to examine a) hazard of converting to SPMS and b) hazard of attaining EDSS 6.0 and 8.0 in SPMS.Results1611 R-MS patients were included. Older age at MS onset (hazard ratio [HR] 1.02, 95%CI 1.01–1.03), male sex (HR 1.71, 95%CI 1.41–2.08), and residual disability after onset (HR 1.38, 95%CI 1.11–1.71) were asso- ciated with increased hazard of SPMS. Male sex (EDSS 6.0 HR 1.41 [1.04–1.90], EDSS 8.0 HR 1.75 [1.14–2.69]) and higher EDSS at SPMS onset (EDSS 6.0 HR 1.31 [1.17–1.46]; EDSS 8.0 HR 1.38 [1.19–1.61]) were associated with increased hazard of reaching disability milestones, while older age at SPMS was associated with a lower hazard of progression (EDSS 6.0 HR 0.94 [0.92–0.96]; EDSS 8.0: HR 0.92 [0.90–0.95]).ConclusionsDifferent factors are associated with hazard of SPMS compared to hazard of disability progres- sion after SPMS onset. These data may be used to plan services, and provide a baseline for comparison for future interventional studies and has relevance for new treatments for SPMSRobertsonNP@cardiff.ac.uk

BackgroundReal-world, long-term adherence and effectiveness data is vital to complement our under- standing of therapies, which is often based on short-term clinical trials. Here we explored disease modifying therapy (DMT) durability in a UK-wide cohort of people with Multiple Sclerosis (pwMS).MethodsIn this cohort study, which included 4,415 pwMS from 10 UK MS centres, 6,960 DMT prescrip- tions were included in the analysis (mean 1.7, range 1-6 per patient). Prescriptions without accurate start dates were excluded (n=90). Kaplan-Meier survival analysis was used to model DMT persistence (days from prescription start to stop), which was used to calculate 2, 5 and 10-year durability (% of prescrip- tions continuing).ResultsTwo-year durability was highest for immune reconstitution therapies cladribine (98%), ocrelizumab (96%), and alemtuzumab (95%). Oral therapies fingolimod (74%) and dimethyl fumarate (73%), and intravenous natalizumab (78%) shared similar durability. Injectable therapies glatiramer acetate (51%) and interferon (55%), had lowest durability. Potential confounding factors include variable date of DMT licensing, change in DMT algorithms over time and increasing DMT options.ConclusionThis multi-centre study has revealed highly variable durability between DMTs over time, which may impact real-world effectiveness. These results may inform DMT clinical decision-making and improve outcomes for pwMS.

The median survival time of newly-diagnosed MS patients without severe disabilities is approximately 30-35 years. The prognosis after the onset of severe disability has not been reported. Based on Harding et al.'s 2018 study of the Southeast Wales MS registry, we calculated life expectancies according to the Expanded Disability Status Scale (EDSS). Upon loss of independent ambulation (EDSS 6-6.5; mean age 51.2) life expectancy was 13.3 additional years. At EDSS 9-9.5 (mean age 70.8) life expectancy was 1.1 additional years. These figures provide an empirical basis for discussions of advanced MS care planning.

PURPOSE:This study assesses investigations, referrals and admissions in patients presenting to the Emergency Department (ED) with seizures, and the effect of the COVID-19 pandemic on such management. Outcomes in patients with learning disabilities, active significant mental health concerns, and from the most socioeconomically deprived areas were compared to those of the general cohort.METHODS:Investigations, referrals and admissions were recorded for 120 patients across two cohorts; pre-pandemic (September 2019) and during the pandemic (December 2020). Retrospective review of individual patient electronic health care records was used for data collection.RESULTS:There was a decrease in patient numbers from 2019 to 2020. A greater proportion of patients presented with organic cause seizures and fewer presented with non-epileptic attacks. Frequent use of CT heads (45%) is likely to represent improper use of limited resources. There were low referral rates, both to acute neurology (28%) and to the adult epilepsy team (32%). Patients with active significant mental health concerns were significantly less likely to be referred to neurology or admitted.CONCLUSIONS:Despite a greater proportion of admissions during the Covid-19 pandemic, referrals to acute neurology and the epilepsy team remained low. Failure to refer prevents the most vulnerable seizure patients from receiving appropriate support, as seen in patients with active significant mental health concerns. Neurology staff were unaware of a significant number of patients presenting with seizures, which is of concern in an already over-stretched department. This offers an opportunity to improve care for people with epilepsy.