ENTIMOS: Decision Support Tool Highlights Potential Impact of Non-intravenous Therapies for Multiple Sclerosis on Patient Care via Clinical Scenario Simulation.

INTRODUCTION: Administration of intravenous (IV), high-efficacy treatments (HETs) for the treatment of multiple sclerosis (MS) poses a high resourcing and planning burden on infusion centres, resulting in treatment delays that may increase the risk of breakthrough disease activity. Simulation tools can be used to systematically analyse capacity scenarios and identify and better understand constraints, therefore enabling decision-makers to optimise patient care. We have previously applied ENTIMOS, a discrete event simulation model, to assess scenarios of patient flow and care delivery using real-life data inputs from the neurology infusion suite at Charing Cross Hospital London. The model predicted that, given current capacity and projected demand, patients would experience high-risk treatment delays within 30 months. OBJECTIVE: This study aimed to address key healthcare challenges for MS patient care management as seen from a neurologist's perspective. We used ENTIMOS to predict the impact of several distinct and clinically plausible scenarios on patient waiting times at the same MS infusion suite and to quantify mitigation strategies needed to assure continuity of care. METHODS: We used real-world experience of an expert neurologist to identify five clinical scenarios: (1) switching patients to a subcutaneous (SC) MS treatment of the same therapeutic agent, in the same hospital setting; (2) extending opening times to the weekend; (3) reducing the number of infusion chairs (to simulate social distancing measures applied during the coronavirus disease 2019 [COVID-19] pandemic); (4) increasing demand for infusions; and (5) increasing the scheduling approval time. Patient waiting time for next due infusion and time to high-risk treatment delays (≥ 30 days) were the main analysed model outputs. Previously published base case results were used as reference. All hypothetical scenarios were run over a 3-year horizon (with the exception of scenario 1, which was run over a 3- and 5-year horizon). Strategies to mitigate treatment delays were analysed and discussed. RESULTS: Switching 50% of patients to SC treatment of the same therapeutic agent administered in hospital postponed the predicted high-risk treatment delays to shortly beyond the 3-year simulation timeframe (month 38). Weekend opening reduced waiting times from 20 days to 4 days and prevented treatment delays, however, at elevated labour costs. Reducing the infusion chairs increased waiting time to 53 days on average and 86 days at the end of the simulation, leading to high-risk treatment delays within 6 months. An increased demand for infusions increased waiting time to 26 days on average and 47 days at the end of the simulation, leading to high-risk treatment delays within 22 months. Prolonged scheduling approval time did not reduce the waiting time, nor postpone the high-risk treatment delays. CONCLUSION: Decision makers need transparency on capacity constraints to better plan resourcing at infusion suites and MS treatments. Our results showed that various mitigation measures, such as increasing capacity by additional infusion chairs per year and transferring patients to other infusion suites, may help prevent treatment delays. Switching patients from IV to an SC version of the same therapeutic agent reduced the waiting time moderately and postponed high-risk treatment delays. It was insufficient to prevent high-risk treatment delays in the long term.

Patients with multiple sclerosis and other neurological conditions receive therapies that are often given intravenously. Due to increasing demand for intravenous infusions, specialist infusion centres face challenges with scheduling and insufficient personnel numbers, which contributes to the increasing costs of care. Computer-based decision support tools can help hospital administrators predict demand for infusions, plan resources and estimate overall costs. We used a computer-based decision support tool, "ENTIMOS", to predict demand at a multiple sclerosis infusion suite in London and to simulate possible solutions. The tool predicted that over the next 3 years patients would face increasing waiting time for their treatment and many would experience high-risk treatment delays of 30 days or longer. We tested several different, realistic scenarios where treatment demand was exacerbated and alleviated: we tested what would happen if patients were discharged from the infusion suite (decreasing demand), if the centre opened for 7 days instead of 5 days a week (increasing capacity), if social distancing measures were in place (decreasing capacity), and other scenarios. We found that high-risk treatment delays could be avoided if the centre adds infusion chairs to the suite or switches patients out of the infusion suite (e.g. to a treatment administered at home). The most effective long-term solution would be to have treatment options for multiple sclerosis that could be taken by patients at home. These treatments would be required to have the same benefits and the same or lower risk as the intravenous infusion therapies that are used today. It would help reduce labour costs of healthcare and may enable patients with multiple sclerosis to manage their disease at home.

A systematic review and meta-analysis of Dietary Inflammatory Index and the likelihood of multiple sclerosis/ demyelinating autoimmune disease.

Diet and inflammation may contribute to the development of multiple sclerosis (MS). The aim of this systematic review and meta-analysis was to assess the association between proinflammatory diet, as estimated by the Dietary Inflammatory Index (DII®), and the likelihood of developing MS or other demyelinating autoimmune diseases. A systematic search was performed of search engines and databases (PubMed, ISI Web of Sciences, Scopus, and Embase) to identify relevant studies before 10th June 2023. The search identified 182 potential studies, from which 39 full-text articles were screened for relevance. Five articles with case-control design (n = 4,322, intervention group: 1714; control group: 2608) met the study inclusion criteria. The exposure variable was DII, with studies using two distinct models: quartile-based comparisons of DII and assessment of continuous DII. The meta-analysis of high versus low quartiles of DII with four effect sizes showed a significant association with MS/demyelinating autoimmune disease likelihood, with an odds ratio (OR) of 3.26 (95% confidence interval (CI) 1.16, 9.10). The meta-analysis of four studies with DII fit as a continuous variable showed a 31% increased likelihood of MS per unit increment; which was not statistically significant at the nominal alpha equals 0.05 (OR 1.31; 95% CI 0.95, 1.81). In conclusion, this systematic review and meta-analysis provides evidence of a positive association between higher DII scores with the likelihood of developing MS, highlighting that diet-induced inflammation could play a role in MS or other demyelinating autoimmune diseases risk.

Long-term colchicine for the prevention of vascular recurrent events in non-cardioembolic stroke (CONVINCE): a randomised controlled trial.

BACKGROUND: Anti-inflammatory therapy with long-term colchicine prevented vascular recurrence in coronary disease. Unlike coronary disease, which is typically caused by atherosclerosis, ischaemic stroke is caused by diverse mechanisms including atherosclerosis and small vessel disease or is frequently due to an unknown cause. We aimed to investigate the hypothesis that long-term colchicine would reduce recurrent events after ischaemic stroke. METHODS: We did a randomised, parallel-group, open-label, blinded endpoint assessed trial comparing long-term colchicine (0·5 mg orally per day) plus guideline-based usual care with usual care only. Hospital-based patients with non-severe, non-cardioembolic ischaemic stroke or high-risk transient ischaemic attack were eligible. The primary endpoint was a composite of first fatal or non-fatal recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation (defined as an admission to an inpatient unit or a visit to an emergency department that resulted in at least a 24 h stay [or a change in calendar date if the hospital admission or discharge times were not available]) for unstable angina. The p value for significance was 0·048 to adjust for two prespecified interim analyses conducted by the data monitoring committee, for which the steering committee and trial investigators remained blinded. The trial was registered at ClinicalTrials.gov (NCT02898610) and is completed. FINDINGS: 3154 patients were randomly assigned between Dec 19, 2016, and Nov 21, 2022, with the last follow-up on Jan 31, 2024. The trial finished before the anticipated number of outcomes was accrued (367 outcomes planned) due to budget constraints attributable to the COVID-19 pandemic. Ten patients withdrew consent for analysis of their data, leaving 3144 patients in the intention-to-treat analysis: 1569 (colchicine and usual care) and 1575 (usual care alone). A primary endpoint occurred in 338 patients, 153 (9·8%) of 1569 patients allocated to colchicine and usual care and 185 (11·7%) of 1575 patients allocated to usual care alone (incidence rates 3·32 vs 3·92 per 100 person-years, hazard ratio 0·84; 95% CI 0·68-1·05, p=0·12). Although no between-group difference in C-reactive protein (CRP) was observed at baseline, patients treated with colchicine had lower CRP at 28 days and at 1, 2, and 3 years (p<0·05 for all timepoints). The rates of serious adverse events were similar in both groups. INTERPRETATION: Although no statistically significant benefit was observed on the primary intention-to-treat analysis, the findings provide new evidence supporting the rationale for anti-inflammatory therapy in further randomised trials. FUNDING: Health Research Board Ireland, Deutsche Forschungsgemeinschaft (German Research Foundation), and Fonds Wetenschappelijk Onderzoek Vlaanderen (Research Foundation Flanders), Belgium.

Carotid atherosclerotic plaque microcalcification is independently associated with recurrent neurovascular events: a pilot study.

BACKGROUND: Microcalcification and macrocalcification are critical processes in atherosclerotic plaque progression, though how these processes relate to the risk of stroke recurrence in symptomatic carotid atherosclerosis is poorly understood. METHODS: We performed a post-hoc analysis of data from the ICARUSS study, where individuals with acute ischemic stroke originating from ipsilateral carotid stenosis of ≥50% underwent 18F-sodium fluoride-positron emission tomography (NaF-PET) to measure microcalcification. Tracer uptake was quantified using maximum tissue-to-background ratio (TBRmax). Macrocalcification was measured on computed tomography (CT) using Agatston scoring. Patients were followed up for six months for recurrent ipsilateral neurovascular events. RESULTS: Five (27.8%) of 18 individuals had a recurrent ischemic stroke or transient ischemic attack. Ipsilateral carotid plaque NaF uptake at baseline was higher in those with recurrent events compared to those without, and this association remained after adjustment for other vascular risk factors (OR 1.24, 1.03-1.50). Macrocalcification score in the symptomatic artery was also significantly independently associated with ipsilateral recurrence, but the effect size was relatively smaller (OR 1.12, 1.06-1.17 for each 100 unit increase). CONCLUSIONS: Our findings indicate that microcalcification in symptomatic carotid plaques is independently associated with ipsilateral ischemic stroke recurrence. Furthermore, differences in the extent of active microcalcification in macrocalcified plaques may help explain variation in the relationship between calcified carotid plaques and stroke recurrence reported in the literature. Our pilot study indicates that evaluation of carotid artery microcalcification using NaF-PET may be a useful method for risk-stratification of carotid atherosclerosis, though our findings require confirmation in larger cohorts.

Algorithmic approach to finding people with multiple sclerosis using routine healthcare data in Wales.

BACKGROUND: Identification of multiple sclerosis (MS) cases in routine healthcare data repositories remains challenging. MS can have a protracted diagnostic process and is rarely identified as a primary reason for admission to the hospital. Difficulties in identification are compounded in systems that do not include insurance or payer information concerning drug treatments or non-notifiable disease. AIM: To develop an algorithm to reliably identify MS cases within a national health data bank. METHOD: Retrospective analysis of the Secure Anonymised Information Linkage (SAIL) databank was used to identify MS cases using a novel algorithm. Sensitivity and specificity were tested using two existing independent MS datasets, one clinically validated and population-based and a second from a self-registered MS national registry. RESULTS: From 4 757 428 records, the algorithm identified 6194 living cases of MS within Wales on 31 December 2020 (prevalence 221.65 (95% CI 216.17 to 227.24) per 100 000). Case-finding sensitivity and specificity were 96.8% and 99.9% for the clinically validated population-based cohort and sensitivity was 96.7% for the self-declared registry population. DISCUSSION: The algorithm successfully identified MS cases within the SAIL databank with high sensitivity and specificity, verified by two independent populations and has important utility in large-scale epidemiological studies of MS.

Prevalence, treatment and correlates of depression in multiple sclerosis.

BACKGROUND: The prevalence of depression in Multiple Sclerosis (MS) is often assessed by administering patient reported outcome measures (PROMs) examining depressive symptomatology to population cohorts; a recent review summarised 12 such studies, eight of which used the Hospital Anxiety and Depression Scale-Depression (HADS-D). In clinical practice, depression is diagnosed by an individual structured clinical interview; diagnosis often leads to treatment options including antidepressant medication. It follows that an MS population will include those whose current depressive symptoms meet threshold for depression diagnosis, plus those who previously met diagnostic criteria for depression and have been treated such that depressive symptoms have improved below that threshold. We examined a large MS population to establish a multi-attribute estimate of depression, taking into account probable depression on HADS-D, as well as anti-depressant medication use and co-morbidity data reporting current treatment for depression. We then studied associations with demographic and health status measures and the trajectories of depressive symptoms over time. METHODS: Participants were recruited into the UK-wide Trajectories of Outcome in Neurological Conditions-MS (TONiC-MS) study, with demographic and disease data from clinical records, PROMs collected at intervals of at least 9 months, as well as co-morbidities and medication. Interval level conversions of PROM data followed Rasch analysis. Logistic regression examined associations of demographic characteristics and symptoms with depression. Finally, a group-based trajectory model was applied to those with depression. RESULTS: Baseline data in 5633 participants showed the prevalence of depression to be 25.3 % (CI: 24.2-26.5). There were significant differences in prevalence by MS subtype: relapsing 23.2 % (CI: 21.8- 24.5), primary progressive 25.8 % (CI: 22.5-29.3), secondary progressive 31.5 % (CI: 29.0-34.0); disability: EDSS 0-4 19.2 % (CI: 17.8-20.6), EDSS ≥4.5 31.9 % (CI: 30.2-33.6); and age: 42-57 years 27.7 % (CI: 26.0-29.3), above or below this range 23.1 % (CI: 21.6-24.7). Fatigue, disability, self-efficacy and self esteem correlated with depression with a large effect size (>0.8) whereas sleep, spasticity pain, vision and bladder had an effect size >0.5. The logistic regression model (N = 4938) correctly classified 80 % with 93 % specificity: risk of depression was increased with disability, fatigue, anxiety, more comorbidities or current smoking. Higher self-efficacy or self esteem and marriage reduced depression. Trajectory analysis of depressive symptoms over 40 months in those with depression (N = 1096) showed three groups: 19.1 % with low symptoms, 49.2 % with greater symptoms between the threshold of possible and probable depression, and 31.7 % with high depressive symptoms. 29.9 % (CI: 27.6-32.3) of depressed subjects were untreated, conversely of those treated, 26.1 % still had a symptom level consistent with a probable case (CI: 23.5-28.9). CONCLUSION: A multi-attribute estimate of depression in MS is essential because using only screening questionnaires, diagnoses or antidepressant medication all under-estimate the true prevalence. Depression affects 25.3 % of those with MS, almost half of those with depression were either untreated or still had symptoms indicating probable depression despite treatment. Services for depression in MS must be pro-active and flexible, recognising the heterogeneity of outcomes and reaching out to those with ongoing symptoms.

Management of carotid atherosclerosis in stroke.

Internal carotid artery atherosclerosis is a major risk factor for stroke, accounting for 15-20% of ischaemic strokes. Revascularisation procedures-either carotid endarterectomy or carotid artery stenting-can reduce the risk of stroke for those with significant (>50%) luminal stenosis but particularly for those with more severe (70-99%) stenosis. However, advances in medical pharmacotherapy have implications for the relative benefit from surgery for symptomatic carotid atherosclerosis, as well as our approach to asymptomatic disease. This review considers the evidence underpinning the current medical and surgical management of symptomatic carotid atherosclerosis, the importance of factors beyond the degree of luminal stenosis, and developments in therapeutic strategies. We also discuss the importance of non-stenotic but high-risk carotid atherosclerotic plaques on the cause of stroke, and their implications for clinical practice.

Optic chiasm involvement in multiple sclerosis, aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein-associated disease.

BACKGROUND: Optic neuritis (ON) is a common feature of inflammatory demyelinating diseases (IDDs) such as multiple sclerosis (MS), aquaporin 4-antibody neuromyelitis optica spectrum disorder (AQP4 + NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). However, the involvement of the optic chiasm (OC) in IDD has not been fully investigated. AIMS: To examine OC differences in non-acute IDD patients with (ON+) and without ON (ON-) using magnetisation transfer ratio (MTR), to compare differences between MS, AQP4 + NMOSD and MOGAD and understand their associations with other neuro-ophthalmological markers. METHODS: Twenty-eight relapsing-remitting multiple sclerosis (RRMS), 24 AQP4 + NMOSD, 28 MOGAD patients and 32 healthy controls (HCs) underwent clinical evaluation, MRI and optical coherence tomography (OCT) scan. Multivariable linear regression models were applied. RESULTS: ON + IDD patients showed lower OC MTR than HCs (28.87 ± 4.58 vs 31.65 ± 4.93; p = 0.004). When compared with HCs, lower OC MTR was found in ON + AQP4 + NMOSD (28.55 ± 4.18 vs 31.65 ± 4.93; p = 0.020) and MOGAD (28.73 ± 4.99 vs 31.65 ± 4.93; p = 0.007) and in ON- AQP4 + NMOSD (28.37 ± 7.27 vs 31.65 ± 4.93; p = 0.035). ON+ RRMS had lower MTR than ON- RRMS (28.87 ± 4.58 vs 30.99 ± 4.76; p = 0.038). Lower OC MTR was associated with higher number of ON (regression coefficient (RC) = -1.15, 95% confidence interval (CI) = -1.819 to -0.490, p = 0.001), worse visual acuity (RC = -0.026, 95% CI = -0.041 to -0.011, p = 0.001) and lower peripapillary retinal nerve fibre layer (pRNFL) thickness (RC = 1.129, 95% CI = 0.199 to 2.059, p = 0.018) when considering the whole IDD group. CONCLUSION: OC microstructural damage indicates prior ON in IDD and is linked to reduced vision and thinner pRNFL.

Soluble CD27 is an intrathecal biomarker of T-cell-mediated lesion activity in multiple sclerosis.

OBJECTIVE: Soluble CD27 is a promising cerebrospinal fluid inflammatory biomarker in multiple sclerosis. In this study, we investigate relevant immune and neuro-pathological features of soluble CD27 in multiple sclerosis. METHODS: Protein levels of soluble CD27 were correlated to inflammatory cell subpopulations and inflammatory cytokines and chemokines detected in cerebrospinal fluid of 137 patients with multiple sclerosis and 47 patients with inflammatory and non-inflammatory neurological disease from three independent cohorts. Production of soluble CD27 was investigated in cell cultures of activated T and B cells and CD27-knockout T cells. In a study including matched cerebrospinal fluid and post-mortem brain tissues of patients with multiple sclerosis and control cases, levels of soluble CD27 were correlated with perivascular and meningeal infiltrates and with neuropathological features. RESULTS: We demonstrate that soluble CD27 favours the differentiation of interferon-γ-producing T cells and is released through a secretory mechanism activated by TCR engagement and regulated by neutral sphingomyelinase. We also show that the levels of soluble CD27 correlate with the representation of inflammatory T cell subsets in the CSF of patients with relapsing-remitting multiple sclerosis and with the magnitude of perivascular and meningeal CD27 + CD4 + and CD8 + T cell infiltrates in post-mortem central nervous system tissue, defining a subgroup of patients with extensive active inflammatory lesions. INTERPRETATION: Our results demonstrate that soluble CD27 is a biomarker of disease activity, potentially informative for personalized treatment and monitoring of treatment outcomes.

Determinants and Biomarkers of Progression Independent of Relapses in Multiple Sclerosis.

Clinical, pathological, and imaging evidence in multiple sclerosis (MS) suggests that a smoldering inflammatory activity is present from the earliest stages of the disease and underlies the progression of disability, which proceeds relentlessly and independently of clinical and radiological relapses (PIRA). The complex system of pathological events driving "chronic" worsening is likely linked with the early accumulation of compartmentalized inflammation within the central nervous system as well as insufficient repair phenomena and mitochondrial failure. These mechanisms are partially lesion-independent and differ from those causing clinical relapses and the formation of new focal demyelinating lesions; they lead to neuroaxonal dysfunction and death, myelin loss, glia alterations, and finally, a neuronal network dysfunction outweighing central nervous system (CNS) compensatory mechanisms. This review aims to provide an overview of the state of the art of neuropathological, immunological, and imaging knowledge about the mechanisms underlying the smoldering disease activity, focusing on possible early biomarkers and their translation into clinical practice. ANN NEUROL 2024;96:1-20.

Disease-modifying therapy initiation patterns in multiple sclerosis in three large MS populations.

Background: Treatment guidelines recommend early disease-modifying therapy (DMT) initiation after diagnosis of multiple sclerosis (MS). Multinational comparative studies that assess time to DMT initiation in MS may allow detection of barriers inherent to healthcare systems to explain potential adverse systematic delays in commencing DMTs. Objectives: To investigate and compare the time to first DMT and its association with sociodemographic and clinical variables after MS diagnosis in three large MS registries. Design: This observational study was conducted using data from the German MS Registry (GMSR), the North American Research Committee on MS Registry (NARCOMS, US data only), and the United Kingdom MS Registry (UKMSR, both self- and clinician-reported). Methods: Data from relapsing people with MS (PwMS), with a diagnosis of MS between 2014 and 2019, and available DMT and disability status were pooled using a meta-analytic approach. Results: A total of 5395 PwMS were included in the analysis (GMSR: n = 2658; NARCOMS: n = 447; UKMSR: n = 2290). Kaplan-Meier estimates for the time to first DMT [median months (95% CI)] were 2.0 (1.9-2.0), 3.0 (2-4), and 9.0 (7.7-10.6) for GMSR, NARCOMS, and UKMSR, respectively. Pooled multivariable Cox regression demonstrated shorter time to first DMT for PwMS diagnosed after 2017 [1.65 (1.42-1.92), p < 0.01], and longer time to DMT when a higher-efficacy DMT was selected (0.69 (0.54-0.90), p < 0.0001]. Conclusion: Time to DMT initiation differs across the populations studied, indicating that barriers may exist in early access to DMT, particularly in the United Kingdom. However, a consistent decrease in time to DMT initiation was noted since 2017 across all registries. Further studies are warranted comparing the effects of time to DMT and time to higher-efficacy DMT on long-term outcome.

Efficacy and safety of autologous haematopoietic stem cell transplantation versus alemtuzumab, ocrelizumab, ofatumumab or cladribine in relapsing remitting multiple sclerosis (StarMS): protocol for a randomised controlled trial.

INTRODUCTION: Autologous haematopoietic stem cell transplantation (aHSCT) is increasingly used as treatment for patients with active multiple sclerosis (MS), typically after failure of disease-modifying therapies (DMTs). A recent phase III trial, 'Multiple Sclerosis International Stem Cell Transplant, MIST', showed that aHSCT resulted in prolonged time to disability progression compared with DMTs in patients with relapsing remitting MS (RRMS). However, the MIST trial did not include many of the current high-efficacy DMTs (alemtuzumab, ocrelizumab, ofatumumab or cladribine) in use in the UK within the control arm, which are now offered to patients with rapidly evolving severe MS (RES-MS) who are treatment naïve. There remain, therefore, unanswered questions about the relative efficacy and safety of aHSCT over these high-efficacy DMTs in these patient groups. The StarMS trial (Autologous Stem Cell Transplantation versus Alemtuzumab, Ocrelizumab, Ofatumumab or Cladribine in Relapsing Remitting Multiple Sclerosis) will assess the efficacy, safety and long-term impact of aHSCT compared with high-efficacy DMTs in patients with highly active RRMS despite the use of standard DMTs or in patients with treatment naïve RES-MS. METHODS AND ANALYSIS: StarMS is a multicentre parallel-group rater-blinded randomised controlled trial with two arms. A total of 198 participants will be recruited from 19 regional neurology secondary care centres in the UK. Participants will be randomly allocated to the aHSCT arm or DMT arm in a 1:1 ratio. Participants will remain in the study for 2 years with follow-up visits at 3, 6, 9, 12, 18 and 24 months postrandomisation. The primary outcome is the proportion of patients who achieve 'no evidence of disease activity' during the 2-year postrandomisation follow-up period in an intention to treat analysis. Secondary outcomes include efficacy, safety, cost-effectiveness and immune reconstitution of aHSCT and the four high-efficacy DMTs. ETHICS AND DISSEMINATION: The study was approved by the Yorkshire and Humber-Leeds West Research Ethics Committee (20/YH/0061). Participants will provide written informed consent prior to any study specific procedures. The study results will be submitted to a peer-reviewed journal and abstracts will be submitted to relevant national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN88667898.

University education facilitates uptake of disease-modifying therapies for multiple sclerosis: A community-based study using the UK MS Register.

BACKGROUND: Higher education is associated with better job opportunities and higher income. OBJECTIVES: Herein, the impact of education on the uptake of disease-modifying therapies (DMTs) for multiple sclerosis (MS) in a publicly funded health care system was examined using the UK MS Register. METHODS: All adult participants with relapsing remitting MS diagnosed between 2008 and 2021 were included. Those without data regarding their education levels were excluded. Binary, multinomial and Cox regression models were used to examine the association between education levels and uptake of DMTs. RESULTS: A total of 6317 participants fulfilled all inclusion and exclusion criteria. A total of 1826/2923 (62%) participants with a university education were treated with DMTs, compared to 1788/3394 (53%) participants with school/diploma received DMTs with an odds ratio of 1.318 (1.178-1.473). Participants with a university education were more likely to be treated with both moderate- and high-efficacy DMTs, compared to others, with odds ratios of 1.227 (1.087-1.385) and 1.545 (1.325-1.802), respectively. University education was also a positive predictor for faster initiation of DMTs, and, importantly, higher-efficacy DMTs. CONCLUSION: In a publicly funded health care system, despite intended equality of access, university education was associated with a higher uptake of DMTs.

Characterization of cortico-meningeal translocator protein expression in multiple sclerosis.

Compartmentalized meningeal inflammation is thought to represent one of the key players in the pathogenesis of cortical demyelination in multiple sclerosis. PET targeting the 18 kDa mitochondrial translocator protein (TSPO) is a molecular-specific approach to quantifying immune cell-mediated density in the cortico-meningeal tissue compartment in vivo. This study aimed to characterize cortical and meningeal TSPO expression in a heterogeneous cohort of multiple sclerosis cases using in vivo simultaneous MR-PET with 11C-PBR28, a second-generation TSPO radioligand, and ex vivo immunohistochemistry. Forty-nine multiple sclerosis patients (21 with secondary progressive and 28 with relapsing-remitting multiple sclerosis) with mixed or high affinity binding for 11C-PBR28 underwent 90-min 11C-PBR28 simultaneous MR-PET. Tracer binding was measured using 60-90 min normalized standardized uptake value ratios sampled at mid-cortical depth and ∼3 mm above the pial surface. Data in multiple sclerosis patients were compared to 21 age-matched healthy controls. To characterize the nature of 11C-PBR28 PET uptake, the meningeal and cortical lesion cellular expression of TSPO was further described in post-mortem brain tissue from 20 cases with secondary progressive multiple sclerosis and five age-matched healthy donors. Relative to healthy controls, patients with multiple sclerosis exhibited abnormally increased TSPO signal in the cortex and meningeal tissue, diffusively in progressive disease and more localized in relapsing-remitting multiple sclerosis. In multiple sclerosis, increased meningeal TSPO levels were associated with increased Expanded Disability Status Scale scores (P = 0.007, by linear regression). Immunohistochemistry, validated using in situ sequencing analysis, revealed increased TSPO expression in the meninges and adjacent subpial cortical lesions of post-mortem secondary progressive multiple sclerosis cases relative to control tissue. In these cases, increased TSPO expression was related to meningeal inflammation. Translocator protein immunostaining was detected on meningeal MHC-class II+ macrophages and cortical-activated MHC-class II+ TMEM119+ microglia. In vivo arterial blood data and neuropathology showed that endothelial binding did not significantly account for increased TSPO cortico-meningeal expression in multiple sclerosis. Our findings support the use of TSPO-PET in multiple sclerosis for imaging in vivo inflammation in the cortico-meningeal brain tissue compartment and provide in vivo evidence implicating meningeal inflammation in the pathogenesis of the disease.

Partnership in Cancer Research (PCAR) Program Increases Medical Student Knowledge and Confidence to Perform Cancer Research.

Arkansas has a high cancer burden, and a pressing need exists for more medical students to pursue oncology as a career. The Partnership in Cancer Research (PCAR) program provides a summer research experience at the University of Arkansas for Medical Sciences for 12 medical students who have completed their first year of medical training. A majority of participants spend time pursuing cancer research in basic science, clinical, or community-based research. Students report on their research progress in an interactive "Live from the Lab!" series and assemble a final poster presentation describing their findings. Other activities include participation in a moderated, cancer-patient support group online, lecture series on cancer topics, medical simulations, palliative care clinic visit, "Death Over Dinner" event, and an entrepreneurship competition. Students completed surveys over PCAR's first 2 years in operation to evaluate all aspects of the program. Surveys reveal that students enthusiastically embraced the program in its entirety. This was especially true of the medical simulations which received the highest evaluations. Most significantly, surveys revealed that the program increased cancer knowledge and participant confidence to perform cancer research.

Comparing the Pathology, Clinical, and Demographic Characteristics of Younger and Older-Onset Multiple Sclerosis.

OBJECTIVE: Older people with multiple sclerosis (MS) have a less active radiological and clinical presentation, but many still attain significant levels of disability; but what drives worsening disability in this group? METHODS: We used data from the UK MS Register to characterize demographics and clinical features of late-onset multiple sclerosis (LOMS; symptom onset at ≥50 years), compared with adult-onset MS (AOMS; onset 18-49 years). We performed a pathology study of a separate MS cohort with a later onset (n = 18, mean age of onset 54 years) versus AOMS (n = 23, mean age of onset 29 years). RESULTS: In the Register cohort, there were 1,608 (9.4%) with LOMS. When compared with AOMS, there was a lower proportion of women, a higher proportion of primary progressive MS, a higher level of disability at diagnosis (median MS impact scale 36.7 vs. 28.3, p < 0.001), and a higher proportion of gait-related initial symptoms. People with LOMS were less likely to receive a high efficacy disease-modifying treatment and attained substantial disability sooner. Controlling for age of death and sex, neuron density in the thalamus and pons decreased with onset-age, whereas actively demyelinating lesions and compartmentalized inflammation was greatest in AOMS. Only neuron density, and not demyelination or the extent of compartmentalized inflammation, correlated with disability outcomes in older-onset MS patients. INTERPRETATION: The more progressive nature of older-onset MS is associated with significant neurodegeneration, but infrequent inflammatory demyelination. These findings have implications for the assessment and treatment of MS in older people. ANN NEUROL 2024;95:471-486.

High Levels of Perivascular Inflammation and Active Demyelinating Lesions at Time of Death Associated with Rapidly Progressive Multiple Sclerosis Disease Course: A Retrospective Postmortem Cohort Study.

OBJECTIVE: Analysis of postmortem multiple sclerosis (MS) tissues combined with in vivo disease milestones suggests that whereas perivascular white matter infiltrates are associated with demyelinating activity in the initial stages, leptomeningeal immune cell infiltration, enriched in B cells, and associated cortical lesions contribute to disease progression. We systematically examine the association of inflammatory features and white matter demyelination at postmortem with clinical milestones. METHODS: In 269 MS brains, 20 sites were examined using immunohistochemistry for active lesions (ALs) and perivenular inflammation (PVI). In a subset of 22, a detailed count of CD20+ B cells and CD3+ T cells in PVIs was performed. RESULTS: ALs were detected in 22%, whereas high levels of PVI were detected in 52% of cases. ALs were present in 35% of cases with high levels of PVI. Shorter time from onset of progression to death was associated with increased prevalence and higher levels of PVI (both p < 0.0001). Shorter time from onset of progression to wheelchair use was associated with higher prevalence of ALs (odds ratio [OR] = 0.921, 95% confidence interval [CI] = 0.858-0.989, p = 0.0230) and higher level of PVI (OR = 0.932, 95% CI = 0.886-0.981, p = 0.0071). High levels of PVI were associated with meningeal inflammation and increased cortical demyelination and significantly higher levels of B lymphocytes within the PVI. INTERPRETATION: ALs, a feature of early disease stage, persist up to death in a subgroup with high levels of PVI. These features link to a rapid progressive phase and higher levels of meningeal inflammation and B-cell infiltrates, supporting the hypothesis that chronic inflammation drives progression in MS. ANN NEUROL 2024;95:706-719.

The impact of healthcare systems on the clinical diagnosis and disease-modifying treatment usage in relapse-onset multiple sclerosis: a real-world perspective in five registries across Europe.

Introduction: Prescribing guidance for disease-modifying treatment (DMT) in multiple sclerosis (MS) is centred on a clinical diagnosis of relapsing-remitting MS (RRMS). DMT prescription guidelines and monitoring vary across countries. Standardising the approach to diagnosis of disease course, for example, assigning RRMS or secondary progressive MS (SPMS) diagnoses, allows examination of the impact of health system characteristics on the stated clinical diagnosis and treatment access. Methods: We analysed registry data from six cohorts in five countries (Czech Republic, Denmark, Germany, Sweden and United Kingdom) on patients with an initial diagnosis of RRMS. We standardised our approach utilising a pre-existing algorithm (DecisionTree, DT) to determine patient diagnoses of RRMS or secondary progressive MS (SPMS). We identified five global drivers of DMT prescribing: Provision, Availability, Funding, Monitoring and Audit, data were analysed against these concepts using meta-analysis and univariate meta-regression. Results: In 64,235 patients, we found variations in DMT use between countries, with higher usage in RRMS and lower usage in SPMS, with correspondingly lower usage in the UK compared to other registers. Factors such as female gender (p = 0.041), increasing disability via Expanded Disability Status Scale (EDSS) score (p = 0.004), and the presence of monitoring (p = 0.029) in SPMS influenced the likelihood of receiving DMTs. Standardising the diagnosis revealed differences in reclassification rates from clinical RRMS to DT-SPMS, with Sweden having the lowest rate Sweden (Sweden 0.009, range: Denmark 0.103 - UK portal 0.311). Those with higher EDSS at index (p < 0.03) and female gender (p < 0.049) were more likely to be reclassified from RRMS to DT-SPMS. The study also explored the impact of diagnosis on DMT usage in clinical SPMS, finding that the prescribing environment and auditing practices affected access to treatment. Discussion: This highlights the importance of a healthcare system's approach to verifying the clinical label of MS course in facilitating appropriate prescribing, with some flexibility allowed in uncertain cases to ensure continued access to treatment.

Patient-reported outcomes in multiple sclerosis: a prospective registry cohort study.

Registries have the potential to tackle some of the current limitations in determining the long-term impact of multiple sclerosis. Online assessments using patient-reported outcomes can streamline follow-up enabling large-scale, long-term, cost-effective, home-based, and patient-focused data collection. However, registry data are sparsely sampled and the sensitivity of patient-reported outcomes relative to clinician-reported scales is unknown, making it hard to fully leverage their unique scope and scale to derive insights. This retrospective and prospective cohort study over 11 years involved 15 976 patients with multiple sclerosis from the United Kingdom Multiples Sclerosis Register. Primary outcomes were changes in two patient-reported outcomes: Multiple Sclerosis Impact Scale motor component, and Multiple Sclerosis Walking Scale. First, we investigated their validity in measuring the impact of physical disability in multiple sclerosis, by looking at their sensitivity to disease subtype and duration. We grouped the available records (91 351 for Multiple Sclerosis Impact Scale motor and 68 092 for Multiple Sclerosis Walking Scale) by these two factors, and statistically compared the resulting groups using a novel approach based on Monte Carlo permutation analysis that was designed to cope with the intrinsic sparsity of registry data. Next, we used the patient-reported outcomes to draw novel insights into the developmental time course of subtypes; in particular, the period preceding the transition from relapsing to progressive forms. We report a robust main effect of disease subtype on the patient-reported outcomes and interactions of disease subtype with duration (all P < 0.0001). Specifically, patient-reported outcomes worsen with disease duration for all subtypes (all P < 0.0001) apart from benign multiple sclerosis (Multiple Sclerosis Impact Scale motor: P = 0.796; Multiple Sclerosis Walking Scale: P = 0.983). Furthermore, the patient-reported outcomes of each subtype are statistically different from those of the other subtypes at all time bins (Multiple Sclerosis Impact Scale motor: all P < 0.05; Multiple Sclerosis Walking Scale: all P < 0.01) except when comparing relapsing-remitting multiple sclerosis with benign multiple sclerosis and primary progressive multiple sclerosis with secondary progressive multiple sclerosis. Notably, there were statistically significant differences between relapsing-remitting and progressive subtypes at disease onset. Critically, the patient-reported outcomes are sensitive to future transitions to progressive subtypes, with individuals who transition presenting with higher patient-reported outcomes in their relapsing-remitting phase compared to individuals who don't transition since onset (all P < 0.0001). Patient-reported outcomes capture different patterns of physical worsening over disease length and across subtypes; therefore, they are a valid tool to measure the physical impact of multiple sclerosis over the long-term and cost-effectively. Furthermore, more advanced physical disability manifests years before clinical detection of progressive subtypes, adding evidence to the presence of a multiple sclerosis prodrome.

Is Clostridium perfringens epsilon toxin associated with multiple sclerosis?

Clostridium perfringens epsilon toxin is associated with enterotoxaemia in livestock. More recently, it is proposed to play a role in multiple sclerosis (MS) in humans. Compared to matched controls, strains of C. perfringens which produce epsilon toxin are significantly more likely to be isolated from the gut of MS patients and at significantly higher levels; similarly, sera from MS patients are significantly more likely to contain antibodies to epsilon toxin. Epsilon toxin recognises the myelin and lymphocyte (MAL) protein receptor, damaging the blood-brain barrier and brain cells expressing MAL. In the experimental autoimmune encephalomyelitis model of MS, the toxin enables infiltration of immune cells into the central nervous system, inducing an MS-like disease. These studies provide evidence that epsilon toxin plays a role in MS, but do not yet fulfil Koch's postulates in proving a causal role.