Central vein sign for multiple sclerosis: A systematic review and meta-analysis.

AIMS: To systematically review the diagnostic value of the central vein sign (CVS) in multiple sclerosis (MS) and to meta-analyse the proportion of positive lesions for CVS needed to distinguish MS from non-MS mimics. MATERIALS AND METHODS: A literature review was performed and a proportion meta-analysis was performed to examine the proportion of the CVS in MS lesions. Studies reporting a threshold of the CVS containing lesions with 100% diagnostic accuracy were included in the meta-analysis. This was compared to MS mimics in order to establish the discriminative value of the CVS. RESULTS: The CVS was found to be viable at lower field strengths (3 T and 1.5 T) and automated analysis is currently less accurate than manual counting. Five studies were included for the proportional meta-analysis. From the analysis, a proportion of 45% of lesions having the CVS was suggested given that the findings that the weighted proportion was 46.4% (95% confidence interval [CI]: of 40.3%-52.6%) with low heterogeneity (I2 = 0.0%; p=0.5). CONCLUSION: Although the CVS is a clinically relevant and viable sign, further work is needed to integrate this into the existing diagnostic criteria. As manual determination is a time-consuming process, the development of automated methods will be beneficial. With improvements in computational imaging techniques, the CVS will have an important role in the diagnosis and differentiation of MS.

Uveitis and optic perineuritis in the context of myelin oligodendrocyte glycoprotein antibody seropositivity.

BACKGROUND AND PURPOSE: Antibodies to myelin oligodendrocyte glycoprotein (MOG) have been identified in both children and adults with demyelination, with a strong association with bilateral or recurrent optic neuritis (ON). However, the full clinical spectrum of this newly described condition is unknown. We sought to describe non-ON inflammatory ophthalmological presentations such as uveitis and optic perineuritis in the context of MOG antibody seropositivity. METHODS: Using a live cell-based assay analysed by flow cytometry, we identified seropositive patients referred for MOG antibody testing in Australasia between 2014 and 2017. We identified four MOG antibody-positive patients with non-ON inflammatory ophthalmological presentations and present their detailed clinical information in this case series. RESULTS: Three patients had uveitis either in association with, or remote from, ON. One patient had optic perineuritis and peripheral ulcerative keratitis. We describe the presentation, examination, investigation findings and clinical course of these four patients. CONCLUSIONS: Recognition of these novel clinical associations may expand the clinical spectrum of MOG antibody-associated presentations. An expedited diagnosis may guide the management of these complex patients.

Anti-inflammatory disease-modifying treatment and disability progression in primary progressive multiple sclerosis: a cohort study.

BACKGROUND AND PURPOSE: Treatment options in primary progressive multiple sclerosis (PPMS) are scarce and, with the exception of ocrelizumab, anti-inflammatory agents have failed to show efficacy in ameliorating disability progression. The aim of this study was to investigate a potential effect of anti-inflammatory disease-modifying treatment on disability outcomes in PPMS. METHODS: Using MSBase, a large, international, observational database, we identified patients with PPMS who were either never treated or treated with a disease-modifying agent. Propensity score matching was used to select subpopulations with similar baseline characteristics. Expanded Disability Status Scale (EDSS) outcomes were compared with an intention-to-treat and an as-treated approach in paired, pairwise-censored analyses. RESULTS: Of the 1284 included patients, 533 were matched (treated, n = 195; untreated n = 338). Median on-study pairwise-censored follow-up was 3.4 years (quartiles 1.2-5.5). No difference in the hazard of experiencing 3-month confirmed EDSS progression events was observed between the groups [hazard ratio (HR), 1.0; 95% confidence interval (CI), 0.6-1.7, P = 0.87]. We did not find significant differences in the hazards of confirmed EDSS improvement (HR, 1.0; 95% CI, 0.6-1.6, P = 0.91) or reaching a confirmed EDSS step ≥7 (HR, 1.1; 95% CI, 0.7-1.6, P = 0.69). CONCLUSION: Our pooled analysis of disease-modifying agents suggests that these therapies have no substantial effect on short- to medium-term disability outcomes in PPMS.

Response to interferon-beta treatment in multiple sclerosis patients: a genome-wide association study.

Up to 50% of multiple sclerosis (MS) patients do not respond to interferon-beta (IFN-ß) treatment and determination of response requires lengthy clinical follow-up of up to 2 years. Response predictive genetic markers would significantly improve disease management. We aimed to identify IFN-ß treatment response genetic marker(s) by performing a two-stage genome-wide association study (GWAS). The GWAS was carried out using data from 151 Australian MS patients from the ANZgene/WTCCC2 MS susceptibility GWAS (responder (R)=51, intermediate responders=24 and non-responders (NR)=76). Of the single-nucleotide polymorphisms (SNP) that were validated in an independent group of 479 IFN-ß-treated MS patients from Australia, Spain and Italy (R=273 and NR=206), eight showed evidence of association with treatment response. Among the replicated associations, the strongest was observed for FHIT (Fragile Histidine Triad; combined P-value 6.74 × 10-6) and followed by variants in GAPVD1 (GTPase activating protein and VPS9 domains 1; combined P-value 5.83 × 10-5) and near ZNF697 (combined P-value 8.15 × 10-5).

Natural killer cell subpopulations are associated with MRI activity in a relapsing-remitting multiple sclerosis patient cohort from Australia.

BACKGROUND: The importance of the innate immune system in multiple sclerosis (MS) is increasingly recognized and the role of natural killer (NK) cells in controlling autoimmunity may be an important modulator of disease activity. OBJECTIVE: To examine NK subsets in MS patients on different treatments and to evaluate the role of NK subsets as indicators for disease activity. METHODS: We measured NK subset levels in blood obtained from 110 relapsing-remitting MS patients. Patients were either off treatment or on treatment with natalizumab, fingolimod, glatiramer acetate or beta-interferon. Disease activity was defined according to 'No Evidence of Disease Activity' (NEDA) criteria within an observation period of up to 2.4 years. The mean NK subset levels were compared among treatment groups using multivariate analysis of variance (ANOVA) and association analysis with disease activity performed using multi-factor logistic regression. RESULTS: Our analysis revealed differences in NK cells and subsets on treatment compared to off treatment ( p < 0.0005). A high proportion of bright NK cells were significantly associated with stable magnetic resonance imaging (MRI) imaging after adjusting for treatment effects ( p < 0.05). CONCLUSION: The independent association of NK subsets with MRI stability needs to be confirmed in prospective studies to test their usefulness in predicting disease activity in MS patients.

Risk of early relapse following the switch from injectables to oral agents for multiple sclerosis.

BACKGROUND AND PURPOSE: Early relapse outcomes in long-term stable patients switching from interferon ß/glatiramer acetate (IFNß/GA) to oral therapy are unknown. OBJECTIVE: The objective of this study was to compare early relapse and progression in multiple sclerosis (MS) patients switching to oral therapy following a period of stable disease on IFNß/GA, relative to a propensity-matched comparator of patients remaining on IFNß/GA. METHODS: The MSBase cohort study is a global, longitudinal registry for MS. Time to first 6-month relapse in previously stable MS patients switching from platform injectables ('switchers') to oral agents were compared with propensity-matched patients remaining on IFNß/GA ('stayers') using a Cox marginal model. RESULTS: Three-hundred and ninety-six switchers were successfully matched to 396 stayers on a 1:1 basis. There was no difference in the proportion of patients recording at least one relapse in the first 1-6 months by treatment arm (7.3% switchers, 6.6% stayers; P = 0.675). The mean annualized relapse rate (P = 0.493) and the rate of first 6-month relapse by treatment arm (hazard ratio 1.22, 95% confidence interval 0.70, 2.11) were also comparable. There was no difference in the rate of disability progression by treatment arm (hazard ratio 1.43, 95% confidence interval 0.63, 3.26). CONCLUSION: This is the first study to compare early relapse switch probability in the period immediately following switch to oral treatment in a population previously stable on injectable therapy. There was no evidence of disease reactivation within the first 6 months of switching to oral therapy.

Anxiety, depression and fatigue at 5-year review following CNS demyelination.

BACKGROUND: Anxiety and depression are common in multiple sclerosis (MS). We evaluated the prevalence and factors associated with anxiety, depression and fatigue at the 5-year review of a longitudinal cohort study following a first clinical diagnosis of CNS demyelination (FCD). METHODS: Cases with a FCD were recruited soon after diagnosis and followed annually thereafter. A variety of environmental, behavioural and clinical covariates were measured at five-year review. Anxiety and depression were measured using the Hospital Anxiety & Depression Scale (HADS), and fatigue by the Fatigue Severity Scale (FSS). RESULTS: Of the 236 cases, 40.2% had clinical anxiety (median HADS-A: 6.0), 16.0% had clinical depression (median HADS-D: 3.0), and 41.3% had clinical fatigue (median FSS: 4.56). The co-occurrence of all three symptoms was 3.76 times greater than expectation. Younger age, higher disability, concussion or other disease diagnosis were independently associated with a higher anxiety score; male sex, higher disability, being unemployed, less physical activity, and antidepressant and/or anxiolytic-sedative medication use were independently associated with a higher depression score. Higher disability, immunomodulatory medication use, other disease diagnosis and anxiolytic-sedative medication use were independently associated with having fatigue, while female sex, higher BMI, having had a concussion, being unemployed and higher disability were associated with a higher fatigue score. CONCLUSION: These results support previous findings of the commonality of anxiety, depression and fatigue in established MS and extend this to post-FCD and early MS cases. The clustering of the three symptoms indicates that they may share common antecedents.

BREMSO: a simple score to predict early the natural course of multiple sclerosis.

BACKGROUND AND PURPOSE: Early prediction of long-term disease evolution is a major challenge in the management of multiple sclerosis (MS). Our aim was to predict the natural course of MS using the Bayesian Risk Estimate for MS at Onset (BREMSO), which gives an individual risk score calculated from demographic and clinical variables collected at disease onset. METHODS: An observational study was carried out collecting data from MS patients included in MSBase, an international registry. Disease impact was studied using the Multiple Sclerosis Severity Score (MSSS) and time to secondary progression (SP). To evaluate the natural history of the disease, patients were analysed only if they did not receive immune therapies or only up to the time of starting these therapies. RESULTS: Data from 14 211 patients were analysed. The median BREMSO score was significantly higher in the subgroups of patients whose disease had a major clinical impact (MSSS≥ third quartile vs. ≤ first quartile, P < 0.00001) and who reached SP (P < 0.00001). The BREMSO showed good specificity (79%) as a tool for predicting the clinical impact of MS. CONCLUSIONS: BREMSO is a simple tool which can be used in the early stages of MS to predict its evolution, supporting therapeutic decisions in an observational setting.

Methylation differences at the HLA-DRB1 locus in CD4+ T-Cells are associated with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is thought to be caused by T-cell mediated autoimmune dysfunction. Risk of developing MS is influenced by environmental and genetic factors. Modifiable differences in DNA methylation are recognized as epigenetic contributors to MS risk and may provide a valuable link between environmental exposure and inherited genetic systems. OBJECTIVES AND METHODS: To identify methylation changes associated with MS, we performed a genome-wide DNA methylation analysis of CD4+ T cells from 30 patients with relapsing-remitting MS and 28 healthy controls using Illumina 450K methylation arrays. RESULTS: A striking differential methylation signal was observed at chr. 6p21, with a peak signal at HLA-DRB1. After prioritisation, we identified a panel of 74 CpGs associated with MS in this cohort. Most notably we found evidence of a major effect CpG island in DRB1 in MS cases (pFDR < 3 × 10(-3)). In addition, we found 55 non-HLA CpGs that exhibited differential methylation, many of which localise to genes previously linked to MS. CONCLUSIONS: Our findings provide the first evidence for association of DNA methylation at HLA-DRB1 in relation to MS risk. Further studies are now warranted to validate and understand how these findings are involved in MS pathology.

A pro-inflammatory diet is associated with long-term depression and anxiety levels but not fatigue in people with multiple sclerosis.

BACKGROUND: Multiple sclerosis is characterised by acute and chronic inflammation in the CNS. Diet may influence inflammation, and therefore MS outcomes. OBJECTIVE: To determine whether the Dietary Inflammatory Index (DII®)) is associated with depression, anxiety, and fatigue in a prospective cohort of people with MS. METHODS: People with a first clinical diagnosis of demyelination were followed over 10 years (n=223). DII and energy-adjusted DII (E-DIITM) scores were calculated from the dietary intake in the preceding 12 months measured by food frequency questionnaire. Depression and anxiety were assessed by the Hospital Anxiety and Depression Scale (HADS-A and HADS-D, respectively), and fatigue by the Fatigue Severity Scale. RESULTS: A higher E-DII score was associated with higher levels of depression and anxiety five years later (e.g., highest vs lowest E-DII quartile, HADS-D score: ß=2.23, 95%CI=0.98,3.48, p<0.001; HADS-A score: ß=1.90, 95%CI=0.59,3.21, p<0.001). A cumulative E-DII score was associated with depression (p<0.01) and anxiety (p=0.05) at the 10-year review. No associations were seen for fatigue. CONCLUSION: Our findings suggest that, in people with MS, a more pro-inflammatory diet may long-term adverse impact on depression and anxiety, but not fatigue.

Onboarding of siponimod in secondary progressive multiple sclerosis patients in Australia: Novel, real-world evidence from the MSGo digital support programme.

Background: Siponimod is approved for use in people with secondary progressive multiple sclerosis (pwSPMS). An integrated digital platform, MSGo, was developed for pwSPMS and clinicians to help navigate the multiple steps of the pre-siponimod work-up. Objective: To explore real-world onboarding experiences of siponimod amongst pwSPMS in Australia. Methods: Retrospective, non-interventional, longitudinal, secondary analysis of data extracted from MSGo (20 April 2022). The primary endpoint was the average time for siponimod onboarding; secondary endpoints were adherence and sub-group analyses of variables influencing onboarding. Results: Mixed-cure modelling estimated that 58% of participants (N = 368, females 71%, median age of 59 years) registered in MSGo would ever initiate siponimod. The median time to initiation was 56 days (95% CI [47-59] days). Half of the participants cited 'waiting for vaccination' as the reason for initiation delay. Cox regression analyses found participants with a nominated care partner had faster onboarding (HR 2.1, 95% CI [1.5-3.0]) and were more likely to continue self-reporting daily siponimod dosing than were those without a care partner (HR 2.2, 95% CI [1.3-3.7]). Conclusions: Despite the limitations of self-reported data and the challenges of the COVID-19 pandemic, this study provides insights into siponimod onboarding in Australia and demonstrates the positive impact of care partner support.

Fluctuations of MS births and UV-light exposure.

BACKGROUND: Patients with multiple sclerosis (MS) are more frequently born in spring when compared to autumn. Fluctuation of UV-light has been hypothesized to drive this phenomenon. AIM: To assess the correlation between fluctuation of sunlight and birth season in persons with MS. METHODS: For this record-linkage study, we collected from the international MSBase and the Italian MS iMed-web databases the dates of birth of 11,415 patients with MS from 36 centres from 15 countries worldwide and compared these to dates of live-births from national registries. From all participating sites, we collected data on UV-light fluctuation and assessed its correlation with seasonal fluctuation in MS births. RESULTS: Compared with the reference cohort, an increased proportion of persons with MS were born in spring and a decreased proportion in autumn (odds ratio (OR) to be born in spring versus autumn = 1.158, χ² = 36.347, P < 0.001). There was no significantly increased fluctuation of MS births with increased quartile of ambient UV-light fluctuation (Ptrend = 0.086). CONCLUSION: Seasonal fluctuation of MS births as found in this worldwide cohort of patients with MS did not correlate with variation in seasonal fluctuation of UV-light. Most likely, it results from a complex interplay between fluctuation of sunlight, behavioural factors, other environmental factors and (epi)genetic factors.

Higher dietary quality is prospectively associated with lower MRI FLAIR lesion volume, but not with hazard of relapse, change in disability or black hole volume in people with Multiple Sclerosis.

BACKGROUND: The influence of diet quality on multiple sclerosis (MS) progression or inflammatory activity is not well understood. METHODS: Study participants with MS from the AusLong cohort, were followed annually (10 years, n = 223 post-onset). At baseline, 5 and 10-year reviews, indices of dietary quality - the Australian Recommended Food Score (ARFS) and Diet Quality Tracker (DQT) - were calculated from self-reported dietary intake data of the preceding 12 months (Food Frequency Questionnaire, Dietary Questionnaire for Epidemiological Studies v2). Associations were examined between measures of dietary quality with measures of MS progression and inflammatory activity hazard of relapse, annualised disability progression (Expanded Disability Status Scale, EDSS) and Magnetic Resonance Imaging (MRI) outcomes. MRI outcomes included fluid-attenuated inversion recovery (FLAIR, T2 MRI) lesion volume and black hole volume (T1 MRI) in the juxtacortical, periventricular, and infratentorial regions of the brain, as well as total calculated from the sum of the three regions. RESULTS: A higher diet quality (at least with the ARFS) was associated with lower FLAIR lesion volume in the periventricular region only (highest vs lowest quartile: ß=-1.89,95%CI=-3.64, -0.13, p = 0.04, periventricular FLAIR region median (IQR) for 5-year review: 4.41 (6.06) and 10-year review: 4.68 (7.27)). Associations with black hole lesion volume, hazard of relapse, and annualised EDSS progression, lacked in significance and/or dose-dependency. CONCLUSION: We found evidence that diet quality may have a role in modulating one aspect of MS inflammatory activity (periventricular MRI FLAIR lesion volume), but not other MRI and clinical outcome measures.

Long-term dietary acid load is associated with depression in multiple sclerosis, but less evidence was found with fatigue and anxiety.

BACKGROUND: Diet-dependent acid-base load has been associated with worsening in mental health, but to date no study has examined this in people with multiple sclerosis (PwMS). We examined the association between potential renal acid load (PRAL) and net endogenous acid production (NEAP) scores and depression, anxiety, and fatigue in PwMS. METHODS: Participants with a first clinical diagnosis of CNS demyelination were followed prospectively as part of the AusLong Study (aged 18-59 years at cohort entry). At baseline, 5- and 10-year reviews, PRAL and NEAP scores were calculated using dietary intake in the preceding 12 months calculated from a food frequency questionnaire. At 5- and 10-year reviews, the Hospital Anxiety and Depression Scale was used to assess depression and anxiety, and the Fatigue Severity Scale assessed fatigue. RESULTS: Higher PRAL and NEAP scores were associated with increased subsequent absolute value and change in HADS depression scores over five years' follow-up (e.g., highest vs lowest PRAL quartile, 5-year change in HADS-D score: ß=+3.01, 95%CI= 1.54, 4.48, p<0.001). The level of depression at the 10-year review was determined by both the baseline dietary acid scores and baseline-5-year changes in dietary acid scores (e.g., PRAL change from baseline to 5-year review, 10-year review HADS-D score: ß=+0.09, 95%CI= 0.03, 0.15, p<0.001, NEAP change from baseline to 5-year review, 10-year review HADS-D score: ß=+0.07, 95%CI= 0.01, 0.14, p=0.03). Some associations were observed with anxiety and fatigue but were much weaker and less consistent. CONCLUSION: Our findings indicate that a higher dietary acid load potentially has a long-term influence on the level of depression in PwMS. The evidence is less convincing for anxiety and fatigue.

The frequency of CSF oligoclonal banding in multiple sclerosis increases with latitude.

BACKGROUND: With the advent of MRI scanning, the value of lumbar puncture to assess oligoclonal band (OCB) status-for the diagnosis of multiple sclerosis (MS) is increasingly uncertain. One major issue is that the reported frequency of cerebrospinal fluid (CSF)-restricted oligoclonal banding for the diagnosis of MS varies considerably in different studies. In addition, the relationship between OCB positivity and disease outcome remains uncertain, as reported studies are generally too small to assess comparative disability outcomes with sufficient power. METHODS: In order to further investigate variation of OCB positivity in patients with MS, we utilized MSBase, a longitudinal, Web-based collaborative MS outcomes registry following clinical cohorts in several continents and latitudes. We also assessed whether OCB positivity affects long-term disability outcome. RESULTS: A total of 13,242 patient records were obtained from 37 MS specialist centres in 19 different countries. OCB status was documented in 4481 (34%) patients and 80% of these were OCB positive. The presence of OCB was associated with degree of latitude (p = 0.02). Furthermore, the outcome of patients negative for CSF-specific OCB was significantly better in comparison to the OCB positive patients, as assessed by Expanded Disability Status Scale change (p < 0.001). CONCLUSIONS: The results of this study indicate that latitude could explain some of the inconsistencies in OCB status reported in different populations. The study confirms that OCB positivity in MS is associated with a worse long-term prognosis.

Associations between diet quality and depression, anxiety, and fatigue in multiple sclerosis.

BACKGROUND: Many people with multiple sclerosis (MS) modify their dietary intake post diagnosis, but there is little evidence that dietary modifications influence MS outcomes. METHODS: People with a first clinical diagnosis of central nervous system demyelination were followed annually for 10 years. Depression, anxiety, and fatigue were assessed at the 5-and 10-year reviews using the Hospital Anxiety and Depression Scale and Fatigue Severity Scale, respectively. Dietary intake in the preceding 12 months was assessed at baseline, and 5-and 10-year reviews using a food frequency questionnaire. We used the Australian Recommended Food Score (ARFS) and the Diet Quality Tracker (DQT) to assess diet quality. RESULTS: A higher diet quality in the previous 12 months using the ARFS score, but not the DQT, was associated with lower levels of depression (e.g., highest vs lowest quartile: ß=-1.35,95%CI=-2.44,-0.26,p=0.01), but neither score was associated with anxiety or fatigue. After assessing diet quality prospectively with outcomes five years later, we found that higher ARFS score, but not DQT score, was associated with lower levels of subsequent anxiety and depression (highest vs lowest quartile; Anxiety: ß=-1.61,95%CI=-2.76,-0.46,p=0.01, Depression: ß=-1.25,95%CI=-2.44,-0.07,p=0.04), but not fatigue. No associations were observed between diet quality and subsequent change in depression and anxiety over five years, although an association was observed between diet quality and change in fatigue (e.g., highest vs lowest DQT quartile: ß=-1.06,95%CI=-1.92,-0.21,p=0.02). When examining the cumulative effect of diet quality across the study period with our 10-year outcomes, only the cumulative DQT score was associated with depression but not anxiety or fatigue. CONCLUSION: We found significant inverse associations between diet quality and depression and anxiety, but the effect sizes were modest and there was a lack of consistency between the two diet quality measures (ARFS and DQT). A diet measure that correlates with diet quality might underlie our observed associations.

A non-synonymous SNP within membrane metalloendopeptidase-like 1 (MMEL1) is associated with multiple sclerosis.

Several single-nucleotide polymorphism (SNP) genome-wide association studies (GWASs) have been completed in multiple sclerosis (MS). Follow-up studies of the variants with the most promising rankings, especially when supplemented by informed candidate gene selection, have proven to be extremely successful. In this study we report the results of a multi-stage replication analysis of the putatively associated SNPs identified in the Wellcome Trust Case Control Consortium non-synonymous SNP (nsSNP) screen. In total, the replication sample consisted of 3444 patients and 2595 controls. A combined analysis of the nsSNP screen and replication data provides evidence implicating a novel additional locus, rs3748816 in membrane metalloendopeptidase-like 1 (MMEL1; odds ratio=1.16, P=3.54 × 10⁻6) in MS susceptibility.

The Audio Recorded Cognitive Screen (ARCS) in patients with multiple sclerosis: a practical tool for multiple sclerosis clinics.

BACKGROUND: Cognitive impairment is a common complication of multiple sclerosis, even in early stage disease, with significant impacts on life quality and social interaction. However, its detection is highly test-dependent. OBJECTIVE: To validate a recently described screening tool, the ARCS, for detecting cognitive impairment in a multiple sclerosis population. METHODS: The ARCS administers tests of executive function, memory, visual spatial construction and language via an audio device to unsupervised patients who write their responses for later scoring. Some 127 patients with a wide variety of disease course and severity were assessed by ARCS, of whom 87 also completed the Paced Auditory Serial Addition Test (PASAT) and 45 underwent formal ('gold standard') neuropsychological testing. RESULTS: Compared with PASAT, we found that the ARCS showed better sensitivity (86% versus 68%) at equivalent specificity (71%) for detection of impairment in any cognitive domain, and superiority in the detection of memory and executive impairments. Acceptance and completion rates for the ARCS were as good or better than for the PASAT. CONCLUSIONS: ARCS is sensitive, well-tolerated, easy to administer and facilitates comprehensive cognitive assessment in less than 5 min of clinician time. It has several advantages over the PASAT for detecting cognitive impairment in patients with multiple sclerosis.