Initially recognised as an important factor for bone health, vitamin D is now known to have a range of effects on the immune system. Vitamin D deficiency is associated with an increased risk of ...multiple sclerosis (MS), a chronic immune‐mediated demyelinating disease of the CNS. In this review, we explore the links between vitamin D deficiency, MS risk, and disease activity. We also discuss the known immune effects of vitamin D supplementation and the relevance of these observations to the immunopathology of MS. Finally, we review the existing evidence for vitamin D supplementation as an MS therapy, highlighting several recent clinical studies and trials.
There are a broad range of disease-modifying therapies (DMTs) available in relapsing-remitting multiple sclerosis (RRMS), but limited biomarkers exist to personalise DMT choice. All DMTs, including ...monoclonal antibodies such as rituximab and ocrelizumab, are effective in preventing relapses and preserving neurological function in MS. However, each agent harbours its own risk of therapeutic failure or adverse events. Pharmacogenetics, the study of the effects of genetic variation on therapeutic response or adverse events, could improve the precision of DMT selection. Pharmacogenetic studies of rituximab in MS patients are lacking, but pharmacogenetic markers in other rituximab-treated autoimmune conditions have been identified. This review will outline the wider implications of pharmacogenetics and the mechanisms of anti-CD20 agents in MS. We explore the non-MS rituximab literature to characterise pharmacogenetic variants that could be of prognostic relevance in those receiving rituximab, ocrelizumab or other monoclonal antibodies for MS.
Objectives:
We investigated choroid plexus (CP) volume in patients presenting with optic neuritis (ON) as a clinically isolated syndrome (CIS), compared to a cohort with established ...relapsing–remitting multiple sclerosis (RRMS) and healthy controls (HCs).
Methods:
Three-dimensional (3D) T1, T2-FLAIR and diffusion-weighted sequences were acquired from 44 ON CIS patients at baseline, 1, 3, 6 and 12 months after the onset of ON. Fifty RRMS patients and 50 HCs were also included for comparison.
Results:
CP volumes was larger in both ON CIS and RRMS groups compared to HCs, but not significantly different between ON CIS and RRMS patients (analysis of covariance (ANCOVA) adjusted for multiple comparisons). Twenty-three ON CIS patients who converted to clinically definite MS (MS) demonstrated CP volume similar to RRMS patients, but significantly larger compared to HCs. In this sub-group, CP volume was not associated with the severity of optic nerve inflammation or long-term axonal loss, not with brain lesion load. A transient increase of CP volume was observed following an occurrence of new MS lesions on brain magnetic resonance imaging (MRI).
Interpretation:
Enlarged CP can be observed very early in a disease. It transiently reacts to acute inflammation, but not associated with the degree of tissue destruction.
Background and purpose
The validity, reliability, and longitudinal performance of the Patient‐Determined Disease Steps (PDDS) scale is unknown in people with multiple sclerosis (MS) with mild to ...moderate disability. We aimed to examine the psychometric properties and longitudinal performance of the PDDS.
Methods
We included relapsing–remitting MS patients with an Expanded Disability Status Scale (EDSS) score of less than 4. Validity and test–retest reliability was examined. Longitudinal data were analysed with mixed‐effect modelling and Cohen's kappa for concordance in confirmed disability progression (CDP).
Results
We recruited a total of 1093 participants, of whom 904 had complete baseline data. The baseline correlation between PDDS and EDSS was weak (ρ = 0.45, p < 0.001). PDDS had stronger correlations with patient‐reported outcomes (PROs). Conversely, EDSS had stronger correlations with age, disease duration, Kurtzke's functional systems and processing speed test. PDDS test–retest reliability was good to excellent (concordance correlation coefficient = 0.73–0.89). Longitudinally, PDDS was associated with EDSS, age and depression. A higher EDSS score was associated with greater PDSS progression. The magnitude of these associations was small. There was no concordance in CDP as assessed by PDDS and EDSS.
Conclusion
The PDDS has greater correlation with other PROs but less correlation with other MS‐related outcome measures compared to the EDSS. There was little correlation between PDDS and EDSS longitudinally. Our findings suggest that the PDDS scale is not interchangeable with the EDSS.
Aims:
To retrospectively assess factors associated with John Cunningham virus (JCV) seroconversion in natalizumab-treated patients.
Background:
Natalizumab is highly effective for the treatment of ...relapsing–remitting multiple sclerosis (RRMS), but its use is complicated by opportunistic JCV infection. This virus can result in progressive multifocal leukoencephalopathy (PML). Serial assessment of JCV serostatus is mandated during natalizumab treatment.
Methods:
Patients treated with natalizumab for RRMS at six tertiary hospitals in Melbourne, Australia (n = 865) and 11 MS treatment centres in Brazil (n = 136) were assessed for change in JCV serostatus, duration of exposure to natalizumab and prior immunosuppression. Sensitivity analyses examined whether sex, age, tertiary centre, prior immunosuppression or number of JCV tests affected time to seroconversion.
Results:
From a cohort of 1001 natalizumab-treated patients, durable positive seroconversion was observed in 83 of 345 initially JCV negative patients (24.1%; 7.3% per year). Conversely, 16 of 165 initially JCV positive patients experienced durable negative seroconversion (9.7%; 3.8% per year). Forty patients (3.9%) had fluctuating serostatus. Time-to-event analysis did not identify a relationship between JCV seroconversion and duration of natalizumab exposure. Prior exposure to immunosuppression was not associated with an increased hazard of positive JCV seroconversion. Male sex was associated with increased JCV seroconversion risk adjusted hazard ratio 2.09 (95% confidence interval 1.17–3.71) p = 0.012.
Conclusion:
In this large international cohort of natalizumab-treated patients we observed an annual durable positive seroconversion rate of 7.3%. This rate exceeds that noted in registration and post-marketing studies for natalizumab. This rate also greatly exceeds that predicted by epidemiological studies of JCV seroconversion in healthy populations. Taken together, our findings support emerging evidence that natalizumab causes off-target immune changes that may be trophic for JCV seroconversion. In addition, male sex may be associated with increased positive JCV seroconversion.
Background:
As of September 2022, there was no globally recommended set of core data elements for use in multiple sclerosis (MS) healthcare and research. As a result, data harmonisation across ...observational data sources and scientific collaboration is limited.
Objectives:
To define and agree upon a core dataset for real-world data (RWD) in MS from observational registries and cohorts.
Methods:
A three-phase process approach was conducted combining a landscaping exercise with dedicated discussions within a global multi-stakeholder task force consisting of 20 experts in the field of MS and its RWD to define the Core Dataset.
Results:
A core dataset for MS consisting of 44 variables in eight categories was translated into a data dictionary that has been published and disseminated for emerging and existing registries and cohorts to use. Categories include variables on demographics and comorbidities (patient-specific data), disease history, disease status, relapses, magnetic resonance imaging (MRI) and treatment data (disease-specific data).
Conclusion:
The MS Data Alliance Core Dataset guides emerging registries in their dataset definitions and speeds up and supports harmonisation across registries and initiatives. The straight-forward, time-efficient process using a dedicated global multi-stakeholder task force has proven to be effective to define a concise core dataset.
Background:
Patients with relapsing–remitting multiple sclerosis commonly switch between disease-modifying therapies (DMTs). Identifying predictors of relapse when switching could improve outcomes.
...Objective:
To determine predictors of relapse hazard when switching to cladribine.
Methods:
Data of patients who switched to cladribine, grouped by prior disease-modifying therapy (pDMT; interferon-β/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab (NTZ)), were extracted from the MSBase Registry. Predictors of relapse hazard during the treatment gap and the first year of cladribine therapy were determined.
Results:
Of 513 patients, 22 relapsed during the treatment gap, and 38 within 1 year of starting cladribine. Relapse in the year before pDMT cessation predicted treatment gap relapse hazard (hazard ratio (HR) = 2.43, 95% confidence interval (CI) = 1.03–5.71). After multivariable adjustment, relapse hazard on cladribine was predicted by relapse before pDMT cessation (HR = 2.00, 95% CI = 1.01–4.02), treatment gap relapse (HR = 6.18, 95% confidence interval (CI) = 2.65–14.41), switch from NTZ (HR compared to injectable therapies 4.08, 95% CI = 1.35–12.33) and age at cladribine start (HR = 0.96, 95% CI = 0.91–0.99).
Conclusion:
Relapse during or prior to the treatment gap, and younger age, are of prognostic relevance in the year after switching to cladribine. Switching from NTZ is also independently associated with greater relapse hazard.
Background:
Gait in people with multiple sclerosis (PwMS) is affected even when no changes can be observed on clinical examination. A sensitive measure of gait deterioration is stability; however, ...its correlation with motor tract damage has not yet been established.
Objective:
To compare stability between PwMS and healthy controls (HCs) and determine associations between stability and diffusion magnetic resonance image (MRI) measures of axonal damage in selected sensorimotor tracts.
Methods:
Twenty-five PwMS (Expanded Disability Status Scale (EDSS) < 2.5) and 15 HCs walked on a treadmill. Stability from sacrum (LDESAC), shoulder (LDESHO) and cervical (LDECER) was calculated using the local divergence exponent (LDE). Participants underwent a 7T-MRI brain scan to obtain fibre-specific measures of axonal loss within the corticospinal tract (CST), interhemispheric sensorimotor tract (IHST) and cerebellothalamic tract (CTT). Correlation analyses between LDE and fibre density (FD) within tracts, fibre cross-section (FC) and FD modulated by FC (FDC) were conducted. Between-groups LDE differences were analysed using analysis of variance (ANOVA).
Results:
Correlations between all stability measures with CSTFD, between CSTFDC with LDESAC and LDECER, and LDECER with IHSTFD and IHSTFDC were significant yet moderate (R < −0.4). Stability was significantly different between groups.
Conclusions:
Poorer gait stability is associated with corticospinal tract (CST) axonal loss in PwMS with no-to-low disability and is a sensitive indicator of neurodegeneration.
Background:
Optic nerve sheath fenestration (ONSF) longitudinal outcomes remain unclear and are vital in the assessment of vision failure in patients with raised intracranial pressure (ICP). ...Furthermore, limited observational data exists regarding its use in other causes of raised ICP.
Objective:
To determine the efficacy and safety of ONSF for idiopathic intracranial hypertension (IIH), cerebral venous sinus thrombosis (CVST), and other indications.
Method:
Multicentre study from a tertiary hospital and specialty eye referral hospital in Melbourne, Australia, from July 2000 to December 2020. A total of 116 eyes from 70 patients undergoing ONSF were retrospectively reviewed with patient demographics, surgery indications, visual acuity (VA), visual fields, fundus photos of optic discs, retinal nerve fibre layer (RNFL) thickness, average thickness of optic discs on optical coherence tomography (OCT), and complications recorded. Parametric tests were used to compare the treatment groups pre- and post-operatively.
Results:
A total of 116 eyes from 70 patients underwent ONSF, which involved 92 eyes with IIH, 9 eyes with CVST, and 15 eyes with other aetiologies (‘Other’). Post ONSF, there was a best corrected visual acuity (BCVA) improvement or stabilisation in 84% of patients in all groups, with 50% achieving a BCVA of 6/6 or better at the final follow-up. RNFL, visual fields, and fundus grades all trended towards improvement, with most improvement noted by day 360. Common complications included transient diplopia (n = 29, 25%) and worsening of visual function requiring further cerebrospinal fluid (CSF) diversion procedures (n = 20, 17%). Complications were most significant in the ‘Other’ group with 1/3 of eyes requiring further CSF diversion procedures.
Conclusion:
Our data demonstrates effectiveness in the use of ONSF in papilloedema with visual failure due to IIH or CVST and when other CSF diversion procedures or medical therapies have failed.
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