Validating a novel web-based method to capture disease progression outcomes in multiple sclerosis

The Expanded Disability Status Scale (EDSS) is the current ‘gold standard’ for monitoring disease severity in multiple sclerosis (MS). The EDSS is a physician-based assessment. A patient-related surrogate for the EDSS may be useful in remotely capturing information. Eighty-one patients (EDSS range 0–8) having EDSS as part of clinical trials were recruited. All patients carried out the web-based survey with minimal assistance. Full EDSS scores were available for 78 patients. The EDSS scores were compared to those generated by the online survey using analysis of variance, matched pair test, Pearson’s coefficient, weighted kappa coefficient, and the intra-class correlation coefficient. The internet-based EDSS scores showed good correlation with the physician-measured assessment (Pearson’s coefficient = 0.85). Weighted kappa for full agreement was 0.647. Full agreement was observed in 20 patient

Correction: Meta-Analysis of the Relationship between Multiple Sclerosis and Migraine.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.PMCID: PMC3613438PMCID: PMC3613438PMCID: PMC3613438PMCID: PMC3613438[This corrects the article on p. e45295 in vol. 7.]

How to do it: Vitamin D supplementation

Vitamin D testing and supplementation is of great interest to neurologists and their patients. Recommended nutritional intakes of vitamin D in the UK remain focused on bone health, despite increasing evidence for a role outside this area. Here we discuss how neurologists might approach vitamin D testing and supplementation, focusing on two conditions associated with vitamin D deficiency that have an increased risk of downstream complications resulting from these: multiple sclerosis and epilepsy. We set out a rationale for testing serum 25-hydroxyvitamin D concentrations and discuss our personal practice in terms of supplementation, with evidence where available

Evaluation of no evidence of progression or active disease (NEPAD) in patients with primary progressive multiple sclerosis in the ORATORIO trial.

ObjectiveNo evidence of progression or active disease (NEPAD) is a novel combined endpoint defined by the absence of both progression and inflammatory disease activity in primary progressive multiple sclerosis (PPMS). In the placebo-controlled phase III ORATORIO study (NCT01194570), we investigated the effect of ocrelizumab on this comprehensive outcome and its components in a post-hoc analysis.MethodsThe proportion of patients with NEPAD (no evidence of progression [NEP; no 12-week confirmed progression of ≥1/≥0.5 points on the Expanded Disability Status Scale if the baseline score was ≤5.5/>5.5 points, respectively; no 12-week confirmed progression of ≥20% on the Timed 25-Foot Walk test and 9-Hole Peg Test], no brain magnetic resonance imaging activity [no new/enlarging T2 lesions and no T1 gadolinium-enhancing lesions], and no protocol-defined relapse) from baseline to week 120 was determined in ocrelizumab- (600 mg; n = 465) and placebo-treated (n = 234) patients.ResultsThe majority of ORATORIO study patients with PPMS experienced clinical progression or evidence of disease activity. From baseline to week 120, 29.9% and 42.7% ocrelizumab-treated compared to 9.4% and 29.1% placebo-treated patients maintained NEPAD (relative risk [95% confidence interval {CI}], 3.15 [2.07-4.79]; p < 0.001) and NEP (relative risk [95% CI], 1.47 [1.17-1.84]; p < 0.001), respectively. Effects on the individual components of both measures were consistent with the compound outcomes.InterpretationCompared to placebo, ocrelizumab enhanced 3-fold the proportion of PPMS patients with no evidence of either progression or inflammatory disease activity. NEPAD may represent a sensitive and meaningful comprehensive measure of disease control in patients with PPMS. Ann Neurol 2018;84:527-536

No evidence of disease activity (NEDA) analysis by epochs in patients with relapsing multiple sclerosis treated with ocrelizumab vs interferon beta-1a.

BackgroundNo evidence of disease activity (NEDA; defined as no 12-week confirmed disability progression, no protocol-defined relapses, no new/enlarging T2 lesions and no T1 gadolinium-enhancing lesions) using a fixed-study entry baseline is commonly used as a treatment outcome in multiple sclerosis (MS).ObjectiveThe objective of this paper is to assess the effect of ocrelizumab on NEDA using re-baselining analysis, and the predictive value of NEDA status.MethodsNEDA was assessed in a modified intent-to-treat population (n = 1520) from the pooled OPERA I and OPERA II studies over various epochs in patients with relapsing MS receiving ocrelizumab (600 mg) or interferon beta-1a (IFN β-1a; 44 μg).ResultsNEDA was increased with ocrelizumab vs IFN β-1a over 96 weeks by 75% (p < 0.001), from Week 0‒24 by 33% (p < 0.001) and from Week 24‒96 by 72% (p < 0.001). Among patients with disease activity during Weeks 0‒24, 66.4% vs 24.3% achieved NEDA during Weeks 24‒96 in the ocrelizumab and IFN β-1a groups (relative increase: 177%; p < 0.001).ConclusionSuperior efficacy with ocrelizumab compared with IFN β-1a was consistently seen in maintaining NEDA status in all epochs evaluated. By contrast with IFN β-1a, the majority of patients with disease activity early in the study subsequently attained NEDA status with ocrelizumab

Neuroprotection in an Experimental Model of Multiple Sclerosis via Opening of Big Conductance, Calcium-Activated Potassium Channels

Big conductance calcium-activated (BK) channel openers can inhibit pathologically driven neural hyperactivity to control symptoms via hyperpolarizing signals to limit neural excitability. We hypothesized that BK channel openers would be neuroprotective during neuroinflammatory, autoimmune disease. The neurodegenerative disease was induced in a mouse experimental autoimmune encephalomyelitis model with translational value to detect neuroprotection in multiple sclerosis. Following the treatment with the BK channel openers, BMS-204253 and VSN16R, neuroprotection was assessed using subjective and objective clinical outcomes and by quantitating spinal nerve content. Treatment with BMS-204253 and VSN16R did not inhibit the development of relapsing autoimmunity, consistent with minimal channel expression via immune cells, nor did it change leukocyte levels in rodents or humans. However, it inhibited the accumulation of nerve loss and disability as a consequence of autoimmunity. Therefore, in addition to symptom control, BK channel openers have the potential to save nerves from excitotoxic damage and could be useful as either stand-alone neuroprotective agents or as add-ons to current disease-modifying treatments that block relapsing MS but do not have any direct neuroprotective activity

Neuroprotection in a Novel Mouse Model of Multiple Sclerosis

The authors acknowledge the support of the Barts and the London Charity, the Multiple Sclerosis Society of Great Britain and Northern Ireland, the National Multiple Sclerosis Society, USA, notably the National Centre for the Replacement, Refinement & Reduction of Animals in Research, and the Wellcome Trust (grant no. 092539 to ZA). The siRNA was provided by Quark Pharmaceuticals. The funders and Quark Pharmaceuticals had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis.

OBJECTIVE: To test blood and CSF neurofilament light chain (NfL) levels in relation to disease progression and survival in amyotrophic lateral sclerosis (ALS). METHODS: Using an electrochemiluminescence immunoassay, NfL levels were measured in samples from 2 cohorts of patients with sporadic ALS and healthy controls, recruited in London (ALS/control, plasma: n = 103/42) and Oxford (ALS/control, serum: n = 64/36; paired CSF: n = 38/20). NfL levels in patients were measured at regular intervals for up to 3 years. Change in ALS Functional Rating Scale-Revised score was used to assess disease progression. Survival was evaluated using Cox regression and Kaplan-Meier analysis. RESULTS: CSF, serum, and plasma NfL discriminated patients with ALS from healthy controls with high sensitivity (97%, 89%, 90%, respectively) and specificity (95%, 75%, 71%, respectively). CSF NfL was highly correlated with serum levels (r = 0.78, p < 0.0001). Blood NfL levels were approximately 4 times as high in patients with ALS compared with controls in both cohorts, and maintained a relatively constant expression during follow-up. Blood NfL levels at recruitment were strong, independent predictors of survival. The highest tertile of blood NfL at baseline had a mortality hazard ratio of 3.91 (95% confidence interval 1.98-7.94, p < 0.001). CONCLUSION: Blood-derived NfL level is an easily accessible biomarker with prognostic value in ALS. The individually relatively stable levels longitudinally offer potential for NfL as a pharmacodynamic biomarker in future therapeutic trials. CLASSIFICATION OF EVIDENCE: This report provides Class III evidence that the NfL electrochemiluminescence immunoassay accurately distinguishes patients with sporadic ALS from healthy controls

Evaluating more naturalistic outcome measures:A 1-year smartphone study in multiple sclerosis

Objective: In this cohort of individuals with and without multiple sclerosis (MS), we illustrate some of the novel approaches that smartphones provide to monitor patients with chronic neurologic disorders in their natural setting. Methods: Thirty-eight participant pairs (MS and cohabitant) aged 18–55 years participated in the study. Each participant received an Android HTC Sensation 4G smartphone containing a custom application suite of 19 tests capturing participant performance and patient-reported outcomes (PROs). Over 1 year, participants were prompted daily to complete one assigned test. Results: A total of 22 patients with MS and 17 cohabitants completed the entire study. Among patients with MS, low scores on PROs relating to mental and visual function were associated with dropout (p < 0.05). We illustrate several novel features of a smartphone platform. First, fluctuations in MS outcomes (e.g., fatigue) were assessed against an individual's ambient environment by linking responses to meteorological data. Second, both response accuracy and speed for the Ishihara color vision test were captured, highlighting the benefits of both active and passive data collection. Third, a new trait, a person-specific learning curve in neuropsychological testing, was identified using spline analysis. Finally, averaging repeated measures over the study yielded the most robust correlation matrix of the different outcome measures. Conclusions: We report the feasibility of, and barriers to, deploying a smartphone platform to gather useful passive and active performance data at high frequency in an unstructured manner in the field. A smartphone platform may therefore enable large-scale naturalistic studies of patients with MS or other neurologic diseases