Background

Most patients with multiple sclerosis without previous optic neuritis have thinner retinal layers than healthy controls. We assessed the role of peripapillary retinal nerve fibre layer (pRNFL) thickness and macular volume in eyes with no history of optic neuritis as a biomarker of disability worsening in a cohort of patients with multiple sclerosis who had at least one eye without optic neuritis available.

Methods

In this multicentre, cohort study, we collected data about patients (age ≥16 years old) with clinically isolated syndrome, relapsing-remitting multiple sclerosis, and progressive multiple sclerosis. Patients were recruited from centres in Spain, Italy, France, Germany, Czech Republic, Netherlands, Canada, and the USA, with the first cohort starting in 2008 and the latest cohort starting in 2013. We assessed disability worsening using the Expanded Disability Status Scale (EDSS). The pRNFL thickness and macular volume were assessed once at study entry (baseline) by optical coherence tomography (OCT) and was calculated as the mean value of both eyes without optic neuritis for patients without a history of optic neuritis or the value of the non-optic neuritis eye for patients with previous unilateral optic neuritis. Researchers who did the OCT at baseline were masked to EDSS results and the researchers assessing disability with EDSS were masked to OCT results. We estimated the association of pRNFL thickness or macular volume at baseline in eyes without optic neuritis with the risk of subsequent disability worsening by use of proportional hazards models that included OCT metrics and age, disease duration, disability, presence of previous unilateral optic neuritis, and use of disease-modifying therapies as covariates.

Findings

879 patients with clinically isolated syndrome (n=74), relapsing-remitting multiple sclerosis (n=664), or progressive multiple sclerosis (n=141) were included in the primary analyses. Disability worsening occurred in 252 (29%) of 879 patients with multiple sclerosis after a median follow-up of 2·0 years (range 0·5–5 years). Patients with a pRNFL of less than or equal to 87 μm or less than or equal to 88 μm (measured with Spectralis or Cirrus OCT devices) had double the risk of disability worsening at any time after the first and up to the third years of follow-up (hazard ratio 2·06, 95% CI 1·36–3·11; p=0·001), and the risk was increased by nearly four times after the third and up to the fifth years of follow-up (3·81, 1·63–8·91; p=0·002). We did not identify meaningful associations for macular volume.

Interpretation

Our results provide evidence of the usefulness of monitoring pRNFL thickness by OCT for prediction of the risk of disability worsening with time in patients with multiple sclerosis.

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Background

Technological advances now make it feasible to administer cognitive assessments at-home on mobile and touch-screen devices such as an iPad or tablet computer. Validation of these techniques is necessary to assess their utility in clinical trials.

Objectives

We used a Computerized Cognitive Composite for Preclinical Alzheimer’s Disease (C3-PAD) developed for iPad 1) to determine the feasibility of performing the C3-PAD at home by older individuals without the presence of a trained psychometrician; 2) to explore the reliability of in-clinic compared to at-home C3-PAD performance and 3) to examine the comparability of C3-PAD performance to standardized neuropsychological tests.

Design, Setting, Participants

Forty-nine cognitively normal older individuals (mean age, 71.467.7 years; 20% non-Caucasian) were recruited from research centers at the Massachusetts General Hospital and Brigham and Women’s Hospital. Participants made two in-clinic visits one-week apart and took five 30-minute alternate versions of the C3-PAD at-home measuring episodic memory, reaction time and working memory.

Measurements

A reliability analysis explored equivalence of the six alternate C3-PAD test versions. A feasibility assessment calculated the percentage of individuals who completed all at-home tests correctly, in contrast to incomplete assessments. Correlational analyses examined the association between C3-PAD-clinic compared to C3-PAD-home assessments and between C3-PAD performance and standardized paper and pencil tests.

Results

Excellent reliability was observed among the 6 C3-PAD alternate versions (Cronbach alpha coefficient=0.93). A total of 28 of 49 participants completed all at-home sessions correctly and 48 of 49 completed four out of five correctly. There were no significant differences in participant age, sex or education between complete and incomplete at-home assessments. A single in-clinic C3-PAD assessment and the at-home C3-PAD assessments were highly associated with each other (r2=0.508, p<0.0001), suggesting that at-home tests provide reliable data as in-clinic assessments. There was also a moderate association between the at-home C3-PAD assessments and the in-clinic standardized paper and pencil tests covering similar cognitive domains (r2= 0.168, p< 0.003).

Conclusions

Reliable and valid cognitive data can be obtained from the C3-PAD assessments in the home environment. With initial in-clinic training, a high percentage of older individuals completed at-home assessments correctly. At-home cognitive testing shows promise for inclusion into clinical trial designs.

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Background

This is an update of the Cochrane review "Teriflunomide for multiple sclerosis" (first published in The Cochrane Library 2012, Issue 12).

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system. It is clinically characterized by recurrent relapses or progression, or both, often leading to severe neurological disability and a serious decline in quality of life. Disease-modifying therapies (DMTs) for MS aim to prevent occurrence of relapses and disability progression. Teriflunomide is a pyrimidine synthesis inhibitor approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as a DMT for adults with relapsing-remitting MS (RRMS).

Objectives

To assess the absolute and comparative effectiveness and safety of teriflunomide as monotherapy or combination therapy versus placebo or other disease-modifying drugs (DMDs) (interferon beta (IFNβ), glatiramer acetate, natalizumab, mitoxantrone, fingolimod, dimethyl fumarate, alemtuzumab) for modifying the disease course in people with MS.

Search methods

We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Specialised Trials Register (30 September 2015). We checked reference lists of published reviews and retrieved articles and searched reports (2004 to September 2015) from the MS societies in Europe and America. We also communicated with investigators participating in trials of teriflunomide and the pharmaceutical company, Sanofi-Aventis.

Selection criteria

We included randomized, controlled, parallel-group clinical trials with a length of follow-up of one year or greater evaluating teriflunomide, as monotherapy or combination therapy, versus placebo or other approved DMDs for people with MS without restrictions regarding dose, administration frequency and duration of treatment.

Data collection and analysis

We used the standard methodological procedures of Cochrane. Two review authors independently assessed trial quality and extracted data. Disagreements were discussed and resolved by consensus among the review authors. We contacted the principal investigators of included studies for additional data or confirmation of data.

Main results

Five studies involving 3231 people evaluated the efficacy and safety of teriflunomide 7 mg and 14 mg, alone or with add-on IFNβ, versus placebo or IFNβ-1a for adults with relapsing forms of MS and an entry Expanded Disability Status Scale score of less than 5.5.

Overall, there were obvious clinical heterogeneities due to diversities in study designs or interventions and methodological heterogeneities across studies. All studies had a high risk of detection bias for relapse assessment and a high risk of bias due to conflicts of interest. Among them, three studies additionally had a high risk of attrition bias due to a high dropout rate and two studies had an unclear risk of attrition bias. The studies of combination therapy with IFNβ (650 participants) and the study with IFNβ-1a as controls (324 participants) also had a high risk for performance bias and a lack of power due to the limited sample.

Two studies evaluated the benefit and the safety of teriflunomide as monotherapy versus placebo over a period of one year (1169 participants) or two years (1088 participants). A meta-analysis was not conducted. Compared to placebo, administration of teriflunomide at a dose of 7 mg/day or 14 mg/day as monotherapy reduced the number of participants with at least one relapse over one year (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.59 to 0.87, P value = 0.001 with 7 mg/day and RR 0.60, 95% CI 0.48 to 0.75, P value < 0.00001 with 14 mg/day) or two years (RR 0.85, 95% CI 0.74 to 0.98, P value = 0.03 with 7 mg/day and RR 0.80, 95% CI 0.69 to 0.93, P value = 0.004 with 14 days). Only teriflunomide at a dose of 14 mg/day reduced the number of participants with disability progression over one year (RR 0.55, 95% CI 0.36 to 0.84, P value = 0.006) or two years (RR 0.74, 95% CI 0.56 to 0.96, P value = 0.02). When taking the effect of drop-outs into consideration, the likely-case scenario analyses still showed a benefit in reducing the number of participants with at least one relapse, but not for the number of participants with disability progression. Both doses also reduced the annualized relapse rate and the number of gadolinium-enhancing T1-weighted lesions over two years. Quality of evidence for relapse outcomes at one year or at two years was low, while for disability progression at one year or at two years was very low.

When compared to IFNβ-1a, teriflunomide at a dose of 14 mg/day had a similar efficacy to IFNβ-1a in reducing the proportion of participants with at least one relapse over one year, while teriflunomide at a dose of 7 mg/day was inferior to IFNβ-1a (RR 1.52, 95% CI 0.87 to 2.67, P value = 0.14; 215 participants with 14 mg/day and RR 2.74, 95% CI 1.66 to 4.53, P value < 0.0001; 213 participants with 7 mg/day). However, the quality of evidence was very low.

In terms of safety profile, the most common adverse events associated with teriflunomide were diarrhoea, nausea, hair thinning, elevated alanine aminotransferase, neutropenia and lymphopenia. These adverse events had a dose-related effects and rarely led to treatment discontinuation.

Authors' conclusions

There was low-quality evidence to support that teriflunomide at a dose of 7 mg/day or 14 mg/day as monotherapy reduces both the number of participants with at least one relapse and the annualized relapse rate over one year or two years of treatment in comparison with placebo. Only teriflunomide at a dose of 14 mg/day reduced the number of participants with disability progression and delayed the progression of disability over one year or two years, but the quality of the evidence was very low. The quality of available data was too low to evaluate the benefit teriflunomide as monotherapy versus IFNβ-1a or as combination therapy with IFNβ. The common adverse effects were diarrhoea, nausea, hair thinning, elevated alanine aminotransferase, neutropenia and lymphopenia. These adverse effects were mostly mild-to-moderate in severity, but had a dose-related effect. New studies of high quality and longer follow-up are needed to evaluate the comparative benefit of teriflunomide on these outcomes and the safety in comparison with other DMTs.

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A recent review published in the Journal of Neurology, Neurosurgery and Psychiatry about the involvement of olfactory system in the pathogenesis if CNS demyelinating diseases.

Abstract

Olfactory dysfunction is recognised across an ever broadening spectrum of neuropsychiatric conditions including central nervous system (CNS) demyelinating diseases such as multiple sclerosis (MS) and neuromyelitis optica (NMO). In this review, we unravel the striking evidence highlighting how olfactory loss is a common clinical feature in MS and NMO. We provide an overview of the supportive psychophysical, electrophysiological, radiological and pathological data that point to the anatomical substrate of olfactory deficits in these diseases. The pattern of underlying pathology affecting the olfactory system is shown to be complex, involving multiple structures that are affected in different ways throughout the course of the disease. This review is the first to synthesise the expanding body of literature on the topic, provides novel insight into the way in which the olfactory system is affected in CNS demyelinating diseases, and raises intriguing questions about the role of this system in the pathogenesis of these diseases.

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