Background

Pre-existing chronic illness is associated with increased psychiatric distress due to the spread of COVID-19, specifically increased stress, anxiety and depression. This potentially placed individuals with MS in a uniquely vulnerable position to experience greater psychiatric symptomatology.

Objectives

To examine the impact of the COVID-19 pandemic on emotional symptomatology and quality of life in individuals with Progressive Multiple Sclerosis (PMS).

Methods

Data were obtained during a randomized clinical trial on rehabilitation taking place at 11 centers in North America and Europe (The CogEx Trial, ClinicalTrials.gov Identifier: NCT03679468). Participants included 131 individuals with PMS. Study procedures were interrupted in accordance with governmental restrictions as COVID-19 spread. During study closure, a COVID Impact Survey was administered via telephone or email to all participants, along with patient report outcome (PRO) measures of depressive and anxiety symptoms, quality of life and MS symptomatology that were previously administered pre-pandemic.

Results

The time between baseline PRO completion and lockdown survey completion varied (M=9.5 months, SD=4.1 months). 4% of respondents reported COVID-19 infection. No significant changes were noted in anxiety, quality of life, or the impact of MS symptomatology on daily life from baseline to lockdown. While total HADS depression scores increased significantly at follow up, this did not translate into more participants scoring above the HADS threshold for clinically significant depression. No significant relationships were noted between disease duration, processing speed ability or EDSS and changes in symptoms of depression or anxiety.

Most participants reported impact of the virus on their psychological well-being, with little impact on financial well-being. Perceived impact of the pandemic on physical and psychological well-being correlated significantly with the impact of MS symptomatology on daily life, as well as changes in depression.

Conclusions

Overall, in a sample confined exclusively to people with chronic progressive MS, little clinically significant change was noted in symptoms of depression or anxiety or quality of life during the pandemic lockdown.

Background

There is to our knowledge few validated electronic tool in MS that measures the distance walked by a person with MS (PwMS). Utilising global positioning systems (GPS), WI-FI positioning and an in-built smartphone accelerometer to measure distance walked by a PwMS outdoors or indoors, could alleviate the uncertainty around using pedometers in those with gait disturbances, and is an attractive option.

Objectives

To pilot an accurate measure of distance walked using a smartphone application (mSteps) to facilitate Expanded Disability Status Scale (EDSS) measurement, indoors and outdoors, using both an MS and a control cohort.

Methods

The pilot study recruited 25 PwMS and 10 controls. mSteps utilised the iPhone’s inbuilt accelerometer and GPS functionalities to calculate the distance walked and time taken, indoors and outdoors. Due to unpredictable weather the physician monitored walk took place indoors which was fitted with location beacons to allow for WI-FI indoor positioning. The control cohort did the same walk indoors and outdoors to validate the use of the GPS functionality.

The participant was instructed to walk 25 feet, without rest, whilst the study phone was attached to their arm using a runner’s arm band and study personnel walked alongside them with a trundle wheel. Measurements were taken at 3 separate time points within a 3-month period.

95% levels of agreement between app and trundle wheel (gold standard) were calculated using the Bland-Altman repeated measures analysis. Levels of agreement, app vs trundle, were calculated for indoor measurements on both PwMS and controls with additional app vs trundle outdoor measurements for controls only. The a priori defined clinically acceptable difference was 1.52m.

Results

The 95% levels of agreement for indoor measurements on PwMS were -2.46 to 2.27m; and for controls were -2.02 to 2.71m. The 95% levels of agreement for outdoor measurements on controls were -0.45 to 0.43m.

Conclusions

The outdoor GPS functionality of mSteps is very accurate as shown by the 95% levels of agreements compared to the a priori clinically determined difference. The indoor WI-FI positioning function of mSteps however, was not accurate enough and shows that it is not reliable enough for further use. The control cohort showed the same inaccuracy indoors which eliminates the possibility that an uneven gait pattern in the MS cohort contributed to the error margin. A further validity study is being carried out, looking at a cohort of PwMS walking outdoors using mSteps and a trundle wheel.

Background

There is a clear need for biomarker development in progressive multiple sclerosis (PMS). Serum neurofilament light (sNFL), and to a lesser extent neurofilament heavy (sNFH), are leading candidates. Whilst sNFL in particular has been examined in relapsing remitting MS, data from PMS are limited and in contrast to immunosuppressive treatments, candidate neuroprotective treatments show a variable effect on these biomarkers [1]. We examine data from the original MS-STAT trial [2].

Objectives

To analyses serum neurofilament data from the MS-STAT trial, assessing cross-sectional and longitudinal sNFL and sNFH and their relationship with MRI and clinical variables.

Methods

Serum samples were acquired at months 0, 6, 12 and 24. sNFL and sNFH were quantified using Single Molecule Array (Simoa). Linear mixed models were used to assess for treatment effects between simvastatin and placebo, and regression, linear mixed and bivariate models to assess association with MRI and clinical variables.

Results

Median baseline sNFL was 14.6pg/ml (IQR 10.8-20.2) and sNFH 64.2pg/ml (23.9-119), rising to 16.0pg/ml (11.9-22.2) and 70.9pg/ml (26.5-123) by 24 months. Higher baseline sNFL was associated with greater subsequent brain atrophy. Similarly, higher sNFL was associated with higher T2 lesion volume (T2LV), and increases in sNFL were associated with increases in T2LV.

High baseline sNFL was associated with worse baseline EDSS (95% CI of coefficient: 0.120 to 0.633), 9-hole peg test (-0.009 to -0.002) and 25 foot walk (-0.515 to -0.019), and a greater deterioration in 25 foot walk from baseline to 2 years (-0.448 to -0.152). There was no evidence of an association between sNFH and these variables.

There was no evidence of a simvastatin treatment effect on either sNFL (95% CI -0.07 to 0.10, p=0.716) or sNFH (95% CI -0.17 to 0.22, p=0.827).

Conclusions

The mode of action of simvastatin in reducing brain atrophy remains to be elucidated, with actions upon vascular comorbidity and intermediate metabolites from cholesterol synthesis pathways as possible candidates [3]. Simvastatin is not immunosuppressive, and in common with other purportedly neuroprotective treatments, there is no evidence from this study that sNFL or sNFH can act as biomarkers of simvastatin treatment. The relationship between sNFL and T2LV supports the hypothesis that in MS, sNFL may act predominantly as a marker of neuroinflammation, even in this typical SPMS cohort.

1. Williams T et al (2020) Neurofilaments in progressive multiple sclerosis: a systematic review. J Neurol.

2. Chataway J et al (2014) Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet

3. Palladino R et al (2020) Evaluating the Risk of Macrovascular Events and Mortality among People with Multiple Sclerosis in England. JAMA Neurol

Background

Wearable technology refers to any sensor worn on the person, which as a result makes continuous and remote monitoring available to many people with chronic diseases, including multiple sclerosis (MS). Daily monitoring seems an ideal solution either as an outcome measure or as an adjunct to support rater-based monitoring in both clinical and research settings. There has been an increase in solutions that are available and we look to identify next generation wearables.

Objectives

To identify all validated wearable solutions for PwMS and identify areas of focus for wearable solutions in multiple sclerosis.

Methods

We completed a scoping review (using the PRISMA-ScR guidelines) to summarise the wearable solutions currently available in MS.

Our search strategy utilized subject heading searches: ‘Multiple Sclerosis’ and ‘wearable electronic devices’, as well as keywords ‘wearable technology’, and ‘electronic devices’. The literature search was conducted using MEDLINE (via PubMed) and Embase (via OVID) databases. This search included articles published from database inception to 30 May 2019. Additional searches looked at frequently published authors with different devices, as well as forward and backward citation tracking of included papers.

Results

We identified 35 validated unique solutions that measure gait, cognition, upper limb function, activity, mood and fatigue with most of these solutions being phone applications. Of these, 51% looked at lower limb function with activity levels being looked at by 37% of the total solutions. There was least focus on visual, and mood solutions at 3%, closely followed by quality of life and balance at 5%. Cognition and fatigue accounted for 14% of the total.

Conclusions

Looking forward, there is a change occurring from single measure solutions to multi-measure and multi-sensor solutions, such as the Floodlight Open app, which utilises multiple sensors within a smart-phone to remotely measure gait, cognition and upper limb function. Future research should consider costs and include implementation science as part of their research and design to ensure cost of delivery strategy is also accounted for.

As development in wearable technology in MS is still on-going, we can expect to see newer wearables focusing on other areas with technology advancements that allow for more upper body and cognitive measures. There is a dearth of validated solutions available for fatigue, mood, and pain.

Background

Whilst the introduction of disease modifying treatments (DMTs) has transformed the management of people with early/relapsing MS (pwRMS), the use of DMTs in people with MS who are largely or completely wheel chair-dependent (EDSS>6.5) remains controversial. Evidence suggests that slowing or stopping disease deterioration is possible even past this arbitrary (loss of ambulatory function) threshold. Pathology and anecdotal clinical data support the hypothesis that even at an advanced stage of MS (AMS) inflammatory activity is a key driver of functional decline and that effective immunotherapy may halt this process. Cladribine tablets are a highly effective and central nervous system (CNS) penetrant DMT for people with highly-active RMS. It effectively depletes B cells, particularly memory B cells, a likely key mechanism of disease control in MS. Evidence, suggesting that (i) a significantly higher number of CNS axons supply upper compared to lower limb functions and (ii) longer axons are more vulnerable to the effects of focal inflammatory demyelination than shorter ones, corroborate our hypothesis that upper limb function can be protected even beyond EDSS=6.5.

Objectives

Primary Objective: To investigate whether cladribine tablets over 24 months is an effective DMT in people with AMS (pwAMS; EDSS=6.5-8.5) as measured using the 9-hole peg test (9HPT) peg speed.

Secondary Objectives: To establish whether there is a difference in pwAMS between treatment with cladribine tablets or placebo in (i) blood/serum biomarkers of inflammation (lymphocyte subsets) and/or neurodegeneration (neurofilament light chain), (ii) MRI loss of brain volume and spinal cord cross sectional area, (iii) T₂ lesion burden, (iv) hypo-intense lesions on T₁ weighted scans, (v) quality of life, and (vi) whether cladribine is a cost-effective treatment for pwAMS.

Methods

Randomised, double-blind, placebo-controlled phase IIb trial. To detect a 15% treatment effect in 9HPT peg speed with 90% power at 5% significance and 20% drop-out over 104 weeks n=200 pwAMS will be recruited across 20 UK MS centres.

Results

Protocol and ancillary documents have been submitted for ethics approval. So far 17 centres have agreed to recruit pwAMS for ChariotMS. Due to the COVID-19 pandemic start of recruitment has been deferred to 04 Jan 2021.

Conclusions

ChariotMS will be the first DMT-trial focussing on pwAMS. If successful, ChariotMS would expand the DMT landscape to include pwAMS and provide a platform for add-on therapies.

Background

Depression is associated with an increased risk of macrovascular disease and mortality in the general population. Depression is also the most frequent comorbidity in people with multiple sclerosis (PWMS); however, it is unknown whether it might disproportionally affect the risk of vascular disease and all-cause mortality in PWMS as compared with the general population.

Objectives

Assess whether the association between depression, vascular disease, and mortality differs in PWMS as compared with the general population.

Methods

Population-based retrospective matched cohort study, which included PWMS diagnosed between 1-Jan 1987 and 30-Sep 2018 and registered with general practices in England, and up to 6 controls matched by age, sex, and general practice. We used Cox proportional hazard regression models to assess differences in the risk of any macrovascular disease (acute coronary syndrome, cerebrovascular,and peripheral arterial disease) and mortality. We included an interaction term between MS status and depression in the model. Covariates included sex, age, ethnicity, smoking status, diabetes, treatment with antidiabetic, anti-hypertensive, antilipid, anti-platelet, and anti-coagulant medications, deprivation index, number of primary care visits, and MS diagnosis year. Analyses were also stratified by sex. We present results as adjusted hazard ratios (HR), attributable proportion due to interaction (API), and 95% confidence intervals (95%CI).

Results

We matched 12,251 PWMS to 72,572 controls. 21% (2535) PWMS and 8.7% (6,278) controls had a depression diagnosis at index year. As compared with controls without depression, risk of any macrovascular disease was greater in controls with depression (HR 2.93, 95%CI 2.53-3.40), greater in PWMS without depression (HR 1.38, 95%CI 1.17-1.62), and greater in PWMS with depression (HR 3.53, 95%CI 2.83-4.40). Mortality risk was greater in controls with depression (HR 1.74, 95%CI 1.60-1.90), greater in PWMS without depression (HR 3.59, 95%CI 3.39-3.81), and 5-fold greater in PWMS with depression (HR 4.99, 95%CI 4.53-5.50). 13% of the combined effect of MS and depression on mortality was due to interaction (API 0.13, 95%CI 0.04-0.22). Differences were greater in men.

Conclusions

Depression is associated with increased risk of macrovascular disease and mortality in PWMS. The effect of depression and MS on mortality risk is synergistic overall and offers a clear treatment opportunity which is likely to be under-utilised.

Background

Neurometabolites measured by proton magnetic resonance spectroscopic imaging (MRSI) can be used to examine the relationship between metabolic markers of brain injury and clinical disability in secondary progressive multiple sclerosis (SPMS). Current work has shown an association between normal appearing white matter (NAWM) total N-acetyl aspartate plus N-acetyl aspartyl glutamate (tNAA) and both arm function and measures of processing speed.

Objectives

To determine if baseline tNAA and tNAA/tCr in NAWM are associated with upper limb function (9-hole peg test) and information processing speed (Paced auditory serial addition test) after 96 weeks of follow-up.

Methods

108 participants from the recently reported MS-SMART trial were included.¹ All participants had chemical shift imaging in a single slice in the brain (2D-PRESS, TE/TR = 35/2000ms) at 3T and metabolite levels were determined for grey matter and NAWM. Absolute concentrations and ratios to total creatine (tCr) were calculated with LCModel, using an unsuppressed water scan as the internal reference. Along with MRSI, baseline T2 lesion volume (T2LV) and normalised brain volume (NBV) were calculated. Clinical measures were acquired as per MS-SMART protocol at baseline and 96 weeks.² To determine the association between baseline neurometabolites and 9-hole peg test (9HPT) and Paced auditory serial addition test (PASAT) scores at 96 weeks, multiple regression analysis was used with trial arm, age, sex, disease duration, relapses preceding study entry, T2LV and NBV at baseline as the covariates.

Results

At baseline, mean age of the cohort was 55 years (sd 7.1) and 67% female, mean disease duration was 22 years (sd 9.6), median EDSS 6.0 (IQR 1.0), mean PASAT score 42.8, 95% CI [40.4-45.2], mean 9HPT (sec^-1) 0.036, 95% CI [0.034-0.037] and median T2LV 9.0mL (IQR 13.6). At 96 weeks, mean 9HPT (sec^-1) was 0.034, 95% CI [0.032-0.036] and mean PASAT3 score was 43.6, 95% CI [40.8-46.3]. Baseline tNAA (β = 0.22, 95% CI [0.02-0.41], p = 0.03) and tNAA/tCr (β = 0.23, 95% CI [0.5-0.42], p = 0.02) in NAWM were associated with 9HPT at 96 weeks. Baseline NAWM tNAA and tNAA/tCr were not significantly associated with 96-week PASAT scores.

Conclusions

Baseline neuroaxonal integrity in NAWM as measured by tNAA and tNAA/tCr are associated with upper limb function at 96-weeks. Baseline neuroaxonal integrity in NAWM was not associated with a measure of processing speed at 96 weeks.

1. Chataway J et al. Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial. Lancet Neurol 2020

2. Connick P et al. Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART): a multiarm phase IIb randomised, double-blind, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis. BMJ Open 2018

Background

MS-SMART is a recently reported phase 2b randomised placebo controlled multi-arm study of the neuroprotective potential of amiloride, fluoxetine and riluzole in secondary progressive multiple sclerosis [NCT01910259]. No change in atrophy rate was observed in any arm compared to placebo. We obtained brain metabolic data using proton magnetic resonance spectroscopic imaging (MRSI) at baseline and 96 weeks to explore postulated candidate drug mechanisms of action for the three interventions. Fluoxetine has previously shown an increase in total N-acetyl aspartate plus N-acetyl aspartyl glutamate [tNAA]; myoinositol was also examined as a marker of astrogliosis. Amiloride blocks the acid sensing ion channel-1 receptor that mediates sodium and calcium and therefore could increase neuroaxonal integrity (tNAA). It is known that riluzole decreases glutaminergic transmission.

Objectives

MRSI data at baseline and then 96 weeks was used to interrogate drug specific effects of fluoxetine on tNAA and myoinositol (mIns); riluzole on Glx (glutamate + glutamine); and amiloride on tNAA levels, all compared to placebo.

Methods

108 participants from the MS-SMART trial were included and had chemical shift imaging in a single slice in the brain (2D-PRESS, TE/TR =35/2000ms) at 3T. Metabolite levels and ratios to creatine (tCr) were determined for normal appearing white matter (NAWM) and grey matter (GM) with LCModel using an unsuppressed water scan as the internal reference. Multiple regression models adjusting for age, sex and baseline Expanded Disability Status Scale (EDSS) were used.

Results

Mean age of the entire cohort was 55 (sd 7.1) years, 67% female, mean disease duration was 22 years (sd 9.6), median EDSS 6.0 (range 4.0-6.5) and median T2 lesion volume 9.0mL (IQR 6.0).

In the fluoxetine arm, there was no significant change in tNAA (or tNAA/Cr) in NAWM or GM; mIns/tCr (but not mIns) was lower at 96 weeks (β = -0.21, 95% CI [-0.40 to -0.02], p = 0.03) in NAWM (but not GM).

In the riluzole arm, there was a reduction in GM Glx (β = -0.25, 95% CI [-0.47 to -0.04], p = 0.02) and Glx/tCr (β = -0.29, 95% CI [-0.50 to -0.08], p = 0.007), but no change was seen in NAWM.

In the amiloride arm, there was no change in tNAA (or tNAA/tCr) in NAWM or GM.

Conclusions

Neither fluoxetine nor amiloride had any effect on proposed measures of neuroaxonal integrity in NAWM or GM as reflected in tNAA levels. There was a fluoxetine reduction in NAWM mIns/tCr perhaps reflecting some decrease in astrogliosis. Riluzole decreased GM Glx levels as anticipated. However, despite these target effects for these drugs, ultimately they did not translate into a reduction in atrophy rate in the trial.

Background

Cognitive dysfunction is common in multiple sclerosis (MS) and is particularly prevalent in patients with progressive forms of the disease [1]. Exploring neurofilament associations has clear value in trying to develop treatments for cognition.

Objectives

To perform a post-hoc analysis of the MS-STAT trial [2], assessing serum neurofilament light (sNFL) and heavy (sNFH) as predictive biomarkers of future cognitive performance.

Methods

Serum samples were analysed for sNFL and sNFH using Single Molecule Array (Simoa). Cognition was assessed at months 0, 12 and 24 with a detailed neuropsychometric battery including the Wechsler Abbreviated Scale of Intelligence (WASI) and Brain Injury Rehabilitation Trust Memory and Information Processing Battery (BMIPB), as previously described [3]. Multivariate regression models were used for cross-sectional analysis, and linear mixed models were used to assess the predictive value of dichotomised baseline sNFL and sNFH on changes in cognition. All analyses controlled for the established MRI variables of whole brain volume (WBV) and T2 lesion volume (T2LV) in order to assess the extent to which sNFL and sNFH provided additional prognostic value.

Results

Cross-sectional analyses:

After adjusting for demographics, T2LV and WBV, neither sNFL nor sNFH demonstrated cross-sectional associations with current cognitive performance.

Longitudinal analyses:

Patients with high baseline sNFL experienced significantly greater cognitive decline from 0 to 24 months in WASI full-scale IQ (95% CI of coefficient -0.238 to -0.024), WASI Verbal IQ (-0.281 to -0.011), and in both immediate and delayed BMIPB figure recall (-0.489 to -0.046 and -0.399 to -0.025, respectively). sNFH was not associated with changes in cognitive performance.

Conclusions

Our results demonstrate the prognostic value of sNFL on future changes in cognitive performance in SPMS, assessed through a detailed neuropsychometric battery. sNFL remained significantly associated with future cognitive decline whilst controlling for established MRI biomarkers, suggesting that it may provide additional utility in identifying those who may benefit most from interventions aimed at preventing cognitive decline.

1. Sumowski JF et al (2018) Cognition in multiple sclerosis: State of the field and priorities for the future. Neurology

2. Chataway J et al (2014) Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet

3. Chan D et al (2017) Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial. Lancet Neurol

Background

In recent years, instruments have been developed that provide wellbeing equivalents to the health-related quality-adjusted life-year (QALY) for use in cost-effectiveness analyses (CEA). Little is known about the relevance of these instruments to people with multiple sclerosis (MS) or the implications of their use for decision-making regarding treatments for MS. This research is part of a study that aims to assess two wellbeing measures which can be used in CEA - the Adult Social Care Outcomes Toolkit (ASCOT) and ICEpop CAPability measure for Adults (ICECAP-A) – in the context of MS.

Objectives

To compare the psychometric properties of the ASCOT and ICECAP-A when used with people with MS, with those of two health-related QALY measures designed for use in CEAs: the EuroQol EQ-5D-3L and the Multiple Sclerosis Impact Scale – Eight Dimensions (MSIS-8D).

Methods

Via a literature review and the involvement of with people with MS, we identified significant illness-related events (IREs) that affect the wellbeing of people with MS. We developed a questionnaire for respondents to report whether they had experienced each of 27 IREs over the previous six months. This questionnaire was administered online alongside the ASCOT and ICECAP-A via the UK MS Register. This is a website via which people with MS living in the UK directly complete questionnaires about their MS. Responses were linked to MS Register data: age, gender, type of MS, and responses to the EQ-5D, Multiple Sclerosis Impact Scale (MSIS-29) (from which the MSIS-8D can be calculated), Fatigue Severity Scale (FSS), Hospital Anxiety and Depression Scale (HADS) and Multiple Sclerosis Walking Scale-12 (MSWS-12). The relevance and validity of the wellbeing measures for people with MS were analysed and compared with the EQ-5D and MSIS-8D.

Results

Responses were provided by 2825 people with MS. Completion rates were high for all instruments (³95%). Each of the wellbeing and QALY measures discriminated between groups based on: MS type; published cut-off points for the FSS, HADS and MSWS-12; and incidence of 15 of the IREs including relapses, and changes in treatment, support or employment (p<0.0001). Typically, absolute effect sizes were higher for the EQ-5D, while standardised effect sizes were higher for the MSIS-8D and wellbeing measures.

Conclusions

These psychometric properties of the ASCOT and ICECAP-A wellbeing measures support their use with people with MS. However, their lower absolute effect sizes could result in less favourable outcomes when assessing treatments for MS, compared to the EQ-5D-3L.

Abstract

Abstract

Abstract