Real-world persistence of multiple sclerosis disease-modifying therapies.

BACKGROUND AND PURPOSE: Treatment persistence is the continuation of therapy over time. It reflects a combination of treatment efficacy and tolerability. We aimed to describe real-world rates of persistence on disease-modifying therapies (DMTs) for people with multiple sclerosis (pwMS) and reasons for DMT discontinuation. METHODS: Treatment data on 4366 consecutive people with relapse-onset multiple sclerosis (MS) were pooled from 13 UK specialist centres during 2021. Inclusion criteria were exposure to at least one MS DMT and a complete history of DMT prescribing. PwMS in blinded clinical trials were excluded. Data collected included sex, age at MS onset, age at DMT initiation, DMT treatment dates, and reasons for stopping or switching DMT. For pwMS who had received immune reconstituting therapies (cladribine/alemtuzumab), discontinuation date was defined as starting an alternative DMT. Kaplan-Meier survival analyses were used to express DMT persistence. RESULTS: In 6997 treatment events (1.6 per person with MS), median time spent on any single maintenance DMT was 4.3 years (95% confidence interval = 4.1-4.5 years). The commonest overall reasons for DMT discontinuation were adverse events (35.0%) and lack of efficacy (30.3%). After 10 years, 20% of people treated with alemtuzumab had received another subsequent DMT, compared to 82% of people treated with interferon or glatiramer acetate. CONCLUSIONS: Immune reconstituting DMTs may have the highest potential to offer a single treatment for relapsing MS. Comparative data on DMT persistence and reasons for discontinuation are valuable to inform treatment decisions and in personalizing treatment in MS.

Developing evidence-based guidelines for the safety of symptomatic drugs in multiple sclerosis during pregnancy and breastfeeding: A systematic review and Delphi consensus.

BACKGROUND: Multiple sclerosis (MS) is frequently diagnosed in people of reproductive age, many of whom will become pregnant following diagnosis. Although many women report an improvement in symptoms and relapses during pregnancy, symptoms such as fatigue and spasticity are commonly reported and can worsen. Prescribing medications during pregnancy and breastfeeding presents unique challenges and guidance on the use of symptomatic therapies is limited. OBJECTIVES: This paper aims to provide a consensus on the current evidence base to facilitate informed decision-making and optimise pre-conception counselling. METHODS: A list of most commonly prescribed medications for symptom management in MS was created using pregnancy and MS-related READ codes in the Welsh GP Dataset, followed by a review by MS neurologists. RESULTS: A final list of 24 medications was generated for review. Searches were performed on each medication, and evidence graded using standardised criteria. Evidence-based recommendations were developed and distributed to experts in the field and revised according to feedback using modified Delphi criteria. CONCLUSIONS: Our guidelines provide evidence-based recommendations on the safety of symptomatic therapies during pregnancy and breastfeeding for general practitioners and specialist teams working with people with MS who are hoping to embark on pregnancy or are currently pregnant. Individual risk-benefit ratios should be considered during pre-conception counselling to optimise symptom burden and minimise harm to both parent and child.

The impact of smoking cessation on multiple sclerosis disease progression.

The negative impact of smoking in multiple sclerosis is well established; however, there is much less evidence as to whether smoking cessation is beneficial to progression in multiple sclerosis. Adults with multiple sclerosis registered on the United Kingdom Multiple Sclerosis Register (2011-20) formed this retrospective and prospective cohort study. Primary outcomes were changes in three patient-reported outcomes: normalized Multiple Sclerosis Physical Impact Scale (MSIS-29-Phys), normalized Multiple Sclerosis Walking Scale (MSWS-12) and the Hospital Anxiety and Depression Scale (HADS). Time to event outcomes were clinically significant increases in the patient-reported outcomes. The study included 7983 participants; 4130 (51.7%) of these had ever smoked, of whom 1315 (16.5%) were current smokers and 2815/4130 (68.2%) were former smokers. For all patient-reported outcomes, current smokers at the time of completing their first questionnaire had higher patient-reported outcomes scores indicating higher disability compared to those who had never smoked (∼10 points difference in MSIS-29-Phys and MSWS-12; 1.5-1.8 points for HADS-Anxiety and HADS-Depression). There was no improvement in patient-reported outcomes scores with increasing time since quitting in former smokers. Nine hundred and twenty-three participants formed the prospective parallel group, which demonstrated that MSIS-29-Phys [median (IQR) 5.03 (3.71, 6.34)], MSWS-12 [median (IQR) 5.28 (3.62, 6.94)] and HADS-Depression [median (IQR) 0.71 (0.47, 0.96)] scores worsened over a period of 4 years, whereas HADS-Anxiety remained stable. Smoking status was significant at Year 4; current smokers had higher MSIS-29-Phys and HADS-Anxiety scores [median (IQR) 3.05 (0.22, 5.88) and 1.14 (0.52, 1.76), respectively] while former smokers had a lower MSIS-29-Phys score of -2.91 (-5.03, -0.79). A total of 4642 participants comprised the time to event analysis. Still smoking was associated with a shorter time to worsening event in all patient-reported outcomes (MSIS-29-Phys: n = 4436, P = 0.0013; MSWS-12: n = 3902, P = 0.0061; HADS-Anxiety: n = 4511, P = 0.0017; HADS-Depression: n = 4511, P < 0.0001). Worsening in motor disability (MSIS-29-Phys and MSWS-12) was independent of baseline HADS-Anxiety and HADS-Depression scores. There was no statistically significant difference in the rate of worsening between never and former smokers. When smokers quit, there is a slowing in the rate of motor disability deterioration so that it matches the rate of motor decline in those who have never smoked. This suggests that smoking cessation is beneficial for people with multiple sclerosis.

Anti-CD20 therapies in pregnancy and breast feeding: a review and ABN guidelines.

Neurologists increasingly use anti-CD20 therapies, including for women of childbearing age, despite these medications being unlicensed for use in pregnancy. Current evidence suggests that women can safely conceive while taking anti-CD20 therapy. Women should not be denied treatment during pregnancy when it is clinically indicated, although they should be counselled regarding live vaccinations for their infant. Women receiving regular ocrelizumab for multiple sclerosis should preferably wait 3 months before trying to conceive. There are few data around ofatumumab in pregnancy, and while there is probably a class effect across all anti-CD20 therapies, ofatumumab may need to be continued during pregnancy to maintain efficacy. We recommend that anti-CD20 therapies can be safely given while breast feeding. It is important to make time to discuss treatments with women of childbearing age to help them choose their most suitable treatment. Outcomes should be monitored in pregnancy registries.

Measuring coping in multiple sclerosis: The Coping Index-MS.

BACKGROUND: Coping in multiple sclerosis (MS) refers to cognitive and behavioural efforts to manage stresses imposed by the illness. Existing generic and disease-specific coping scales do not meet modern guidelines for scale development and cannot produce interval-level metrics to allow for change scores. OBJECTIVE: The main aim of this study was to develop a brief patient-reported outcome measure for coping in MS, capable of interval-level measurement. METHODS: Qualitative work in 43 people with MS leads to a draft scale which was administered to 5747 participants, with longitudinal collection in 2290. A calibration sample of 1000 subjects split into development and validation sets was used to generate three scales consistent with Rasch model expectations. RESULTS: The total Coping Index-MS (CI-MS-T), CI-MS-Internal (CI-MS-I) and CI-MS-External (CI-MS-E) cover total, internal and externally focused coping. All three scales are capable of interval-level measurement. Trajectory analysis of 9000 questionnaires showed two trajectories in CI-MS-T: Group 1 showed a low level of coping with slight decline over 40 months, while Group 2 had a better and stable level of coping due to improving CI-MS-I which compensated for the deteriorating CI-MS-E over time. CI-MS-T < 30 identified group membership at baseline. CONCLUSION: The CI-MS-T, CI-MS-I and CI-MS-E, comprising 20 items, provide interval-level measurement and are free-for-use in not-for-profit settings.

Multiple sclerosis and the risk of infection: Association of British Neurologists consensus guideline.

Infection in people with multiple sclerosis (MS) is of major concern, particularly for those receiving disease-modifying therapies. This article explores the risk of infection in people with MS and provides guidance-developed by Delphi consensus by specialists involved in their management-on how to screen for, prevent and manage infection in this population.

Internet of Things Smart Sunscreen Station: Descriptive Proof-of-Concept Study.

BACKGROUND: Skin cancer is the most prevalent but also most preventable cancer in Australia. Outdoor workers are at increased risk of developing skin cancer, and improvements in sun protection are needed. Sunscreen, when applied at the recommended concentration (2 mg/cm2), has been shown to block the harmful molecular effects of ultraviolet radiation in vivo. However, sunscreen is often not applied, reapplied sufficiently, or stored adequately to yield protection and reduce sunburns. OBJECTIVE: The primary aim of this study was to test an Internet of Things approach by deploying a smart sunscreen station to an outdoor regional mining site. METHODS: We deployed a smart sunscreen station and examined the key technological considerations including connectivity, security, and data management systems. RESULTS: The smart sunscreen station was deployed for 12 days at a mining workplace (Dalby, Australia). The smart sunscreen station's electrical components remained operational during field testing, and data were received by the message queuing telemetry transport server automatically at the end of each day of field testing (12/12 days, 100% connectivity). CONCLUSIONS: This study highlights that an Internet of Things technology approach can successfully measure sunscreen usage and temperature storage conditions.

Metre-per-second microfluidic flow velocimetry with dual beam optical coherence tomography.

A novel dual beam Optical Coherence Tomography (OCT) instrument has been developed for high velocity flow measurement, principally in microfluidics applications. The scanned dual beam approach creates a pair of image-frames separated by a small spatiotemporal offset. Metre-per-second flow measurement is achieved by rapid re-imaging by the second beam allowing for particle tracking between each image-frame of the pair. Flow at 1.06 m/s using a single optical access port has been measured, more than two orders of magnitude larger than previously reported OCT systems, at centimetre depth and with millimetre scale depth of field within a microfluidic chip, whilst simultaneously imaging the microfluidic channel structure.

Psychological determinants of job retention in multiple sclerosis.

BACKGROUND: Maintaining paid work is a key issue for people with multiple sclerosis (PwMS). Different factors, including psychological attributes, can influence job retention. Understanding their role should inform potential interventions to help PwMS retain employment. OBJECTIVES: The aim of this study was to identify the key factors which improve job retention in an employed cohort of PwMS. METHODS: This three-year longitudinal study used validated self-completed measures of physical and psychological factors at four time points over 28 months. RESULTS: Of 208 employed PwMS, just over 1 in 10 was no longer working at the end of the study. Three variables were predictive of continuing employment; low 'work instability' at baseline increased the odds of job retention by a factor of 12.76; high levels of self-efficacy by a factor of 4.66 and being less than 50 years of age increased the odds of job retention by a factor of 3.90. Path analysis demonstrated the mediating role of self-efficacy between the physical impact of MS and the level of work instability at exit. CONCLUSION: Screening for work instability and self-efficacy in a clinical setting followed by appropriate interventions to increase self-efficacy and reduce work instability could aid job retention in MS.

UV detection stickers can assist people to reapply sunscreen.

Sunscreen when applied at the recommended concentration (2 mg/cm2) has been shown to block the harmful molecular effects of ultraviolet radiation (UVR) in vivo. In real world conditions, however, sunscreen is often not applied/reapplied sufficiently to yield protection. This field study tested the effectiveness of UV detection stickers to prevent sunburn and improve reapplication of sunscreen. During the Ashes Cricket Test match event (November 2017) in Brisbane, Australia interested spectators were recruited into the control group on DAY-1 and during subsequent days (DAY-2, DAY-3, DAY-4) new participants were recruited into the UV-Sticker group. Participants in both groups were provided with free sunscreen and participants in the UV-Sticker group were additionally provided with a UV detection sticker. Primary outcomes were self-reported sunburns and reapplication of sunscreen. Secondary endpoints included satisfaction with the UV detection stickers. 813 participants enrolled in the study, and complete data is available for 428 participants (52.6% response rate, n = 369 UV detection sticker, n = 59 control). Participants provided with a UV detection sticker were more likely to re-apply sunscreen than controls (80% vs 68%, p = 0.04); but do not reduce sunburn rates. UV detection stickers may improve sunscreen re-application in a high UV-environment. Trial registration: Australian and New Zealand clinical trials register (ACTRN12617001572358).

Influence of aberrations on confocal-based remote refractive index measurements.

Confocal scanning combined with low-coherence interferometry is used to provide remote refractive index and thickness measurements of transparent materials. The influence of lens aberrations in the confocal measurement is assessed through ray-trace modeling of the axial point-spread functions generated using optical configurations comprised of paired aspherics and paired achromats. Off-axis parabolic mirrors are suggested as an alternative to lenses and are shown to exhibit much more symmetric profiles provided the system numerical aperture is not too high. The modeled results compare favorably with experimental data generated using an optical instrument comprised of a broadband source and line-scan spectrometer. Refractive index and thickness measurements are made with each configuration with most mirror pairings offering better than twice the repeatability and accuracy of either lens pairing.

Managing the (In)visibility of Chronic Illness at Work: Dialogism, Parody, and Reported Speech.

Interactionally, the workplace may be dilemmatic for a person with "invisible" chronic illness. Risks of stigmatization exist if they disclose their condition to colleagues. Meanwhile, not disclosing threatens well-being and entitlements. Using Bakhtin's dialogism as a theoretical framework, we explored these social aspects of illness: inductively analyzing narratives from 20 participants with multiple sclerosis (MS). Capitalizing on concepts from dialogical and conversation analysis, links between (in)visibility, knowledge, and belief were examined with respect to symptoms and co-worker judgment. Perceived medical legitimacy creates a core social dilemma. At the intersection of genre and action, participants systematically used parody to subvert the traditional workplace hierarchy. "Oh-prefaced" direct reported speech (OPDRS) was deployed to exaggerate workplace interactions, undermining managers/colleagues who misattributed (in)visible symptoms. Parodic OPDRS index emotive interactional dilemmas. As subversions of organizational power, OPDRS denote those very areas where employees feel disempowered. Sensitivity to OPDRS can provide diagnostic support and complement evaluation frameworks.

Spectrometer-based refractive index and dispersion measurement using low-coherence interferometry with confocal scanning.

This paper describes a technique for measuring refractive index and thickness of transparent plates using a fibre-optic low-coherence interferometer. The interferometer is used to independently measure quantities related to the phase and group refractive indices, np and ng, of the material under investigation. Additionally, the dispersion of the phase index dependent quantity is measured by taking advantage of the range of wavelengths available from a broadband source. These three quantities are related to simultaneously yield np and ng as well as the geometrical thickness t of the sample. Measurements are presented for a range of transparent materials including measurements of the ordinary and extraordinary refractive indices of a birefringent sapphire window. The mean percentage errors across all the samples tested were 0.09% for np, 0.08% for np, and 0.11% for t.

Passively-coupled, low-coherence interferometric duct profiling with an astigmatism-corrected conical mirror.

Duct-profiling in test samples up to 25 mm in diameter has been demonstrated using a passive, low-coherence probe head with a depth resolution of 7.8 µm, incorporating an optical-fibre-linked conical mirror addressed by a custom-built array of single-mode fibres. Zemax modelling, and experimental assessment of instrument performance, show that degradation of focus, resulting from astigmatism introduced by the conical mirror, is mitigated by the introduction of a novel lens element. This enables a good beam focus to be achieved at distances of tens of millimetres from the cone axis, not achievable when the cone is used alone. Incorporation of the additional lens element is shown to provide a four-fold improvement in lateral imaging resolution, when compared with reflection from the conical mirror alone.

Unusual case of bilateral hand weakness.

A 35-year-old man presented with myalgia and bilateral hand weakness, 3 days after the onset of lethargy, fevers and rigours. The hand weakness caused functional impairment including difficulty pressing keys on his mobile phone. On examination, there was mild bilateral hand weakness with normal reflexes. His serum creatine kinase was mildly raised at 503 U/L (24-195), viral PCR throat swab was negative and electromyogram showed subtle myopathic changes in the distal forearm muscles. Nerve conduction studies found no evidence of neuropathy. Forced vital capacity was reduced on admission (1.5 L) but improved within 24 hours (2.3 L). We gave supportive intravenous fluids and his weakness improved within 48 hours. He was discharged and reported that the weakness had fully resolved within weeks. The diagnosis was viral myositis. Distal forearm myositis rarely follows H1N1 influenza in adults but is an important differential for postinfective neurological symptoms.

Myocarditis and diffuse skeletal muscle oedema: new features of neuromyelitis optica spectrum disorder? A case report.

We present a case report of newly diagnosed neuromyelitis optica spectrum disorder (NMOSD) with associated myocarditis and diffuse oedema of the pelvic and anterior compartment thigh muscles on magnetic resonance imaging. Aquaporin 4 antibodies are expressed in skeletal myofibres but involvement of skeletal muscle is rarely reported in NMOSD and myocarditis has not previously been described in this context. This case highlights the need for further research into the involvement of cardiac and skeletal muscle in NMOSD.

A novel tool for characterising upper limb function in progressive multiple sclerosis through kinematic assessment.

INTRODUCTION: Current upper limb assessment methods in MS rely on measuring duration in tasks like the nine-hole peg test (9HPT). Kinematic techniques may provide a more useful measure of functional change in clinical and research practice. The aim of this study was to assess upper limb function prospectively in people with progressive MS using a kinematic 3D motion capture system and compare with current measures. METHODS: 42 people with progressive MS (PwPMS) and 15 healthy controls reached-and-grasped different objects whilst recorded by a kinematic assessment system. 9HPT, Expanded Disability Status Scale (EDSS), and patient reported outcome measures (PROs) were collected. All measures were taken at baseline for PwPMS and controls, and again at six months for PwPMS. RESULTS: Relative to controls, PwPMS had significantly longer reaction (0.11 s, p < 0.05) and reach (0.25 s, p < 0.05) times. PwPMS took longer to pick-up (0.34 s, p < 0.05), move (0.14 s, p < 0.05), and place (0.18 s, p < 0.05) objects. PwPMS had lower peak velocities when reaching (7.4 cm/s, p < 0.05) and moving (7.3 cm/s, p < 0.05) objects. Kinematic assessment demonstrated consistent differences between PwPMS with mild and severe upper limb dysfunction as defined by PROs, which were not captured by 9HPT or EDSS in this group. PwPMS demonstrated altered grip apertures profiles, as measured by their ability to complete individual parts of the reach and grasp task, between the baseline and follow-up timepoints. CONCLUSIONS: We have created and tested a novel upper limb function assessment tool which has detected changes and characteristics in hand function, not currently captured by the EDSS and 9HPT.

The Impact of COVID-19 on the Employment of People With Multiple Sclerosis: A Multiple Methods Study.

BACKGROUND: The COVID-19 pandemic led to approximately half of the working population in the United Kingdom being unable to work temporarily. This study aims to understand the employment needs and experiences of people with multiple sclerosis (MS) in the UK during this period. METHODS: Multiple methods were used, including an online survey and follow-up interviews with people with MS who were employed prior to the start of the pandemic restrictions in March 2020. RESULTS: The online survey was completed by 101 eligible participants and we interviewed 15 of them for qualitative data in the follow-up. Survey data indicated that the work experience of people with MS improved during the pandemic because they were allowed to work from home. However, participants experienced increased feelings of anxiety and loneliness. From the interviews, we extracted 5 themes: (1) the benefits of working from home; (2) the challenges of working during the COVID-19 pandemic; (3) the relevance of managers; (4) returning to "normal"; and (5) the need for vocational support. CONCLUSIONS: The pandemic showed that MS symptom management was improved by work flexibility (eg, working from home, breaks, flexible working hours); for people with MS, these accommodations improved both their ability to work and their self-perceived productivity. Future research should explore the support needs of people with MS who work remotely and determine whether pandemic-influenced work accommodations are sustainable over time.

Prevalence, treatment and correlates of depression in multiple sclerosis.

BACKGROUND: The prevalence of depression in Multiple Sclerosis (MS) is often assessed by administering patient reported outcome measures (PROMs) examining depressive symptomatology to population cohorts; a recent review summarised 12 such studies, eight of which used the Hospital Anxiety and Depression Scale-Depression (HADS-D). In clinical practice, depression is diagnosed by an individual structured clinical interview; diagnosis often leads to treatment options including antidepressant medication. It follows that an MS population will include those whose current depressive symptoms meet threshold for depression diagnosis, plus those who previously met diagnostic criteria for depression and have been treated such that depressive symptoms have improved below that threshold. We examined a large MS population to establish a multi-attribute estimate of depression, taking into account probable depression on HADS-D, as well as anti-depressant medication use and co-morbidity data reporting current treatment for depression. We then studied associations with demographic and health status measures and the trajectories of depressive symptoms over time. METHODS: Participants were recruited into the UK-wide Trajectories of Outcome in Neurological Conditions-MS (TONiC-MS) study, with demographic and disease data from clinical records, PROMs collected at intervals of at least 9 months, as well as co-morbidities and medication. Interval level conversions of PROM data followed Rasch analysis. Logistic regression examined associations of demographic characteristics and symptoms with depression. Finally, a group-based trajectory model was applied to those with depression. RESULTS: Baseline data in 5633 participants showed the prevalence of depression to be 25.3 % (CI: 24.2-26.5). There were significant differences in prevalence by MS subtype: relapsing 23.2 % (CI: 21.8- 24.5), primary progressive 25.8 % (CI: 22.5-29.3), secondary progressive 31.5 % (CI: 29.0-34.0); disability: EDSS 0-4 19.2 % (CI: 17.8-20.6), EDSS ≥4.5 31.9 % (CI: 30.2-33.6); and age: 42-57 years 27.7 % (CI: 26.0-29.3), above or below this range 23.1 % (CI: 21.6-24.7). Fatigue, disability, self-efficacy and self esteem correlated with depression with a large effect size (>0.8) whereas sleep, spasticity pain, vision and bladder had an effect size >0.5. The logistic regression model (N = 4938) correctly classified 80 % with 93 % specificity: risk of depression was increased with disability, fatigue, anxiety, more comorbidities or current smoking. Higher self-efficacy or self esteem and marriage reduced depression. Trajectory analysis of depressive symptoms over 40 months in those with depression (N = 1096) showed three groups: 19.1 % with low symptoms, 49.2 % with greater symptoms between the threshold of possible and probable depression, and 31.7 % with high depressive symptoms. 29.9 % (CI: 27.6-32.3) of depressed subjects were untreated, conversely of those treated, 26.1 % still had a symptom level consistent with a probable case (CI: 23.5-28.9). CONCLUSION: A multi-attribute estimate of depression in MS is essential because using only screening questionnaires, diagnoses or antidepressant medication all under-estimate the true prevalence. Depression affects 25.3 % of those with MS, almost half of those with depression were either untreated or still had symptoms indicating probable depression despite treatment. Services for depression in MS must be pro-active and flexible, recognising the heterogeneity of outcomes and reaching out to those with ongoing symptoms.