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.

Real-world data on siponimod-related lymphopenia among people with secondary progressive multiple sclerosis.

BACKGROUND: Siponimod-related lymphopenia in real-world clinical practice has implications for dose adjustment and infection risk. OBJECTIVE: To characterise siponimod-related lymphopenia in people with secondary progressive multiple sclerosis (pwSPMS). METHODS: This is a retrospective cohort of 188 pwSPMS. The development of grade 4 lymphopenia was interrogated with Kaplan-Meier survival analysis and binary logistic regression. RESULTS: Lymphopenia develops soon after commencing siponimod. In total, 15 (8.5%) of 176 experienced grade 4 lymphopenia at 1 month after initiation. There were no clinically significant associations between patient characteristics and development of grade 4 lymphopenia. CONCLUSION: Grade 4 lymphopenia can occur soon after siponimod initiation and cannot be predicted.

Assessing treatment response to oral drugs for multiple sclerosis in real-world setting: a MAGNIMS Study.

BACKGROUND: The assessment of treatment response is a crucial step for patients with relapsing-remitting multiple sclerosis on disease-modifying therapies (DMTs). We explored whether a scoring system developed within the MAGNIMS (MRI in Multiple Sclerosis) network to evaluate treatment response to injectable drugs can be adopted also to oral DMTs. METHODS: A multicentre dataset of 1200 patients who started three oral DMTs (fingolimod, teriflunomide and dimethyl fumarate) was collected within the MAGNIMS network. Disease activity after the first year was classified by the 'MAGNIMS' score based on the combination of relapses (0-≥2) and/or new T2 lesions (<3 or ≥3) on brain MRI. We explored the association of this score with the following 3-year outcomes: (1) confirmed disability worsening (CDW); (2) treatment failure (TFL); (3) relapse count between years 1 and 3. The additional value of contrast-enhancing lesions (CELs) and lesion location was explored. RESULTS: At 3 years, 160 patients experienced CDW: 12% of them scored '0' (reference), 18% scored '1' (HR=1.82, 95% CI 1.20 to 2.76, p=0.005) and 37% scored '2' (HR=2.74, 95% CI 1.41 to 5.36, p=0.003) at 1 year. The analysis of other outcomes provided similar findings. Considering the location of new T2 lesions (supratentorial vs infratentorial/spinal cord) and the presence of CELs improved the prediction of CDW and TFL, respectively, in patients with minimal MRI activity alone (one or two new T2 lesions). CONCLUSIONS: Early relapses and substantial MRI activity in the first year of treatment are associated with worse short-term outcomes in patients treated with some of the oral DMTs.

Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis.

Cognitive impairment in multiple sclerosis (MS) can adversely impact participation in employment, activities of daily living, and wider society. It affects 40-70% of people living with MS (pwMS). There are few effective treatments for cognitive impairment in people with MS. Neuromodulation with intermittent theta-burst stimulation (iTBS) has potential for treating cognitive impairment in pwMS. This single-centre mixed-methods feasibility randomised controlled trial (NCT04931953) will assess feasibility, acceptability, and tolerability of procedures used for applying iTBS for improving cognitive performance in pwMS. Participants will be randomised into three intervention groups with varying lengths of iTBS treatment (from 1 to 4 weeks) and a sham-control group. Quantitative data will be collected at three time points (baseline, end of intervention, and 8-week follow-up). End of the intervention semi-structured interviews will explore the views and experiences of the participants receiving the intervention, analysed using framework analysis. Quantitative and qualitative data will be synthesised to explore the impact of the iTBS intervention. Ethical approval has been received from the Health Research Authority (21/LO/0506) and recruitment started in June 2022. The results will inform the design of an RCT of the efficacy of iTBS as a therapeutic intervention for cognitive impairment in pwMS.

Risk of COVID-19 in people with multiple sclerosis who are seronegative following vaccination.

BACKGROUND: People with multiple sclerosis (pwMS) treated with certain disease-modifying therapies (DMTs) have attenuated IgG response following COVID-19 vaccination; however, the clinical consequences remain unclear. OBJECTIVE: To report COVID-19 rates in pwMS according to vaccine serology. METHODS: PwMS with available (1) serology 2-12 weeks following COVID-19 vaccine 2 and/or vaccine 3 and (2) clinical data on COVID-19 infection/hospitalisation were included. Logistic regression was performed to examine whether seroconversion following vaccination predicted risk of subsequent COVID-19 infection after adjusting for potential confounders. Rates of severe COVID-19 (requiring hospitalisation) were also calculated. RESULTS: A total of 647 pwMS were included (mean age 48 years, 500 (77%) female, median Expanded Disability Status Scale (EDSS) 3.5% and 524 (81%) exposed to DMT at the time of vaccine 1). Overall, 472 out of 588 (73%) were seropositive after vaccines 1 and 2 and 222 out of 305 (73%) after vaccine 3. Seronegative status after vaccine 2 was associated with significantly higher odds of subsequent COVID-19 infection (odds ratio (OR): 2.35, 95% confidence interval (CI): 1.34-4.12, p = 0.0029), whereas seronegative status after vaccine 3 was not (OR: 1.05, 95% CI: 0.57-1.91). Five people (0.8%) experienced severe COVID-19, all of whom were seronegative after most recent vaccination. CONCLUSION: Attenuated humoral response to initial COVID-19 vaccination predicts increased risk of COVID-19 in pwMS, but overall low rates of severe COVID-19 were seen.

ADAMS project: a genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis based in the UK.

PURPOSE: Genetic studies of multiple sclerosis (MS) susceptibility and severity have focused on populations of European ancestry. Studying MS genetics in other ancestral groups is necessary to determine the generalisability of these findings. The genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis (ADAMS) project aims to gather genetic and phenotypic data on a large cohort of ancestrally-diverse individuals with MS living in the UK. PARTICIPANTS: Adults with self-reported MS from diverse ancestral backgrounds. Recruitment is via clinical sites, online (https://app.mantal.co.uk/adams) or the UK MS Register. We are collecting demographic and phenotypic data using a baseline questionnaire and subsequent healthcare record linkage. We are collecting DNA from participants using saliva kits (Oragene-600) and genotyping using the Illumina Global Screening Array V.3. FINDINGS TO DATE: As of 3 January 2023, we have recruited 682 participants (n=446 online, n=55 via sites, n=181 via the UK MS Register). Of this initial cohort, 71.2% of participants are female, with a median age of 44.9 years at recruitment. Over 60% of the cohort are non-white British, with 23.5% identifying as Asian or Asian British, 16.2% as Black, African, Caribbean or Black British and 20.9% identifying as having mixed or other backgrounds. The median age at first symptom is 28 years, and median age at diagnosis is 32 years. 76.8% have relapsing-remitting MS, and 13.5% have secondary progressive MS. FUTURE PLANS: Recruitment will continue over the next 10 years. Genotyping and genetic data quality control are ongoing. Within the next 3 years, we aim to perform initial genetic analyses of susceptibility and severity with a view to replicating the findings from European-ancestry studies. In the long term, genetic data will be combined with other datasets to further cross-ancestry genetic discoveries.

Real-world annualized relapse rates from contemporary multiple sclerosis clinics in the UK: a retrospective multicentre cohort study.

BACKGROUND: Annualized relapse rate (ARR) is used as an outcome measure in multiple sclerosis (MS) clinical trials. Previous studies demonstrated that ARR has reduced in placebo groups between 1990 and 2012. This study aimed to estimate real-world ARRs from contemporary MS clinics in the UK, in order to improve the feasibility estimations for clinical trials and facilitate MS service planning. METHODS: A multicentre observational, retrospective study of patients with MS from 5 tertiary neuroscience centres in the UK. We included all adult patients with a diagnosis of MS that had a relapse between 01/04/2020 and 30/06/2020. RESULTS: One hundred thirteen out of 8783 patients had a relapse during the 3-month study period. Seventy-nine percent of the patients with a relapse were female, the mean age was 39 years, and the median disease duration was 4.5 years; 36% of the patients that had a relapse were on disease-modifying treatment. The ARR from all study sites was estimated at 0.05. The ARR for relapsing remitting MS (RRMS) was estimated at 0.08, while the ARR for secondary progressive MS (SPMS) was 0.01. CONCLUSIONS: We report a lower ARR compared to previously reported rates in MS.

An update on the use of sphingosine 1-phosphate receptor modulators for the treatment of relapsing multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is an immune-mediated disorder of the CNS manifested by recurrent attacks of neurological symptoms (related to focal inflammation) and gradual disability accrual (related to progressive neurodegeneration and neuroinflammation). Sphingosine-1-phosphate-receptor (S1PR) modulators are a class of oral disease-modifying therapies (DMTs) for relapsing MS. The first S1PR modulator developed and approved for MS was fingolimod, followed by siponimod, ozanimod, and ponesimod. All are S1P analogues with different S1PR-subtype selectivity. They restrain the S1P-dependent lymphocyte egress from lymph nodes by binding the lymphocytic S1P-subtype-1-receptor. Depending on their pharmacodynamics and pharmacokinetics, they can also interfere with other biological functions. AREAS COVERED: Our narrative review covers the PubMed English literature on S1PR modulators in MS until August 2022. We discuss their pharmacology, efficacy, safety profile, and risk management recommendations based on the results of phase II and III clinical trials. We briefly address their impact on the risk of infections and vaccines efficacy. EXPERT OPINION: S1PR modulators decrease relapse rate and may modestly delay disease progression in people with relapsing MS. Aside their established benefit, their place and timing within the long-term DMT strategy in MS, as well as their immunological effects in the new and evolving context of the post-COVID-19 pandemic and vaccination campaigns warrant further study.

Predictors of long-term disability in multiple sclerosis patients using routine magnetic resonance imaging data: A 15-year retrospective study.

INTRODUCTION: Early identification of patients at high risk of progression could help with a personalised treatment strategy. Magnetic resonance imaging (MRI) measures have been proposed to predict long-term disability in multiple sclerosis (MS), but a reliable predictor that can be easily implemented clinically is still needed. AIM: Assess MRI measures during the first 5 years of the MS disease course for the ability to predict progression at 10+ years. METHODS: Eighty-two MS patients (53 females), with ≥10 years of clinical follow-up and having two MRI scans, were included. Clinical data were obtained at baseline, follow-up and at ≥10 years. White matter lesion (WML) counts and volumes, and four linear brain sizes were measured on T2/FLAIR 'Fluid-Attenuated-Inversion-Recovery' and T1-weighted images. RESULTS: Baseline and follow-up inter-caudate diameter (ICD) and third ventricular width (TVW) measures correlated positively with Expanded Disability Status Scale, ≥10 or more of WMLs showed a high sensitivity in predicting progression, at ≥10 years. A steeper rate of lesion volume increase was observed in subjects converting to secondary progressive MS. The sensitivity and specificity of both ICD and TVW, to predict disability at ≥10 years were 60% and 64%, respectively. CONCLUSION: Despite advances in brain imaging and computerised volumetric analysis, ICD and TVW remain relevant as they are simple, fast and have the potential in predicting long-term disability. However, in this study, despite the statistical significance of these measures, the clinical utility is still not reliable.

Nitrous oxide-induced subacute combined degeneration of the cord: diagnosis and treatment.

Recreational use of nitrous oxide (N2O) has increased rapidly in recent years and is now the second most commonly used recreational drug among young people in the UK. There has been a corresponding rise in cases of nitrous oxide-induced subacute combined degeneration of the cord (N2O-SACD), a pattern of myeloneuropathy usually associated with severe vitamin B12 deficiency. This can cause serious and permanent disability in young people but, if recognised early, may be effectively treated. All neurologists should be aware of N2O-SACD and its treatment; however, there are currently no agreed guidelines. Based on our experience in East London, an area of high N2O use, we provide practical advice on its recognition, investigation and treatment.

Developing a patient care pathway for emotional support around the point of multiple sclerosis diagnosis: A stakeholder engagement study.

BACKGROUND: Diagnosing multiple sclerosis (MS) can be a lengthy process, which can negatively affect psychological well-being, condition management, and future engagement with health services. Therefore, providing timely and appropriate emotional support may improve adjustment and health outcomes. PURPOSE: To develop a patient care pathway for providing emotional support around the point of diagnosing MS, and to explore potential barriers and facilitators to delivery and implementation. METHODS: Focus groups were conducted with 26 stakeholders, including 16 people living with MS, 5 carers/family members and 5 professionals working with people living with MS (3 MS nurses, 1 psychiatrist, and 1 charity staff member). Discussions were audio-recorded, transcribed verbatim and analyzed using framework analysis. RESULTS: Participants suggested that a patient care pathway should include comprehensive information provision as a part of emotional support at diagnosis, and follow-up sessions with a healthcare professional. Barriers including increasing staff workloads and financial costs to health services were acknowledged, thus participants suggested including peer support workers to deliver additional emotional support. All participants agreed that elements of a care pathway and embedded interventions should be individually tailored, yet provided within a standardized system to ensure accessibility. CONCLUSIONS: A patient care pathway was developed with stakeholders, which included an embedded MS Nurse support intervention supplemented with peer support sessions. Participants suggested that the pathway should be delivered within a standardized system to ensure equity of service provision across the country. PATIENT OR PUBLIC CONTRIBUTION: This research was conceptualized and designed collaboratively with Nottingham Multiple Sclerosis Patient and Public Involvement and Engagement (PPIE) group members. One member is a co-author and was actively involved in every key stage of the research process, including co-design of the pathway and research protocol, data collection (including presenting to participants and moderating group discussions), analysis and write-up. Authors consulted with PPIE members at two meetings (9 and 11 PPIE attendees per meeting) where they gave feedback on the research design, findings and the resulting pathway. People living with MS and carers of people with MS were included in the focus groups as participants.

Decentralised clinical trials in multiple sclerosis research.

Randomised controlled trials (RCTs) play an important role in multiple sclerosis (MS) research, ensuring that new interventions are safe and efficacious before their introduction into clinical practice. Trials have been evolving to improve the robustness of their designs and the efficiency of their conduct. Advances in digital and mobile technologies in recent years have facilitated this process and the first RCTs with decentralised elements became possible. Decentralised clinical trials (DCTs) are conducted remotely, enabling participation of a more heterogeneous population who can participate in research activities from different locations and at their convenience. DCTs also rely on digital and mobile technologies which allows for more flexible and frequent assessments. While hospitals quickly adapted to e-health and telehealth assessments during the COVID-19 pandemic, the conduct of conventional RCTs was profoundly disrupted. In this paper, we review the existing evidence and gaps in knowledge in the design and conduct of DCTs in MS.

Experiences of receiving a diagnosis of multiple sclerosis: a meta-synthesis of qualitative studies.

PURPOSE: This meta-synthesis aimed to synthesise qualitative evidence on experiences of people with Multiple Sclerosis (MS) in receiving a diagnosis, to derive a conceptual understanding of adjustment to MS diagnosis. METHODS: Five electronic databases were systematically searched to identify qualitative studies that explored views and experiences around MS diagnosis. Papers were quality-appraised using a standardised checklist. Data synthesis was guided by principles of meta-ethnography, a well-established interpretive method for synthesising qualitative evidence. RESULTS: Thirty-seven papers were selected (with 874 people with MS). Synthesis demonstrated that around the point of MS diagnosis people experienced considerable emotional upheaval (e.g., shock, denial, anger, fear) and difficulties (e.g., lengthy diagnosis process) that limited their ability to make sense of their diagnosis, leading to adjustment difficulties. However, support resources (e.g., support from clinicians) and adaptive coping strategies (e.g., acceptance) facilitated the adjustment process. Additionally, several unmet emotional and informational support needs (e.g., need for personalised information and tailored emotional support) were identified that, if addressed, could improve adjustment to diagnosis. CONCLUSIONS: Our synthesis highlights the need for providing person-centred support and advice at the time of diagnosis and presents a conceptual map of adjustment for designing interventions to improve adjustment following MS diagnosis.Implications for RehabilitationThe period surrounding Multiple Sclerosis diagnosis can be stressful and psychologically demanding.Challenges and disruptions at diagnosis can threaten sense of self, resulting in negative emotions.Adaptive coping skills and support resources could contribute to better adjustment following diagnosis.Support interventions should be tailored to the needs of newly diagnosed people.

Strengthening Mental Abilities with Relational Training (SMART) in multiple sclerosis (MS): study protocol for a feasibility randomised controlled trial.

BACKGROUND: Multiple sclerosis (MS) is a chronic condition of the central nervous system, affecting around 1 in every 600 people in the UK, with 130 new diagnoses every week. Cognitive difficulties are common amongst people with MS, with up to 70% experiencing deficits in higher-level brain functions-such as planning and problem-solving, attention, and memory. Cognitive deficits make it difficult for people with MS to complete everyday tasks and limit their abilities to work, socialise, and live independently. There is a clear need-and recognised research priority-for treatments that can improve cognitive functioning in people with MS. The absence of effective cognitive interventions exacerbates burdens on the services accessed by people with MS-requiring these services to manage sequelae of untreated cognitive deficits, including reduced quality of life, greater disability and dependence, and poorer adherence to disease-modifying treatments. Our planned research will fill the evidence gap through developing-and examining the feasibility of trialling-a novel online cognitive rehabilitation programme for people with MS (SMART). The SMART programme directly trains relational skills (the ability to flexibly relate concepts to one another) based on theory that these skills are critical to broader cognitive functioning. METHODS: The primary objective of this study aims to conduct a feasibility study to inform the development of a definitive trial of SMART for improving cognitive functioning in people with MS. The secondary objective is to develop the framework for a cost-effectiveness analysis alongside a definitive trial, and the exploratory objective is to assess the signal of efficacy. DISCUSSION: As a feasibility trial, outcomes are unlikely to immediately effect changes to NHS practice. However, this is a necessary step towards developing a definitive trial-and will give us a signal of efficacy, a prerequisite for progression to a definitive trial. If found to be clinically and cost-effective, the latter trial could create a step-change in MS cognitive rehabilitation-improving service delivery and optimising support with limited additional resources. TRIAL REGISTRATION: Registration ID: ClnicalTrials.gov: NCT04975685-registered on July 23rd, 2021. PROTOCOL VERSION: 2.0, 25 November 2021.

Psychological flexibility, distress, and quality of life in secondary progressive multiple sclerosis: A cross-sectional study.

INTRODUCTION: One of the strongest predictors of successful coping in multiple sclerosis (MS) is the extent to which one can accept the diagnosis and limitations associated with the disease. Acceptance is also one of three core processes of psychological flexibility - a malleable treatment target of some psychological therapies. This is the ability to notice and accept the presence of thoughts and feelings without being swept along by them, engaging in the present moment, and making decisions in line with personal values. Poor psychological flexibility is associated with elevated levels of distress in the general population. However, we do not know the level of psychological flexibility in people with MS, or its relationship to distress or quality of life when the disease becomes more physically disabling. The aims of this study were to determine the level of psychological flexibility, and its relationship with distress and quality of life in secondary progressive multiple sclerosis (SPMS), a subtype of MS with increased severity of disability and distress. METHOD: This cross-sectional analytic study used data collected by the UK MS Register. Pre-existing data on distress, quality of life, disability, and demographics collected by the UK MS Register were combined with a psychological flexibility measure and its component parts, collected for the purpose of this study. Patient demographics and questionnaire data were recorded for distress, quality of life, and psychological flexibility. Pearson's correlations were used to examine bivariate relationships between distress, quality of life, disability and psychological flexibility. Whether psychological flexibility moderated the relationship between disability (predictor), distress and quality of life (outcomes) was also investigated. RESULTS: Between February and March 2020, 628 participants with SPMS completed the CompACT and had a recent (<12 months) HADS questionnaire (Mage = 60.66, 70.90% women). On the HADS questionnaire subscales, 44% of the sample scored above the MS clinical cut-off (≥8) for anxiety (M = 7.09, SD = 4.57), and 30% above the clinical cut off (≥11) for depression (M = 8.35, SD = 4.21). Psychological flexibility (M = 81.94, SD = 22.60) and its components were each moderately negatively correlated with total distress (r = -0.65), anxiety (r = -0.58), and depression (r = -0.56). A second subsample (n = 434) completed the EQ-5D-5L health-related quality of life measure, which was moderately positively correlated with psychological flexibility (r = 0.47). A third subsample (n = 210) found a weak negative relationship between psychological flexibility and disability (r = -0.16), a weak positive relationship between distress and disability (r = 0.26), and a moderate negative relationship between quality of life and disability (r = -0.56). Psychological flexibility was not found to moderate the relationships between disability and anxiety, depression, or quality of life in SPMS. DISCUSSION: Greater psychological flexibility was associated with lower self-reported distress and higher quality of life in this SPMS sample. It was not shown to moderate the extent to which physical disability predicts distress or quality of life in SPMS. These findings demonstrate that greater psychological flexibility is related to better coping outcomes (lower distress, higher quality of life) in SPMS. If psychological flexibility can be increased in people with SPMS, this could lead to a reduction in distress and improvement in quality of life, although directionality could not be attributed with these methods. Further longitudinal evidence and trials of psychological flexibility-focussed interventions are needed.

Longitudinal clinical study of patients with iron rim lesions in multiple sclerosis.

BACKGROUND: Iron rims (IRs) surrounding white matter lesions (WMLs) are suggested to predict a more severe disease course. Only small longitudinal cohorts of patients with and without iron rim lesions (IRLs) have been reported so far. OBJECTIVE: To assess whether the presence and number of IRLs in patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS) are associated with long-term disability or progressive disease. METHODS: Ninety-one CIS/MS patients were recruited between 2008 and 2013 and scanned with 7 T magnetic resonance imaging (MRI). Expanded Disability Status Scale (EDSS) was used to calculate Age-related Multiple Sclerosis Severity Score (ARMSS) at the time of scan and at the latest clinical follow-up after 9 years. WMLs were assessed for the presence of IRL using Susceptibility weighted imaging (SWI)-filtered phase images. RESULTS: In all, 132 IRLs were detected in 42 patients (46%); 9% of WMLs had IRs; 54% of the cohort had no rims, 30% had 1-3 rims and 16% had ⩾4. Patients with IRL had a higher EDSS and ARMSS. Presence of IRL was also a predictor of long-term disability, especially in patients with ⩾4 IRLs. IRLs have a greater impact on disability compared to the WML number and volume. CONCLUSION: The presence and number of perilesional IR on MRI hold prognostic value for long-term clinical disability in MS.

Paramagnetic rims are a promising diagnostic imaging biomarker in multiple sclerosis.

BACKGROUND: White matter lesions (WMLs) on brain magnetic resonance imaging (MRI) in multiple sclerosis (MS) may contribute to misdiagnosis. In chronic active lesions, peripheral iron-laden macrophages appear as paramagnetic rim lesions (PRLs). OBJECTIVE: To evaluate the sensitivity and specificity of PRLs in differentiating MS from mimics using clinical 3T MRI scanners. METHOD: This retrospective international study reviewed MRI scans of patients with MS (n = 254), MS mimics (n = 91) and older healthy controls (n = 217). WMLs, detected using fluid-attenuated inversion recovery MRI, were analysed with phase-sensitive imaging. Sensitivity and specificity were assessed for PRLs. RESULTS: At least one PRL was found in 22.9% of MS and 26.1% of clinically isolated syndrome (CIS) patients. Only one PRL was found elsewhere. The identification of ⩾1 PRL was the optimal cut-off and had high specificity (99.7%, confidence interval (CI) = 98.20%-99.99%) when distinguishing MS and CIS from mimics and healthy controls, but lower sensitivity (24.0%, CI = 18.9%-36.6%). All patients with a PRL showing a central vein sign (CVS) in the same lesion (n = 54) had MS or CIS, giving a specificity of 100% (CI = 98.8%-100.0%) but equally low sensitivity (21.3%, CI = 16.4%-26.81%). CONCLUSION: PRLs may reduce diagnostic uncertainty in MS by being a highly specific imaging diagnostic biomarker, especially when used in conjunction with the CVS.

Response to COVID-19 booster vaccinations in seronegative people with multiple sclerosis.

BACKGROUND: People with MS treated with anti-CD20 therapies and fingolimod often have attenuated responses to initial COVID-19 vaccination. However, uncertainties remain about the benefit of a 3rd (booster) COVID-19 vaccine in this group. METHODS: PwMS without a detectable IgG response following COVID-19 vaccines 1&2 were invited to participate. Participants provided a dried blood spot +/- venous blood sample 2-12 weeks following COVID-19 vaccine 3. Humoral and T cell responses to SARS-CoV-2 spike protein and nucleocapsid antigen were measured. RESULTS: Of 81 participants, 79 provided a dried blood spot sample, of whom 38 also provided a whole blood sample; 2 provided only whole blood. Anti-SARS-CoV-2-spike IgG seroconversion post-COVID-19 vaccine 3 occurred in 26/79 (33%) participants; 26/40 (65%) had positive T-cell responses. Overall, 31/40 (78%) demonstrated either humoral or cellular immune response post-COVID-19 vaccine 3. There was no association between laboratory evidence of prior COVID-19 and seroconversion following vaccine 3. CONCLUSIONS: Approximately one third of pwMS who were seronegative after initial COVID-19 vaccination seroconverted after booster (third) vaccination, supporting the use of boosters in this group. Almost 8 out of 10 had a measurable immune response following 3rd COVID-19 vaccine.

Neuropsychological evaluation and rehabilitation in multiple sclerosis (NEuRoMS): protocol for a mixed-methods, multicentre feasibility randomised controlled trial.

BACKGROUND: Cognitive problems affect up to 70% of people with multiple sclerosis (MS), which can negatively impact mood, ability to work, and quality of life. Addressing cognitive problems is a top 10 research priority for people with MS. Our ongoing research has systematically developed a cognitive screening and management pathway (NEuRoMS) tailored for people with MS, involving a brief cognitive evaluation and rehabilitation intervention. The present study aims to assess the feasibility of delivering the pathway and will inform the design of a definitive randomised controlled trial (RCT) to investigate the clinical and cost-effectiveness of the intervention and eventually guide its clinical implementation. METHODS: The feasibility study is in three parts. Part 1 involves an observational study of those who receive screening and support for cognitive problems, using routinely collected clinical data. Part 2 is a two-arm, parallel group, multicentre, feasibility RCT with a nested fidelity evaluation. This part will evaluate the feasibility of undertaking a definitive trial comparing the NEuRoMS intervention plus usual care to usual care only, amongst people with MS with mild cognitive problems (n = 60). In part 3, semi-structured interviews will be undertaken with participants from part 2 (n = 25), clinicians (n = 9), and intervention providers (n = 3) involved in delivering the NEuRoMS cognitive screening and management pathway. MS participants will be recruited from outpatient clinics at three UK National Health Service hospitals. DISCUSSION: Timely screening and effective management of cognitive problems in MS are urgently needed due to the detrimental consequences of cognitive problems on people with MS, the healthcare system, and wider society. The NEuRoMS intervention is based on previous and extant literature and has been co-constructed with relevant stakeholders. If effective, the NEuRoMS pathway will facilitate timely identification and management of cognitive problems in people with MS. TRIAL REGISTRATION: ISRCTN11203922 . Prospectively registered on 09.02.2021.

Effectiveness of acceptance and commitment therapy for improving quality of life and mood in individuals with multiple sclerosis: A systematic review and meta-analysis.

OBJECTIVE: To review the evidence for the effectiveness of Acceptance and Commitment Therapy (ACT) intervention on quality of life and mood, for individuals with Multiple Sclerosis (MS). METHOD: A systematic search was conducted of PsycINFO, CINAHL, Embase, MEDLINE, Web of Science, Scopus and ContextualScience.org up to 13/01/2022. Grey literature was also searched via ProQuest Dissertations and Theses, and PROSPERO. We included Randomised Controlled Trials (RCTs) published in English, that examined the effectiveness of ACT for people with a diagnosis of MS. We were interested in outcomes of Quality of Life (QoL), mood (e.g., anxiety, depression and stress), and ACT-targeted processes. Methodological quality was assessed using the Cochrane Risk of Bias Tool v2. Where available, the extracted data were entered into a meta-analysis to determine weighted effect size estimates for the outcomes of interest. RESULTS: Six studies (191 participants), out of 142 identified, met inclusion criteria. Meta-analyses indicated a statistically significant small effect on stress (SMD = -0.49 [95% CI of -0.89 - -0.08]), in favour of ACT. There were no statistically significant effects of ACT on anxiety (SMD = -0.41 [95% CI of -0.93 - 0.11]), depression (SMD = -0.92 [95% CI of -1.91 - 0.06]), or ACT-targeted processes (SMD = -0.18 [95% CI of -0.62 - 0.25]). There was a small, nonsignificant effect on QoL, in favour of control conditions (SMD=0.39 [95% CI of -0.08 - 0.85]). Methodological quality of the studies was variable; all but one study had at least one high risk of bias. CONCLUSIONS: Findings suggest a small effect of ACT on reducing stress for people with MS, but not reducing anxiety or depression, or improving quality of life. Due to small sample sizes and few studies within this area, generalisability of findings is limited. Future trials should be pay more attention to methodological rigour.