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Background People with progressive multiple sclerosis (pwPMS), who typically have established lower limb dysfunction, experience greater disability from upper limb dysfunction (ULD). The 9‐hole peg test (9HPT) is the primary clinical measure for ULD but does not fully capture the patient experience. The ABILHAND‐23 is a well‐validated patient‐reported outcome measure (PROM) that evaluates bimanual ability in daily function. However, no large‐scale studies have assessed if the 9HPT reflects the individual ULD experience in pwPMS. Objectives We sought to (van Munster et al. 2023) assess the associations between the ABILHAND‐23 and 9HPT, and (Huertas‐Hoyas et al. 2020) to assess the ability of the 9HPT and other relevant covariables to predict ABILHAND‐23 scores, using baseline data from the MS‐STAT2 trial, a phase 3 study on simvastatin for secondary progressive MS (SPMS). Methods A cross‐sectional analysis of baseline data from the UCLH cohort of the MS‐STAT2 trial was performed using multiple linear regression to predict ABILHAND‐23 logit scores by 9HPT. Results 225 participants were analyzed. ABILHAND‐23 scores moderately correlated with the 9HPT (rho = 0.47). Regression analysis showed that better 9HPT performance modestly predicted ABILHAND‐23 logits (β = –0.05, SE 0.008, p‐value < 0.001). Conclusion The 9HPT only modestly predicts the ABILHAND‐23 but does not fully capture the individual's daily disability experience, underscoring the value of patient‐reported outcome measures (PROMs) like the ABILHAND‐23 in clinical trials. This graphical summarises the relationship between the 9‐Hole Peg Test (9HPT) and the ABILHAND‐23 in people with progressive multiple sclerosis (pwPMS). Baseline data from MS‐STAT2 (n = 225), showed that the 9HPT moderately correlated with ABILHAND‐23 scores (? = 0.47), but only modestly predicted patient‐reported functional ability. This highlights that timed assessments like the 9HPT do not fully capture the lived experience of upper limb disability, underscoring the complementary value of PROMs such as ABILHAND‐23 in trials and practice.

Vascular risk factors are associated with increased disease activity and disability progression in multiple sclerosis (MS). This has been studied mainly in cohorts with relapsing-remitting MS. However, the association between vascular comorbidities (VCM) and clinical disability in secondary progressive MS (SPMS) is less well studied. Our aim was to investigate the association between VCM, non-VCM, comorbidity burden and both physical and cognitive performance in SPMS. Longitudinal analysis of 445 patients from the MS secondary progressive multi-arm trial (MS-SMART)-a multi-arm multicentre phase-2b randomised placebo-controlled trial of three agents in SPMS (NCT01910259). VCM (hypertension and hyperlipidaemia) and non-VCM (asthma, hypothyroidism and osteoporosis) were recorded. A comorbidity score was also determined (0, 1, ≥ 2). Physical disability and processing speed were assessed at baseline, 48- and 96 weeks. Multiple linear regression and mixed models were used to investigate the cross-sectional and longitudinal relationships between baseline VCM, non-VCM, comorbidity score and clinical outcome measures. The cohort was predominantly female (67%), median Expanded Disability Status Scale (EDSS) 6.0. 13% and 9% had hypertension and hyperlipidaemia (VCM), respectively. 7%, 9% and 5% had asthma, hypothyroidism and osteoporosis (non-VCM), respectively. Co-morbidity counts were 0,63%; 1, 23% and with > = 2, 11%. In cross-sectional models, both hypertension (β = 0.36, 95% CI 0.18-0.54) and an increased comorbidity count (β = 0.47, 95% CI 0.28-0.67) were associated with higher EDSS scores. In longitudinal models, hyperlipidaemia (β = 0.22, 95% CI 0.02-0.42) and increased comorbidity count (β = 0.21, 95% CI 0.01-0.41) were associated with increased EDSS scores over 48/96 weeks. No associations were seen with the non-VCM. VCM and also increased comorbidity burden per se are associated with increased disability. Disability worsening over 96 weeks was most evident in those with hyperlipidaemia and increased comorbidity burden.

Background Slower than planned recruitment is a major factor contributing to the delay or failure of randomised controlled trials to report on time. There is a limited evidence base regarding the optimisation of recruitment strategies. Here we performed an observational review of our experience in recruitment for two large randomised controlled trials for people with secondary progressive multiple sclerosis. We aimed to explicitly determine those factors which can facilitate trial recruitment in progressive neurodegenerative disease. Methods Recruitment data from the sequential MS-SMART [NCT01910259] and MS-STAT2 [NCT03387670] UK randomised controlled trials was reviewed from the largest recruiting site, University College London (UCL). The trial population was similar which allowed comparison over the two recruitment periods of 2015–2016 and 2018–2021. This included sources of referral, progress through stages of recruitment, reasons for participant ineligibility and the impact of publicity events upon recruitment. Results In MS-SMART, 18% of patients contacted were enrolled, compared to 27% for MS-STAT2. Online registration of interest portals provided the greatest number of referrals (76% in MS-SMART, and 51% in MS-STAT2), with publicity in national media outlets producing a demonstrable increase in the number of potential participants. The introduction of an online self-screening questionnaire for MS-STAT2 resulted in 67% of potential participants (3080 of 4605) automatically determining their own ineligibility . In both studies, however, around 60% of those directly telephoned to discuss the study were not eligible, with difficulties related to travel to trial visits, or excluded medication, being the most common issues. Eighty-four percent of those deemed potentially eligible following telephone calls were enrolled in the MS-STAT2 study, compared to only 55% for MS-SMART. Conclusions Through a detailed review of recruiting participants at the largest centre into two large randomised controlled trials with similar entry criteria, we have identified a number of approaches that may improve recruitment efficiency. We highlight here the importance of mandatory online self-screening questionnaires, a coordinated publicity campaign, and simple interventions such as eligibility checklists and appointment reminders. Recruitment approaches should be further assessed through a studies within a trial (SWAT) design. Trial registration MS-SMART: NCT01910259 ; registered July 2013 and MS-STAT2: NCT03387670 ; registered Jan 2018

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system characterised by inflammation, demyelination and neurodegeneration. Although several drugs are approved for MS, their efficacy in progressive disease is modest. Addressing disease progression as a treatment goal in MS is challenging due to several factors. These include a lack of complete understanding of the pathophysiological mechanisms driving MS and the absence of sensitive markers of disease progression in the short-term of clinical trials. MS usually begins at a young age and lasts for decades, whereas clinical research often spans only 1-3 years. Additionally, there is no unifying definition of disease progression. Several drugs are currently being investigated for progressive MS. In addition to new medications, the rise of new technologies and of adaptive trial designs is enabling larger and more integrated data collection. Remote assessments and decentralised clinical trials are becoming feasible. These will allow more efficient and large studies at a lower cost and with less burden on study participants. As new drugs are developed and research evolves, we anticipate a concurrent change in patient care at various levels in the foreseeable future. We conducted a narrative review to discuss the challenges of accurately measuring disease progression in contemporary MS drug trials, some new research trends and their implications for patient care.

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system characterised by inflammation, demyelination and neurodegeneration. Although several drugs are approved for MS, their efficacy in progressive disease is modest. Addressing disease progression as a treatment goal in MS is challenging due to several factors. These include a lack of complete understanding of the pathophysiological mechanisms driving MS and the absence of sensitive markers of disease progression in the short-term of clinical trials. MS usually begins at a young age and lasts for decades, whereas clinical research often spans only 1–3 years. Additionally, there is no unifying definition of disease progression. Several drugs are currently being investigated for progressive MS. In addition to new medications, the rise of new technologies and of adaptive trial designs is enabling larger and more integrated data collection. Remote assessments and decentralised clinical trials are becoming feasible. These will allow more efficient and large studies at a lower cost and with less burden on study participants. As new drugs are developed and research evolves, we anticipate a concurrent change in patient care at various levels in the foreseeable future. We conducted a narrative review to discuss the challenges of accurately measuring disease progression in contemporary MS drug trials, some new research trends and their implications for patient care.

What you need to know: Disease-modifying therapies (DMTs) early in the course of active relapsing multiple sclerosis can prevent relapses, new brain and spinal cord lesions, and worsening neurological disability; Some DMTs are associated with potentially serious adverse reactions, and careful monitoring is required, usually through a specialist multiple sclerosis clinic; Newer DMTs have better short term outcomes than older DMTs, but there are insufficient data about their long term effectiveness and harms. A 32 year old woman with multiple sclerosis presented to her general practitioner with a five day history of numbness and weakness in the right leg. She felt well in herself and did not describe any symptoms to suggest an intercurrent infection. She had been taking weekly intramuscular injections of interferon beta-1a for the previous 18 months and reported flu-like symptoms that could last for up to 24 hours after each dose. She asked if there was a need to change her treatment and what alternatives were available.

Multiple sclerosis is an immune-mediated inflammatory disease of the central nervous system characterised by demyelination, neuroaxonal loss and a heterogeneous clinical course. Multiple sclerosis presents with different phenotypes, most commonly a relapsing–remitting course and, less frequently, a progressive accumulation of disability from disease onset (primary progressive multiple sclerosis). The majority of people with relapsing–remitting multiple sclerosis, after a variable time, switch to a stage characterised by gradual neurological worsening known as secondary progressive multiple sclerosis. We have a limited understanding of the mechanisms underlying multiple sclerosis, and it is believed that multiple genetic, environmental and endogenous factors are elements driving inflammation and ultimately neurodegeneration. Axonal loss and grey matter damage have been regarded as amongst the leading causes of irreversible neurological disability in the progressive stages. There are over a dozen disease-modifying therapies currently licenced for relapsing–remitting multiple sclerosis, but none of these has provided evidence of effectiveness in secondary progressive multiple sclerosis. Recently, there has been some early modest success with siponimod in secondary progressive multiple sclerosis and ocrelizumab in primary progressive multiple sclerosis. Finding treatments to delay or prevent the courses of secondary progressive multiple sclerosis is an unmet and essential goal of the research in multiple sclerosis. In this review, we discuss new findings regarding drugs with immunomodulatory, neuroprotective or regenerative properties and possible treatment strategies for secondary progressive multiple sclerosis. We examine the field broadly to include trials where participants have progressive or relapsing phenotypes. We summarise the most relevant results from newer investigations from phase II and III randomised controlled trials over the past decade, with particular attention to the last 5 years.

Background Pisa Syndrome or Pleurothotonus is a relatively rare truncal dystonia, characterized by tonic flexion of the trunk and head to one side with slight rotation of the body. Since frequently associated to specific drugs such as antipsychotics and cholinesterase inhibitors or to Parkinson Disease, a pathophysiological role of cholinergic-dopaminergic imbalance has been suggested. We report here the first case of Pisa Syndrome due to an extracerebral pathology as subdural haematoma. Case presentation A hypertensive patient was admitted to Our Department for subacute onset of tonic flexion and slight rotation of the trunk associated to progressive motor deficit in left upper limb after a mild head trauma without loss of consciousness occurred around three month before. No previous or current pharmacological interventions with antidepressant, neuroleptic or anticholinergic drugs were anamnestically retrieved. Familiar and personal history was negative for neurological disorders other than acute cerebrovascular diseases. Acutely performed cerebral MRI with DWI showed a voluminous right subdural haematoma with mild shift of median line. After surgical evacuation, both motor deficit and truncal dystonia were dramatically resolved. At one-year follow up, the patient did not develop any extrapyramidal and cognitive signs or symptoms. Conclusions According to many Authors, the occurrence of truncal dystonia during several pharmacologic treatments and neurodegenerative disorders (such as Alzheimer disease and parkinsonian syndromes) supported the hypothesis that a complex dysregulation of multiple neurotransmitter systems are involved. We suggest a possible role of basal ganglia compression in pathogenesis of truncal dystonia by means of thalamo-cortical trait functional disruption and loss of proprioceptive integration. A further contribution of the subcortical structure displacement that alters motor cortex connectivity to basal ganglia may be postulated.

Secondary progressive multiple sclerosis (SPMS) is diagnosed retrospectively and involves a clinical course characterized by a progressive accumulation of neurological disability, independent of relapses, following an initial relapsing–remitting (RR) phase. Our incomplete understanding of the pathological mechanisms underlying neurodegeneration in multiple sclerosis (MS) may explain why, to date, there is no definitive imaging or laboratory test that is able to inform us when the disease is clearly entering into a progressive phase and why the vast majority of clinical trials testing immunosuppressant and immunomodulating drugs in SPMS patients has so far yielded disappointing or mixed results. Here we discuss the definition(s) of SPMS and how it may vary, outcome measurements (current and emerging) and modern trial design.