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About 10–15% of patients with multiple sclerosis (MS) present with gradually increasing neurological disability, a disorder known as primary-progressive multiple sclerosis (PPMS). Compared with relapse-onset multiple sclerosis, people with PPMS are older at onset and a higher proportion are men. Inflammatory white-matter lesions are less evident but diffuse axonal loss and microglial activation are seen in healthy-looking white matter, in addition to cortical demyelination, and quantitative MRI shows atrophy and intrinsic abnormalities in the grey matter and the white matter. Spinal cord atrophy corresponds to the usual clinical presentation of progressive spastic paraplegia. Although neuroaxonal degeneration seems to underlie PPMS, the pathogenesis and the extent to which immune-mediated mechanisms operate is unclear. MRI of the brain and spinal cord, and examination of the CSF, are important investigations for diagnosis; conventional immunomodulatory therapies, such as interferon beta and glatiramer acetate, are ineffective. Future research should focus on the clarification of the mechanisms of axonal loss, improvements to the design of clinical trials, and the development of effective neuroprotective treatments.

The Association of British Neurologists last published guidelines on disease-modifying treatment (DMT) in multiple sclerosis (MS) in 2015. Since then, additional DMTs have been licensed and approved for prescribing within the National Health Service for relapsing-remitting MS, early primary progressive MS and active secondary progressive MS. This updated guidance provides a consensus-based approach to using DMTs. We provide recommendations for eligibility, starting, monitoring, switching and stopping of DMTs; pregnancy; equitable access to DMT; autologous haemopoietic stem-cell transplantation; and use of generics. We highlight best practice where it exists and discuss future priorities.

Intraluminal thrombus (ILT) is present in 75% of clinically-relevant abdominal aortic aneurysms (AAAs) yet, despite much research effort, its role in AAA biomechanics remains unclear. The aim of this work is to further evaluate the biomechanics of ILT and determine if different ILT morphologies have varying mechanical properties. Biaxial mechanical tests were performed on ILT samples harvested from 19 patients undergoing open surgical repair. ILT were separated into luminal, medial and medial/abluminal layers. A total of 356 tests were performed and the Cauchy stress (σ) and tangential modulus (TM) at a stretch ratio (λ) of 1.14 were recorded for each test in both the circumferential (θ) and longitudinal (L) directions. Our data revealed three distinct types of ILT morphologies, each with a unique set of mechanical properties. All ILT layers were found to be isotropic and inhomogeneous. Type 1 (n=10) was a multi-layered ILT (thick medial/abluminal layer) whose strength and stiffness decreased gradually from the luminal to the medial/abluminal layer. Type 2 (n=6) was a multi-layered ILT (thin/highly degraded medial/abluminal layer) whose strength and stiffness decreased abruptly between the luminal and medial/abluminal layer and Type 3 (n=3) is a single layered ILT with a lower strength and stiffness than Types 1 and 2. In a sub-study, we found the luminal layer to be stronger and stiffer in the posterior than the anterior region. This work provides further insights to the biomechanical behaviour of ILT and the use of our ILT classification may be useful in future studies.

IntroductionPeople with MS (PwMS) leave work earlier than expected. Work instability can be linked to psychological factors. Resilience-training interventions may improve psychological factors such as self-efficacy. An online resilience-training resource (‘READY’) based in Acceptance and Commitment Therapy (ACT) was co-developed with PwMS and piloted.MethodsFollowing co-production of the digital ‘READY’ programme, PwMS (n=92) from Leeds, London and Cardiff were randomised to a pilot trial. Self-efficacy, work instability and other psychological variables were self-reported at baseline (n=88), week 8 (n=51) and month 6 (n=65).ResultsThe ‘READY’ programme was delivered to a pilot sample of n=88 (44 Intervention: 44 Control) PwMS. Improvements in the intervention group over the control group were observed for work instability, self-efficacy, anxiety, physical and psychological impact of MS and psychological flexibility. Work insta- bility levels improved over time in the intervention group and worsened in the control group. All other improvements peaked at 8 weeks and then dropped off at 6 months, but remained above baseline levels.ConclusionsThis pilot trial provides an initial proof of concept that an ACT-based resilience-training digital tool may lead to improvements to work instability for PwMS, and related psychological factors such as self-efficacy and anxiety.

[...] despite diffi culties in obtaining reliable data outside of controlled clinical trials, long-term results for therapeutic eff ects in multiple sclerosis are much needed.

BackgroundHaemorrhagic cerebrovascular events have been reported during Alemtuzumab treatment for relapsing-remitting multiple sclerosis (RRMS) leading to changes in the marketing authorisation in Europe. Hypertension is the proposed mechanism.AimsTo characterise systolic blood pressure (SBP) changes during Alemtuzumab administration and the frequency of significant hypertension.MethodWe recorded SBP measurements during Alemtuzumab infusions from a random sample of RRMS patients. Mean SBP changes were calculated for each day and the 5-day treatment course. Common Terminology Criteria for Adverse Events was used to grade hypertension.Results2412 SBP measurements from 50 RRMS patients (mean age 35.9 years; 70% female) were recorded. No patients had premorbid hypertension. The mean (SD) SBP change was -0.7 (7.59) mmHg over 5 days. Two (4%) patients developed sustained grade III hypertension (SBP ≥160mmHg) over two or more readings >15 minutes apart, which resolved spontaneously. No patients had immediate cerebrovascular complications.ConclusionsClinically-significant hypertension is uncommon during Alemtuzumab treatment and should prompt close clinical observation. Slowing (or stopping) the rate of infusion should be considered in patients with sustained hypertension.hui.chingong@nhs.net

Interferon- beta (IFNbeta) acts by a variety of mechanisms in relapsing-remitting multiple sclerosis (MS). One of these is a cellular down-regulation of gelatinase B or matrix metalloproteinase-9 (MMP-9), which is known from biochemical, biological and immunohistochemical evidences to play a disease-promoting role in MS. a) To investigate the influence of IFNbeta-1a (30 or 60 micro g I. M./week) on serum MMP-9 levels in patients with primary progressive MS (PPMS). b) To correlate serum MMP-9 levels with clinical and magnetic resonance imaging (MRI) findings. Serial blood samples were collected every 3 months from 49 patients participating in a phase II trial of IFNbeta-1a in PPMS. Serum MMP-9 was quantified by ELISA and correlations with clinical (EDSS) as well as MRI findings (brain and spinal cord atrophy, ventricular volume, T1 and T2 lesion load) were calculated. No significant differences were found between serial serum MMP-9 levels in IFNbeta-treated versus placebo-treated patients. MMP-9 levels did not differ between patients who progressed or did not progress during the study interval. Although mean absolute serum MMP-9 levels over the study period correlated with an increase in T2 lesion load (relative T2 change: r=0.51, p<0.001; absolute T2 change: r=0.30, p=0.038), absolute increase in brain ventricular volume (r=0.29, p=0.05) and increased brain atrophy (r=0.35, p=0.02), only the correlation with T2 lesion load was sustained throughout the study period. No correlations were found between MMP-9 levels and relative changes in ventricular volume or with relative/absolute changes in T1 lesion load and in spinal cord atrophy. None of the MRI measures correlated with MMP-9 changes between baseline levels and those on treatment. Although some evidence suggests a down-regulating effect of IFNbeta on MMP-9, this was not confirmed for a once weekly intramuscular dose of IFNbeta-1a in patients with PPMS. The sustained correlation between serum MMP-9 and changes in T2 volumes, and the lack of correlation with clinical or MRI measures of disease progression may suggest that MMP-9 is more directly related to non-specific central nervous system damage than to axonal loss.

Objective: To assess the effect of intrathecal baclofen on spastic dysarthia in cerebral palsy. Design: Single case study. Methods: Functional outcome measures, including the Assessment of Intelligibility of Dysarthric Speech, were performed before and after a trial of intrathecal baclofen in an adult patient with spastic dysarthria due to cerebral palsy. The patient proceeded to intrathecal baclofen pump implantation and was reassessed after six months of continuous intrathecal baclofen therapy. Results: Improvement in function including speech intelligibility was seen following the intrathecal baclofen trial. The improvement was sustained at six months post pump implantation. Conclusions: Intrathecal baclofen improved functional intelligibility of speech in a carefully selected subject. The Assessment of Intelligibility of Dysarthric Speech was found to be a useful quantitative tool to assess the effect of intrathecal baclofen on spastic dysarthria.