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.

Efficacy and safety of autologous haematopoietic stem cell transplantation versus alemtuzumab, ocrelizumab, ofatumumab or cladribine in relapsing remitting multiple sclerosis (StarMS): protocol for a randomised controlled trial.

INTRODUCTION: Autologous haematopoietic stem cell transplantation (aHSCT) is increasingly used as treatment for patients with active multiple sclerosis (MS), typically after failure of disease-modifying therapies (DMTs). A recent phase III trial, 'Multiple Sclerosis International Stem Cell Transplant, MIST', showed that aHSCT resulted in prolonged time to disability progression compared with DMTs in patients with relapsing remitting MS (RRMS). However, the MIST trial did not include many of the current high-efficacy DMTs (alemtuzumab, ocrelizumab, ofatumumab or cladribine) in use in the UK within the control arm, which are now offered to patients with rapidly evolving severe MS (RES-MS) who are treatment naïve. There remain, therefore, unanswered questions about the relative efficacy and safety of aHSCT over these high-efficacy DMTs in these patient groups. The StarMS trial (Autologous Stem Cell Transplantation versus Alemtuzumab, Ocrelizumab, Ofatumumab or Cladribine in Relapsing Remitting Multiple Sclerosis) will assess the efficacy, safety and long-term impact of aHSCT compared with high-efficacy DMTs in patients with highly active RRMS despite the use of standard DMTs or in patients with treatment naïve RES-MS. METHODS AND ANALYSIS: StarMS is a multicentre parallel-group rater-blinded randomised controlled trial with two arms. A total of 198 participants will be recruited from 19 regional neurology secondary care centres in the UK. Participants will be randomly allocated to the aHSCT arm or DMT arm in a 1:1 ratio. Participants will remain in the study for 2 years with follow-up visits at 3, 6, 9, 12, 18 and 24 months postrandomisation. The primary outcome is the proportion of patients who achieve 'no evidence of disease activity' during the 2-year postrandomisation follow-up period in an intention to treat analysis. Secondary outcomes include efficacy, safety, cost-effectiveness and immune reconstitution of aHSCT and the four high-efficacy DMTs. ETHICS AND DISSEMINATION: The study was approved by the Yorkshire and Humber-Leeds West Research Ethics Committee (20/YH/0061). Participants will provide written informed consent prior to any study specific procedures. The study results will be submitted to a peer-reviewed journal and abstracts will be submitted to relevant national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN88667898.

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.

Tolerability of subcutaneous ofatumumab with long-term exposure in relapsing multiple sclerosis.

Background: Ofatumumab is approved for treating relapsing multiple sclerosis (RMS). Examining tolerability will enable understanding of its risk-benefit profile. Objective: Report the tolerability profile of ofatumumab in RMS during treatment of up to 4 years and the effect of pre-medication. Methods: Cumulative data from the overall safety population included patients taking continuous ofatumumab or being newly switched from teriflunomide. Injection-related reactions (IRRs) by incidence and severity, and post-marketing surveillance data, with an exposure of 18,530 patient-years, were analyzed. Results: Systemic IRRs affected 24.7% of patients (487/1969) in the overall safety population; most (99.2% [483/487]) were mild (333/487) to moderate (150/487) in Common Terminology Criteria for Adverse Events severity; most systemic IRRs occurred after first injection. Local-site IRRs affected 11.8% (233/1969) and most (99.6% [232/233]) were mild/moderate. Incidence and severity of systemic and localized IRRs were similar between continuous and newly switched patients across repeated injections. Systemic IRR incidence and severity were not substantially affected by steroidal or non-steroidal pre-medication. Post-marketing surveillance identified no new tolerability issues. Conclusion: Ofatumumab is well tolerated, displays a consistent safety profile during continuous use or after switching from teriflunomide and does not require pre-medication. This enables home management of RMS with a high-efficacy treatment.

Psychometric Properties of LUN-MS: A New Questionnaire to Identify the Unmet Needs of People With Multiple Sclerosis.

Background: We developed a 29-item Questionnaire, Long-term Unmet Needs in MS (LUN-MS) to identify the unmet needs of people with multiple sclerosis (pwMS). Objective: To assess acceptability, test-retest reliability, internal consistency, and validity of the LUN-MS. Methods: Participants completed the LUN-MS and MSIS-29 twice, four weeks apart. Acceptability was assessed by looking at the response rate in each time point. Reliability was calculated by comparing the response during the two time points using Cohen's weighted kappa. Using principal component analysis, the dimensionality of the questionnaire's items was reduced, to five domains and the internal consistency of each domain was assessed using Cronbach's alpha. Concurrent validity was tested by comparing the total LUN-MS score against MSIS-29 and EQ-5D-3L using Pearson's product-moment correlation coefficient. Results: Among 88 participants, rate of completion at time points-1 and 2 was 96 and 80% respectively. Test-retest reliability for individual items was between fair to near-perfect (weighted Cohen's kappa 0.39-0.81). The unmet needs could be divided into five internally consistent domains (Cronbach's alpha 0.83-0.74): neuropsychological, ambulation, physical, interpersonal relationship and informational. Concurrent validity with MSIS-29 (r = 0.705, P < .001) and EQ-5D-3L (r = 0.617, P < .001) were good. Conclusion: LUN-MS is a reliable, valid, and acceptable tool to identify the unmet needs of pwMS.

The Development of Ofatumumab, a Fully Human Anti-CD20 Monoclonal Antibody for Practical Use in Relapsing Multiple Sclerosis Treatment.

The importance of B cells in multiple sclerosis (MS) has been demonstrated through the advent of B-cell-depleting anti-CD20 antibody therapies. Ofatumumab is the first fully human anti-CD20 monoclonal antibody (mAb) developed and tested for subcutaneous (SC) self-administration at monthly doses of 20 mg, and has been approved in the US, UK, EU, and other regions and countries worldwide for the treatment of relapsing MS. The development goal of ofatumumab was to obtain a highly efficacious anti-CD20 therapy, with a safety and tolerability profile that allows for self-administration by MS patients at home and a positive benefit-risk balance for use in the broad relapsing MS population. This development goal was enabled by the unique binding site, higher affinity to B cells, and higher potency of ofatumumab compared to previous anti-CD20 mAbs; these properties of ofatumumab facilitate rapid B-cell depletion and maintenance with a low dose at a low injection volume (20 mg/0.4 ml). The high potency in turn enables the selective targeting of B cells that reside in the lymphatic system via subcutaneous (SC) administration. Through a comprehensive dose-finding program in two phase 2 studies (one intravenous and one SC) and model simulations, it was found that safety and tolerability can be further improved, and the risk of systemic injection-related reactions (IRRs) minimized, by avoiding doses ≥ 30 mg, and by reaching initial and rapid B-cell depletion via stepwise weekly administration of ofatumumab at Weeks 0, 1, and 2 (instead of a single high dose). Once near-complete B-cell depletion is reached, it can be maintained by monthly doses of 20 mg/0.4 ml. Indeed, in phase 3 trials (ASCLEPIOS I/II), rapid and sustained near-complete B-cell depletion (largely independent of body weight, race and other factors) was observed with this dosing regimen, which resulted in superior efficacy of ofatumumab versus teriflunomide on relapse rates, disability worsening, neuronal injury (serum neurofilament light chain), and imaging outcomes. Likely due to its fully human nature, ofatumumab has a low immunogenic risk profile-only 2 of 914 patients receiving ofatumumab in ASCLEPIOS I/II developed anti-drug antibodies-and this may also underlie the infrequent IRRs (20% with ofatumumab vs. 15% with the placebo injection in the teriflunomide arm) that were mostly (99.8%) mild to moderate in severity. The overall rates of infections and serious infections in patients treated with ofatumumab were similar to those in patients treated with teriflunomide (51.6% vs. 52.7% and 2.5% vs. 1.8%, respectively). The benefit-risk profile of ofatumumab was favorable compared to teriflunomide in the broad RMS population, and also in the predefined subgroups of both recently diagnosed and/or treatment-naïve patients, as well as previously disease-modifying therapy-treated patients. Interim data from the ongoing extension study (ALITHIOS) have shown that long-term treatment with ofatumumab up to 4 years is well-tolerated in RMS patients, with no new safety risks identified. In parallel to the phase 3 trials in which SC administration was carried out with a pre-filled syringe, an autoinjector pen for more convenient self-administration of the ofatumumab 20 mg dose was developed and is available for use in clinical practice.

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.

Fatigue in multiple sclerosis: A UK MS-register based study.

BACKGROUND: Fatigue is a widely experienced, incapacitating symptom of MS. It hinders daily functioning and has deleterious effects on quality of life. The UK MS Register is an online registry of over 20,000 participants with MS. The aim of this study was to estimate the prevalence, predictors, and impact of fatigue on people with MS using data from the UKMS register. METHODS: All participants who completed the Fatigue Severity Scale (FSS), WebEDSS, Hospital Anxiety and Depression Scale (HADS) within 28 days of each other were selected from the UK MS Register. Data on age, gender, duration and type of MS, use of disease modifying drugs and comorbidities were obtained from the UKMS register. We categorised people with FSS score of 5 or more as with fatigue and those with scores of 4 or less as without fatigue. Descriptive statistics and logistical and multiple regressions were used to explore predictors of fatigue and the effect of fatigue on mobility (MS Walking Scale), physical and psychological aspects of life (MS Impact Scale) and quality of life (European Quality of Life 5D-3 L). RESULTS: Amongst the 20,946 participants of the UK MS registry, 4620 completed FSS. Out of these, 775 (mean age= 54.71 years, SD= 10.90; mean duration of MS diagnosis =13.21 years, SD=9.75) had completed the FSS, Web EDSS and Hospital Anxiety and Depression Scale within 28 days of each other. 427 (55.1%) of pwMS had a FSS score >5 consistent with clinical fatigue. Logistic regression analysis showed that depression (p=<0.001), duration of MS (p = 0.017), secondary progressive MS (p = 0.001) and EDSS (p=<0.001) predicted fatigue. FSS scores had a significant negative impact on both psychological (p > 0.001) and physical (p > 0.001) domains of the MS Impact scale, MS walking scale (p = 0.003) and EQoL (p = 0.005). CONCLUSIONS: Fatigue was a common symptom amongst people with MS. Depression, longer duration of MS, secondary progressive MS, and high EDSS predicted fatigue. Fatigue had an adverse effect on physical activities, mobility, psychological wellbeing, and quality of life of people with MS.

The four self-efficacy trajectories among people with multiple sclerosis: Clinical associations and implications.

BACKGROUND: Longitudinal studies among people with Multiple Sclerosis (pwMS) have shown that self-efficacy is linked to physical, cognitive and psychological functioning. OBJECTIVES: To determine the distribution of self-efficacy in a large sample of pwMS, examining whether there are distinct groups which show different self-efficacy trajectories over time, and the health status characteristics of any groups identified. METHODS: Participants completed serial questionnaire packs, including Unidimensional Self-efficacy-MS (USE-MS) scale, for the Trajectories of Outcome in Neurological Conditions-MS (TONiC-MS) study over an average 46-month period. The resulting longitudinal data were analysed by a group-based trajectory model. RESULTS: 5887 pwMS were studied: mean age 50.2 years (SD 12.0); 73.6% female; Relapsing Remitting MS (61.8%), Secondary Progressive (22.9%), Primary Progressive (11.1%), Rapidly Evolving Relapsing Remitting MS (4.2%). Four distinct self-efficacy trajectories emerged, with declining, slightly declining, stable or improving self-efficacy, each showing different patterns of health status indicators such as EQ-5D-5L, disability and depression. USE-MS ≤ 18 at baseline detected all participants in the two declining groups. CONCLUSION: Future trials on interventions for self-efficacy should assume a priori that those with low levels of self-efficacy (USE-MS ≤ 18 at baseline) are likely to be on a declining trajectory and may need different interventions from those with stable self-efficacy.

A Systematic Review of Resting-State Functional MRI Connectivity Changes and Cognitive Impairment in Multiple Sclerosis.

Introduction: Cognitive impairment in multiple sclerosis (MS) is increasingly being investigated with resting-state functional MRI (rs-fMRI) functional connectivity (FC). However, results remain difficult to interpret, showing both high and low FC associated with cognitive impairment. We conducted a systematic review of rs-fMRI studies in MS to understand whether the direction of FC change relates to cognitive dysfunction, and how this may be influenced by the choice of methodology. Methods: Embase, Medline, and PsycINFO were searched for studies assessing cognitive function and rs-fMRI FC in adults with MS. Results: Fifty-seven studies were included in a narrative synthesis. Of these, 50 found an association between cognitive impairment and FC abnormalities. Worse cognition was linked to high FC in 18 studies, and to low FC in 17 studies. Nine studies found patterns of both high and low FC related to poor cognitive performance, in different regions or for different magnetic resonance (MR) metrics. There was no clear link to increased FC during the early stages of MS and reduced FC in later stages, as predicted by common models of MS pathology. Throughout, we found substantial heterogeneity in study methodology, and carefully consider how this may impact on the observed findings. Discussion: These results indicate an urgent need for greater standardization in the field-in terms of the choice of MRI analysis and the definition of cognitive impairment. This will allow us to use rs-fMRI FC as a biomarker in future clinical studies, and as a tool to understand mechanisms underpinning cognitive symptoms in MS.

Mechanisms of Network Changes in Cognitive Impairment in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Cognitive impairment in multiple sclerosis (MS) is associated with functional connectivity abnormalities. While there have been calls to use functional connectivity measures as biomarkers, there remains to be a full understanding of why they are affected in MS. In this cross-sectional study, we tested the hypothesis that functional network regions may be susceptible to disease-related "wear and tear" and that this can be observable on co-occurring abnormalities on other magnetic resonance metrics. We tested whether functional connectivity abnormalities in cognitively impaired patients with MS co-occur with (1) overlapping, (2) local, or (3) distal changes in anatomic connectivity and cerebral blood flow abnormalities. METHODS: Multimodal 3T MRI and assessment with the Brief Repeatable Battery of Neuropsychological tests were performed in 102 patients with relapsing-remitting MS and 27 healthy controls. Patients with MS were classified as cognitively impaired if they scored ≥1.5 SDs below the control mean on ≥2 tests (n = 55) or as cognitively preserved (n = 47). Functional connectivity was assessed with Independent Component Analysis and dual regression of resting-state fMRI images. Cerebral blood flow maps were estimated, and anatomic connectivity was assessed with anatomic connectivity mapping and fractional anisotropy of diffusion-weighted MRI. Changes in cerebral blood flow and anatomic connectivity were assessed within resting-state networks that showed functional connectivity abnormalities in cognitively impaired patients with MS. RESULTS: Functional connectivity was significantly decreased in the anterior and posterior default mode networks and significantly increased in the right and left frontoparietal networks in cognitively impaired relative to cognitively preserved patients with MS (threshold-free cluster enhancement corrected at p ≤ 0.05, 2 sided). Networks showing functional abnormalities showed altered cerebral blood flow and anatomic connectivity locally and distally but not in overlapping locations. DISCUSSION: We provide the first evidence that functional connectivity abnormalities are accompanied by local cerebral blood flow and structural connectivity abnormalities but also demonstrate that these effects do not occur in exactly the same location. Our findings suggest a possibly shared pathologic mechanism for altered functional connectivity in brain networks in MS.

A Multifactorial Model of Multiple Sclerosis Gait and Its Changes Across Different Disability Levels.

OBJECTIVE: Mobility assessment is critical in the clinical management of people with Multiple Sclerosis (pwMS). Instrumented gait analysis provides a plethora of metrics for quantifying concurrent factors contributing to gait deterioration. However, a gait model discriminating underlying features contributing to this deterioration is lacking in pwMS. This study aimed at developing and validating such a model. METHODS: The gait of 24 healthy controls and 114 pwMS with mild, moderate, or severe disability was measured with inertial sensors on the shanks and lower trunk while walking for 6 minutes along a hospital corridor. Twenty out of thirty-six initially explored metrics computed from the sensor data met the quality criteria for exploratory factor analysis. This analysis provided the sought model, which underwent a confirmatory factor analysis before being used to characterize gait impairment across the three disability groups. RESULTS: A gait model consisting of five domains (rhythm/variability, pace, asymmetry, and forward and lateral dynamic balance) was revealed by the factor analysis, which was able to highlight gait abnormalities across the disability groups: significant alterations in rhythm/variability-, asymmetry-, and pace-based features were present in the mild group, but these were more profound in the moderate and severe groups. Deterioration in dynamic balance-based features was only noted in pwMS with a moderate and severe disability. CONCLUSION: A conceptual model of gait for disease-specific mobility assessment in pwMS was successfully developed and tested. SIGNIFICANCE: The new model, built with metrics that represent gait impairment in pwMS, highlighted clinically relevant changes across different disability levels, including those with no clinically observable walking disability. This shows the clear potential as a monitoring biomarker in pwMS.

A network-based cognitive training induces cognitive improvements and neuroplastic changes in patients with relapsing-remitting multiple sclerosis: an exploratory case-control study.

Cognitive impairments are commonly observed in patients with multiple sclerosis and are associated with lower levels of quality of life. No consensus has been reached on how to tackle effectively cognitive decline in this clinical population non-pharmacologically. This exploratory case-control study aims to investigate the effectiveness of a hypothesis-based cognitive training designed to target multiple domains by promoting the synchronous co-activation of different brain areas and thereby improve cognition and induce changes in functional connectivity in patients with relapsing-remitting multiple sclerosis. Forty-five patients (36 females and 9 males, mean age 44.62 ± 8.80 years) with clinically stable relapsing-remitting multiple sclerosis were assigned to either a standard cognitive training or to control groups (sham training and non-active control). The standard training included twenty sessions of computerized exercises involving various cognitive functions supported by distinct brain networks. The sham training was a modified version of the standard training that comprised the same exercises and number of sessions but with increased processing speed load. The non-active control group received no cognitive training. All patients underwent comprehensive neuropsychological and magnetic resonance imaging assessments at baseline and after 5 weeks. Cognitive and resting-state magnetic resonance imaging data were analyzed using repeated measures models. At reassessment, the standard training group showed significant cognitive improvements compared to both control groups in memory tasks not specifically targeted by the training: the Buschke Selective Reminding Test and the Semantic Fluency test. The standard training group showed reductions in functional connectivity of the salience network, in the anterior cingulate cortex, associated with improvements on the Buschke Selective Reminding Test. No changes were observed in the sham training group. These findings suggest that multi-domain training that stimulates multiple brain areas synchronously may improve cognition in people with relapsing-remitting multiple sclerosis if sufficient time to process training material is allowed. The associated reduction in functional connectivity of the salience network suggests that training-induced neuroplastic functional reorganization may be the mechanism supporting performance gains. This study was approved by the Regional Ethics Committee of Yorkshire and Humber (approval No. 12/YH/0474) on November 20, 2013.

Simultaneous ALS and SCA2 associated with an intermediate-length ATXN2 CAG-repeat expansion.

Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) share a common molecular basis: both are associated with CAG-repeat expansion of ATXN2 and TDP-43-positive neuronal cytoplasmic inclusions. To date, the two disorders are viewed as clinically distinct with ALS resulting from 30-33 CAG-repeats and SCA2 from >34 CAG-repeats. We describe a 67-year old with a 32 CAG-repeat expansion of ATXN2 who presented with simultaneous symptoms of ALS and SCA2. Our case demonstrates that the clinical dichotomy between SCA2 and ATXN2-ALS is false. We suggest instead that CAG-repeat expansion length determines the timing of SCA2 clinical symptoms relative to onset of ALS; consistent with this age of onset of SCA2 but not ATXN2-ALS, is dependent upon expansion length. Review of the literature and our local cohort provides evidence for occurrence of ALS in late stage SCA2, which may be under-recognised by clinicians who think of the two diseases as distinct.

Wearable sensors can reliably quantify gait alterations associated with disability in people with progressive multiple sclerosis in a clinical setting.

Gait disability in people with progressive multiple sclerosis (MS) is difficult to quantify using existing clinical tools. This study aims to identify reliable and objective gait-based biomarkers to monitor progressive multiple sclerosis (MS) in clinical settings. During routine clinical visits, 57 people with secondary progressive MS and 24 healthy controls walked for 6 minutes wearing three inertial motion sensors. Fifteen gait measures were computed from the sensor data and tested for between-session reliability, for differences between controls and people with moderate and severe MS disability, and for correlation with Expanded Disability Status Scale (EDSS) scores. The majority of gait measures showed good to excellent between-session reliability when assessed in a subgroup of 23 healthy controls and 25 people with MS. These measures showed that people with MS walked with significantly longer step and stride durations, reduced step and stride regularity, and experienced difficulties in controlling and maintaining a stable walk when compared to controls. These abnormalities significantly increased in people with a higher level of disability and correlated with their EDSS scores. Reliable and objective gait-based biomarkers using wearable sensors have been identified. These biomarkers may allow clinicians to quantify clinically relevant alterations in gait in people with progressive MS within the context of regular clinical visits.

Effect of remote ischaemic preconditioning on walking in people with multiple sclerosis: double-blind randomised controlled trial.

BACKGROUND: Remote ischaemic preconditioning (RIPC) is the exposure of body parts to brief periods of circulatory occlusion and reperfusion. Recent studies have also shown that RIPC can improve exercise performance in healthy individuals. OBJECTIVE: This study aimed to assess the effect of RIPC on walking in people with multiple sclerosis (MS). METHODS: This was a double-blind randomised controlled clinical trial. We used three cycles of RIPC delivered by occluding the upper arm with a blood pressure (BP) cuff inflated to a pressure of 30 mm Hg above the systolic BP. In patients in the sham intervention group, the BP cuff was inflated only to 30 mm Hg below diastolic BP. Outcome measures included the Six-Minute Walk Test (6MWT), gait speed, the Borg rate of perceived exertion (RPE) scale, the tolerability of the RIPC using a Numerical Rating Scale for discomfort from 0 to 10, and adverse events. We identified responders meeting the minimal clinically important difference (MCID) established in the literature in each group. RESULTS: Seventy-five participants completed the study (RIPC: 38 and Sham: 37). The distance walked during the 6MWT improved by 1.9% in the sham group and 5.7% in the RIPC group (p=0.012). The number of responders meeting MCID criteria in the RIPC group was significantly greater compared with the sham intervention group. No serious adverse events occurred. CONCLUSION: Single cycle of RIPC resulted in immediate improvement in walking distances during 6MWT in people with MS. TRIAL REGISTRATION NUMBERS: NCT03153553.

Is a Wearable Sensor-Based Characterisation of Gait Robust Enough to Overcome Differences Between Measurement Protocols? A Multi-Centric Pragmatic Study in Patients with Multiple Sclerosis.

Inertial measurement units (IMUs) allow accurate quantification of gait impairment of people with multiple sclerosis (pwMS). Nonetheless, it is not clear how IMU-based metrics might be influenced by pragmatic aspects associated with clinical translation of this approach, such as data collection settings and gait protocols. In this study, we hypothesised that these aspects do not significantly alter those characteristics of gait that are more related to quality and energetic efficiency and are quantifiable via acceleration related metrics, such as intensity, smoothness, stability, symmetry, and regularity. To test this hypothesis, we compared 33 IMU-based metrics extracted from data, retrospectively collected by two independent centres on two matched cohorts of pwMS. As a worst-case scenario, a walking test was performed in the two centres at a different speed along corridors of different lengths, using different IMU systems, which were also positioned differently. The results showed that the majority of the temporal metrics (9 out of 12) exhibited significant between-centre differences. Conversely, the between-centre differences in the gait quality metrics were small and comparable to those associated with a test-retest analysis under equivalent conditions. Therefore, the gait quality metrics are promising candidates for reliable multi-centric studies aiming at assessing rehabilitation interventions within a routine clinical context.

Optic neuritis as presenting primary hypoparathyroidism.

Papilloedema and raised intracranial pressure have been frequently reported with hypoparathyroidism, but very rarely optic neuritis. We report a case of a 54-year-old male patient who presented with classical optic neuritis which is believed to be secondary to primary hypoparathyroidism.

Brain connectivity and cognitive processing speed in multiple sclerosis: A systematic review.

BACKGROUND: Processing speed (PS) decline is the most commonly observed cognitive deficit in people with multiple sclerosis (MS) resulting in a significant impact on quality of life. Despite its importance, knowledge of the underlying neural substrates is lacking. OBJECTIVE: As MS is increasingly recognised as a disconnection syndrome, our aim was to carry out a systematic literature review to clarify the relationship between PS performance and MRI measures of structural and functional brain connectivity in people with MS. SEARCH METHODS: A literature search was carried out on PubMed and Web of Science that included publications predating September 2017. Additional articles were added after inspection of the reference lists of all selected papers. DATA EXTRACTION: All selected papers were categorised in three sections according to the MRI measures investigated, independently or both. Quality assessment was carried out using a customised set of criteria. RESULTS: Thirty-two articles met the inclusion criteria and were included in the review. Microstructural integrity of the anterior corpus callosum and functional connectivity of frontal areas were more consistently found to correlate with PS performance, though high variability of findings was observed across studies. Several methodological flaws emerged from the reviewed literature. CONCLUSIONS: Despite the observed trends, no definite conclusions can be drawn on the relationship between brain connectivity and PS decline in MS given the limitations of the current literature. Future investigations may benefit from theoretical and methodological advances to clarify how MS-related brain damage affects patients' cognition.

Multiple sclerosis update: use of MRI for early diagnosis, disease monitoring and assessment of treatment related complications.

MRI has long been established as the most sensitive in vivo technique for detecting multiple sclerosis (MS) lesions. The 2010 revisions of the McDonald Criteria have simplified imaging criteria, such that a diagnosis of MS can be made on a single contrast-enhanced MRI scan in the appropriate clinical context. New disease-modifying therapies have proven effective in reducing relapse rate and severity. Several of these therapies, most particularly natalizumab, but also dimethyl fumarate and fingolimod, have been associated with progressive multifocal leukoencephalopathy (PML). PML-immune reconstitution inflammatory syndrome (IRIS) has been recognized in patients following cessation of natalizumab owing to PML, and discontinuation for other reasons can lead to the phenomenon of rebound MS. These complications often provide a diagnostic dilemma and have implications for imaging surveillance of patients. We demonstrate how the updated McDonald Criteria aid the diagnosis of MS and describe the imaging characteristics of conditions such as PML and PML-IRIS in the context of MS. Potential imaging surveillance protocols are considered for the diagnosis and assessment of complications. We will explain how changes in MS treatment are leading to new imaging demands in order to monitor patients for disease progression and treatment-related complications.