bluuebunny/crossref_metadata_2025_split huggingface dataset:
142  Severe peripheral sensory axonopathy with retained H-reflexes: a distinctive form of non-paraneoplastic ganglionopathy
Authors: McKenna Mary Clare , Kinsella Justin , O’Riordan Seán , Connolly Seán 
Published: May 2022

BackgroundSensory ganglionopathies classically present with subacute onset of marked sensory loss with ataxia and preserved strength. These clinical findings are complemented by nerve conduction studies (NCS) demonstrating absent or markedly reduced amplitudes of the sensory nerve action potentials (SNAPs) with normal motor nerve conduction studies.CaseWe present two cases in their 6th and 7th decade of life who present with a 5-year history of gradual onset of unsteadiness and ‘burning’ sensory symptoms, worst in the lower limbs. Clinically, they had mild ataxia and preserved deep tendon reflexes.Results of Investigations: NCS demonstrated marked reduction in the amplitudes of the SNAPs in upper and lower limbs. The motor nerve conduction studies were normal. Unexpectedly, H-reflexes were per- sistently retained. There was no significant change in interval neurophysiological studies. These findings indicate a marked peripheral sensory axonopathy with sparing of the Ia afferents. Extensive investigations for underlying infectious, autoimmune or paraneoplastic cause all returned negative.DiscussionWe describe a distinctive neurophysiological pattern with preserved H-reflexes without severe clinical ataxia. We hypothesise that this is a unique type of ganglionopathy due to the selective sparing of the Ia afferents.mary.mc-kenna.1@ucdconnect.ie
144  Investigating the molecular mechanisms of mutant C9orf72 human iPSC- derived astrocyte-mediated motor neuron deficits
Authors: Stavrou Maria , Selvaraj Bhuvaneish , Bolado Alfonso , James Longden , Neil Carragher , Margaret Frame , Hardingham Giles , Chandran Siddharthan 
Published: May 2022

Amyotrophic Lateral Sclerosis (ALS) is a progressive, incurable and invariably fatal neurodegenerative condition characterised by loss of motor neurons. Over the last two decades, there are multiple lines of evidence from pathology, genetics and experimental systems that implicate a central role for non- neuronal cells, astrocytes in particular, with ALS pathogenesis. This is not surprising given the intimate structural and functional association of astrocytes with, inter alia, the synapse and vasculature. Yet, the nature of this astrocyte-neuronal crosstalk remains understudied. Harnessing the power of genetic dis- coveries combined with human iPS cellular platforms and gene editing technologies, we seek to better understand the non-cell autonomous effect of astrocytes carrying the C9orf72 mutation – the commonest genetic cause of ALS – on motor neurons.We generate human astrocytes and motor neurons from three pairs of independent patient-derived mutant C9orf72 iPSC lines and their corresponding CRISPR-Cas9 gene-edited isogenic controls. Having isogenic controls allows causality to be assigned to any given phenotype and overcomes transcriptional heterogeneity across iPSC lines. We utilise these cells to investigate astrocyte-mediated neuronal toxicity and changes in secretome profiles. By using unbiased mass spectrometric analysis and molecular tech- niques, we aim to identify the underpinning molecular mechanisms of astrocyte-mediated neuronal toxicity. This will potentially lead to the identification of putative neuroprotective targets as well as novel biomarkers.mstavrou@ed.ac.uk|NIHR Bursary97
009  Abnormal blood-brain barrier permeability in progressive multiple sclerosis
Authors: Varatharaj Aravinthan , Darekar Angela , Gawne-Cain Mary , Cramer Stig P , Larsson Henrik BW , Galea Ian 
Published: May 2022

Disruption of the blood-brain barrier (BBB) is a hallmark of multiple sclerosis (MS). In clinical practice this is detected using contrast-enhanced magnetic resonance imaging (MRI). There is biochemical evidence, based on cerebrospinal fluid protein assays, to suggest that BBB permeability is associated with disease severity and may be greater in progressive than in relapsing-remitting disease. Therefore, it is paradoxi- cal that when using conventional contrast MRI the detection of focal BBB disruption is relatively rare in progressive MS. A diffuse low-level BBB leak in progressive MS is hypothesised to explain this apparent discrepancy. Our group is investigating the use of dynamic contrast-enhanced MRI (DCE-MRI), which enables the quantification of subtle BBB disruption. Here we present a small case series of DCE-MRI in people with progressive MS as well as age-matched healthy controls. Diffuse low-level BBB leakage is demonstrated in the brains of people with progressive MS, which is invisible to conventional MRI. We discuss the implications of these early findings for our understanding of disease biology, as well as the search for an effective treatment for disability progression.a.varatharaj@soton.ac.uk
012  164 second conceptual film without dialogue, successfully conveys the impor- tance of early intervention in MS
Authors: Wilkie David , Middleton Rod , Cook James , Nicholas Richard 
Published: May 2022

ObjectivesEarly treatment in MS often needs to be started in the absence of symptoms. This preventa- tive approach is a complex concept to convey to a naïve population. We produced a 164 second film without dialogue with the aim of assessing whether it delivered its message successfully.MethodsPwMS were recruited from clinics, the UK MS Register and a general population. Based upon industry standards, pre-specified outcomes included 50% viewer retention equivalent to watching 30 seconds and 50% understanding of 4 concepts. The film was incorporated into a website explaining the concepts and participants answered questions about the concepts.ResultsViewer retention was 887/1102 (80%) in the total population with an average viewing duration of 149/164 seconds (91%), significantly above the pre-specified outcome percent (p<0.0001). In the MS Register population 757/959 (78.9%) pwMS had total understanding (4/4 concepts) compared with 29/42 (69%) in pwMS from outpatients and 136/149 (91%) in the general population. Understanding in all cohorts were significantly above the pre-specified outcomes (p<0.0001) with greatest understanding in the general population versus pwMS (p<0.0001).ConclusionsA short, targeted film successfully conveys the importance of early intervention to both MS and non-MS audiences.d.wilkie@imperial.ac.uk
013  An exploration of risk factors for dimethyl fumarate-induced lymphopenia in patients with multiple sclerosis
Authors: Roberts Jack , MacLeod Nicola , Justin Matthew , Harrison Emily , Williams Anna 
Published: May 2022

Dimethyl fumarate (DMF) is a commonly used first-line immunomodulatory drug used for the treatment of relapsing-remitting multiple sclerosis. It has been found to cause lymphopenia in a proportion of patients, and the incidence of several cases of progressive multifocal leukoencephalopathy in patients taking DMF has given rise to concerns regarding its safety.The purpose of this study was to identify risk factors for DMF-induced lymphopenia.: We performed ret- rospective analysis of 323 patients prescribed DMF in our NHS Lothian MS clinic in Edinburgh since the drug was introduced in 2014.Older age (>45), and lower baseline absolute lymphocyte count (ALC) both increased the risk of devel- oping grade 2 lymphopenia, with the latter also increasing the risk of severe, grade 3 lymphopenia. We also found that the decline in ALC happens within the first 6 months of DMF treatment, and after this point it no longer declines but has a tendency to rise.Increased vigilance with ALC monitoring is required in the first 6 months, especially in those who are older and have a low baseline ALC. By knowing the risk factors for DMF-induced lymphopenia, clinicians will be able to make more informed decisions when choosing a drug to start a patient on with multiple sclerosis.s1504225@sms.ed.ac.uk
014  Long-term effectiveness of natalizumab for RRMS: UK and global interim results from TYSABRI observational program
Authors: Nicholas Richard , Harrower Timothy , Su Ray , Licata Stephanie , Vonsy Jean 
Published: May 2022

IntroductionThe TYSABRI Observational Program (TOP) is a large, ongoing observational study in relapsing- remitting multiple sclerosis (RRMS) patients treated with natalizumab. Country-specific data on relapse and disability outcomes, alongside global data, can provide information on natalizumab’s effectiveness in local practice.MethodsAnnualised relapse rate (ARR) and cumulative probability of 24-week confirmed disability worsening (CDW; increase in Expanded Disability Status Scale [EDSS] score ≥1.5 from a baseline of 0.0,≥1.0 from a baseline between 1.0–5.5, or ≥0.5 from a baseline of ≥6.0) and improvement (CDI; decrease≥1.0 from a baseline EDSS score ≥2.0) were analysed in TOP UK (n=134) and global (N=6295) cohorts using data from July 2007 to November 2018. Updated data (as of November 2019) will be presented.ResultsARR decreased in UK patients from 2.21 in the year before initiation to 0.19 on natalizumab (P<0.0001), consistent with a global decrease from 2.00 to 0.21 (P<0.0001). At 7 years, probabilities of CDW and CDI were, respectively, 26.2% and 35.3% in UK patients and 27.9% and 32.1% globally.ConclusionsThese TOP UK results show disease control that is generally consistent with global TOP results, supporting natalizumab’s long-term effectiveness in real-world settings.SupportBiogen. Disclosures: Included on the poster.richard.nicholas@btinternet.com
016  Long-term disease stability in patients treated with cladribine tablets in CLARITY and CLARITY extension
Authors: Giovannoni Gavin , Comi Giancarlo , Rammohan Kottil , Rieckmann Peter , Vermersch Patrick , Dangond Fer- nando , Keller Birgit , Jack Dominic 
Published: May 2022

BackgroundThis post-hoc analysis evaluated long-term disease stability of relapsing-remitting multiple sclerosis (RRMS) patients, according to Expanded Disability Status Scale (EDSS), after treatment with clad- ribine tablets 10mg (cumulative dose 3.5mg/kg [CT3.5] over 2 years) in CLARITY and CLARITY Extension.MethodsPatients randomised to CT3.5 in CLARITY then placebo in CLARITY Extension, with ≥1 post- baseline EDSS measurement, were included (CP3.5, n=98). EDSS score over time (CLARITY randomisation to end of follow-up in CLARITY Extension, including the bridging interval between studies) was assessed at 6-month intervals, and separately at time to 3- and 6-month confirmed EDSS score progression from CLARITY baseline.ResultsFive years after CLARITY baseline, median EDSS remained stable compared with baseline. Median EDSS score (95%CI) for CP3.5 was 2.5(2.0–3.5) vs 3.0(2.5–3.5) at baseline. In each 12-month period, EDSS score was stable in >50% of patients, 21–30% improved and 0–25% worsened. During Year 5, EDSS was stable in 53.9% of patients, 21.3% improved and 24.7% worsened; <30% of patients reached 3- or 6-month confirmed EDSS progression.ConclusionsEDSS score was stable up to 5 years post-CLARITY baseline for CP3.5 patients. Between 20–30% of patients demonstrated improvement in EDSS score vs baseline each year. CLARITY:NCT00213135.CLARITY ExtensionNCT00641537g.giovannoni@qmul.ac.uk
017  Year 1 performance of adveva® programme for patients taking cladribine tablets for relapsing-remitting multiple sclerosis
Authors: Morgan Kate , Lott Nadine , Lyons Marco 
Published: May 2022

BackgroundThe nurse-led, telephone-based adveva® programme - including dosing advice, appoint- ment reminders and a home-based phlebotomy service - supports patients with relapsing-remitting multiple sclerosis (RRMS) in taking cladribine tablets (CT) as prescribed (the full first year cumulative dose of 1.75 mg/kg). We report year 1 results of the adveva® progamme for patients with highly active RRMS taking CT.MethodsAggregated and anonymised telephone conversation records were reviewed between December 2017 and August 2018. Patient-reported adherence, plus basic and additional support data, were analysed.Results262 patients were registered with adveva® and 133 were included in this assessment as they self- reported to have completed treatment in year 1 at the time of assessment. 130 (98%) patients completed their first-year course as prescribed (the remaining 3 patients received the required dose at a different time interval to that recommended). 22 (17%) patients required additional support during their treatment days, included advice on treatment/dosing/adverse events.ConclusionsAll 133 patients self-reported that they achieved the required CT dose in year 1; the adveva® programme was of particular value to patients requiring additional support. This is the first report in a post- approval and real-world setting suggesting the majority of patients find CT simple-to-take.kate.morgan@merckgroup.com
Personalised immunotherapy in active multiple sclerosis using injectable cladrib- ine: Follow-up of the BartsMS cohort
Authors: Allen-Philbey Kimberley , Trane Stefania De , Yildiz Ozlem , Adams Ashok , Turner Ben , Marta Monica , Mathews Joela , Altmann Dan , Giovannoni Gavin , Schmierer Klaus 
Published: May 2022

IntroductionCladribine tablets (Mavenclad®) are licensed for treating people with relapsing multiple sclerosis (pwRMS). We treated people with relapsing (pwRMS) and progressive MS (pwPMS) using sub- cutaneously administered cladribine (SCAC) since 2014. Here, we present up to five year follow-up on safety and efficacy.MethodsSCAC 10mg was given on 3–4 days during week 1. 0–3 doses were administered at week 5, according to week 4 lymphocyte count. A second cycle of SCAC was administered 11 months later. Follow-up included clinical outcome evaluation and pharmacovigilance. The proportion of pwMS with no evidence of (i) disease activity (NEDA) and (ii) progression or active disease (NEPAD) was calculated.Results211 pwMS received SCAC. 154/211 completed two treatment cycles. At baseline age was 44 (17–72) years, EDSS 1–8.5. Tolerability was good. One myocardial infarction and one breast cancer occurred. Two severely disabled pwMS died (one of influenza, one of encephalitis). Lymphopenia grade 3 was detected in <3%. At 2 years, 71% (CI 54%, 85%) of pwRMS had NEDA; 38% (CI 23%, 54%) of pwPMS had NEPAD.ConclusionsSCAC was well tolerated. Frequency of significant lymphopenia was low. Efficacy in pwRMS corresponds with trial data. NEPAD rates in pwPMS were similar to licensed DMT.k.allen-philbey@nhs.net
021  Determinants of natalizumab-associated PML outcomes
Authors: Kappos Ludwig , McGuigan Chris , Derfuss Tobias , Giovannoni Gavin , Oh Jiwon , Ren Zheng , McCarthy Kerry , Chang Ih , Campbell Nolan 
Published: May 2022

IntroductionNatalizumab treatment is associated with risk of progressive multifocal leukoencephalopa- thy (PML). Following PML diagnosis, plasma exchange (PLEX) may be used to enable rapid natalizumab clearance. This analysis explores the impact of PLEX and patient characteristics on natalizumab-associated PML outcomes.MethodsPatients with multiple sclerosis, natalizumab-associated PML, and PLEX treatment status as of September 2018 were included (PLEX+, n=616; PLEX−, n=109). The primary outcome was 2-year survival after PML diagnosis. Kaplan-Meier estimates of cumulative survival for patients with/without PLEX were stratified by log JC virus (JCV) viral copy number (VCN) at PML diagnosis. Hazard ratios for survival were based on a Cox proportional hazards model.ResultsThe cumulative probability of 2-year survival for PLEX+ vs PLEX− patients was 88.2% vs. 89.3% (P=0.857) with log VCN ≤5, 73.8% vs. 89.3% (P=0.097) with log VCN >5 to ≤7, and 68.2% vs. 78.9% (P=0.435) with log VCN >7. Improved survival was associated with younger age, asymptomatic presentation, localized PML lesions, and lower log JCV VCN.ConclusionsPLEX had no significant effect on survival rates. Numerically worse 2-year survival probabilities were observed with PLEX regardless of PML presentation, suggesting PLEX is not effective for improving post-PML outcomes.SupportBiogen. Disclosures: Included on the poster.g.giovannoni@qmul.ac.uk
024  CLARITY study: efficacy outcomes among patients receiving disease-modifying therapies prior to treatment with cladribine tablets
Authors: Vermersch Patrick , Rammohan Kottil , Damian Doris , Jack Dominic , Harty Gerard , Wong Schiffon 
Published: May 2022

BackgroundCladribine tablets 10mg (cumulative dose 3.5mg/kg [CT3.5] over 2 years) showed efficacy vs placebo in patients with relapsing-remitting multiple sclerosis in the CLARITY study. This post-hoc analysis investigated efficacy outcomes for patients with a history of disease-modifying therapy (DMT) use prior to entering CLARITY.MethodsCLARITY included patients previously treated with 0–2 DMTs (patients treated with >2 DMTs were excluded). Analysis of efficacy, annualised relapse rate (ARR), relapse-free rate, MRI activity, and time to 3-month and 6-month confirmed disability progression (CDP), were stratified by prior DMT therapy. P-Values <0.05 were considered nominally significant.ResultsPrior DMT patients were randomised to CT3.5 (n=110) and placebo (n=132). Treatment with CT3.5 vs placebo resulted in a nominally significant reduction in ARR (0.22 vs 0.42; P<0.005), higher relapse-free rate (70.4% vs 55.9%; P=0.0204), numerically lower risk of 3-month CDP (hazard ratio [HR]=0.64, P=0.1589) and 6-month CDP (HR=0.62, P=0.2071), and reductions in brain lesion counts (P<0.001 for each lesion type).ConclusionsPatients who received prior DMT treatment showed significant improvements in efficacy outcomes with CT3.5 compared to placebo. Findings therefore support a consistent effect of cladrib- ine tablets across a broad range of patients, including patients who have used other DMTs.CLARITY:NCT00213135dominic.jack@merckgroup.com
026  Gene-environment interactions in multiple sclerosis: a UK Biobank study
Authors: Jacobs Benjamin , Noyce Alastair , Bestwick Jonathan , Belete Daniel , Giovannoni Gavin , Dobson Ruth 
Published: May 2022

Question: Does genetic risk modify the effect of environmental MS risk factors?MethodsCase-control study of 2151 people with MS and 486,125 controls using data from a longitudinal cohort (UK Biobank). MS was defined using ICD-coding or self-report. Associations with MS risk were quan- tified using multivariate logistic regression. Interaction between environmental and genetic risk factors was quantified using the Attributable Proportion due to interaction (AP). Model fits were quantified using Nagelkerke’s pseudo-R2 metric.ResultsExposures associated with MS were childhood obesity (OR=1.39, 95%CI 1.22–1.58), smoking (OR=1.19, 95%CI 1.07–1.33), and earlier menarche 0.95, 95%CI 0.92–0.98). The autosomal polygenic risk score (PRS) was associated with MS disease status (ORTop-vs-bottom-decile=3.93, 95%CI 3.11–4.97). There was evidence of synergistic interaction between the PRS and both childhood obesity (AP=0.111, 95%CI 0.007–0.202), and smoking (AP=0.106, 95%CI 2.24e-4 to 0.196).ConclusionsWe provide novel evidence for interaction between environmental risk factors for MS and a high burden of autosomal genetic risk. These findings have significant implications for our understanding of MS biology, and may inform targeted prevention strategies.ben.meir.jacobs@gmail.com
027  Eosinophilia and lymphocytosis after natalizumab for relapsing-remitting multiple sclerosis
Authors: Keshvari Milad-Kazava , Sheikh Saima , Someren Fred van , Galea Ian 
Published: May 2022

BackgroundNatalizumab (NTZ), a humanized monoclonal antibody against the integrin VLA4, is a highly effective treatment for relapsing-remitting multiple sclerosis. Eosinophilia and lymphocytosis may occur, but their frequency, kinetics, risk factors, consequences and ideal monitoring frequency are unknown.MethodsHere we present preliminary results from an ongoing retrospective review of the medical and haematological electronic records of 195 patients in a multiple sclerosis specialist centre, who had started NTZ between January 2008 and April 2019, received NTZ up to January 2020, had at least two doses and had blood results available.ResultsThe study included 833 patient-years of NTZ exposure. 72% were female. Mean age was 37.1 years (standard deviation: 10.2 years). Only 3.6% of NTZ doses were missed. 6% were JC virus seroposi- tive before NTZ was started. Of the JC-seronegative patients before NTZ was started, 32% seroconverted whilst on NTZ. The mean eosinophil and lymphocyte count whilst on NTZ was above the reference range in 14% and 25% of patients. The kinetics, risk factors, and consequences of these two haematological abnormalities will be presented in detail.ConclusionEosinophilia and lymphocytosis are common, and have clinical and service implications, affecting medical management and monitoring frequency. Data presented will inform practice.milad_kazava@yahoo.co.uk
034  Updated safety analysis of ocrelizumab in multiple sclerosis
Authors: Schmierer Klaus , Hauser Stephen L , Kappos Ludwig , Montalban Xavier , Craveiro Licinio , Hughes Richard , Prajapati Kalpesh , Koendgen Harold , Pradhan Ashish , Wolinsky Jerry S 
Published: May 2022

BackgroundOngoing safety reporting is crucial to understanding the long-term benefit-risk profile of ocrelizumab in multiple sclerosis (MS). Safety/efficacy of ocrelizumab have been characterised in Phase II (NCT00676715) and III (NCT01247324/NCT01412333/NCT01194570) trials in relapsing-remitting MS, relapsing MS (RMS) and primary progressive MS (PPMS). Here, we report safety evaluations from ocrelizumab clinical trials and open-label extensions up to January 2019, and selected post-marketing data.MethodsSafety outcomes are reported for the ocrelizumab all-exposure population in Phase II/III and ongoing Phase IIIb trials. To account for different exposure lengths, rates per 100 patient years (PY) are presented.ResultsIn clinical trials, 4,611 patients with MS received ocrelizumab (14,329 PY exposure). Reported rates per 100 PY (95% confidence interval) were: adverse events (AEs), 252 (249–254); serious AEs, 7.33(6.89–7.79); infections, 76.7 (75.3–78.2); serious infections, 1.99 (1.77–2.23); malignancies, 0.46 (0.35–0.58); and AEs leading to discontinuation, 1.08 (0.92–1.27). Updated ocrelizumab all-exposure population data and selected post-marketing data will be presented.ConclusionsReported event rates in the ocrelizumab all-exposure clinical trial population and post-mar- keting settings remain generally consistent with the controlled treatment period in RMS/PPMS populations. Regular reporting of long-term safety data will continue.k.schmierer@qmul.ac.uk
037  Treating secondary progressive multiple sclerosis in the UK: use of guidelines and stopping criteria
Authors: Duddy Martin , Wilkinson Carmel , Rhys Katherine , Medhurst Steve 
Published: May 2022

BackgroundAs new treatment approaches emerge for progressive forms of multiple sclerosis (MS), it is important to understand the factors underlying current practice.MethodsWe used a structured questionnaire to interview 59 healthcare professionals (HCPs) from geo- graphically-dispersed UK MS centres about current disease modifying therapy (DMT) management of patients with suspected/confirmed secondary progressive MS (SPMS).ResultsOf 43 HCPs (73%) who follow guidelines for DMT management of patients transitioning from relapsing-remitting multiple sclerosis (RRMS) to SPMS, most (n=37/43, 86%) use the NHS England (NHSE) algorithm; 7/43 (16%) use ABN guidance. Fifty-eight (98%) HCPs use DMTs to treat patients with RRMS whom they suspect may be transitioning to SPMS and 30 (51%) for (a minority of) patients with newly- diagnosed SPMS. Expanded Disability Status Scale (EDSS) 7.0 was the most frequently-reported criterion used for stopping DMTs (n=29, 49%), however, a variety of other criteria were used and a small majority of HCPs reported continuing DMTs beyond EDSS 7.0 in certain circumstances (most commonly recent relapse activity [n=32, 54%] or in younger patients [n=20, 34%]).ConclusionsAlthough most HCPs follow NHSE guidelines, a range of DMT stopping criteria are employed in clinical practice and treatment decisions may be based on individual patient circumstances.katherine.rhys@novartis.com