bluuebunny/crossref_metadata_2025_split huggingface dataset:
128 Visuoperceptual deficits as measures of cognitive dysfunction in multiple sclerosis: a pilot study
Authors: Whitford Victoria , Leddy Sara , Waters Sheena , Karania Tasvee , Marshall Charles , Dobson Ruth 
Published: August 2022

ObjectiveWe investigated whether computerised measurement of visuoperceptual deficits can detect cognitive dysfunction in multiple sclerosis (MS).MethodsWe assessed people with MS (PwMS; N=31, 58% female, 64% White, mean age 40.1) and controls (N=18, 61% female, 83% White, mean age 37.3) on novel, culturally-fair, psychophysical “stress” tests that detect subtle deficits in visuoperceptual processing in early neurological disease: the ‘Cats ‘N Dogs Task’ (CNDT, which presents images with varying degrees of skew for differentiation into ‘cat’ or ‘dog’) and ‘Point Light Walker Task’ (PLWT, which presents motion patterns for differentiation into ‘human’ and ‘nonhuman’). Visual acuity, physical function, depression, anxiety, fatigue, and acceptability of the tests were also collected for PwMS.ResultsFor the CNDT, relative to controls, PwMS showed significantly lower accuracy (82% vs 86%) and slower reaction time (1.48s vs 1.17s). For PLWT, they showed significantly reduced difficulty level (psycho- physical threshold). Analysis of Variance with the factors MS status, sex, ethnicity, and age revealed a significant main effect of MS for each of these measures (all F>7.3, p<0.0097). In PwMS, clinical severity measures (EDSS, 9-hole peg) showed modest, significant correlation with accuracy, reaction time, or dif- ficulty. All tasks were well-tolerated.ConclusionDetection of cognitive dysfunction via measurement of visuoperceptual processing is possible in MS using culturally fair, well-tolerated, computerised cognitive “stress” tests. Further testing across a range of disability with a larger control group is needed.
131 Understanding the administration and monitoring time burden of several disease-modifying therapies for relapsing multiple sclerosis
Authors: Rog David , Brownlee Wallace , Carod-Artal Francisco Javier , Kalra Seema , Cock Erwin De , Leclerc Stephanie , Amin Amerah , Ashton Luke , Evans Hannah 
Published: August 2022

BackgroundTo assist neurologists with effectively planning multiple sclerosis (MS) services in the NHS, this study quantified the administration and monitoring time burden associated with selected high-efficacy disease-modifying therapies (DMTs; alemtuzumab, cladribine tablets [CladT], fingolimod, natalizumab, and ocrelizumab) for highly-active relapsing MS in the UK.MethodsA time and motion study was conducted across four MS centres over 3–4 months per-site (Aug 2019–Feb 2021). Time dedicated by healthcare professionals (HCPs) to pre-specified drug administration and monitoring activities was assessed for each of the selected DMTs. Data were extrapolated over 4 years per-patient, based on the relevant Summaries of Product Characteristics, and analysed descriptively.ResultsFor oral DMTs, projected total active HCP time (monitoring only) per-patient over 4 years was 12.3 hours for CladT and 15.9 hours for fingolimod. For infusion DMTs, total time (administration and monitoring) was 35.5 hours for alemtuzumab (6.1 and 29.4 hours), 46.5 hours for natalizumab (17.2 and 29.3 hours), and 21.6 hours for ocrelizumab (6.2 and 15.4 hours).ConclusionsWhile active HCP time varies across sites, infusion DMTs are projected to require the greatest amount of HCP time associated with administration and monitoring over 4 years versus oral DMTs.
140 Long-term effectiveness of natalizumab for RRMS: UK and global interim results from TYSABRI observational program
Authors: Nicholas Richard , Harrower Timothy , Sun Zhaonan , Vonsy Jean 
Published: August 2022

IntroductionThe TYSABRI Observational Program (TOP) is an ongoing observational study of natalizumab treatment in relapsing-remitting multiple sclerosis (RRMS) patients. 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) was analysed in TOP UK (n=134) and global (N=6321) cohorts using data from July 2007 to November 2021. A subgroup analysis assessed ARR in patients with one prior disease modifying therapy (DMT) in the UK (n=64) and global (n=2757) cohorts. Cumulative probabilities of 24-week confirmed disability worsening and improvement will be presented subsequently.ResultsARR decreased in UK patients from 2.21 in the year before initiation to 0.15 on natalizumab (P<0.0001), consistent with a global decrease from 2.00 to 0.18 (P<0.0001). In patients with one prior DMT, ARR decreased in UK patients from 2.13 in the year before initiation to 0.15 on natalizumab (P<0.0001), similar to the global decrease from 2.03 to 0.16 (P<0.0001).ConclusionsThe reduction in ARR on natalizumab was similar in the TOP UK and global cohorts, including in the subset of patients with one prior DMT. These findings support the real-world effectiveness of natalizumab.SupportBiogen. Disclosures on poster.
141 Cognitive processing speed predicts disease progression in SPMS: post hoc analysis from the EXPAND study
Authors: Penner Iris-Katharina , Giovannoni Gavin , Chitnis Tanuja , Vermesch Patrick , Arnould Sophie , DeLasHeras Virginia , Karlsson Goeril , Piani-Meier Daniela , Kappos Ludwig , Benedict Ralph 
Published: August 2022

ObjectiveAssess the predictive value of cognitive processing speed (CPS), using the Symbol Digit Modali- ties Test (SDMT) score, on disability progression in secondary progressive multiple sclerosis (SPMS).Design/MethodsSPMS patients from the Phase 3 EXPAND study (core part [CP] and core+extension part [CP+EP]) were categorised into quartiles of baseline SDMT score (worst-WQ [Q1], intermediate [Q2-Q3], and best-BQ [Q4] quartile). The predictive value of baseline SDMT quartiles for time-to-wheelchair (T2W; i.e., Expanded Disability Status Scale [EDSS] score ≥7) sustained until end of follow-up, or 6-month confirmed disability progression (6mCDP) by EDSS, were assessed at the end of the CP (up to 37-months) and CP+EP (up to 5-years) by Cox regression (adjusted for treatment, age, gender, baseline EDSS, baseline SDMT quartile, and treatment-by-baseline SDMT quartile interaction).ResultsAnalyses included 1628/1651 patients (98.6%) randomised in EXPAND (baseline SDMT: WQ, n=435; intermediate, n=808; BQ, n=385). Risk of T2W (WQ vs BQ) was higher in the CP (HRWQ/BQ=1.31, 95% CI:0.72–2.38; p=0.37) and increased with long-term follow-up (HRWQ/BQ=1.81; 1.17–2.78; p=0.01). Baseline SDMT was not predictive of 6mCDP. The predictive value of on-study SDMT score change will be presented.ConclusionsThe results support the predictive value of CPS for long-term physical disability progression in SPMS. Funding: Novartis Pharma AG, Basel, Switzerland.
144 Long-term efficacy of ofatumumab in patients with relapsing multiple sclerosis
Authors: Hauser Stephen , Fox Edward , Aungst Angela , Su Wendy , Zielman Ronald , Gupta Ayan Das , Stoneman Dee , Robertson Derrick , Cohen Jeffrey , Kappos Ludwig 
Published: August 2022

ObjectiveTo assess the long-term efficacy of ofatumumab treatment for up to ~4 years in patients with relapsing multiple sclerosis (RMS).MethodsThis analysis (data cut-off: 25-Sep-2021) will include cumulative data from patients randomised to ofatumumab/teriflunomide in the ASCLEPIOS I/II trials (core study) and the ongoing, open-label, ALITHIOS extension study. Patients will be analyzed in two groups: those randomised to ofatumumab in the core (continuous group) and those randomised to teriflunomide in the core with potential switch to ofatumumab in the extension (switch group). Annualised relapse rate (ARR), disability worsening (time- to-3-month/6-month confirmed disability worsening), disability improvement (time-to-6-month confirmed disability improvement), and brain MRI outcomes (number of Gd+T1 lesions and annualised T2 lesion rate) will be assessed.ResultsOverall, 1882 patients who were randomised in the ASCLEPIOS I/II trials (ofatumumab/terifluno- mide: 946/936) will be included in the analysis. In total, 690/946 patients treated with ofatumumab and 677/936 patients treated with teriflunomide entered ALITHIOS. Updated efficacy results for up to ~4 years will be presented at the congress.ConclusionsThese analyses will provide insights on the sustained efficacy of continuous ofatumumab treatment for up to 4 years in patients with RMS, and on ofatumumab efficacy in patients newly switched from teriflunomide. Funding: Novartis Pharma AG, Basel, Switzerland.
157 Natalizumab treatment satisfaction in the TONiC-MS study: study design
Authors: James Bethan , Mills Roger , Vonsy Jean , Langdon Dawn , Ando Hikari , Young Carolyn 
Published: August 2022

BackgroundThe Trajectories of Outcome in Neurological Conditions-MS (TONiC-MS) is an ongoing observational study of people with MS in the UK, collecting patient reported outcome measures. In 2021, natalizumab became available in s.c. formulation in addition to the i.v. formulation first licensed in UK in 2006. There are currently no data on patient preference between the two formulations.MethodsThis is a prospective, observational, open-label questionnaire study nested in the TONiC-MS study. Following informed consent, participants on natalizumab-i.v. in TONiC-MS receive a baseline question- naire pack covering: treatment duration, frequency of administration, cannulation experience; adverse events; Neurological Fatigue Index-MS; Hospital Anxiety and Depression Scale; Stigma Scale for Chronic Illness; WHOQol-BREF; MSIS 29 Psychological; Warwick-Edinburgh Mental Well-being Scale. If the subject switches to natalizumab-s.c., one and three months later they will complete a follow-on pack repeating the above alongside the Patient Preference Questionnaire.ResultsEnrolment of participants on natalizumab-i.v. started in August 2021. Study design and interim data will be presented.DiscussionThis study will provide real-world data on experience with natalizumab-i.v. and natalizumab-s.c. in the UK. The data collected will allow examination of quality of life, MS psychological impact, well-being and adverse events on the different formulations of natalizumab.
177 An unusual presentation in motor neurone disease
Authors: Terry Robyn , Tanti Matthew , Jung Agam , Mavroudis Ioannis , Devinuwara Kanch , Sivakumar Gnanamurthy 
Published: August 2022

Motor Neurone Disease (MND) is a life limiting neurodegenerative condition. Spasticity in MND is usually managed with oral medications. Intrathecal baclofen (ITB) is occasionally used. While there is some expe- rience of ITB in Primary Lateral Sclerosis (PLS) there are few reports of ITB in the context of Amyotrophic Lateral Sclerosis (ALS). Paroxysmal sympathetic hyperactivity (PSH) is known to occur with central nervous system (CNS) insults, but there is only one prior reported case of MND with PSH in the literature.We report a patient with an eight-year history of PLS, sleep apnoea, recent immobility and conversion to ALS who developed PSH after ITB pump insertion. His spasticity was severe despite oral medications and the ITB insertion resulted in dramatic improvement. Two months post procedure he developed recurrent episodes of facial flushing, hypertension, tachycardia and headache, typical of PSH, which seemed to follow episodes of sleep apnoea. Other somatovisceral triggers were not found. Imaging of the neuraxis revealed peri-rolandic atrophy in keeping with ALS but no new CNS lesions.PSH in our patient seemed to follow ITB insertion despite ITB being a treatment for PSH. More studies are required to assess efficacy and complications of ITB for patients with MND.
179 Impact inventory development in neurological pathways
Authors: Chappell Rachel , Fearn Sarah , Raftery James , Kipps Christopher 
Published: August 2022

BackgroundQuantification of the economic burden within long-term neurological conditions pathways is difficult, and little evidence is available on how best to approach this. With the ambition to deliver care differently through digital mechanisms, and enhanced provision of self-management support, it is impera- tive that we develop mechanisms that can help measure the economic impact of pathway interventions in long-term neurological conditions. An impact inventory is a recognised initial step in defining the costs of an intervention from a range of perspectives including health/non-health and known/unknown cost itemsMethodsWe used thematic analysis to analyse survey data on events causing an increase in care needs, grouped these as health- or care-related, calculated reported event frequencies and then applied NHS (National Tariff workbook) and social care reference costs (PSSRU, 2020) to them.ResultsWe identified 728 events comprising 35 event types across 5 long-term neurological conditions. Six events were common across conditions, and 13 were condition-specific. Post-event care costs were significantly greater than health-related costs (mean 7.9 times), and total pathway event costs varied nearly five-fold across conditions (£5,395 vs £23,258).ConclusionCosts can be quantified in neurological pathways using an impact inventory to characterise events that change care requirements.
182 Pooled safety data from the risdiplam clinical development programme
Authors: Baranello Giovanni , Servais Laurent , Chiriboga Claudia , Darras Basil , Bader-Weder Silvia , Gorni Ksenija , Jaber Birgit , McIver Tammy , Scalco Renata , Mercuri Eugenio 
Published: August 2022

Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) premRNA splicing modifier approved by the EMA and MHRA for the treatment of patients aged ≥2 months, with a clinical diagnosis of Type 1, 2 or 3 spinal muscular atrophy (SMA) or 1–4 copies of SMN2.Safety data were pooled from three studies within the risdiplam clinical development programme:FIREFISH (NCT02913482) assesses safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of risdiplam in infants with Type 1 SMASUNFISH (NCT02908685) assesses safety, tolerability, PK, PD and efficacy of risdiplam in patients with Types 2/3 SMAJEWELFISH (NCT03032172) assesses safety, tolerability, PK and PD of risdiplam in patients who previously received RG7800 (RO6885247), nusinersen (SPINRAZA®), olesoxime or onasemnogene abeparvovec (ZOLGENSMA®).Pooled analyses from FIREFISH, SUNFISH and JEWELFISH showed no treatment-related safety findings leading to withdrawal from risdiplam in 465 patients treated for up to 38.9 months (data-cut-offs: 14 November 2019, 15 January 2020 and 31 January 2020, respectively). The differences in adverse event profiles between Type 1 and Types 2/3 SMA populations appeared to be driven by the severity of the underlying disease. Here we will present updated pooled safety analyses for the risdiplam studies.
183 Lumbar ports to deliver nusinersen in SMA: first adult and paediatric patients in the UK
Authors: Hewamadduma Channa , Childs Annemarie , Lacy Patricia de , Sivakumar Gnanamurthy , Nevin Katie , Ahmad Faizan , Khan Almas , Ali Ayesha , Marley Fiona , McMullan John 
Published: August 2022

5q- Spinal muscular atrophy (SMA) is a progressive inherited disorder of the motor neurons due to bi allelic mutations in SMN1 gene responsible for a high mortality in infancy, and significant morbidity in childhood, adolescence and into adult life. Advent of SMN1 gene splice modifiers have revolutionised the therapeutic landscape in SMA. Nusinersen is the first such treatment in SMA and is delivered intrathecally via lumbar puncture (LP). Nusinersen is currently accessible to the UK SMA patients via a managed access agreement.LPs are difficult in some patients due to previous spinal fusion surgery (especially in Type 2 SMA), obesity, and other anatomical challenges. Some patients and families find repeat LPs intolerable. A proportion of SMA patients therefore have not been able to access nusinersen for the above reasons, although they would otherwise choose nusinersen as the treatment of first-choice. Nusinersen delivery via a lumbar port and catheter system is not licensed. However it has been successfully attempted in other European and US centres before.Here we report the details and protocols of the first UK adult and paediatric SMA patients who underwent lumbar port and catheter insertion to successfully deliver nusinersen treatment, thereby maintaining the choice of a therapeutic option for a proportion of SMA patients.
207 Bayesian revolution in stroke research – a four-arm hypothetical study for neuro- protection in the hyperacute stage
Authors: Das Abhijit , Chatterjee Somenath , Sekhar Alakendu 
Published: August 2022

Background and AimsThe treatment of acute ischemic stroke (AIS) still has multiple equipoises and the current time-consuming and inefficient process of clinical translation is a major hindrance. Bayesian approaches offer an alternative method that can accelerate the development of novel treatments. These designs allow multiple treatment options to be tested simultaneously and these features significantly reduce sample size and allow for faster and more efficient clinical translation. Unfortunately, unlike other fields, Stroke researchers are yet to adopt these methodologies.MethodsWe propose the “leapfrog design” to evaluate multiple treatments simultaneously. This allows continual treatment improvement and finding one or more treatments that are better than the current ‘gold standard’ which is accomplished by allowing replacement of the comparison arm (the arm against which all other arms are compared) by new treatment arms that achieve a prespecified threshold for demonstrating superiority. For the hypothetical study we simulated a 4-arm study involving – a) Nerinetide b) TRPM7 c) SRC-ND2 and d) uric acid in patients undergoing thrombectomy. We used the BFDA – an R package for Bayes factor (BF) design analysis.ResultsWe chose Cohen’s d = 0.4, as in early stage of development, with a BFfail of 1/4, and BFsuccess of 5. The Nmin and Nmax were found much smaller than traditional RCT numbers.ConclusionsThis will be a much-needed paradigm shift for further progress in stroke research beyond current equipoises.
Evaluating the feasibility of a real world pharmacovigilance study (OPTIMISE:MS)
Authors: Dobson Ruth , Craner Matthew , Waddingham Ed , Miller Aleisha , Pindoria Jayant , Cavey Ana , Matthews Paul M ,   on behalf of all OPTIMISE:MS investigators
Published: August 2022

BackgroundClinical trial populations do not fully reflect routine practice. The power of routinely collected data is increasingly recognised.MethodsThe OPTIMISE:MS pharmacovigilance study is a prospective, pragmatic observational study, conducted across 13 UK MS centres. Data were collected at the time of routine clinical visits. The first participant was recruited on 24th May 2019; data were extracted on 11th November 2021.Results2112 participants were included (median age 44.0 years; 1570 (72%) female; 1981 (94%) relapsing- remitting MS). 639 (30%) were untreated at study entry, 205 (10%) taking interferon beta/copaxone, 1004 (47%) were taking second/third generation DMT first line (including dimethyl fumarate, oral cladribine, natalizumab, ocrelizumab), and 264 (13%) had escalated from either interferon beta or copaxone. 342 clinical events were reported, of which 108 were infections. There was an increased risk of adverse events in people taking second/third generation DMT (RR 3.45, 95%CI 1.57-7.60, p<0.01 vs no DMT). Unadjusted Poisson regression demonstrated increased incident adverse events in people taking natalizumab (IRR 5.28, 95%CI 1.41-19.74, p<0.05), ocrelizumab (IRR 3.24, 95%CI 1.22-8.62, p<0.05), and GA biosimilar (Brabio) (IRR 4.89, 95%CI 1.31-18.21, p<0.05) vs no DMT.ConclusionsRoutinely collected healthcare data can be used to evaluate DMT safety in people with MS. These data highlight the potential of pragmatic studies to guide understanding of risks and benefits associated with DMT.
Network changes predicting language decline following anterior temporal lobe resection
Authors: Binding Lawrence , Taylor Peter , Baxendale Sallie , McEvoy Andrew , Miserocchi Anna , Duncan John , Vos Sjoerd 
Published: August 2022

Anterior temporal lobe resection (ATLR), while successful can result in lasting impairment of language function. White matter bundles have been shown to explain some of the variance seen in language decline after ATLR. Network analysis of the structural connectome has been shown superior in predicting preoperative language ability but remains unexplored in predicting postoperative ability.Diffusion MRI-based tractography was used to generate the preoperative connectome on 54 left-lat- eralised (as determined by functional MRI), left-hemisphere ATLR. Postoperative connectomes were estimated via manually drawn resection masks. Graded naming test (GNT), semantic, and letter fluency were binarised into significant decline or not (via their reliable change indices). Strength (sum of connec- tions) and betweenness centrality (interconnectivity) network changes were generated using pre- and postoperative connectomes as predictor variables. Each model was entered into a linear support vector machine incorporating synthetic minority over-sampling technique for class imbalances.Strength changes alone accurately predicted 81.6% of patients who had GNT decline. Betweenness centrality changes accurately predicted 73.3% of patients who had letter fluency decline. Patients with semantic decline were predicted equally as well by strength and betweenness centrality changes (accuracy=71.1%).These findings demonstrate the usefulness of the structural network in predicting and potentially prevent- ing postoperative language decline.
Attenuated heart-brain integration predicts functional non-epileptic seizures
Authors: Elkommos Samia , Martin-Lopez David , Koreki Akihiro , Jolliffe Claire , Mula Marco , Critch-ley Hugo , Edwards Mark , Garfinkel Sarah , Richardson Mark P , Yogarajah Mahinda 
Published: August 2022

BackgroundPatients with functional seizures (FS) can experience dissociation (depersonalisation) before their seizures. Depersonalisation encompasses a feeling of disembodiment, putatively caused by reduced afferent visceral mapping, that is, changes in interoceptive processing. The heartbeat-evoked potential (HEP) is an electroencephalographic (EEG) index of synchronised neural responses to individual heart- beats, and a marker of interoceptive representation. HEP amplitude is reported to be reduced in dep- ersonalisation-derealisation disorder.PurposeTo assess whether alterations in interoceptive processing indexed by the HEP occur prior to FSs, and compare this with epileptic seizures (ES).MethodsHEP amplitudes were calculated from EEG during video-EEG monitoring in 25 patients with FS and 19 patients with ES, and compared between interictal and preictal states.ResultsThe FS group demonstrated a significant reduction in HEP amplitude between interictal and preictal states at F8 (rB=0.612, p=0.006) and C4 (rB=0.600, p=0.007). No differences in HEP amplitude were found between interictal and preictal states in the ES group. Findings were not related to heart rate, mean ECG or QRS amplitudes, which did not differ between states or groups.ConclusionOur data support the notion that aberrant interoception underpins disembodiment prior to dissociative FS. Changes in HEP amplitude may reflect a neurophysiological biomarker of FS.