bluuebunny/crossref_metadata_2025_split huggingface dataset:
138 Clinical spectrum ofAIFM1-associated phenotype in an irish family
Authors: Bogdanova-Mihaylova Petya , Alexander Michael D , Murphy Raymond P , Chen Hongying , Walsh Richard A , Murphy Sinéad M 
Published: March 2023

Mutations in Apoptosis-inducing factor mitochondrion-associated-1 (AIFM1) cause X-linked peripheral neuropathy (Cowchock syndrome, CMT4X); however, more recently a cerebellar presentation has been described.We describe a large family with seven affected males. They presented with variable age of onset, 18 months-39 years of age. All developed variably present sensorineural deafness, peripheral neuropathy, cerebellar ataxia and pyramidal involvement. Scale for the Assessment and Rating of Ataxia (SARA) ranged 2–23/40, while Charcot-Marie-Tooth neuropathy score 2 varied between 7–13/36. In addition, three had colour vision deficiency.All individuals had normal cognitive assessment.Neurophysiology demonstrated length-dependent large-fibre sensorimotor axonal neuropathy, with particular involvement of superficial radial sensory responses. Brain imaging, performed in four, revealed varying extent of cerebellar atrophy, and white-matter changes in one. Optical coherence tomography was abnormal in one, who had unrelated eye pathology. Two obligate female carriers were assessed clinically and neurophysiologically and were unaffected.Whole genome sequencing demonstrated a previously reported hemizygousAIFM1mutation. Analysis for mutations in other genes associated with colour deficiency was negative.AIFM1-associated phenotype in this family demonstrated significant variability, including previously unreported phenotypic features. Superficial radial nerve was particularly affected neurophysiologically, which may be a phenotypic clue towards this specific genetic diagnosis.
140 Defining clinical and genetic biomarkers in MSA
Authors: Chelban Viorica , Woodside John , Jabbari Edwin , Lamb Ruth , Bocchetta Martina , Rohrer Jonathan , Morris Huw , Houlden Henry 
Published: March 2023

Multiple System Atrophy (MSA) is a rare neurodegenerative condition. As part of the PROSPECT-M a multicentre longitudinal study building a clinical cohort of MSA patients established to improve early diagnosis and track disease progression. Patients who did not fulfil all diagnostic criteria for MSA were also recruited and followed up for phenoconversion.Functional and neuropsychology evaluations are completed at baseline and repeated after 6 and 12 months and annually for a further 3 years and include UMSARS, MoCA, ACE-3 and ECAS, comprehensive brain MRI together with a MSA biobank (plasma, serum, DNA, RNA, spinal fluid, MRI, fibroblasts).So far, 177 MSA patients were recruited of which 52 are longitudinal and 105 are crossectional. Twenty-two patients are followed-up with yearly MRI scan. All longitudinal cases have blood NFL measured yearly for tracking disease progression. We also extracted RNA from brain samples from pathologically confirmed MSA cases and pathological confirmed normal aged controls as well as from blood samples from MSA cases and control to perform expression analysis in search for novel biomarkers of disease. All MSA cases had whole genome sequencing and genotyping.The project contributes with new insights into the natural history of MSA and provides a robust longitudinal in-deapth phenotype data essential for the identification of clinical, neuroimaging and molecular signatures of the disease that can help diagnose or track disease progression.
141 Switching from double-blind entacapone or placebo to open-label opicapone: NMSS results (1-year extension BIPARK-I study)
Authors: Fabregues O , Tolosa E , Ferreira J , Lees A , Santos A , Rocha J , Soares-Da-Silva P 
Published: March 2023

BackgroundOpicapone (OPC), a novel once-daily peripheral COMT inhibitor, has shown to be safe and effective in reducing OFF-time in Parkinson’s disease (PD) patients with motor fluctuations.ObjectiveTo evaluate impact on non-motor symptoms in levodopa-treated PD patients who switched from placebo (PLC) or entacapone (ENT) to OPC in the BIPARK-I open-label extension (OLE).MethodsBIPARK-I, a multinational, multicentre, double-blind, 14–15-week, PLC and active-controlled study evaluated the efficacy of OPC 5 mg, 25 mg or 50 mg in PD patients with end-of-dose motor fluctuations. ENT was included as a reference arm.Following the double-blind BIPARK-I study, all eligible patients were switched to OPC 25 mg once-daily in a 1-year OLE regardless of prior double-blind treatment. After one week either OPC or levodopa could be adjusted according to response.This post-hoc analysis investigated impact on Non-Motor Symptoms Scale (NMSS) score in PLC and ENT ‘switchers’.ResultsFollowing the one-year OLE, NMSS changes (least-square mean [95%CI]) from DB baseline were -5.7, -4.7 and -2.0 and from OL baseline were -3.8, -0.2 and -0.4 for PLC, ENT and OPC 50 mg, respectively.ConclusionNo worsening NMSS score for subjects switching from double-blind ENT. PLC-switched subjects from DB to end of 1 year open-label OPC presented significantly less disability.
15.21 Next-generation sequencing in charcot-marie-tooth disease: opportunities and challenges
Authors: Pipis Menelaos , Rossor Alexander M , Doherty Carolynne M , Laura Matilde , Reilly Mary M 
Published: March 2023

Charcot-Marie-Tooth (CMT) disease and related disorders encompass a phenotypically and genetically heterogeneous group of disorders. Our diagnostic approach to CMT has been revolutionised by the advent and use of next-generation sequencing (NGS) technologies with applications in CMT gene panels, whole exome and whole genome sequencing, mitochondrial sequencing and high-throughput transcriptome sequencing.We present the up to date evidence pertaining to the application of these technologies in CMT diagnostics and also discuss what challenges they bring in relation to variant interpretation. Phenotypic, genetic and bioinformatic evidence should be used to overcome these challenges, and we discuss how setting a maximum credible population allele frequency for pathogenic variants in dominant and recessive CMT genes is crucial in filtering efficiently NGS-derived variants.Whole genome sequencing as a single molecular genetic test is very appealing and, in the context of the 100,000 Genome Project, we suggest how its application into CMT clinical practice can happen with a balance between improved diagnostic yield and burden of variant analysis.
155 Patient support program for RRMS patients treated with DMF
Authors: Monterroso Joana , Curlis Janette , Gribben Leontia 
Published: March 2023

IntroductionIn the UK, the number of patients with relapsing-remitting multiple sclerosis (RRMS) far exceeds the capacity of MS specialist nurses (MSSNs).MethodsBiogen and IQVIA developed a remote, nurse-led, script-based telephone line to provide educational assistance and support treatment adherence among adult RRMS patients receiving delayed-release dimethyl fumarate (DMF). In the year following DMF initiation, 8 calls are scheduled over the first 3 months, followed by 3 quarterly calls. An optional online satisfaction survey was added to the program in July 2017.ResultsBased on summarized call data from March 2015 through November 2018, 1204 patients were enrolled from 136 UK hospitals, with a mean (median, range) of 8.5 (2, 1–168) patients/hospital. An average of 10.8 calls/patient were received. Across 11 scheduled calls, average time/call was 13 minutes. Over this period, cumulative reported DMF discontinuation among enrolled patients was 12.7%. Between July 2017 and September 2018, 76% of survey responders treated for ≥1 year (n=78) would recommend the service (score ≥5, scale: 1 [not at all] to 7 [extremely likely]).ConclusionThis program has been widely used and positively received across the UK by DMF-treated patients and should help reduce the burden on MSSNs.Support: Biogen. Disclosures to be presented on poster.
156 Some mainland Scottish localities have higher incidence rates than orkney
Authors: Kearns Patrick , Connick Peter , MacDonald James , O’Riordan Jonathon , MacDougall Niall , Colville Shuna , Paton Martin , O’Neill Martin , Ascherio Alberto , Chandran Siddharthan 
Published: March 2023

There is wide regional variability in incidence of multiple sclerosis (MS) in Scotland. Extreme high-incidence is well known in Orkney, but most of the Scottish population (98%) lives on the mainland where local patterns are understudied. Well-designed small-areal units of geography and a national prospective incidence register allow us to examine the scale at which incident cases of MS cluster.Using the Scottish Multiple Sclerosis Register (1/1/2010 to 31/12/2017) we created multivariable linear regression models of small area incidence rates adjusted for population structure and latitude on the mainland. To examine the spatial distribution and independence of adjusted-rates, we calculated Moran’s I test for global autocorrelation on the residuals. We then used Getis-Ord Gi* and the isotonic, iterative SatScan statistic to identify local areas with significant positive spatial autocorrelation adjusting for multiple testing and spatial dependency.We can with confidence assert that incidence rates are not spatially random after controlling for latitude. Several localities on the mainland are identified which, over this period, had incidence rates (and populations) higher than Orkney. These may be worthy of monitoring, may generate aetiological hypotheses or be suitable for trials of putative-preventative therapies. Unexplained local variation of incidence suggests missing environmental risk factors.
157 Educational attainment of children born to mothers with MS
Authors: Owen Pickrell W , Lacey Arron S , Harding Katharine , Middleton Rod , Tallantyre Emma C , Ingram Gillian , Pearson Owen R , Rees Mark I , Robertson Neil P 
Published: March 2023

IntroductionMultiple sclerosis (MS) causes long-term disability with broad socioeconomic consequences. This may influence educational attainment in children of affected individuals. We investigated whether having a mother with MS affects performance in Welsh national attainment tests.MethodAnonymised lists of 1584 women with MS diagnosed in two neuroscience centres (Cardiff, Swansea) were linked to population level routinely-collected health and education data. We identified children born to mothers with MS and compared performance in Key Stage (KS) 2–4 tests, taken at ages 11, 14 and 16, to a control group (matched for deprivation score, maternal age, year of birth, gestational age and birth weight). We measured core subject indicator (CSI) as an outcome measure (proportion achieving minimum standard in core subjects).Results525 children from mothers with MS had test results available from 2003–2016; there were 2217 matched controls. There was no significant overall difference in CSI achievement between cases and controls: KS2 (85.3%v84.3%); KS3 (75%v71.5%); KS4 (52.1%v50.5%). Greater Expanded Disability Score Status did not significantly worsen performance but longer time since diagnosis improved performance in KS3 and KS4.ConclusionHaving a mother with MS did not significantly worsen performance in national attainment tests and was associated with improved performance in some subgroups.
159 Delayed-release dimethyl fumarate–associated lymphopenia
Authors: Chan Andrew , Fox Robert J , Bar-Or Amit , Chen Chongshu , Fam Sami , Gold Ralf , Hanna Jerome , Mehta Devangi , Theodore Phillips J 
Published: March 2023

IntroductionFollowing the occurrence of one case of progressive multifocal leukoencephalopathy (PML), the dimethyl fumarate (DMF) label was amended in 2015 to recommend treatment interruption for patients with severe, prolonged lymphopenia (SPL, absolute lymphocyte count [ALC] <0.5×109/L ≥6 months). This study examined clinical implications of DMF-associated lymphopenia and post-treatment ALC dynamics in relapsing-remitting multiple sclerosis patients.MethodsIntegrated analysis of DMF phase 2b, phase 3, and extension studies was conducted using data from first DMF exposure. ALCs were assessed 4, 8, and 12 weeks after DMF initiation and every 12 weeks thereafter.ResultsThe analysis population included 2513 patients (DMF exposure up to 11 years). Patients with SPL and those with ALC always above normal had similar incidences of serious infection (0.016 vs 0.010) and herpes zoster (0.000 vs 0.006). One fatal case of PML was associated with SPL (∼3.5 years duration). In patients with mild/moderate lymphopenia and ALC <0.91×109/L at discontinuation (n=138), median time to ALC ≥0.8×109/L was 6 weeks.ConclusionsThese data support previous reports that DMF-associated lymphopenia is not correlated with increased incidence of serious or opportunistic infections. For most patients, ALCs increased within 2 months following DMF discontinuation.Support: Biogen. Disclosures to be included on poster.
161 Qualitative aspects of cognition in MS & audit of MoCA in LTHTR natalizumab cohort
Authors: Gall Claire 
Published: March 2023

Cognitive impairment in MS is very relevant to treatment decisions & management. It may be a presenting clinical feature of natalizumab-associated PML ; conversely improvement in cognition may be seen in treatment of MS. There is some evidence for the Montreal Cognitive Assessment as a screening tool in MS.MoCA was performed as a cognitive baseline for PML surveillance for patients on natalizumab. 83 natalizumab-treated patients were identified. Moca scores were available for 72 patients. Scores ranged from 15 -30 (Score is out of 30 and the cut off for ‘normal’ is >/=26). Average score 25.7. Age range 18–69, average age 47.30 patients (41.7%) scored below cut off. Subsection scores were available for 27 patients. These will be described in more detail. Patients with low scores were often observed to have frequent DNA letters on file. Two patients had longitudinal data.This audit suggests a high prevalence of cognitive impairment in line with reports which in some cases seems quite severe. MoCA seems to be a usefool screening tool and alerts us to the need for detailed consent & follow-up as well as indicating qualitative aspects of cognitive dysfunction to enable practical strategies to be employed.
162 Doughnuts to sweet diagnosis
Authors: Li Vivien , Ingle Gordon 
Published: March 2023

A 39-year-old professional pastry chef experienced two attacks of longitudinally extensive transverse myelitis over four years. The first presented with lower limb neuropathic pain and urinary retention. CSF was lymphocytic with raised protein and negative oligoclonal bands. MRI spine showed an inflammatory lesion from T2-8. Urinary retention improved over 2 weeks without additional therapy. Re-imaging at 12 months showed resolution of the lesion.The second episode presented with leg weakness, thoracic sensory level and urinary retention. At nadir, power was MRC grade 1–2/5 in the legs and 2–4/5 in the arms. MRI demonstrated abnormal signal and cord swelling from C3-7 and T1-4. By four weeks, power improved to 4–5/5 with IV then high dose oral corticosteroids, but genitourinary symptoms persisted. Azathioprine was later commenced with no further relapses. He is preparing to return to work, following excellent recovery of hand function.Anti-aquaporin-4 and MOG antibodies were repeatedly negative during and between attacks. However, anti-MOG antibodies were positive on re-testing a year after the second attack. While the presentation is typical, the negative result during relapses followed by a positive result while immunosuppressed and clinically stable is unusual. It highlights the value of repeated testing in leading to a defined diagnosis.
164 UK/ireland interim results from a DMF pregnancy registry
Authors: Rog David , Seferta Nicola , McGuigan Christopher , Everage Nicholas , Jones Cynthia 
Published: March 2023

IntroductionData regarding delayed-release dimethyl fumarate (DMF) use, an approved MS treatment, in pregnant women is limited. United Kingdom (UK) and Ireland are enrolling DMF-exposed pregnant women into TecGistry, an ongoing prospective, observational registry to assess pregnancy outcomes.MethodsPregnant women with MS exposed to DMF since the first day of their last menstrual period prior to conception or at any time during pregnancy were included. The UK and Ireland Coordinating Centres (Manchester Centre for Clinical Neurosciences and St. Vincent’s University Hospital, Dublin) liaise directly with DMF-exposed patients and their HCPs.ResultsAs of 24 April 2018, 220 patients (11 patients from UK/Ireland) were enrolled; 161 pregnancy outcomes were reported: 147 (91.3%) live births, 14 (8.7%) spontaneous abortions (< 22 weeks). In UK/Ireland, 9 outcomes were reported: all live births, 8 full term, none premature (details pending on 1 case). Globally, 4 adjudicator-confirmed birth defects were reported: pyloric stenosis (1), transposition of the great vessels (1), ventricular septal defect (2; 1 in UK/Ireland). No maternal, neonatal, perinatal, or infant deaths were reported.ConclusionsConsistent with previous reports, there was no safety signal for DMF exposure on pregnancy outcomes based on ongoing registry results.Support: Biogen; disclosures to be included on poster.
171 Alemtuzumab induced neutropaenia: women at risk
Authors: Tanveer Riffat , Pace Adrian , Rog David , Nazar Sharaf , Talbot Paul , Jackson Fran , Mihalova Tatiana 
Published: March 2023

BackgroundAlemtuzumab, a CD52 - specific monoclonal antibody depletes T and B cell population to reduce relapse in multiple sclerosis. Neutrophils also express low levels of CD52 and can be depleted transiently by alemtuzumab, increasing the risk of infection in the post-alemtuzumab treatment period.AimIn this study in the Greater Manchester Neuroscience Centre (GMNC) we investigated at risk population for alemtuzumab induced neutropaenia. The outcome of these patients is also discussed.MethodRetrospective study of patients who developed neutropaenia following treatment with alemtuzumab at the GMNC. Data of patient demographics, grade of neutropeania, symptoms while neutropaenic and management were evaluated.ResultsOf the 131 patient (86 F: 45 M) treated with alemtuzumab (1.9 F: 1 M ratio), 18 patient (13.7%) developed neutropaenia (17 F Vs 1 M, 19.8% F Vs 2.2% M). Moderate to severe (grade 2–4) neutropaenia was only observed in females. Average duration to develop neutropaenia was 41 days. While neutropaenic 16 patients were asymptomatic, 1 developed flu-like illness and 1 had recurrent chest infection requiring antibiotic.ConclusionIn our experience, women are at significantly higher risk of alemtuzumab induced neutropaenia. Monthly serial blood monitoring is adequate for most patients and specific intervention rarely required.
173 Outcome in a highly active multiple sclerosis cohort in the UK
Authors: Kalam Sabrina , Hill Joe , Baheerathan Ari , Mattascio Miriam , Ali Rehiana , Nicholas Richard , Muraro Paolo 
Published: March 2023

Highly active multiple sclerosis (HAMS) is a clinical phenotype defined by recent disease activity and determines the indication for disease modifying treatments (DMTs). However, prognosis of HAMS is unknown in terms of progression rates.HAMS subjects were recruited to research cohort in 2010. Audits were performed in 2015 and 2019. Progression was assessed according to EDSS criteria by treating clinicians.128/200 subjects had data at all timepoints. Mean age at baseline was 39.5yrs, disease duration 6.6yrs and entry EDSS was 3.3; 80.4% female. Mean relapse number in the year prior to recruitment was 1.9 and 30.5% had gadolinium enhancing lesions. 33% had not received DMTs at baseline and by 33 months 5% were still off DMTs.At 33 months follow-up 17.2% had progressed and 33% by 81 months. However, of those progressing at 33 months 23% of this group had not progressed further or improved by 81 months. There was no difference in progression rates at 81 months in those on DMTs (29/86) at baseline and continued and those who were not (13/42).In HAMS 32.8% had progressed by 6.75 years. Using EDSS progression as an outcome in this cohort, earlier treatment with the DMTs did not appear to affect prognosis.
174 Sclerosing dermopathy after alemtuzumab for multiple sclerosis
Authors: Marastoni Damianou , Lai-Cheong Joey , Magliozzi Roberta , Calabrese Massimiliano , Nicholas Richard 
Published: March 2023

A 48 year-old female with relapsing-remitting multiple sclerosis, diagnosed in 2015, who had failed dimethyl-fumarate treatment with clinical and radiological disease activity - confirmed by a MRI with Gadolinium in January 2018, was started on Alemtuzumab in March 2018. In August 2018, despite clinical improvement, she developed an itchy and painful symmetrical papules in her legs. Skin biopsy showed a patchy perivascular and interstitial inflammatory infiltrate with increased dermal spindle cell numbers most of which had a slender fibrocytic morphology. She partially responded to topical steroids.Clinical and skin histological features indicated nephrogenic systemic fibrosis, a condition usually associated with Gadolinum exposure and renal impairment. There was no evidence of renal disease and bloods excluded other skin fibrotic disorders. The additional histological pattern of interstitial dermatitis seen here, is often observed as a drug reaction. Together these suggested a possible role of Alemtuzumab exposure, though this has not been described. Delayed adverse reactions, in particular B and T cell-driven secondary autoimmunity, are common after Alemtuzumab treatment and indicate the need for long term monitoring of patients exposed to the drug.
177 Updated safety analysis of ocrelizumab in multiple sclerosis
Authors: Young Carolyn , Hauser Stephen , Kappos Ludwig , Montalban Xavier , Hughes Richard , Koendgen Harold , McNamara John , Pradhan Ashish , Wormser David , Wolinsky Jerry 
Published: March 2023

BackgroundOngoing safety reporting is crucial to understanding the long-term benefit–risk profile of ocrelizumab in patients with multiple sclerosis (MS). The safety/efficacy of ocrelizumab have been characterised in Phase II (NCT00676715) and Phase III (NCT01247324;NCT01412333;NCT01194570) trials in patients with relapsing-remitting MS, relapsing MS (RMS) and primary progressive MS (PPMS). We report ongoing safety evaluations from ocrelizumab clinical trials and open-label extension periods up to February 2018.MethodsSafety outcomes were reported for the ocrelizumab all-exposure population in Phase II/III and ongoing Phase IIIb MS trials. The number of post-marketing ocrelizumab-treated patients is based on estimated number of vials sold and US claims data. To account for different exposure lengths, rates per 100 patient years (PY) are presented.ResultsIn clinical trials, 3,811 patients with MS received ocrelizumab (10,919 PY of exposure, as of February 2018). Reported rates per 100 PY (95% confidence interval) were: adverse events (AEs), 242 (239–245); serious AEs, 7.23 (6.73–7.75); infections, 74.5 (72.9–76.1); serious infections, 2.00 (1.74–2.28); and malignancy 0.45 (0.33–0.60). Updated post-marketing data will be presented.ConclusionsReported rates of events in the ocrelizumab all-exposure population continue to be generally consistent with the controlled treatment period in RMS/PPMS populations. Regular reporting of long-term safety data will continue.DisclosuresSponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance was provided by Articulate Science, UK, and funded by F. Hoffmann-La Roche Ltd.