bluuebunny/crossref_metadata_2025 huggingface dataset:
133 Acute parkinsonism
Authors: Gandhi Sacha E , Marshall Vicky
Published: March 2023

Idiopathic Parkinson’s disease (IPD) is typically insidious in onset and gradually progressive. Acute onset Parkinsonism is, conversely, a rare entity. It may be attributable to rapid onset dystonia parkinsonism; post-encephalitic sequelae; vascular lesions, such as stroke or subdural haematoma; acute metabolic disturbance; central and extra-pontine myelinolysis; drug side effects, including neuroleptic malignant syndrome; and toxins, ranging from cadmium to carbon monoxide and organophosphate poisoning.

We report two cases of clinically confirmed IPD (followed up over 7 months and 2 years, respectively), which presented atypically with abrupt onset Parkinsonism in the context of significant psychosocial stress. A comprehensive blood panel (including ATP1A3 in Patient B) and brain magnetic resonance imaging (MRI) were unremarkable. (123)I-FP-CIT SPECT (single photon emission computed tomography) confirmed a marked presynaptic dopaminergic deficit in the basal ganglia for both patients, consistent with degenerative Parkinsonism. Both had asymmetrical parkinsonism (without dystonia or functional signs) and progressed as expected for IPD, with typical motor fluctuations in one patient. Patient B, who was commenced on drug therapy, exhibited a significant Levodopa response consistent with IPD. These cases highlight the potential for IPD to present atypically with rapid symptom evolution in the presence of significant psychological stress.
135 Hyperhidrosis as an identifier in parkinson’s disease subtyping
Authors: Wamelen Daniel van , Leta Valentina , Podlewska Aleksandra , Wan Yi-Min , Krbot Katarina , Jaakkola Elina , Rizos Alexandra , Parry Miriam , Metta Vinod , Ray Chaudhuri K
Published: March 2023

Objective

To identify associated (non-)motor profiles of Parkinson’s disease (PD) patients with hyperhidrosis.

Methods

Cross-sectional analysis of participants enrolled in the non-motor Longitudinal International Cohort Study (NILS; UKCRN No: 10084) at the Parkinson’s Centre at King’s College Hospital (London, UK). Hyperhidrosis responses (yes/no) on question 28 of the Non-Motor Symptom Questionnaire (NMSQ) were used to classify patients with normal sweat function (n=172) and chronic hyperhidrosis (n=56) (analysis 1; n=228). The grade rating NMS scale (NMSS) question 30 scores were then used for severity grading (analysis 2; n=352): absent score 0 (n=267), mild 1–4 (n=49), moderate 5–8 (n=17), and severe 9–12 (n=19).

Results

Baseline demographics were similar between groups. Patients with hyperhidrosis exhibited significantly higher NMSS burden (as graded from total score; p<0.001). Secondary analyses revealed significantly higher dyskinesia scores, worse quality of life and sleep, and higher anxiety levels in hyperhidrosis patients (p<0.001). Tertiary analyses showed higher scores for dysautonomia (orthostatic hypotension, sialorrhea, constipation, urinary urgency and frequency) as well as fatigue and somnolence, among other NMS (p<0.001).

Conclusions

Chronic hyperhidrosis is associated with a dysautonomia dominant clinical picture combined with fatigue and somnolence in PD patients. These patients also are likely to be dyskinetic. This is the first description of motor and nonmotor correlates of hyperhidrosis in PD.
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

Background

Opicapone (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.

Objective

To 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).

Methods

BIPARK-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’.

Results

Following 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.

Conclusion

No 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

Introduction

In the UK, the number of patients with relapsing-remitting multiple sclerosis (RRMS) far exceeds the capacity of MS specialist nurses (MSSNs).

Methods

Biogen 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.

Results

Based 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]).

Conclusion

This 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

Introduction

Multiple 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.

Method

Anonymised 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).

Results

525 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.

Conclusion

Having 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

Introduction

Following 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.

Methods

Integrated 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.

Results

The 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.

Conclusions

These 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

Introduction

Data 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.

Methods

Pregnant 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.

Results

As 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.

Conclusions

Consistent 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

Background

Alemtuzumab, 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.

Aim

In 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.

Method

Retrospective 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.

Results

Of 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.

Conclusion

In 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.
176 Fingolimod associated immune haemolytic anaemia
Authors: AlMasri Omar , Hobart Jeremy
Published: March 2023

We report on the case of a 28 year old (at the time of presentation) man with a diagnosis of relapsing remitting multiple sclerosis (Satisfying McDonald 2010 and 2017 criteria). He has a previous history of mild Haemophilia A (Factor 8 level 8 to 14%). Given his high lesion load and frequency of relapses the decision was made to commence Fingolimod, a sphingosine-1-phosphate receptor modulator. 11 months later he was admitted with jaundice (Bilirubin peak 163 umol/L) and anaemia (Haemoglobin nadir 43 g/L - baseline Haemoglobin 156 g/L, LDH peak 767), and was found to have immune mediated haemolytic anaemia and then delayed liver injury (Alanine transaminase peak 1126 iu/L). These improved after blood transfusion, treatment with prednisolone, and stopping Fingolimod. We believe his presentation was due to drug induced immune mediated haemolytic anaemia and possibly hepatitis. We present his case in the context of the known anglophone literature.
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

Background

Ongoing 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.

Methods

Safety 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.

Results

In 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.

Conclusions

Reported 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.

Disclosures

Sponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance was provided by Articulate Science, UK, and funded by F. Hoffmann-La Roche Ltd.
178 Long-term efficacy of ocrelizumab in relapsing multiple sclerosis
Authors: Giovannoni Gavin , Hauser Stephen L , Brochet Bruno , Montalban Xavier , Naismith Robert T , Wolinsky Jerry S , Hubeaux Stanislas , Mehta Lahar , Model Fabian , Kappos Ludwig
Published: March 2023

Background

The efficacy and safety of ocrelizumab in relapsing multiple sclerosis were demonstrated in the double-blind control period of the Phase III OPERA I/II trials (NCT01247324/NCT01412333). Here we assessed the efficacy of switching to or maintaining ocrelizumab therapy after 3 years’ follow-up in the open-label extensions (OLEs) of these studies.

Methods

At OLE commencement, patients continued ocrelizumab (OCR-OCR) or switched from interferon-β-1a (IFN) to ocrelizumab (IFN-OCR). Adjusted annualised relapse rate (ARR) and time-to-onset of 24-week confirmed disability progression (CDP24) were analysed.

Results

Among IFN-OCR patients, ARR decreased from 0.20 in the year pre-switch to 0.10, 0.08 and 0.07 at Years 1, 2 and 3 post-switch. OCR-OCR continuers maintained low ARRs through the year pre-OLE and the 3 years of OLE (0.13, 0.11, 0.08, 0.07). CDP24 was less frequent in OCR-OCR continuers versus IFN-OCR switchers in the year pre-switch and Years 1, 2 and 3 of OLE (7.7%/12.0%, 10.1%/15.6%, 13.9%/18.1% and 16.1%/21.3%; p<0.05, all comparisons).

Conclusions

Switching from IFN to ocrelizumab at the start of the OLE provided rapid reductions in ARR, maintained throughout the 3-year follow-up. After 5 years’ follow-up, patients who initiated ocrelizumab 2 years earlier accrued significant, sustained reductions in disability progression compared with patients switching from IFN.

Disclosures

Sponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance was provided by Articulate Science, UK, and funded by F. Hoffmann-La Roche Ltd.
15.45 Recessive pentanucleotide repeat expansion in RFC1 causes CANVAS and late-onset sensory ataxia
Authors: Cortese Andrea , Reilly Mary M , Houlden Henry
Published: March 2023

Late-onset ataxia is a reason of frequent neurological consultation, but its cause often remains unknown. Cerebellar dysfunction, proprioceptive loss or vestibular impairment can cause ataxia, when in combination, also termed cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). Both sporadic and familial cases of CANVAS have been reported, which led us to hypothesise a recessive transmission. By applying non-parametric linkage analysis and whole-genome sequencing, we have identified an intronic pentanucleotide repeat expansion in RFC1 as the cause of CANVAS and a common cause of late-onset sensory ataxia. The biallelic repeat expansion showed complete segregation in 23 cases from 11 families. Thirty-three (22%) out of 150 sporadic cases with late-onset ataxia tested also carried the biallelic repeat expansion and frequency was higher in patients with sensory neuronopathy and cerebellar involvement or full-blown CANVAS disease. The expansion is located in the polyA tail of an Alu element and differs in terms of both size and nucleotide sequence from the reference allele. The high frequency of the repeat expansion tested cases, together with an allelic carrier frequency of 0.7% of Europeans, indicate that it represents a frequent cause of late-onset ataxia, with clinical similarities and disease frequency to Friedreich’s ataxia.
180 Cognitive diagnostic criteria lead to distinct patterns of functional connectivity in secondary progressive MS
Authors: Doshi Anisha , Castellazzi Gloria , Muhlert Nils , Alahmadi Adnan , Prados Ferran , Wheeler-Kingshott Claudia , Ciccarelli Olga , Chataway Jeremy
Published: March 2023

Resting state functional MRI(rsfMRI) is an established tool for investigating cognitive impairment(CI) (affecting 40–70% dependent on criteria) in Multiple Sclerosis(MS). This study used rsfMRI to investigate the pattern of functional connectivity (FC) in cognitively impaired(CI) and cognitively preserved(CP) secondary progressive MS(SPMS) patients based on criteria.

70 SPMS subjects (age54±7.1, disease duration 22±9.1 years, EDSS 6.0 (range 4.0–6.5), progression duration8.03±5.2 years) were recruited locally. Cognition was assessed by a battery of neuropsychometric tests and defined using the conservative criteria (z-score of -1.96 standard deviations (SD) on ≥2 tests) and lenient criteria (z-score of -1.5SDs on ≥2 tests). RsfMRI obtained using a 3T Philips scanner was pre-processed and underwent Independent Component Analysis(ICA) to identify the Resting State Networks(RSNs). Dual regression compared group-specific maps(i.e. CI vs CP according to criteria).

We found that the proportion of SPMS-CI changes by 17.1% when using the more stringent conservative(30%) versus the lenient(47.1%) criteria. Overall, 14 RSNs were identified. The greatest FC differences between CI and CP patients within RSNs occurred with the conservative criteria. Independent of the CI criteria used, the left ventral attention network(LVAN), involved in attention processing, is overall the most impaired network in SPMS-CI suggesting that pathological changes in this RSN may underpin global cognitive problems in SPMS.
186 Familial multiple sclerosis: a community based epidemiological study in cumbria
Authors: Nwe May , Footitt David
Published: March 2023

Multiple Sclerosis is an autoimmune inflammatory disease of the central nervous system. Recent studies have revealed that both genetic and environmental factors, principally latitude affect the prevalence.

In Cumbria, the vast majority of multiple sclerosis patients are under the care of a single consultant and specialist nurse-led service. Being community-based we believe there are very few people with MS who are not known to the service and this makes the population especially suitable for epidemiological study. The fact that the clinical team has access to the whole GP record through a shared clinical record enhances the data available research.

Nursing staff in the MS team have prospectively recorded the presence or absence of a family history of MS, and where present the affected family members. We will report upon the prevalence of a family history in our cohort of patients with MS, Clinically isolated syndrome and Radiologically syndrome which numbers 1300, of whom 1150 have an established MS diagnosis. We will compare this with expected rates of familial MS based upon a review of existing literature.
191 MOBILE/ENHANCE integrated efficacy analysis of PR-fampridine
Authors: Hupperts Raymond , Hobart Jeremy , Gasperini Claudio , Lycke Jan , Ziemssen Tjalf , Feys Peter , McNeill Manjit , Acosta Carlos
Published: March 2023

Introduction

The MOBILE and ENHANCE studies evaluated prolonged-release fampridine (PR-FAM) vs placebo (MOBILE, n=68 vs 64; ENHANCE, n=315 vs 318) in people with multiple sclerosis (PwMS) over 24 weeks. PR-FAM-associated improvements in walking and physical performance were assessed using an integrated efficacy analysis.

Methods

Pooled analyses of MOBILE/ENHANCE included the proportion of PR-FAM–treated PwMS with pre-specified threshold improvement in MSWS-12 and in Timed Up and Go (TUG) speed, and mean changes from baseline in MS Impact Scale physical subscale (MSIS-29 PHYS) and Berg Balance Scale (BBS).

Results

Over 24 weeks, significantly more PR-FAM–treated PwMS achieved ≥8-point mean improvement in MSWS-12 (44.3% vs 33.0%; OR: 1.68 [95%CI: 1.23, 2.29]; P<0.001) and ≥15% mean improvement in TUG speed (44.1% vs 34.5%; OR: 1.54 [95%CI: 1.13, 2.11]; P=0.007) vs placebo. Significant improvements from baseline were also registered in MSIS-29 PHYS (least square mean [LSM] difference: −3.18 [95%CI: −4.84, −1.52]; P<0.001) and BBS (LSM difference: 0.62 [95%CI: 0.09, 1.14]; P=0.021) vs placebo.

Conclusions

This post-hoc pooled analysis strengthens evidence that PR-FAM produces clinically meaningful improvements in self-reported walking and benefits self-reported physical function, mobility, balance, and quality of life over 24 weeks for PwMS.

Support: Biogen. Disclosures to be included on poster.
206 Follow your nose to the diagnosis
Authors: Li Vivien , Vivekanandam Vinojini , Lunn Michael
Published: March 2023

A 47-year-old female presented with episodic cranial neuropathies. Over four years, she had bilateral hearing impairment. Right maxillary distribution pain was attributed to sinusitis, with subsequent sinus surgery. She developed bilateral abducens palsies and left optic neuropathy, each lasting several weeks before resolution.

She was diagnosed with hypopituitarism and commenced hormonal replacement after prolonged amenorrhoea. She noticed altered smell, and most recently, developed right facial weakness, which resolved with prednisolone.

MRI brain demonstrated nodular dural thickening of cranial fossa floor, with symmetrical T2 white matter and basal ganglia hyperintensity. Bloods and CSF were non-diagnostic. FDG-PET showed multifocal uptake particularly involving the upper aerodigestive tract.

Differentials included inflammatory or infiltrative aetiologies. Meningeal biopsy was considered, but recent corticosteroids and hydrocortisone replacement would potentially mask tissue appearances. A history of tonsillectomy and sinus surgery four years earlier coinciding with neurological symptoms led to re-review of external histology, showing 40% of IgG-positive plasma cells expressing IgG4. IgG4 disease was diagnosed and immunosuppression commenced, with clinical stability and radiological improvement.

This case illustrates the chronic fluctuating presentation of IgG4 disease, and the forensic medicine required to make a diagnosis with relevant historical histology, when both presentation and tissue have been modified by steroid treatment.
209 ‘How rare do we dare’ – hickam’s dictum taken to the extreme
Authors: Bunting EE , Lunn MP
Published: March 2023

Solitary CNS Lymphomatoid granulomatosis (LG), a rare lymphoproliferative disorder, was discovered in a patient collecting rare neurological disorders.

A patient diagnosed with Charcot-Marie-Tooth type 4C (SH3CT2) and Myasthenia Gravis, treated with mycophenolate, presented with musical hallucinosis, described as choral music occurring in short bursts. Investigations deemed this secondary to hearing loss. Neuro-imaging revealed a cerebellar cavernoma and a developmental venous anomaly, thought to be incidental. A rapidly expanding, right frontal lesion was noted on subsequent imaging. Biopsy of this lesion revealed a florid inflammatory infiltrate composed of small lymphocytes, macrophages and non-caseating granulomata. Immunohistochemical staining for CD20 showed moderate numbers of B-lymphocytes, positive for Epstein Barr virus-encoded small RNA, suggesting a diagnosis of LG.

Immunosupression is a risk factor for EBV mediated lymphoproliferative disorders. SH3TC2 is involved in myelination and maintenance of the node of Ranvier and mutations disturb interactions with the GTPase Rab11. Outside of the peripheral nervous system mutated Rab11 molecules are known to have neoplastic potential through prevention of the normal function of binding the oncogene Evi5, potentially explaining the development of LG as another rare disorder. Despite tenuous links, these rare neurological disorders appear unrelated in this individual.
212 Is there an ethnicity bias of access to MS services? The barts health experience revisited
Authors: Allen-Philbey Kimberley , Silveira Facundo , Turner Ben , Giovannoni Gavin , Schmierer Klaus
Published: March 2023

Introduction

Principle 1 of the NHS constitution states that access to services should be non-discriminatory including ethnic background. Early diagnosis and initiation of disease modifying treatment (DMT) in people with multiple sclerosis (pwMS) is important for prognosis. We report findings from a re-audit of ethnic equity of clinical service experience in pwMS in east London.

Methods

Retrospective cohort of pwMS ≥18 years old, diagnosed between 2014–2017 with 2 years of follow-up, attending Neurology services at Barts Health NHS Trust. We compared access to MS services between ethnic groups. Result variables included (i) first symptom to diagnosis (S2D) and (ii) diagnosis to DMT (D2T).

Results

59 pwMS fulfilled inclusion criteria, 7/59 were Black, 13/59 South Asian, 22/59 White and 17/59 as Other. There was a non-significant trend towards shorter S2D in White pwMS (1.2 years) compared to the other groups (Black 1.94, South Asian 1.93 and Other 1.55) (p=0.54). No difference was observed regarding D2T (Black 0.51 years, South Asian 0.31, White 0.58 and Other 0.47, p=0.25).

Conclusion

Reassuringly, no ethnic inequity of access to MS services was detected, confirming findings of the original audit.
14.57 How much of anti-CGRP monoclonal antibody preventive therapy for migraine is contextual (Placebo) effect?
Authors: Forbes Raeburn B , McCarron Mark O
Published: March 2023

Background

Randomised Controlled Trials (RCTs) of Anti-CGRP monoclonal antibodies prove their efficacy in preventing Episodic Migraine (EM) and Chronic Migraine (CM), but will cost c£350 per patient per month. Many headache interventions have significant placebo responses. The aim is to quantify the contribution of placebo and other non-specific effects by estimating the Proportion Contextual Effects from available RCTs.

Methods

Search of clinicaltrials.gov for RCTs in adults with EM or CM. Data extracted from peer reviewed publications, conference abstracts and company websites January 2013-Sep 2018. Primary outcome - Reduction in Monthly Migraine Days. Effect Size (Standardised Mean Difference - SMD) and Proportion Contextual Effect (Response Ratio) calculated with 95%CI. Risk of bias not estimated.

Results

56 registered studies identified, of which 28 were RCTs (8 incomplete or non-migraine and 2 in children). 18 included trials tested 19 doses of CGRP-antibody in EM and 9 doses in CM. Effect Sizes were small (SMD 0.2–0.49) in 12/19 EM and 7/9 CM doses, moderate (0.5–0.79) in 5/19 EM and 1/9 CM. Proportion Contextual Effects were between 50–70% in 13/19 EM and 8/9 CM doses, and >70% in 5/19 EM and 2/9 CM doses.

Discussion

Anti-CGRP antibodies are effective treatments for EM and CM, but this is primarily due to contextual effects. >50% of the benefit accrued is attributable to health service personnel and infrastructure, not a direct drug effect.
214 Analysis of CSF IgG index, IgG synthesis and clinical presentation among CSF OCBs negative patients
Authors: Mihalova Tatiana , Kwong Jing Ling , Alachkar Hannah
Published: March 2023

Background

Multiple sclerosis, an autoimmune condition, is characterised by high incidence of CSF positive oligoclonal bands (OCBs). Positive OCBs are now used for diagnosis of clinically definite MS. The clinical course of CSF OCBs negative neurological patients can differ.

Method

From total of 987 CSF OCBs negative samples, processed in immunology laboratory 2015–2016, 76 CSF OCBs negative samples have shown other CSF abnormalities – raised CSF IgG index, raised CSF IgG synthesis and reduced blood brain barrier ratio (BBBR). We retrospectively reviewed their clinical presentation, CSF protein, WBC and CSF IgG index, IgG synthesis and BBBR.

Results

4 distinctive clinical groups were identified: inflammatory peripheral nerve disease, neurosarcoidosis, other CNS inflammatory disorders (SLE, vasculitis, ADEM, MS) and degenerative disorders.

CSF OCBs negative patients with neurosarcoidosis presented with significantly raised CSF protein (on average 1.76 g/dl), CSF IgG synthesis (125.3), and IgG index (0.995) and low BBBR (33). Other CNS inflammatory disorders had mildly raised CSF protein (0.74 g/dl), IgG synthesis (30), IgG index (0.835) and reduced BBBR (70), but not as significant as seen in neurosarcoidosis.

Conclusion

The distinctive CSF pattern despite of negative CSF OCBs may be helpful if suspecting diagnosis of neurosarcoidosis, hence performing CSF IgG synthesis and IgG index may be helpful.
215 Demographic, clinical and paraclinical features in a subgroup of patients with NMOSD
Authors: Wegehaupt Thomas , Vundavalli Sriram , Cooper Sarah , Leite Maria , Palace Jacqueline , Fisniku Leonora
Published: March 2023

Background

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune, inflammatory condition more commonly distinguished from multiple sclerosis (MS). Early diagnosis is paramount as NMOSD and MS respond to different immunomodulatory therapies.

Objective

To determine common clinical and paraclinical features at the disease onset of NMOSD-patients.

Methods

All antibody-positive NMOSD-patients seen between 2013 and 2017 at Brighton and Sussex University Hospital were included. Their clinical and paraclinical data at the first presentation was reviewed.

Results

9 patients were included; 8 caucasians; 5 females. Mean age at the onset was 48.8 years. All MOG-positive patients (5/9) presented with optic neuritis; AQP4-positive patients (4/9) presented with transverse myelitis or area postrema syndrome. One patient (AQP4-positive) had an underlying malignancy. Three patients had positive oligoclonal bands. None fulfilled the McDonald radiological criteria for MS. Brain MRI scan was abnormal in 5/9 patients with the lesions being either juxtacortical or subcortical but none periventricular. Spinal cord lesions were 2 or more vertebral length (range 2 – 10) and were isotense. No silent spinal cord lesions were seen. One patient required more than one immunosuppression (AQP4-positive) and one (MOG-positive) was on none.

Conclusion

Early recognition of NMOSD-patients is important in order to direct appropriate treatment.
216 Retinitis pigmentosa and autoimmunity
Authors: Mihalova Tatiana , Pankhania Kishan , McKee David
Published: March 2023

Background

Retinitis pigmentosa (RP) is a genetic disorder with affected gene expressed in rod cells, ultimately leading to death or secondary degeneration of cone cells. Over 170 genes have been associated with RP, but little is known of HLA gene association. Research has suggested link between RP and other autoimmune diseases. MS is a known autoimmune disorder with most important genetic factor being HLA-DRB1*15:01. Primary angiitis of central nervous system is an autoimmune disorder of vessels leading to inflammation and ischaemia. Several genetic associations in the HLA region have been described with systemic vasculitides.

Methods

2 non-related patients with established retinitis pigmentosa and with similar neurological presentation and neuroimaging were reviewed. First patient diagnosed with primary angiitis of CNS was treated with Mycophenolate (steroid-sparing agent), second patient had rapidly evolving severe relapsing remitting MS treated with Natalizumab. Genetic analysis was performed by HLA typing and 170 retinal genes panel.

Results

There was no genetic overlap in the positive retinal genes or HLA-A, B and DRB1 regions. Both patients expressed HLA-C*07 and HLA-DQB1*03 alleles. Patient with vasculitis expressed HLA- DRB1*15:01 and patient with MS expressed HLA-DRB1*03:01 and DRB1*04:04. Results suggest a possible link between RP and autoimmunity as both had HLA-C*07 and HLA-DQB1*03 alleles. Initially both patients were treated with steroids and had a good neurological response.