bluuebunny/crossref_metadata_2025 huggingface dataset:
064  Preserving vision by optimising surveillance of suprasellar lesions, a consensus statement
Authors: Gilmartin Aisling , Nowak Victoria , Marcus Hani , Grieve Joan , Dorward Neil , Petzold Axel , Acheson James , Baldeweg Stephanie , Bremner Fion , Khaleeli Zhaleh ,   et al
Published: May 2022

Introduction

Suprasellar tumours are a heterogenous group which may compromise the optic apparatus. Serial monitoring and timely intervention preserves vision, but consensus regarding optimal surveillance is lacking. An audit at our tertiary centre found that variation in surveillance intervals and methods leads to under- and over-investigation. We present a novel, evidence- and consensus- based guideline for efficient neuro-ophthalmological monitoring of this cohort.

Method

We searched MEDLINE/Pubmed for ‘visual field’, ‘visual acuity’, ‘pituitary’ and ‘macroadenoma’ with filters: Clinical trial, Meta-analysis, Randomised Control Trial, Review, Systematic review (2000–2020). We constructed a guideline which was reviewed by the multidisciplinary pituitary network consultants (neurosurgery, endocrinology, neuro-ophthalmology).

Results

We found 18 relevant publications covering pre- and post-operative tumour evaluation. We recommend visual acuity, colour vision, 24–2 Humphrey Visual Field and OCT assessment in a technician- led clinic, supervised by a named neuro-ophthalmology consultant. We recommend baseline and post- operative assessment, then annual for 5 years, progressing to every 2 years. We suggest how to identify patients who may be safely discharged and those requiring re-referral.

Conclusion

A clear and simple guideline for neuro-ophthalmology surveillance of suprasellar lesions is proposed to optimise safety, efficiency and effectiveness. The guideline will be validated in future through departmental audit.

aisling

gilmartin@nhs.net

57
065  Improving clinical care in patients with bilateral optic disc swelling presenting to ambulatory emergency care
Authors: Huang Yun , Hanbury Georgina , Baheerathan Aravindhan , Muhammed Louwai , Everitt Alex
Published: May 2022

Background

Due to our proximity to the local eye casualty, patients with bilateral optic disc swelling (BODS) and an underlying diagnosis of idiopathic intracranial (IIH) are frequently referred to our ambu- latory emergency care (AEC) centre. The aim of this quality improvement project was to improve the consistency in our diagnostic approach and minimise time in hospital for patients referred with non-sight threatening BODS.

Methods

All patients who presented with BODS to AEC between 1 August to 31 December 2020 were included. Measurements included the recording of body mass index (BMI), investigations requested and total time in hospital. A pathway was developed based on an IIH guideline (1) and local resources.

Results

Baseline data revealed 14% of the patients had their BMI recorded, and that 7% had all of the recommended blood tests. Prospective analysis after pathway implementation showed 100% of patients had recorded BMI and appropriate blood tests requested to investigate secondary causes of IIH. There was no change in the total time in hospital.

Conclusion

The introduction of a pathway for patients with BODS has improved the diagnostic approach for patients with suspected IIH. Further work is underway to assess possible interventions to reduce total time in hospital.

1. Mollan SP, Hornby C, Mitchell J, Sinclair AJ. Evaluation and management of adult idiopathic intracranial hypertension. Pract Neurol. 2018;18(6):485–8.

yun.huang@nhs.net
066  Utilising optical coherence tomography measures as surrogates for raised intracranial pressure in idiopathic intracranial hypertension
Authors: Vijay Vivek , Mollan Susan , Mitchell James , Alimajstorovic Zerin , Markey Keira , Walker Jessica , Lyons Hannah , Yiangou Andreas , Brock Kristian , Sinclair Alex
Published: May 2022

Aim

To determine whether Optical Coherence Tomography (OCT) of the optic nerve head in papil- loedema could act as a surrogate measure of intracranial pressure (ICP).

Methods

This is a longitudinal cohort study using data collected from three randomised controlled trials, between from April 1st, 2014 to August, 1st 2019. OCT imaging and automated perimetry was followed immediately by ICP measurement on the same day. Cohort 1 utilised continuous sitting telemetric ICP monitoring (Raumedic Neurovent P-tel device) on one visit. Cohort 2 were evaluated at baseline, 3, 12 and 24 months and underwent lumbar puncture assessment of ICP.

Results

104 patients were recruited. Amongst cohort 1 (n=15), the range of OCT protocols were evaluated and optic nerve head central thickness was found to be most closely associated with ICP (right eye: p=0.017, r = 0.60; left eye: p = 0.002; r = 0.73). Subsequently, cohort 2 (n=89) confirmed the correlation between central thickness and ICP longitudinally (12 and 24 months). Finally, bootstrap surrogacy analysis noted a positive association between central thickness and ICP treatment effects at all time points (e.g. at 12 months, an decrease in central thickness of 50µm predicted a decrease in ICP of 5 cmCSF).

Conclusion

OCT optic nerve head volume measures reproducibly correlates with ICP and surrogacy analysis demonstrated its ability to inform ICP changes. This data suggests that OCT can non-invasively predict ICP.

soozmollan@doctors.org.uk

58
072  Diffuse Astrocytoma as a radiological mimic of Neuro-Behcet’s Disease
Authors: Leahy Christopher , McNulty Philip , Herwadkar Amit , D’Urso Pietro , Cahill Varduhi
Published: May 2022

We present a case of diffuse astrocytoma mimicking the radiological features of Neuro-Behcet’s disease. A 61 year old man presented with a progressive asymmetric brainstem syndrome (left>right). Examination of cranial nerves revealed a left lateral rectus palsy, a left trigeminal sensory loss V1-V3 and left lower motor facial palsy. There were no oral or genital ulcerations, no ophthalmic symptoms or signs and no skin rashes. MR imaging showed an asymmetric mesencephalic- diencephalic hyperintensity on T2 without contrast enhancement. Cerebrospinal fluid was within normal limits including large volume cytological exam. Whole body CT and FDG-PET demonstrated no evidence of malignancy. IV methylprednisolone (1g daily) for three days was given then a 60mg prednisolone taper.

He subsequently developed a right hemiparesis and was found to have on repeat MR brain a new right prefrontal cortex lesion involving the middle frontal lobe, without contrast enhancement. Biopsy showed a IDH-1 wild-type diffuse astrocytoma. He was administered chemotherapy and whole brain radiotherapy with no interval changes at 2 month follow up. Our case highlights a rare and important presentation of diffuse astrocytoma masquerading as rhombencephalitis syndrome. Timely brain biopsy allows for prompt intervention and improved performance status.

christopherleahy@doctors.org.uk

61
074  COVID-19 as a cause of coma in adult onset vanishing white matter disease
Authors: Leddy Sara , Barden Steven , Skipper Nicholas , Saha Romi
Published: May 2022

A 34 year old female presented with fever, diarrhoea, confusion, and a decline in mobility, having recently tested positive for COVID-19. Her medical history included patent foramen ovale, primary ovarian failure and leukoencephalopathy which had been investigated in her 20s leading to a clinical diagnosis of Vanishing White Matter disease (VWM). On admission she deteriorated rapidly with decreased GCS requiring frequent critical care review. MRI demonstrated mild progression of the cerebral atrophy and slight increase in the “cystic” changes in the white matter. Lumbar puncture was unremarkable. EEG demonstrated widespread cerebral dysfunction with frontotemporal emphasis but without seizure activity. She was managed with supportive care recovering to her baseline function within days. VWM is a leukodystrophy caused by recessive mutations in eukaryotic initiation factor 2B (eIF2b) complex. Adult onset presentations have been described which have a slowly progressive course. Patients with VWM are known to rapidly decline with fever, and mild head injury occasionally resulting in coma. Our case high- lights the potentially devastating effects of a neurotropic virus such as COVID-19 in VWM, and the need to consider rare genetic disorders in adult patients presenting with extensive white matter abnormalities on MRI and premature ovarian failure.

sara

leddy1@nhs.net|ABN Bursary

62
Biological and clinical manifestations of Huntington’s disease in gene carriers very far from predicted onset
Authors: Zeun P , Scahill RI , Osborne-Crowley K , Johnson EB , Gregory S , Parker C , Lowe J , Sampaio C , Zhang H ,   et al
Published: May 2022

Introduction

Crucial to the future success of treatments in Huntington’s disease is identifying a timepoint where there is a measurable biomarker of early neurodegeneration without detectable changes in clinical function. By performing deep phenotyping in premanifest gene carriers (preHD) further from predicted onset than previously studied, we aimed to identify this timepoint and the best measures for efficacy endpoints in future therapeutic trials.

Methods

We recruited 64 young adult preHD, approximately 24 years from predicted clinical onset, and 67 matched controls. All participants underwent detailed cognitive and neuropsychiatric assessments, multi-modal imaging and collection of blood and cerebrospinal fluid (CSF).

Results

We found no significant evidence of cognitive or psychiatric impairment in preHD (minimum q>0.22). The PreHD cohort had smaller putamen volumes (q=0.03), but this was not related to predicted years to onset. There were no group differences in other brain imaging measures (q>0.16). CSF and plasma neurofilament light (NfL) (q<0.0001 and q=0.01) and YKL-40 (q=0.03) were elevated in preHD.

Conclusion

With normal brain function but with sensitive measures of neurodegeneration starting to rise, this stage of preHD may represent an optimal time to initiate future disease-modifying prevention treatments. CSF NfL appears more sensitive at this time than plasma NfL to monitor treatment response.

p.d.zeun@gmail.com
082  Experiences of remote consulting for neurologists and patients during the COVID-19 pandemic: a national survey
Authors: Stavrou Maria , Eva Lioutas , Joanna Lioutas , Davenport Richard
Published: May 2022

Remote consulting is an emerging model in managing chronic neurological conditions and has been widely implemented during the COVID-19 pandemic. The main objective of this national survey was to investigate the initial experiences of remote consulting for neurologists and patients with chronic neuro- logical conditions during the first COVID-19 phase.

In collaboration with the Scottish Association of Neurological Sciences and the Neurological Alliance of Scotland, we conducted a survey of 62 neurologists and 201 patients between October-November 2020.

The overall consensus amongst neurologists was that remote consulting is a way of delivering healthcare efficiently in carefully selected groups of patients. For practical and technical reasons, there was signifi- cantly greater preference for phone over video consultations. The prevailing opinion was that consider- able ongoing effort is required to adapt and align structures, processes and neurology specialty training to successfully embed this new model of care.

The vast majority of patients perceived remote consultations as safe, effective and convenient, with 89% patients being satisfied with their remote consultation experience. Although traditional face-to-face consultations were the favoured way of interaction for 62% of patients, a significant proportion preferred that some of their future consultations were performed remotely.

Although not a replacement for face-to-face consultations, this survey illustrates that remote consulting can serve as an acceptable adjunct to traditional face-to-face consultations for doctors and patients. More research is required to identify its safety and applicability.

mstavrou@ed.ac.uk|NIHR Bursary

66
Biallelic mutations in sord are a common cause of potentially treatable genetic neuropathy
Authors: Cortese Andrea , Zhu Yi , Rebelo Adriana , Negri Sara , Courel Steve , Abreu Lisa , Bacon Chelsea J , Bai Yunhong , Bis-Brewer Dana M ,   et al
Published: May 2022

Introduction

As opposed to CMT1, for which over 90% of cases have mutations in known genes, only 20–30% of CMT2/dHMN patients receive a genetic diagnosis. Since up to 70% of CMT2 and dHMN cases are sporadic, identifying candidate pathogenic genes from single cases remains challenging also for next-generation sequencing techniques.

Methods

We took advantage of the largest collection of over 1,100 CMT patients in whom WES and/or WGS has been performed in the GENESIS analysis platform. We specifically looked for genes for which significant DNA variants are present in multiple families as well as for individual alleles overrepresented in CMT cases.

Results

We identified 45 cases from 38 families across multiple ethnicities, carrying a particular nonsense mutation in SORD, c.753delG;p.Ala253GlnfsTer27, either in homozygous or compound heterozygous state with a second variant. With an allele frequency of 0.004 in healthy controls, the p.Ala253GlnfsTer27 variant represents one of the most common pathogenic alleles in humans. SORD is an enzyme that converts sorbitol into fructose, in the two-step polyol pathway that has been implicated in diabetic neuropathy. In patient-derived fibroblasts, we find a complete loss of SORD protein and increased intracellular sorbitol. Also, as a biomarker, serum fasting sorbitol level was over 100 times higher in patients compared to healthy individuals. In Drosophila, we show that loss of SORD orthologues causes synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibi- tors normalized intracellular sorbitol levels in patient fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes.

Conclusions

We demonstrate biallelic mutations in sorbitol dehydrogenase (SORD) as the most frequent recessive form of hereditary neuropathies. These findings establish a potentially treatable cause in a sig- nificant fraction of patients with inherited neuropathies and may contribute to a better understanding of the pathophysiology of diabetic neuropathy.

andrea.cortese@ucl.ac.uk
092  Eliciting the hidden symptoms in multiple sclerosis
Authors: Kurup Meenakshi , Williams Lesley , Davis Elizabeth
Published: May 2022

Purpose

The hidden symptoms of Multiple sclerosis (MS) adversely impact on patients’ quality of life. NICE recommends that “service professionals in regular contact with people with MS, should consider in a systematic way whether a ‘hidden’ problem is contributing to their clinical situation.” Our aim was to compare trust practice at Walkergate Park Hospital with NICE CG186 guidelines by determining the number of hidden MS symptoms addressed by MS specialists in the outpatient setting.

Methods

A retrospective audit was performed from August to October 2018 on 126 MS patients seen in 34 clinics at Walkergate Park Hospital. Data was collected from clinic letters and MS review proformas going one year back.

Results

The mean number of clinic visits for patients within their most recent year of follow up was 1.76 (SD 0.709). The most elicited hidden symptom was bladder symptoms, followed by bowel symptoms discussed in 91.3% and 90.5% of consultations, respectively. The least commonly elicited hidden symptom was on sex and relationships, followed by advanced care planning (addressed in 16.0% and 23.8% of consultations, respectively). On average, 62.6% (SD 25.1) of 17 hidden symptoms were addressed.

Conclusion

Hidden symptoms may not be volunteered by patients and it is important they are addressed in the clinical context. Areas for improvement include the discussion of sex and relationships and advance care planning to ensure quality of care for MS patients.

meenakshi3@hotmail.co.uk

71
103  Virtual multiple sclerosis (MS) clinics during a global pandemic: the patients’ perspective
Authors: Ramsay Stephen , Turley Niamh , Magill Fiona , Goldsmith Grainne , McKee Jon , Kennedy Fiona , Droogan Aidan , Hughes Stella , McDonnell Gavin
Published: May 2022

Background

Within our service, all scheduled face-to-face neurology clinics were cancelled from March 2020 due to Covid-19. Telephone reviews were initiated to provide continuity of MS care.

Objective

To assess patient satisfaction with MS telephone clinics during the pandemic and opinion regarding potential future use.

Design/Methods

Anonymised questionnaires were posted to 635 patients receiving MS specialist medical telephone review, March to July 2020.

Results

279 (44%) patient questionnaires were returned, mean age 49 years, 72% female, 87% having an EDSS <7.0. On a rating scale, (0–10, 10 = completely satisfied), 95% of patients reported a satisfaction score ≥7. For 99% of patients, clinical interaction was caring/sensitive by telephone. Satisfaction was high with: call duration (96%), opportunity to ask questions (99%) and understanding advice given (98%). During the pandemic, 87% of patients preferred the virtual appointment. Of all patients, 45% expressed preference for telephone review moving forward, rising to 55% among both wheelchair-using patients and those living >50 miles from clinic. Many felt that video call would further improve virtual review (54%).

Conclusions

During the COVID-19 pandemic, satisfaction is high with MS review by telephone. A signifi- cant body of patient opinion supports telephone clinics beyond Covid-19. This is influenced by EDSS and distance from clinic.

sramsay03@qub.ac.uk|ABN Bursary
105  Beyond diagnosis: patient perception of lumbar puncture for clinical management and/or research studies
Authors: Robinson Rebecca , Kee Rachael , Ramsay Stephen , McKee Jon , Kennedy Fiona , Middleton Rod , Rodgers Jeff , Nicholas Richard , McDonnell Gavin , Hughes Stella
Published: May 2022

Background

Given the expanding utility of cerebrospinal fluid biomarkers in clinical practice and research studies, it may become desirable to offer repeat lumbar puncture (LP) beyond diagnosis. Using the United Kingdom Multiple Sclerosis Register (UKMSR), we assessed patient attitude to LP beyond the diagnostic stage.

Design/Methods

An online questionnaire was designed and over 11,000 patients were invited to partici- pate. For specific questions, participants indicated willingness for LP on a Likert scale (0–10).

Results

Almost 2500 patients completed the questionnaire and over half had relapsing remitting MS. Of the 1089 participants on disease-modifying treatment, almost 60% indicated feeling neutral-to-agreeable to having LP to evaluate treatment efficacy or evidence of relapse. Interestingly, those indicating complete willingness represented the modal point on the scale. Respondents were only slightly less receptive to undergoing LP for research, with just under half still neutral-to-agreeable. We did not observe an influence of age or sex on willingness for LP for either indication.

Conclusions

Serial LPs may become informative in evaluating for active MS throughout the disease course. We found that patients on treatment are quite agreeable to considering LP for clinical evaluation. Perhaps understandably, respondents were slightly less willing to have LP solely for research purposes.

rrobinson17@qub.ac.uk
107  The UK multiple sclerosis service and DMT prescribing audit of 70 centres: overview
Authors: Rog David , Hobart Jeremy , Mathews Joela ,   Raising the Bar for 4 MS UK Study Group
Published: May 2022

Introduction

Whilst GIRFT highlights long-recognised variations in MS service provision and disease modifying treatments (DMTs) prescribing, sources of variations weren’t explored.

Aim

The UK MS Service and Prescribing Audit was undertaken to better understand MS care, contextualise sources of variation and facilitate service development.

Methods

We asked all MS services to complete service questionnaires, supplemented with individ- ual clinician interviews covering; caseload, databases, staffing, neuroradiology, MDT, coping. We also requested anonymised blueteq or internal DMT prescribing data for 12 months to 31st March 2019.

Results

70 MS services participated. They care for >105,522 people with MS, ≈85% of the estimated UK MS population. To date, 49 MS services have provided DMT prescribing data for over 21,000 patients, a combined spend of over £261 million in the financial year to March 31st 2019. Consistent findings, detailed in five other abstracts, include: high caseloads, inconsistent team structures, low staffing levels, limited data collection and usage and access to support services.

Conclusions

This audit illustrates significant engagement from the UK MS community, with a representa- tive sample, providing a real opportunity to effect change. We recommend working across the UK MS network with multiple stakeholders to (1) maximise influence for change, (2) develop new ways of working to deal with workload, including enhancing data maturity and optimise team structures, and (3) build MS team resilience and sustainability.

Acknowledgement.Neurology Academy david.rog@srft.nhs.uk
112  Updated analysis of pregnancy outcomes in a dimethyl fumarate exposure registry
Authors: Hellwig Kerstin , Rog David , McGuigan Christopher , Mokliatchouk Oksana , Branco Filipe , Peng Xiaomei , Everage Nicholas
Published: May 2022

Introduction

Dimethyl fumarate (DMF) is not recommended for use during pregnancy and should only be used if the potential benefit justifies the potential foetal risk. Given limited pregnancy data, the UK and Ireland have enrolled DMF-exposed pregnant women in an ongoing international registry assessing pregnancy outcomes. Generally, pregnancies end in live birth (62%), abortion (22%), or foetal loss (16%), with similar rates in MS patients.

Methods

Pregnant women with MS exposed to DMF since the first day of their last menstrual period before conception/during pregnancy were included. UK/Ireland Coordinating Centres liaise directly with patients and healthcare providers.

Results

As of May 2020, 345 patients (18 UK/Ireland) were enrolled. Of the reported 351 pregnancy outcomes (18 UK/Ireland), 277 (79%) represented live births (17 UK/Ireland) and 74 (21%) foetal loss. Of infants with known gestational age (n=274), 249 births (91%) were full-term (17 UK/Ireland) and 25 (9%) premature (<37 weeks). There were 17 spontaneous abortions (1 each ectopic and molar pregnancy) and 1 foetal death (at >28 weeks). No infant or maternal deaths were reported. Ten infants (4%) (2 UK/Ireland) had confirmed birth defects.

Conclusions

Observed safety signals were consistent with MS and general populations.

Support

Biogen. Disclosures: Included on poster 81

david.rog@srft.nhs.uk
123  A case of primary angiitis of central nervous system presenting with cerebral haemorrhage
Authors: Chun Strathan , Lee Pei Ling , McClusky Lauren , Appleton Jason
Published: May 2022

We report an interesting case of a previously fit and well 27-year-old man who initially presented with seizure to his local district general hospital. A series of investigations including a CT head, CT angiogram and a lumbar puncture were performed but no formal diagnosis was confirmed. He was discharged with a label of multifocal primary intracerebral haemorrhage of unknown aetiology. He was discharged to a Neurological Rehabilitation Unit where he was undergoing intensive rehabilitation.

Twelve months later he represented to our regional neuroscience centre with status epilepticus char- acterised by multiple generalised tonic-clonic seizures and reduced level of consciousness. He required intensive care admission and was investigated extensively with multiple diagnostic techniques, including; a CT head, CT venogram, CT angiogram, MRI and a lumbar puncture. Following a long admission the diagnosis of PACNS was made with confirmatory positive histopathology findings.

Unfortunately, the pre-existing neurological deficits and functional disabilities are likely to persist indefi- nitely. The patient was managed with immunosuppressant to reduce recurrence of disease aiming to prevent further decline.

dinochun@hotmail.com
136  Coincidential hydrocephalus in twins with CMT1X
Authors: Doherty Carolynne , Pipis Menelaos , Hosktote Chandrashekar , Rossor Alexander , Reilly Mary
Published: May 2022

Background

The association of CMT1X with white matter abnormalities and “stroke like episodes” has long been recognised, and a recent review of the 133 patients with CMT1X in our cohort found that 10/26 MRI brain scans showed white matter abnormalities.(1) The literature describes very occasional patients who have any type of CMT and hydrocephalus.

Cases

A pair of monozygotic twins have the p.Trp24Cys GJB1 mutation which segregates with CMT in their family, with recognised phenotypic variability in the women, attributable to X-inactivation. One of the twins presented in their 20’s with headache and visual obscurations due to hydrocephalus resulting from decompensation of a previously diagnosed aqueductal stenosis. The second twin had migraine at age 27, an MRI identified lateral and third ventricular dilatation due to focal narrowing with an aqueductal web. An endoscopic third ventriculocysternostomy was performed. An affected cousin with the family GJB1 mutation has normal brain imaging.

Discussion

Despite the finding of hydrocephalus in both affected twins, further family evaluation confirmed the hydrocephalous not to segregate with the GJB1 mutation. This highlights the importance of detailed phenotype segregation studies before diagnosing an atypical phenotype with genetic diseases. Alterna- tive genetic causes for the hydrocephalus are being sought.

1) Vivekanandam V, Hoskote C, Rossor AM, Reilly MM. CNS phenotype in X linked Charcot- Marie-Tooth disease. J Neurol Neurosurg Psychiatry 2018 Dec 5;90(9).

carolynnedoherty@doctors.org.uk|NIHR Bursary

93
142  Severe peripheral sensory axonopathy with retained H-reflexes: a distinctive form of non-paraneoplastic ganglionopathy
Authors: McKenna Mary Clare , Kinsella Justin , O’Riordan Seán , Connolly Seán
Published: May 2022

Background

Sensory ganglionopathies classically present with subacute onset of marked sensory loss with ataxia and preserved strength. These clinical findings are complemented by nerve conduction studies (NCS) demonstrating absent or markedly reduced amplitudes of the sensory nerve action potentials (SNAPs) with normal motor nerve conduction studies.

Case

We present two cases in their 6th and 7th decade of life who present with a 5-year history of gradual onset of unsteadiness and ‘burning’ sensory symptoms, worst in the lower limbs. Clinically, they had mild ataxia and preserved deep tendon reflexes.

Results of Investigations: NCS demonstrated marked reduction in the amplitudes of the SNAPs in upper and lower limbs. The motor nerve conduction studies were normal. Unexpectedly, H-reflexes were per- sistently retained. There was no significant change in interval neurophysiological studies. These findings indicate a marked peripheral sensory axonopathy with sparing of the Ia afferents. Extensive investigations for underlying infectious, autoimmune or paraneoplastic cause all returned negative.

Discussion

We describe a distinctive neurophysiological pattern with preserved H-reflexes without severe clinical ataxia. We hypothesise that this is a unique type of ganglionopathy due to the selective sparing of the Ia afferents.

mary.mc-kenna.1@ucdconnect.ie
144  Investigating the molecular mechanisms of mutant C9orf72 human iPSC- derived astrocyte-mediated motor neuron deficits
Authors: Stavrou Maria , Selvaraj Bhuvaneish , Bolado Alfonso , James Longden , Neil Carragher , Margaret Frame , Hardingham Giles , Chandran Siddharthan
Published: May 2022

Amyotrophic Lateral Sclerosis (ALS) is a progressive, incurable and invariably fatal neurodegenerative condition characterised by loss of motor neurons. Over the last two decades, there are multiple lines of evidence from pathology, genetics and experimental systems that implicate a central role for non- neuronal cells, astrocytes in particular, with ALS pathogenesis. This is not surprising given the intimate structural and functional association of astrocytes with, inter alia, the synapse and vasculature. Yet, the nature of this astrocyte-neuronal crosstalk remains understudied. Harnessing the power of genetic dis- coveries combined with human iPS cellular platforms and gene editing technologies, we seek to better understand the non-cell autonomous effect of astrocytes carrying the C9orf72 mutation – the commonest genetic cause of ALS – on motor neurons.

We generate human astrocytes and motor neurons from three pairs of independent patient-derived mutant C9orf72 iPSC lines and their corresponding CRISPR-Cas9 gene-edited isogenic controls. Having isogenic controls allows causality to be assigned to any given phenotype and overcomes transcriptional heterogeneity across iPSC lines. We utilise these cells to investigate astrocyte-mediated neuronal toxicity and changes in secretome profiles. By using unbiased mass spectrometric analysis and molecular tech- niques, we aim to identify the underpinning molecular mechanisms of astrocyte-mediated neuronal toxicity. This will potentially lead to the identification of putative neuroprotective targets as well as novel biomarkers.

mstavrou@ed.ac.uk|NIHR Bursary

97
009  Abnormal blood-brain barrier permeability in progressive multiple sclerosis
Authors: Varatharaj Aravinthan , Darekar Angela , Gawne-Cain Mary , Cramer Stig P , Larsson Henrik BW , Galea Ian
Published: May 2022

Disruption of the blood-brain barrier (BBB) is a hallmark of multiple sclerosis (MS). In clinical practice this is detected using contrast-enhanced magnetic resonance imaging (MRI). There is biochemical evidence, based on cerebrospinal fluid protein assays, to suggest that BBB permeability is associated with disease severity and may be greater in progressive than in relapsing-remitting disease. Therefore, it is paradoxi- cal that when using conventional contrast MRI the detection of focal BBB disruption is relatively rare in progressive MS. A diffuse low-level BBB leak in progressive MS is hypothesised to explain this apparent discrepancy. Our group is investigating the use of dynamic contrast-enhanced MRI (DCE-MRI), which enables the quantification of subtle BBB disruption. Here we present a small case series of DCE-MRI in people with progressive MS as well as age-matched healthy controls. Diffuse low-level BBB leakage is demonstrated in the brains of people with progressive MS, which is invisible to conventional MRI. We discuss the implications of these early findings for our understanding of disease biology, as well as the search for an effective treatment for disability progression.

a.varatharaj@soton.ac.uk
012  164 second conceptual film without dialogue, successfully conveys the impor- tance of early intervention in MS
Authors: Wilkie David , Middleton Rod , Cook James , Nicholas Richard
Published: May 2022

Objectives

Early treatment in MS often needs to be started in the absence of symptoms. This preventa- tive approach is a complex concept to convey to a naïve population. We produced a 164 second film without dialogue with the aim of assessing whether it delivered its message successfully.

Methods

PwMS were recruited from clinics, the UK MS Register and a general population. Based upon industry standards, pre-specified outcomes included 50% viewer retention equivalent to watching 30 seconds and 50% understanding of 4 concepts. The film was incorporated into a website explaining the concepts and participants answered questions about the concepts.

Results

Viewer retention was 887/1102 (80%) in the total population with an average viewing duration of 149/164 seconds (91%), significantly above the pre-specified outcome percent (p<0.0001). In the MS Register population 757/959 (78.9%) pwMS had total understanding (4/4 concepts) compared with 29/42 (69%) in pwMS from outpatients and 136/149 (91%) in the general population. Understanding in all cohorts were significantly above the pre-specified outcomes (p<0.0001) with greatest understanding in the general population versus pwMS (p<0.0001).

Conclusions

A short, targeted film successfully conveys the importance of early intervention to both MS and non-MS audiences.

d.wilkie@imperial.ac.uk
013  An exploration of risk factors for dimethyl fumarate-induced lymphopenia in patients with multiple sclerosis
Authors: Roberts Jack , MacLeod Nicola , Justin Matthew , Harrison Emily , Williams Anna
Published: May 2022

Dimethyl fumarate (DMF) is a commonly used first-line immunomodulatory drug used for the treatment of relapsing-remitting multiple sclerosis. It has been found to cause lymphopenia in a proportion of patients, and the incidence of several cases of progressive multifocal leukoencephalopathy in patients taking DMF has given rise to concerns regarding its safety.

The purpose of this study was to identify risk factors for DMF-induced lymphopenia.: We performed ret- rospective analysis of 323 patients prescribed DMF in our NHS Lothian MS clinic in Edinburgh since the drug was introduced in 2014.

Older age (>45), and lower baseline absolute lymphocyte count (ALC) both increased the risk of devel- oping grade 2 lymphopenia, with the latter also increasing the risk of severe, grade 3 lymphopenia. We also found that the decline in ALC happens within the first 6 months of DMF treatment, and after this point it no longer declines but has a tendency to rise.

Increased vigilance with ALC monitoring is required in the first 6 months, especially in those who are older and have a low baseline ALC. By knowing the risk factors for DMF-induced lymphopenia, clinicians will be able to make more informed decisions when choosing a drug to start a patient on with multiple sclerosis.

s1504225@sms.ed.ac.uk
014  Long-term effectiveness of natalizumab for RRMS: UK and global interim results from TYSABRI observational program
Authors: Nicholas Richard , Harrower Timothy , Su Ray , Licata Stephanie , Vonsy Jean
Published: May 2022

Introduction

The TYSABRI Observational Program (TOP) is a large, ongoing observational study in relapsing- remitting multiple sclerosis (RRMS) patients treated with natalizumab. Country-specific data on relapse and disability outcomes, alongside global data, can provide information on natalizumab’s effectiveness in local practice.

Methods

Annualised relapse rate (ARR) and cumulative probability of 24-week confirmed disability worsening (CDW; increase in Expanded Disability Status Scale [EDSS] score ≥1.5 from a baseline of 0.0,

≥1.0 from a baseline between 1.0–5.5, or ≥0.5 from a baseline of ≥6.0) and improvement (CDI; decrease

≥1.0 from a baseline EDSS score ≥2.0) were analysed in TOP UK (n=134) and global (N=6295) cohorts using data from July 2007 to November 2018. Updated data (as of November 2019) will be presented.

Results

ARR decreased in UK patients from 2.21 in the year before initiation to 0.19 on natalizumab (P<0.0001), consistent with a global decrease from 2.00 to 0.21 (P<0.0001). At 7 years, probabilities of CDW and CDI were, respectively, 26.2% and 35.3% in UK patients and 27.9% and 32.1% globally.

Conclusions

These TOP UK results show disease control that is generally consistent with global TOP results, supporting natalizumab’s long-term effectiveness in real-world settings.

Support

Biogen. Disclosures: Included on the poster.

richard.nicholas@btinternet.com
016  Long-term disease stability in patients treated with cladribine tablets in CLARITY and CLARITY extension
Authors: Giovannoni Gavin , Comi Giancarlo , Rammohan Kottil , Rieckmann Peter , Vermersch Patrick , Dangond Fer- nando , Keller Birgit , Jack Dominic
Published: May 2022

Background

This post-hoc analysis evaluated long-term disease stability of relapsing-remitting multiple sclerosis (RRMS) patients, according to Expanded Disability Status Scale (EDSS), after treatment with clad- ribine tablets 10mg (cumulative dose 3.5mg/kg [CT3.5] over 2 years) in CLARITY and CLARITY Extension.

Methods

Patients randomised to CT3.5 in CLARITY then placebo in CLARITY Extension, with ≥1 post- baseline EDSS measurement, were included (CP3.5, n=98). EDSS score over time (CLARITY randomisation to end of follow-up in CLARITY Extension, including the bridging interval between studies) was assessed at 6-month intervals, and separately at time to 3- and 6-month confirmed EDSS score progression from CLARITY baseline.

Results

Five years after CLARITY baseline, median EDSS remained stable compared with baseline. Median EDSS score (95%CI) for CP3.5 was 2.5(2.0–3.5) vs 3.0(2.5–3.5) at baseline. In each 12-month period, EDSS score was stable in >50% of patients, 21–30% improved and 0–25% worsened. During Year 5, EDSS was stable in 53.9% of patients, 21.3% improved and 24.7% worsened; <30% of patients reached 3- or 6-month confirmed EDSS progression.

Conclusions

EDSS score was stable up to 5 years post-CLARITY baseline for CP3.5 patients. Between 20–30% of patients demonstrated improvement in EDSS score vs baseline each year. CLARITY:NCT00213135.

CLARITY Extension

NCT00641537

g.giovannoni@qmul.ac.uk
017  Year 1 performance of adveva® programme for patients taking cladribine tablets for relapsing-remitting multiple sclerosis
Authors: Morgan Kate , Lott Nadine , Lyons Marco
Published: May 2022

Background

The nurse-led, telephone-based adveva® programme - including dosing advice, appoint- ment reminders and a home-based phlebotomy service - supports patients with relapsing-remitting multiple sclerosis (RRMS) in taking cladribine tablets (CT) as prescribed (the full first year cumulative dose of 1.75 mg/kg). We report year 1 results of the adveva® progamme for patients with highly active RRMS taking CT.

Methods

Aggregated and anonymised telephone conversation records were reviewed between December 2017 and August 2018. Patient-reported adherence, plus basic and additional support data, were analysed.

Results

262 patients were registered with adveva® and 133 were included in this assessment as they self- reported to have completed treatment in year 1 at the time of assessment. 130 (98%) patients completed their first-year course as prescribed (the remaining 3 patients received the required dose at a different time interval to that recommended). 22 (17%) patients required additional support during their treatment days, included advice on treatment/dosing/adverse events.

Conclusions

All 133 patients self-reported that they achieved the required CT dose in year 1; the adveva® programme was of particular value to patients requiring additional support. This is the first report in a post- approval and real-world setting suggesting the majority of patients find CT simple-to-take.

kate.morgan@merckgroup.com
Personalised immunotherapy in active multiple sclerosis using injectable cladrib- ine: Follow-up of the BartsMS cohort
Authors: Allen-Philbey Kimberley , Trane Stefania De , Yildiz Ozlem , Adams Ashok , Turner Ben , Marta Monica , Mathews Joela , Altmann Dan , Giovannoni Gavin , Schmierer Klaus
Published: May 2022

Introduction

Cladribine tablets (Mavenclad®) are licensed for treating people with relapsing multiple sclerosis (pwRMS). We treated people with relapsing (pwRMS) and progressive MS (pwPMS) using sub- cutaneously administered cladribine (SCAC) since 2014. Here, we present up to five year follow-up on safety and efficacy.

Methods

SCAC 10mg was given on 3–4 days during week 1. 0–3 doses were administered at week 5, according to week 4 lymphocyte count. A second cycle of SCAC was administered 11 months later. Follow-up included clinical outcome evaluation and pharmacovigilance. The proportion of pwMS with no evidence of (i) disease activity (NEDA) and (ii) progression or active disease (NEPAD) was calculated.

Results

211 pwMS received SCAC. 154/211 completed two treatment cycles. At baseline age was 44 (17–72) years, EDSS 1–8.5. Tolerability was good. One myocardial infarction and one breast cancer occurred. Two severely disabled pwMS died (one of influenza, one of encephalitis). Lymphopenia grade 3 was detected in <3%. At 2 years, 71% (CI 54%, 85%) of pwRMS had NEDA; 38% (CI 23%, 54%) of pwPMS had NEPAD.

Conclusions

SCAC was well tolerated. Frequency of significant lymphopenia was low. Efficacy in pwRMS corresponds with trial data. NEPAD rates in pwPMS were similar to licensed DMT.

k.allen-philbey@nhs.net
021  Determinants of natalizumab-associated PML outcomes
Authors: Kappos Ludwig , McGuigan Chris , Derfuss Tobias , Giovannoni Gavin , Oh Jiwon , Ren Zheng , McCarthy Kerry , Chang Ih , Campbell Nolan
Published: May 2022

Introduction

Natalizumab treatment is associated with risk of progressive multifocal leukoencephalopa- thy (PML). Following PML diagnosis, plasma exchange (PLEX) may be used to enable rapid natalizumab clearance. This analysis explores the impact of PLEX and patient characteristics on natalizumab-associated PML outcomes.

Methods

Patients with multiple sclerosis, natalizumab-associated PML, and PLEX treatment status as of September 2018 were included (PLEX+, n=616; PLEX−, n=109). The primary outcome was 2-year survival after PML diagnosis. Kaplan-Meier estimates of cumulative survival for patients with/without PLEX were stratified by log JC virus (JCV) viral copy number (VCN) at PML diagnosis. Hazard ratios for survival were based on a Cox proportional hazards model.

Results

The cumulative probability of 2-year survival for PLEX+ vs PLEX− patients was 88.2% vs. 89.3% (P=0.857) with log VCN ≤5, 73.8% vs. 89.3% (P=0.097) with log VCN >5 to ≤7, and 68.2% vs. 78.9% (P=0.435) with log VCN >7. Improved survival was associated with younger age, asymptomatic presentation, localized PML lesions, and lower log JCV VCN.

Conclusions

PLEX had no significant effect on survival rates. Numerically worse 2-year survival probabilities were observed with PLEX regardless of PML presentation, suggesting PLEX is not effective for improving post-PML outcomes.

Support

Biogen. Disclosures: Included on the poster.

g.giovannoni@qmul.ac.uk
024  CLARITY study: efficacy outcomes among patients receiving disease-modifying therapies prior to treatment with cladribine tablets
Authors: Vermersch Patrick , Rammohan Kottil , Damian Doris , Jack Dominic , Harty Gerard , Wong Schiffon
Published: May 2022

Background

Cladribine tablets 10mg (cumulative dose 3.5mg/kg [CT3.5] over 2 years) showed efficacy vs placebo in patients with relapsing-remitting multiple sclerosis in the CLARITY study. This post-hoc analysis investigated efficacy outcomes for patients with a history of disease-modifying therapy (DMT) use prior to entering CLARITY.

Methods

CLARITY included patients previously treated with 0–2 DMTs (patients treated with >2 DMTs were excluded). Analysis of efficacy, annualised relapse rate (ARR), relapse-free rate, MRI activity, and time to 3-month and 6-month confirmed disability progression (CDP), were stratified by prior DMT therapy. P-Values <0.05 were considered nominally significant.

Results

Prior DMT patients were randomised to CT3.5 (n=110) and placebo (n=132). Treatment with CT3.5 vs placebo resulted in a nominally significant reduction in ARR (0.22 vs 0.42; P<0.005), higher relapse-free rate (70.4% vs 55.9%; P=0.0204), numerically lower risk of 3-month CDP (hazard ratio [HR]=0.64, P=0.1589) and 6-month CDP (HR=0.62, P=0.2071), and reductions in brain lesion counts (P<0.001 for each lesion type).

Conclusions

Patients who received prior DMT treatment showed significant improvements in efficacy outcomes with CT3.5 compared to placebo. Findings therefore support a consistent effect of cladrib- ine tablets across a broad range of patients, including patients who have used other DMTs.

CLARITY:NCT00213135

dominic.jack@merckgroup.com
026  Gene-environment interactions in multiple sclerosis: a UK Biobank study
Authors: Jacobs Benjamin , Noyce Alastair , Bestwick Jonathan , Belete Daniel , Giovannoni Gavin , Dobson Ruth
Published: May 2022

Question: Does genetic risk modify the effect of environmental MS risk factors?

Methods

Case-control study of 2151 people with MS and 486,125 controls using data from a longitudinal cohort (UK Biobank). MS was defined using ICD-coding or self-report. Associations with MS risk were quan- tified using multivariate logistic regression. Interaction between environmental and genetic risk factors was quantified using the Attributable Proportion due to interaction (AP). Model fits were quantified using Nagelkerke’s pseudo-R2 metric.

Results

Exposures associated with MS were childhood obesity (OR=1.39, 95%CI 1.22–1.58), smoking (OR=1.19, 95%CI 1.07–1.33), and earlier menarche 0.95, 95%CI 0.92–0.98). The autosomal polygenic risk score (PRS) was associated with MS disease status (ORTop-vs-bottom-decile=3.93, 95%CI 3.11–4.97). There was evidence of synergistic interaction between the PRS and both childhood obesity (AP=0.111, 95%CI 0.007–0.202), and smoking (AP=0.106, 95%CI 2.24e-4 to 0.196).

Conclusions

We provide novel evidence for interaction between environmental risk factors for MS and a high burden of autosomal genetic risk. These findings have significant implications for our understanding of MS biology, and may inform targeted prevention strategies.

ben.meir.jacobs@gmail.com
027  Eosinophilia and lymphocytosis after natalizumab for relapsing-remitting multiple sclerosis
Authors: Keshvari Milad-Kazava , Sheikh Saima , Someren Fred van , Galea Ian
Published: May 2022

Background

Natalizumab (NTZ), a humanized monoclonal antibody against the integrin VLA4, is a highly effective treatment for relapsing-remitting multiple sclerosis. Eosinophilia and lymphocytosis may occur, but their frequency, kinetics, risk factors, consequences and ideal monitoring frequency are unknown.

Methods

Here we present preliminary results from an ongoing retrospective review of the medical and haematological electronic records of 195 patients in a multiple sclerosis specialist centre, who had started NTZ between January 2008 and April 2019, received NTZ up to January 2020, had at least two doses and had blood results available.

Results

The study included 833 patient-years of NTZ exposure. 72% were female. Mean age was 37.1 years (standard deviation: 10.2 years). Only 3.6% of NTZ doses were missed. 6% were JC virus seroposi- tive before NTZ was started. Of the JC-seronegative patients before NTZ was started, 32% seroconverted whilst on NTZ. The mean eosinophil and lymphocyte count whilst on NTZ was above the reference range in 14% and 25% of patients. The kinetics, risk factors, and consequences of these two haematological abnormalities will be presented in detail.

Conclusion

Eosinophilia and lymphocytosis are common, and have clinical and service implications, affecting medical management and monitoring frequency. Data presented will inform practice.

milad_kazava@yahoo.co.uk