bluuebunny/crossref_metadata_2025 huggingface dataset:
15.09 Inherited peripheral neuropathies: analysis of PDXK gene identifies a new treatable disorder
Authors: Chelban Viorica , Wilson Matthew P , Chardon Jodi Warman , Vandrovcova Jana , Natalia Zanetti M , Zamba-Papanicolaou Eleni , Efthymiou Stephanie , Pope Simon , Conte Maria R , Abis Giancarlo , Liu Yo-Tsen , Tribollet Eloise , Haridy Nourelhoda A , Botía Juan A , Ryten Mina , Nicolaou Paschalis , Minaidou Anna , Christodoulou Kyproula , Kernohan Kristin D , Eaton Alison , Osmond Matthew , Ito Yoko , Bourque Pierre , Jepson James EC , Bello Oscar , Bremner Fion , Cordivari Carla , Reilly Mary M , Foiani Martha , Heslegrave Amanda , Zetterberg Henrik , Heales Simon JR , Wood Nicholas W , Rothman James E , Boycott Kym M , Mills Philippa B , Clayton Peter T , Houlden Henry ,   for the Care4Rare Canada Consortium and the SYNaPS Study Group
Published: March 2023

Polyneuropathies are amongst the most common neurological conditions worldwide affecting over 20 million people. However, 40% of patients with primary polyneuropathies have no disease-causing mutation identified.

We investigated patients with gene-negative primary polyneuropathies using a combination of whole genome sequencing, homozygosity mapping and segregation analysis. Pathogenicity was confirmed via enzymatic assays and mass spectroscopy on recombinant protein and patient-derived fibroblasts, plasma and erythrocytes. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the ATP binding.

We report that biallelic mutations in human PDXK are associated with primary axonal polyneuropathy and optic atrophy. Pyridoxal kinase (PDXK) is involved in converting vitamin B6 to its active form, pyridoxal 5’-phosphate (PLP). We show that PDXK mutations lead to disease via decreased plasma PLP concentrations. Our functional studies revealed conformational rearrangement in the mutant enzyme around the kinase ATP-binding pocket with impaired PDXK ability to bind ATP and leading to reduced erythrocyte PDXK activity. We show that both the human clinical picture and biochemical profile in PDXK mutations are rescued by PLP supplementation. Patients regained their ability to walk independently. Furthermore, treatment-led normalisation of plasma PLP levels, correlated with reduction of neurofilament light chain concentrations, a biomarker of axonal breakdown.

In conclusion, biallelic mutations in human PDXK are associated with a novel disorder leading to treatable primary axonal polyneuropathy and optic atrophy and identifies PLP as therapeutic target.
139 Risk of parkinson’s in idiopathic anosmia
Authors: Rees Richard N , Philpott Carl , Gane Simon , Worth Paul , Noyce Alastair J , Schrag Anette
Published: March 2023

Smell loss (anosmia) is a common finding in people with PD, although it is also quite common in older age (Ross 2008). Population studies assessing the prodromal phase of PD have therefore included individuals with smell loss. However, the differential diagnosis of anosmia is broad, and it is likely that only a subset are linked to neurodegeneration. Some evidence suggests that people with the anosmic prodrome have a different phenotype to other forms of prodromal PD (Rees 2019).

Methods

We assessed neurologically healthy patients aged 60–80y from two specialist ENT clinics (James Paget Hospital, Norfolk; RNTNE, London). All participants had a diagnosis of idiopathic anosmia after comprehensive investigation. Participants completed online PREDICT-PD testing (www.predictpd.com) followed by an in-person assessment with standardised physical, cognitive and autonomic tests.

Results

We recruited 28 participants (17 women) mean age 69.9y (SD 4.9y). Participants had a mean of 14.4 years of education (SD 3.1). Adjusted MoCA scores had a mean of 25.9/30 (SD 2.6). There was a range of subtle motor impairment, median MDS-UPDRS III 4.5 (IQR 1.0- 8.0, max 20) and median 3m up-&-go time 8.5s (IQR 7.8–9.6). Those with the highest risk had higher tremor scores in the MDS-UPDRS

Conclusions

There is a correlation between risk of PD and cognition. There is no significant gross motor or autonomic dysfunction in these patients, but the highest risk participants had higher tremor subscores. Further recruitment will allow clear delineation of the anosmic prodrome of PD.
143 Dopamine transporter SPECT imaging: service evaluation from a tertiary neurosciences centre
Authors: Kobylecki Christopher , Harris Jonathan , Boyle Mark , Hoffmann Sandra
Published: March 2023

Background

The use of dopamine transporter SPECT imaging can improve diagnostic accuracy in the assessment of parkinsonism and tremors. In order to manage demand and ensure appropriate use, our tertiary neurosciences centre set up a policy of screening referrals by a movement disorder specialist (C.K.).

Objective

To audit the use of [123I]-ioflupane SPECT (DaTscanTM) imaging at Manchester Centre for Clinical Neurosciences.

Methods

We audited DaTscan referrals and subsequent results from May 2014-July 2018. The reason for rejection of referrals was documented and subsequent clinical course assessed. We recorded overall indications for imaging and the eventual results.

Results

In total, we received 136 referrals for DaTscan, of which 34 (25%) were rejected. Of these, the subsequent course was consistent with the clinical impression in 30 patients for whom follow-up data were available. The most common indications for scans performed were differentiation of Parkinson’s disease from tremor syndromes (46%), and suspected drug induced parkinsonism (26%). Equivocal imaging results in 9% were reclassified as normal following quantification.

Conclusions

Screening of referrals for DaTscan imaging in a movement disorder service is safe and cost-saving. Appropriate use of DaTscan imaging improves patient management, and equivocal results may be clarified by quantification techniques.
144 Studying corticobasal syndrome across the UK via the BNSU
Authors: Costantini Alyssa , Jabbari Edwin , Lamb Ruth , Darvell Marcia , Woodside John , Rohrer Jon , Lees Andrew , Morris Huw ,   on behalf of PROSPECT-UK & European CBS consortia
Published: March 2023

Background

There are a number of different causes of corticobasal syndrome (CBS) and we are recruiting CBS patients across the UK to the PROSPECT-UK study.

Objective

To define patients with CBS and to define features that are helpful in determining the underlying pathological diagnosis.

Methods

The RaDAR platform enables the recruitment of patients with CBS. Eligible patients are anonymously invited to contact the study team. Following informed consent, patients can participate remotely or be seen at their local study site. A subset of these patients undergo deep phenotyping, including CSF analysis for total Tau and Abeta.

Results

We have established a cohort of 179 patients with CBS for future therapeutic, biomarkers and clinical studies. Mean recruitment is 5/month. The ABN RaDAR scheme has identified 58 CBS patients across the UK through 2018 so far, and we are liaising with consultants to recruit these patients. Deep phenotyping is underway – in patients with CSF analysis, 47% have an Alzheimer disease–like CSF profile highlighting the phenotypic diversity in this group. We are continuing to analyse other features of CBS.

Conclusions

We are continuing to define the diverse pathological causes of CBS with a view to developing future disease modifying treatment trials.
145 Pre-motor phase in autopsy-confirmed multiple system atrophy
Authors: Vichayanrat Ekawat , Pablo-Fernandez Eduardo De , Valerio Fernanda , Mathias Christopher , Panicker Jalesh , Holton Janice , Warner Thomas , Quinn Niall , Iodice Valeria
Published: March 2023

Background

Non-motor features can be presenting symptoms and often precede the motor features in patients with multiple system atrophy (MSA). However there have been no studies specifically looking at the conversion time, clinical features and survival rate in autopsy-confirmed MSA patients.

Methods

Medical records of 47 autopsy-confirmed MSA cases at the Queen Square Brain Bank who underwent clinical examination and cardiovascular autonomic testing at the National Hospital for Neurology were reviewed.

Results

15/47 (32%, M:F/9:6) MSA patients had non-motor autonomic features as an initial presentation before developing motor symptoms. Mean pre-motor phase duration was 3 (range 1–6) years. Among these 15 patients, the most common pre-motor features (87%) were genitourinary (erectile dysfunction in 7, bladder dysfunction in 6 patients); pre-motor symptomatic orthostatic hypotension (OH) and REM sleep behavioural disorder (RBD) occurred in one patient each. 5/15 patients developed cardiovascular autonomic failure and were initially diagnosed with pure autonomic failure (PAF). There was no difference in age of onset between patients presenting with motor and pre-motor autonomic features (p=0.67) or between different pre-motor presenting features and disease duration (p>0.05).

Conclusions

Pre-motor autonomic features, including genitourinary, cardiovascular autonomic failure and RBD, are common presenting symptoms in MSA, accounting for almost one-third of patients. These features can predate motor symptoms by up to 6 years, or longer.
149 Optical coherence tomography in an irishSPG7cohort
Authors: Bogdanova-Mihaylova Petya , Chen Hongying , Plapp Helena , Murphy Sinéad M , Walsh Richard A
Published: March 2023

Reduction of retinal nerve fibre layer (RNFL) thickness has been reported in neurodegenerative conditions, including inherited ataxias and hereditary spastic paraparesis. Mutations inSPG7are increasingly identified as a common cause of spastic ataxia.

Spectral domain optical coherence tomography (OCT) was performed in 25 individuals (six females) with genetically confirmedSPG7-related spastic ataxia to quantify peripapillary RNFL thickness. Standardized examination included age of onset, mean: 40 years (range 12–61); disease duration, mean: 19.6 years (range 6–42 years) and disease severity as quantified with Scale for the Assessment and Rating of Ataxia (SARA), mean: 10.2/40 (range 3–29).

Abnormal RNFL thickness in comparison to controls was detected in 12/22 patients. 3/12 patients had disease duration of less than 10 years and demonstrated predominantly temporal inferior RNFL loss. There was no significant correlation between global RNFL thickness with disease severity (R=-0.13, p=0.75) or disease duration (R=-0.31, p=0.41).

RNFL abnormalities in patients with spastic paraparesis/ataxia may be suggestive ofSPG7-associated disease. OCT, non-invasive and quick, should be considered part of the neurological assessment, especially in patients with late-onset spastic ataxias. Further longitudinal studies are needed to determine whether RNFL thickness could be used as a potential biomarker for disease progression in theSPG7cohort.
151 Improving diagnosis and care in progressive supranuclear palsy (PSP), corticobasal degeneration (CBD)
Authors: Swallow Diane , Grosset Donald , Counsell Carl
Published: March 2023

Background

Misdiagnosis and delayed diagnosis are common in PSP/CBD. After diagnosis there is little evidence on multidisciplinary care access or on prognosis other than survival.

Aims

(1) Describe and improve diagnostic pathways; (2) Validate and develop diagnostic tools; (3) Evaluate care quality from diagnosis to end-of-life; (4) Evaluate patient and carer prognosis; (5) Evaluate activity limitations as measures of disease progression and outcomes for clinical trials.

Methods

Individuals with PSP/CBD are recruited nationally across Scotland. Patients consent to medical record access, data linkage, clinical examination and questionnaires covering multiple domains, postal follow-up and MRI. Each PSP/CBD patient nominates a carer to return questionnaires about their health, carer burden and proxy assessments of their relative’s capabilities. PD controls undergo motor/cognitive examination and MRI.

Results

73 PSP/CBD patients, 63 carers and 26 age-sex matched PD controls have been recruited to date. 69(94.5%) PSP/CBD cases have consented to longitudinal clinical assessment, medical record review and data linkage, and 4(5.5%) to medical record/data linkage only. 56(76.7%) have consented to longitudinal MRI.

Anticipated outcomes: Understanding the causes of delayed diagnosis and the assessment of new diagnostic tools will facilitate improved diagnosis. A better understanding of patient and carer prognosis will improve care planning and provision.
153 The PHQ-9 as a tool to measure depression in people with multiple sclerosis
Authors: Quigley Suzanne , Beswick Emily , Macdonald Pamela , Connick Peter
Published: March 2023

Background

Depression has a point prevalence of 25% and lifetime prevalence of 50% in people with MS (pwMS). Due to its convenience, the PHQ9 may be a useful tool in clinical practice for screening and monitoring of depression in pwMS

Objectives

To evaluate the internal and external reliability of the PHQ-9 measure of depressive symptoms in people with MS. Secondary objectives are; to evaluate the validity of the PHQ-9 as a measure of depressive symptoms in people with MS and to evaluate the acceptability of the PHQ-9 to people with MS

Design: A cross section validation study

Subjects: People with Multiple Sclerosis

Methods

People with MS were recruited from the Rowling Care registry at the Anne Rowling Regenerative Neurology Clinic. Participants complete three questionnaires during a 4 week period using online questionnaires. Statistical analysis will be performed at the end of the study using R Studio

Results

The study is ongoing and now in the follow up phase. Provisional results are based on 92 completed participant datasets- Internal reliability of the PHQ-9 using Cronbach’s Alpha was 0.88. External reliability of the PHQ-9 using intraclass coefficient was 0.72.

Conclusions

Final conclusions are pending due to ongoing data collection.
158 CSF T-cell counts in multiple sclerosis diagnosis and prognosis
Authors: Hrastelj James , Willis Mark , Bishop Mark , Loveless Sam , Tallantyre Emma , Robertson Neil
Published: March 2023

Background

Identifying diagnostic and prognostic biomarkers in multiple sclerosis (MS) remains challenging. Cerebrospinal fluid (CSF) is a potentially valuable source.

Aim

Test association between CSF cell counts and (i) neuroinflammatory diagnosis, (ii) early MS disease activity.

Methods

CD4+/CD8+ T-cells were counted using flow cytometry in CSF collected from 162 patients. Clinical data were collected for 12–52 months. Cell counts were tested for association with: 1) diagnostic group: MS (n=63), clinically isolated syndrome (CIS, n=11), other inflammatory disorders (n=8) and non-inflammatory disorders (NID, n=75)); 2) time to next relapse/treatment commencement; 3) MS initial course. Area under receiver operator characteristic curve (AUC) was calculated for diagnostic utility.

Results

CSF CD4+ and CD8+ counts were higher in MS vs CIS (e.g. CD4+: p=0.0063, AUC=0.76) and NID (e.g. CD4+: p=1.4×10–6, AUC=0.74). NHS laboratory CSF white cell counts (WCC) were also higher in MS vs CIS (p=0.049, AUC=0.68) and NID (p=8.9×10–10, AUC=0.73). In logistic regression models of MS vs CIS in OCB negative patients, NHS WCC explained the greatest proportion of the variance (16.5%, p=0.03, AUC=0.70), but the optimal model also included CD4+ and CD8+ counts. Cell counts did not predict initial course or clinical outcomes.

Conclusions

CSF cell counts could aid diagnosis of MS. CSF cell counts alone did not predict early MS disease activity in this size cohort, but prognostic utility in combination with other biomarkers should be tested in a larger cohort.
160 Ten-year clinical outcomes post treatment with mitoxantrone for relapsing remitting MS
Authors: Foo Eng Chuan , Russell Melanie , Lily Oliver , Ford Helen
Published: March 2023

Mitoxantrone has been used as induction or escalation treatment in highly-active relapsing-remitting multiple sclerosis (RRMS). Whilst effective, its use is limited by adverse events (AE).

Objective

To report the clinical effectiveness and AE profile following mitoxantrone in a patient cohort with RRMS over a 10-year follow-up period.

Methods

This retrospective study included all patients treated with mitoxantrone in the Leeds MS service between 2003 and 2015. We measured expanded disability status scale (EDSS) scores annually and recorded AEs and secondary progression (SPMS).

Results

Forty-two patients (25 female, 17 male) were reviewed. Twenty-three (55%) received disease-modifying therapy (DMT) pre-mitoxantrone (17 interferon beta-1a, 4 glatiramer acetate, 2 natalizumab). Nineteen (45%) received further DMT post-mitoxantrone (1 interferon beta-1a, 9 glatiramer acetate, 5 natalizumab, 2 fingolimod, 2 dimethyl fumarate). Median pre-mitoxantrone EDSS score was 6.0 (95%CI 5–6). Median EDSS score at year 10 was 6.5 (95%CI 5–7). Nine (21%) developed SPMS. Commonest AE was nausea, n=6 (14%). Four (10%) developed serious AEs (1 arrhythmia, 1 left ventricular impairment, 1 pancytopaenia, 1 acute myeloid leukaemia). All serious AEs resolved and AML remains in remission for over 6 years.

Conclusion

Mitoxantrone therapy is effective and relatively low risk with evidence of long-term benefits in RRMS patients.
15.33 Phenotype-genotype characterisation of ‘long survivors’ with motor neurone disease in Scotland
Authors: Leighton Danielle , Newton Judith , Parry David , Colville Shuna , Swingler Robert , Porteous Mary , Aitman Tim , Gorrie George , Chandran Siddharthan , Pal Suvankar
Published: March 2023

The Clinical Audit Research and Evaluation of Motor Neurone Disease (CARE-MND) platform has collected information from people with MND in Scotland since 1989. In a recent analysis, upper range of survival from diagnosis was 25.8 years.

We investigated phenotypes and genotypes of a ‘long-surviving’ cohort (>8 years from diagnosis). 14 phenotypic variables were analysed, and compared with unselected incident patients. DNA samples underwent whole genome sequencing and screening for C9orf72 expansions.

60 long survivors were identified. 46 were alive at censorship, giving a Scottish prevalence of 11.0%. Long survivors were younger than incident patients (p<0.0001) and tended to have lower limb-onset disease (p=0.003). Disease classification differed (p<0.0001); 41.7% had primary lateral sclerosis (PLS). 7/34 (20.6%) had pathogenic/likely-pathogenic mutations. Four had SOD1 mutations; three the Scottish p.I114T founder mutation. Remaining patients had variants in FUS, ALS2 and SPG11. The individual with the SPG11 variant also had a variant of uncertain significance in the same gene.

Long survivors in the Scottish MND population are younger, and have increased prevalence of PLS and lower limb-onset disease. SOD1 p.I114T variant can result in long survival. Compound heterozygosity in SPG11 may be associated with MND. Diagnostic genotyping should be considered in long duration of disease.
175 A model for participant engagement in research: the MS register
Authors: Middleton R , Allen-Philbey K , Schmierer K , Espasandin M , Roberts C , Nicholas R , Rodgers J , Lockhart-Jones H , Tuite-Dalton K , Ford DV
Published: March 2023

Objectives

Increase people with MS (PwMS) engagement with research and provide increased utility to PwMS/Clinicians.

Background

The UK MS Register (UKMSR) was established by the MS Society to collect research and service provision data. We have now collected 8 years of Patient Reported Outcome (PRO) data from PwMS, with more than 300,000 responses, thus far with little feedback given to participants.

Methods

We report our first experience providing feedback to PwMS, Patient Public Involvement (PPI) was utilised to better design data collection and feedback instruments. Gathered responses from UKMSR users by email/phone. Focus groups with clinicians and PwMS at Barts Health NHS Trust.

Output

Comprehensive feedback should be accessible for all that opt-in.

Results

The website was re-designed to graph core instruments and provide a comprehensive ‘feedback report’ for screen/print. All participants were contacted, 5596 logged-in. 4819 existing, 773 were new users. 1291 declined feedback.

Discussion

Allowing feedback clearly addresses unmet needs. The increased completions of questionnaires after re-launch suggests PwMS are more engaged with research. We will carry out further research in exploring PwMS satisfaction with the new format and on the volume and depth of data.

Conclusion

Allowing participants to review their own detailed feedback to questionnaires facilitates increased engagement with research.
179 Early real-world experience of ocrelizumab in MS
Authors: Harding Katharine , Ingram Gillian , Horton Emma , Owen Helen , Joseph Fady , Pearson Owen
Published: March 2023

Background

Ocrelizumab was recently licensed for use in relapsing-remitting multiple sclerosis (MS). We present our clinical experience of ocrelizumab treatment for MS in two specialist centres in south Wales.

Methods

All patients with MS treated with ocrelizumab in Newport and Swansea between 01/08/2018 and 31/12/2018 were included. Sex ratio, age at MS onset and baseline EDSS score were calculated. Data was collated on indication for treatment and adverse effects, and data on previous DMT sequencing will be discussed.

Results

Eighty-one patients (82% female) were treated in total. Mean age at onset was 32.4 years, and mean age at ocrelizumab treatment was 42.8 years. Baseline EDSS was <4.0 in 45 (55%), 4.0–6.0 in 24 (30%), and 6.0–6.5 in 12 (15%). The commonest indication was first-line treatment for active disease (n=26, 32%), followed by side effects from other disease-modifying treatment (n=20, 25%), and high JCV titre on natalizumab (n=15, 19%). Sixty-two patients (77%) had no adverse effects. Eleven patients (14%) had infections. Three patients (4%) had infusion reactions. One patient had an allergic reaction to ocrelizumab and discontinued treatment. There were no cases of PML.

Discussion

Ocrelizumab has been safe and well-tolerated in our cohort. Our study illustrates the value of real-world clinical data in MS.
181 Multiple Sclerosis associated with Psoriasis – is alemtuzumab the drug of choice?
Authors: Karthikeayan Venkatraman , Whittam Daniel , Copeland Yvonne , Huda Saif , Jacob Anu
Published: March 2023

Introduction

Treatment of relapsing remitting (RRMS) may become challenging in the presence of other autoimmune disorders,. The risk of exacerbating coexisting systemic autoimmune illnesses often restricts the choice of DMT, particularly monoclonal antibodies. Psoraisis and MS are both relatively common conditions and may co-exist posing such a problem

Case 1: 39 year old woman with poorly controlled psoriasis on methotrexate was diagnosed with highly active RRMS. Alemtuzumab led to rapid (within 5 days) and sustained (x months) remission of both MS and Psoriasis. Methotrexate was stopped prior to alemtuzumab.

Case 2: A 34 year old man with severe chronic plaque psoriasis was diagnosed with highly active RRMS. Alemtuzumab led to a dramatic remission within days of his psoriatic skin lesions and MS. However after 3 months psoriasis recurred.

Conclusion

The remarkable response of psoriasis in these cases may be reassuring to clinicians wishing to use alemtuzumab in such situations. Though the underlying biology of the response in psoriasis is not well understood, it is primarily mediated by T Cells which Alemtuzumab effectively depletes.
192 Does socioeconomic status impact on the prescription of disease-modifying treatments in people with multiple sclerosis?
Authors: Reyes Saúl , Allen-Philbey Kimberley , Suarez Sebastian , Yildiz Özlem , Turner Ben , Gnanapavan Sharmilee , Schmierer Klaus , Marta Monica , Mathews Joela , Giovannoni Gavin
Published: March 2023

Objective

To examine the association between socioeconomic status (SES) and prescription of disease-modifying treatments (DMTs) in people with multiple sclerosis (pwMS).

Methods

A cross-sectional study was conducted among 734 pwMS aged ≥18 years attending the neuroinflammation service at The Royal London Hospital (Barts Health NHS Trust) between 1997 and 2017. SES was determined by patient income and education extracted from the English Index of Multiple Deprivation. Multinomial logistic regression was performed to assess differences between SES and prescription of DMTs.

Results

DMTs were categorized as follows: moderate efficacy therapies included Glatiramer Acetate and Beta-Interferons (n=81, 11.04%), high efficacy therapies included Cladribine, Fingolimod and Dimethyl Fumarate (n=409, 55.72%), and very-high efficacy therapies included Natalizumab and Alemtuzumab (n=244, 33.24%). Medians for income and education deciles were 4 (IQR 3–7) and 6 (IQR 4–8), respectively. Patient income was not associated with increased odds of being prescribed high efficacy (OR, 1.02; 95% CI, 0.91–1.14; p=0.814) or very-high efficacy DMTs (OR, 1.01; 95% CI, 0.90–1.14; p=0.732). Similarly, patient education was not associated with the prescription of high efficacy (OR, 0.96; 95% CI, 0.84–1.10; p=0.585) or very-high efficacy DMTs (OR, 0.96; 95% CI, 0.84–1.10; p=0.538).

Conclusions

SES was not predictive of prescription of DMTs in this single-centre study. It would be of interest to compare our data with other MS services, and to map these results onto the inequity in access to DMTs across the UK.
194 Natalizumab treatment for MS: UK and global results from TOP
Authors: Nicholas Richard , Harrower Timothy , Jiang Xiaoyu , Licata Stephanie , Vonsy Jean
Published: March 2023

Introduction

The TYSABRI Observational Program (TOP) is the largest real-world study in natalizumab-treated relapsing-remitting MS patients. Country-specific data, 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; Expanded Disability Status Scale [EDSS] score increase from baseline of ≥1.5 from 0.0, ≥1.0 from 1.0–5.5, or ≥0.5 from ≥6.0) and improvement (CDI; decrease ≥1.0 from baseline EDSS score ≥2.0) over 6 years were analysed in TOP UK (n=134) and global (N=6149) cohorts using data from July 2007 to November 2017.

Results

ARR decreased in UK patients from 2.21 in the year before initiation to 0.21 on natalizumab, paralleling the global decrease from 1.99 to 0.21. At 6 years, probabilities of CDW and CDI were, respectively, 27.8% and 34.4% in UK patients and 24.2% and 32.0% globally.

Conclusions

Consistent with global TOP results, natalizumab ARRs and disability worsening rates remained low and disability improvement rates exceeded 30% at 6 years in the UK cohort. These results support natalizumab’s long-term effectiveness in real-world settings.

Support: Biogen. Disclosures will be included on the poster.
195 MS disease modifying therapy (DMT) sequencing – tysabri to mavenclad de-escalation in JC-virus positive MS patients
Authors: Mihalova Tatiana , Vernon Karen , Sharaf Nazar , Talbot Paul , Rog David
Published: March 2023

Background

There is a significant UK variation in the DMT sequencing strategies for high PML risk patients on Tysabri. In Greater Manchester Neuroscience centre we gradually reduced the number of high PML risk patients on Tysabri from 89 in 2016 to 26 in 2018. From our experiences de-escalation strategy from Tysabri to Fingolimod or Lemtrada seemed safe. Fingolimod, less efficacious switch, tends to be delivered quicker than Lemtrada (requiring lesser safety checks), but the efficacy of Lemtrada in MS patients with disease duration >10 years remains uncertain.

Method

Between January 2018 and November 2018 we switched 14 high risk PML patients from Tysabri to Mavenclad. All patients underwent MDT discussion, lumbar puncture with JCV PCR and MRI checks prior to DMT switch.

Results

We present the first UK MS patient cohort de-escalating from Tysabri to Mavenclad. Older (average age of 44) and more disabled patients (average EDSS=4.75) opted for Mavenclad, with equal gender distribution (7:7). Average disease duration was 7.5 (2–10) and patients received 52 (6–107) Tysabri infusions. 5 patients had other DMTs prior to Tysabri (5 Copaxone, 1 Rebif, 1 Tecfidera), 9 patients had Tysabri as their first DMT. Average JC-virus serology titer was 1.86.

Conclusion

Switching high PML risks patients from Tysabri to Mavenclad appears to be well tolerated; regular MRI monitoring showed no PML carry-over risk and no significant MS disease activity.
199 Changes in natalizumab exposure and PML incidence over time
Authors: Giovannoni Gavin , Kappos Ludwig , Berger Joseph , Cutter Gary , Fox Robert , Wiendl Heinz , Chang Ih , Kasliwal Rachna , Lee Lily
Published: March 2023

Introduction

Since the identification in 2012 of three risk factors for natalizumab-associated progressive multifocal leukoencephalopathy (PML), changes in the PML incidence rate have been of interest.

Methods

The incidence of confirmed PML cases in Biogen’s postmarketing global safety database from November 2009 to November 2017 was evaluated retrospectively. Overall incidence in natalizumab-exposed patients was determined by the estimated total number of patients exposed and the number of confirmed cases. Changes in exposure patterns over time were evaluated by 12-infusion epochs.

Results

As of 30 November 2017, 180,656 patients worldwide had received ≥1 dose; overall natalizumab-associated PML incidence was 4.19/1000 patients. Since mid-2016, overall monthly incidence of PML appears to have stabilised, remaining between 4.18 and 4.24/1000. PML incidence was greatest in later, higher risk infusion epochs (≥37 infusions). The relative increase in the proportion of patients in higher-exposure epochs (>24 infusions) has declined from 2013 to 2017.

Conclusions

The stabilisation of overall natalizumab-associated PML incidence beginning mid-2016 coincides with the introduction of a new risk algorithm, suggesting that risk stratification factors are being incorporated into clinical practice and may continue to impact future incidence.

Support: Biogen. Disclosures to be included on poster.
200 AFFINITY: opicinumab in a targeted population of MS patients
Authors: Zhu Bing , Calabresi Peter A , Giovanonni Gavin , Kapoor Raj , Naismith Robert , Hartung Hans-Peter , Arnold Douglas L , Wolstencroft Paul , Johnson Kristina
Published: March 2023

Introduction

Opicinumab is a human monoclonal antibody against LINGO-1, a negative regulator of oligodendrocyte differentiation and axonal regeneration. The phase 2 SYNERGY study identified a patient subpopulation with a potentially enhanced response to opicinumab treatment.

Methods

AFFINITY (NCT03222973) is an ongoing, randomised, double-blind, placebo-controlled phase 2 study to evaluate the efficacy/safety of opicinumab vs placebo as an add-on to disease-modifying therapies in a targeted population. Inclusion criteria include: age 18–58; relapsing multiple sclerosis (MS) with ≤20-year duration; Expanded Disability Status Scale (EDSS) score 2.0–6.0; evidence of disease activity within 24 months prior to enrolment; brain MRI criteria suggestive of low myelin content but preserved tissue integrity in pre-existing T2 lesions; stably treated ≥24 weeks with interferon-beta, dimethyl fumarate, or natalizumab. Primary endpoint is the multicomponent Overall Response Score (based on EDSS, Timed 25-Foot Walk, and 9-Hole Peg Test). Secondary endpoints will evaluate confirmed improvement in disability measures.

Results

Enrolment began in September 2017 and was completed in September 2018. Participant baseline demographic, disease, and MRI characteristics will be presented.

Conclusions

AFFINITY will further investigate the efficacy and safety of opicinumab in a subpopulation of MS patients.

Support: Biogen. Disclosures to be included on poster.
14.45 Maintenance of idebenone treatment results in continued improvement in LHON patients
Authors: Lloria Xavier , Silva Magda , Lawrence- Catherine , Rudolph Guenther , Lob Felice , Livonius Bettina von , Catarino Claudia , Klopstock Thomas
Published: March 2023

Purpose

LHON is a mitochondrial disorder leading to progressive, irreversible loss of visual acuity (VA). Here we report on the long term treatment outcomes in real world clinical practice in which we evaluated the efficacy and safety of idebenone.

Methods

Patients were treated with idebenone as part of an Expanded Access Program. Efficacy was assessed as a clinically relevant recovery (CRR) or a clinically relevant stabilization (CRS). CRR defined as improvement from off-chart to reading 5 letters on the ETDRS chart, or improvement of 10 letters. CRS is defined as maintenance of VA <1.0 logMAR (20/200).

Results

Data from 111 patients was collected.The majority of patients (72.4%) had severe vision loss (>1.0 logMAR). A subset of 24 patients presented with VA <1.0 logMAR, and 50% of these experienced a CRS. CRR at last observation was achieved in 47.1% of patients after a mean of 10 months. For patients achieving CRR, 90.2% (37/41) had done so by 24 months. Mean of magnitude of CRR at last observation was more than seven lines on the ETDRS chart. The safety profile of idebenone in this longer term analysis was consistent with previous reports.

Conclusions

Idebenone is well tolerated and effective in a large proportion of patients. Maximal patient benefit may be achieved by early initiation of treatment, and by prolonged treatment.
201 Alemtuzumab related HPV infection and cervical dysplasia: real world data
Authors: Ruffer Giles , Koniotes Anna , Warren Catherine , Bozzali Marco , Fisniku Leonora
Published: March 2023

Background

Alemtuzumab a disease-modifying-therapy for relapsing-remitting Multiple Sclerosis (RRMS) increases the risk of Human Papilloma Virus (HPV) and cervical dysplasia. Annual HPV-screening is recommended in the Summary of Product Characteristics. 2018 Public of Health cervical screening programme in the United Kingdom recommends no more than three-yearly screening.

Objective

To assess HPV infection rate and cervical dysplasias in RRMS-Alemtuzumab-treated patients at Brighton and Sussex University Hospital.

Method

Review of the cervical screening of Alemtuzumab-treated RRMS female-patients who had received at least one treatment course from March 2015 until January 2019.

Results

The mean age of 80 female-patients who received Alemtuzumab was 39.1 years. Pre-treatment, 4/80 (5%) patients had a degree of dyskaryosis; 1/80 (1.25%) was HPV-positive. At one-year 5/72 (6.9%) patients who completed and had normal pre-treatment screening had abnormal cervical screening with 1/72 (1.39%) being HPV-positive. No extra HPV-positive cases were seen in year 2 (21-patients) and 3 (7-patients).

Conclusion

In Alemtuzumab-treated RRMS-patients, rate of HPV infections and cervical dyspasias are comparable to epidemiological studies. Whereas it is important that women engage with the national cervical screening, more frequent screening may not be justified. Additional testing might not be of any benefit and might be a source of anxiety for the patients.
203 Infectious-like presentation of neuromyelitis optica with pyrexia and CSF lymphocytosis
Authors: Cheema Sanjay , Leddy Sara , Wickremaratchi Mirdhu
Published: March 2023

A 19-year-old Philippine lady presented with persistent pyrexia over 39°C, abdominal pain and back pain. Over three days she then developed paraesthesia in all four limbs, proximal weakness in both legs, and sphincter disturbance. Vision was normal.

Spinal cord MRI showed signal change and oedema from C2 to T12. CSF showed a lymphocytosis of 200 cells/mm3and protein of 1.0 g/L, with normal glucose.

She was persistently febrile and was investigated extensively for an infectious myelitis and empirically treated with acyclovir and ceftriaxone. She made some improvement over the next two weeks and CSF lymphocyte count fell to 25 cells/mm3.

T-SPOT was positive indicating latent Tuberculosis. CT body imaging was normal.

Aquaporin-4 antibodies were positive. She was treated with high dose steroids, and mycophenolate was started after 3 months of anti-tuberculous medications. She went on to make a full neurological recovery.

The persistent pyrexia was likely centrally generated due to high aquaporin-4 expression in the hypothalamus. This and the significant CSF lymphocytosis mimicked an infectious presentation and led to a late diagnosis and treatment with immunosuppression.
204 Therapeutic plasma exchange for neurological disorders: the experience of a tertiary neuroscience centre
Authors: Parker Sarah , Das Joyutpal , Hewamadduma Channa
Published: March 2023

The role of Therapeutic plasma exchange (TPE) in immune-mediated neurologic disorders is expanding. Our experience with TPE at a tertiary neuroscience centre is reported.

Medical records of all patients who received TPE between 2013 and 2018 at Sheffield Teaching Hospitals NHS Foundation Trust were reviewed. The procedure involved the removal of 1–1.5 plasma volumes and replacement with isotonic 4.5% human albumin solution. A typical cycle consisted of 5–7 procedures within 14 days.

A total of 66 patients received 478 TPE procedures over 76 therapeutic cycles. TPE was performed for 16 neurological indications including multiple sclerosis (34.8%), Guillain-Barre syndrome (13.6%) and neuromyelitis optica spectrum disorder (9.1%). 78.8% of patients received TPE for category I or II indications according to The American Society for Apheresis (ASFA) guidelines. 73.8% of patients in our cohort demonstrated neurological improvement following TPE. 21.2% of patients responded to TPE administered for indications outside the ASFA guidelines. There was no treatment related mortality. Complications associated with TPE included bacteraemia, pulmonary embolism, deep vein thrombosis and bacterial endocarditis.

Our data suggests that TPE was associated with favourable outcomes. Further studies are required to assess the efficacy of TPE in those conditions for which there is currently little evidence.
205 An unusual cause of rapid cognitive decline in multiple sclerosis patient on natalizumab
Authors: Elsaddig Amar , Shaik Saifuddin
Published: March 2023

Natalizumab is highly effective disease modifying agent for relapsing remitting multiple sclerosis. However, it’s associated with increased risk of progressive multifocal leukoencephalopathy (PML) caused by John Cunningham virus (JC virus). The risk increases with presence of JC virus antibodies, treatment duration of more than 2 years and previous use of immunosuppressive agents. PML should be suspected whenever MS patients on natalizumab develop rapid cognitive decline and encephalopathy. Here we present a case of RRMS patient on natalizumab (had 18 infusions) for who presented with acute encephalopathy and fluctuant level of consciousness. He was admitted for assessment for PML. Investigations ruled out JC virus related PML and showed unexpected sCJD based on MRI, EEG changes and CSF analysis. To the best of our knowledge this is the first reported case of sCJD in MS patient on natalizumab in the UK.
207 An atypical cause of longitudinally extensive transverse myelitis after an allogeneic haemopoietic stem cell transplant
Authors: Kemp Michael , Keh Yann Shern , Dayanandan Rejith , Saif Muhammad , Nixon John
Published: March 2023

We present an unusual case of longitudinally extensive transverse myelitis (TM) with atypical features following allogeneic stem cell transplant.

A 53 year old male with a history of allogeneic stem cell transplant (SCT) two years earlier for myelofibrosis presented with a two day history of difficulty walking. Clinically he had a left Brown-Sequard syndrome. MRI showed a cord lesion preponderant to the left anterior quadrant at T7-9.

Initially independently mobile he rapidly deteriorated over two days, a week following admission, developing a dense flaccid paraparesis with a sensory level to the costal margin. Repeat imaging showed diffuse cord signal change from C6 downwards. In addition a persistent fever and rash emerged. Treated with high dose steroids and plasma exchange, the clinical course has progressed no further and rehabilitation continues however imaging has shown significant improvement.

Whilst there are case reports of TM after allogeneic SCT, they’ve typically responded quickly to immunosuppressive treatment which we have not yet seen. There was no active graft versus host disease at the time of presentation which makes this to be an unlikely cause of this presentation. This case highlights the lack of detailed cases and imaging of similar reported presentations.
208 Immune checkpoint inhibitor-related neurotoxicity: a case series
Authors: Brown Rachel , Au Lewis , Spain Lavinia , Furness Andrew , Rees Jeremy , Rossor Alex , Morris Emma , Zandi Michael , Lunn Michael , Larkin James , Turajlic Samra ,   on behalf of EXACT consortium, Carr Aisling
Published: March 2023

Immune checkpoint inhibitors (ICI), monoclonal antibodies enhancing T cell responses against tumour cells, have revolutionised the treatment of cancers such as advanced melanoma, leading to enhanced survival. Their action, however, is not tumour-specific, and patients can develop multisystem immune related adverse events (irAE). Neurological irAEs have been reported in 1–14% of patients, depending upon the ICI used, and can affect any part of the neuro-axis. A recent case series from the Royal Marsden Hospital (RMH) identified 10 patients with neurotoxicity following ICI for advanced melanoma between 2010–15, specifically neuropathy (6), plexopathy (1) and aseptic meningitis (3). Exactly how neurological injury occurs, whether cell-, cytokine- or antibody-mediated, is unknown.

We present early data from a newly established collaboration with RMH, aiming to clinically characterize these patients, and identify the cause of neurological injury. To date, we have advised on patients (age range 53–80) with myositis, Guillain-Barré (GBS)-like neuropathy, plexopathy, aseptic meningitis, and encephalitis following ICI (ipilimumab and/or nivolumab) for advanced melanoma. Features common to these patients include their subacute onset, time from ICI administration, and steroid responsiveness (including in GBS-like cases). The incidence of neurological irAEs following ICI will rise with increasing use, and is therefore of concern to practicing neurologists.
210 CASPR2 antibody-related movement disorders: case series
Authors: See Mei , Cahill Varduhi , Scotton Sangeeta , Newman Piers , Sadalage Girija , Cherian Ajith , Divya KP , Jacob Saiju
Published: March 2023

Introduction

Contactin-associated protein 2 (CASPR2) antibodies are implicated in the development of a spectrum of neurological conditions where movement disorders constitute a substantial part of the clinical manifestations along with behavioral and cognitive impairment.

Case report

We report a case series of three patients presenting with a variety of clinical phenotypes associated with choreoathetoid movement disorder, camptocormia and myoclonus. All three patients, in addition to motor manifestations, exhibited a degree of cognitive impairment. One patient was severely debilitated with florid choreoathetoid movements and prominent behavioral disturbance impacting upon daily living. In the other two patients, worsening camptocormia and myoclonus resulted in the loss of ambulation. Their atypical clinical manifestations necessitated an extensive diagnostic workup with the exclusion of neurodegenerative and paraneoplastic causes. Not uncommonly, the possibility of a functional neurological disorder was also raised. The diagnosis was reached with the detection of CASPR2 antibodies in serum and CSF. The causative relationship between CASPR2-antibodies and the clinical manifestations was further substantiated by the good response to immunological therapies including steroid treatment, intravenous immunoglobulin and therapeutic plasma exchange.

Conclusion

The spectrum of CASPR2-associated movement disorders continues to rapidly expand. Increased awareness amongst clinicians is necessary for a timely diagnosis and treatment initiation.
213 ‘Taking the brakes off’- immune checkpoint inhibitor induced neurotoxicity
Authors: Porter Marie-Claire , Papa Sophie , Carroll Paul , Williams Victoria
Published: March 2023

Immune checkpoint inhibitors have greatly improved the survival of patients with advanced melanoma and are now becoming standard therapy for treating a wide range of different forms of cancer. Although immune mediated neurological complications related to these drugs are reported to be uncommon, occurring in around 1% patients, with the increased use of these treatments, there are likely to be more cases of neurotoxicity recognised in patients receiving cancer immunotherapy.

We present a case series of 6 patients, seen in our trust, who developed a range of neurological complications associated with immune checkpoint inhibitor use. The conditions we encountered were:

Myasthenia gravis, autoimmune encephalitis, aseptic meningitis and hypophysitis in 4 patients diagnosed with advanced melanoma treated with both single and combined immunotherapy

Cerebellar ataxia, that re-occurred with each immunotherapy treatment for oesophageal cancer

Worsening of migraine with the commencement of treatment for bladder cancer

These cases illustrate the diverse adverse effects that these drugs can have on both the peripheral and central nervous system and the sometimes complex management required to treat them. We discuss the guidelines for treatment of immune checkpoint inhibitor neurotoxicity and the importance of recognising these conditions.
218 Management strategies for neuroimmunological complications following treatment with immune checkpoint inhibitors
Authors: Bose Smriti , Sumangala Salini , Steven Neil , Jacob Saiju
Published: March 2023

Objective

The use of immune checkpoint inhibitors (CIs) for malignancies has revolutionised oncological management in the last few years. These agents are known to cause immune-mediated complications in various systemic organs. The neurological complications of these are now being increasingly recognised. The cases managed in our institution where there were neuroimmunological complications following CIs were reviewed. We discuss management strategies for early recognition and treatment, thus minimising morbidity.

Method

A joint effort by neurologists and medical oncologists to review clinical practice guidelines for management of neurological adverse effects of checkpoint inhibitors. This was based on a review of several cases reported, as well as experience from all the cases managed in our hospital.

Results

There are no British guidelines from the neurological perspective for early identification of symptoms. Guidelines are based on expert consensus and also on treatments reviewed from literature.

Conclusion

Recommendations advice early identification of signs and symptoms followed by grading them as mild, moderate and severe (grades 1, 2, 3). Grade 1 symptoms require continuation of the CIs and symptomatic management. CIs should be stopped temporarily for grade 2 and permanently for grade 3 symptoms. Steroids plasma exchange, IVIg would be the first line of treatment.