bluuebunny/crossref_metadata_2025 huggingface dataset:
126 The provision of anti-CD20 therapy in inflammatory demyelinating disorders of the CNS during SARS-CoV-2
Authors: Smedley Imogen , O’Riordan Jonathan
Published: August 2022

Objectives

Anti-CD20 therapy for inflammatory demyelinating CNS disorders increases SARS-CoV-2 incidence and severity, demonstrating the value of vaccination in this group. Low vaccine seroconver- sion is observed in those on anti-CD20 therapy. A 12-week interval following anti-CD20 infusion before vaccination and a 2-4-week interval following vaccination before infusion is recommended. Patients are eligible for a third dose and booster. Infusions are given 6-monthly. This schedule cannot be followed without treatment delays, forcing prescribers to prioritise vaccination versus risk of disease progression. We aimed to assess the provision of these recommendations in NHS Tayside by quantifying SARS-CoV-2 incidence and severity.

Methods

All patients receiving anti-CD20 therapy for inflammatory demyelinating CNS disorders were included. SARS-CoV-2 infection incidence was quantified, severity was measured by engagement with secondary care. Vaccine uptake and treatment delays were measured.

Results

66 patients were included. 51 received ocrelizumab (27 RRMS, 24 PPMS). 15 received rituximab

(8 NMOSD, 3 NMOSD/MS overlap, 4 RRMS). 13 patients contracted COVID. 5 patients required hospital admission. 2 had COVID-pneumonitis associated respiratory failure requiring HDU admission. 2 contracted COVID while unvaccinated. Only 3 had received 4 vaccine dosages, 2 of which tested positive due to PCR screening pre-infusion.

33 (67.3%) patients had treatment delays receiving infusions greater than 6-months apart.

Conclusions

Patients receiving anti-CD20 therapy for inflammatory CNS disorders have been complex to manage during the pandemic. Guidance regarding a third primary dosage came late in the pandemic.
128 Visuoperceptual deficits as measures of cognitive dysfunction in multiple sclerosis: a pilot study
Authors: Whitford Victoria , Leddy Sara , Waters Sheena , Karania Tasvee , Marshall Charles , Dobson Ruth
Published: August 2022

Objective

We investigated whether computerised measurement of visuoperceptual deficits can detect cognitive dysfunction in multiple sclerosis (MS).

Methods

We assessed people with MS (PwMS; N=31, 58% female, 64% White, mean age 40.1) and controls (N=18, 61% female, 83% White, mean age 37.3) on novel, culturally-fair, psychophysical “stress” tests that detect subtle deficits in visuoperceptual processing in early neurological disease: the ‘Cats ‘N Dogs Task’ (CNDT, which presents images with varying degrees of skew for differentiation into ‘cat’ or ‘dog’) and ‘Point Light Walker Task’ (PLWT, which presents motion patterns for differentiation into ‘human’ and ‘nonhuman’). Visual acuity, physical function, depression, anxiety, fatigue, and acceptability of the tests were also collected for PwMS.

Results

For the CNDT, relative to controls, PwMS showed significantly lower accuracy (82% vs 86%) and slower reaction time (1.48s vs 1.17s). For PLWT, they showed significantly reduced difficulty level (psycho- physical threshold). Analysis of Variance with the factors MS status, sex, ethnicity, and age revealed a significant main effect of MS for each of these measures (all F>7.3, p<0.0097). In PwMS, clinical severity measures (EDSS, 9-hole peg) showed modest, significant correlation with accuracy, reaction time, or dif- ficulty. All tasks were well-tolerated.

Conclusion

Detection of cognitive dysfunction via measurement of visuoperceptual processing is possible in MS using culturally fair, well-tolerated, computerised cognitive “stress” tests. Further testing across a range of disability with a larger control group is needed.
131 Understanding the administration and monitoring time burden of several disease-modifying therapies for relapsing multiple sclerosis
Authors: Rog David , Brownlee Wallace , Carod-Artal Francisco Javier , Kalra Seema , Cock Erwin De , Leclerc Stephanie , Amin Amerah , Ashton Luke , Evans Hannah
Published: August 2022

Background

To assist neurologists with effectively planning multiple sclerosis (MS) services in the NHS, this study quantified the administration and monitoring time burden associated with selected high-efficacy disease-modifying therapies (DMTs; alemtuzumab, cladribine tablets [CladT], fingolimod, natalizumab, and ocrelizumab) for highly-active relapsing MS in the UK.

Methods

A time and motion study was conducted across four MS centres over 3–4 months per-site (Aug 2019–Feb 2021). Time dedicated by healthcare professionals (HCPs) to pre-specified drug administration and monitoring activities was assessed for each of the selected DMTs. Data were extrapolated over 4 years per-patient, based on the relevant Summaries of Product Characteristics, and analysed descriptively.

Results

For oral DMTs, projected total active HCP time (monitoring only) per-patient over 4 years was 12.3 hours for CladT and 15.9 hours for fingolimod. For infusion DMTs, total time (administration and monitoring) was 35.5 hours for alemtuzumab (6.1 and 29.4 hours), 46.5 hours for natalizumab (17.2 and 29.3 hours), and 21.6 hours for ocrelizumab (6.2 and 15.4 hours).

Conclusions

While active HCP time varies across sites, infusion DMTs are projected to require the greatest amount of HCP time associated with administration and monitoring over 4 years versus oral DMTs.
140 Long-term effectiveness of natalizumab for RRMS: UK and global interim results from TYSABRI observational program
Authors: Nicholas Richard , Harrower Timothy , Sun Zhaonan , Vonsy Jean
Published: August 2022

Introduction

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

Methods

Annualised relapse rate (ARR) was analysed in TOP UK (n=134) and global (N=6321) cohorts using data from July 2007 to November 2021. A subgroup analysis assessed ARR in patients with one prior disease modifying therapy (DMT) in the UK (n=64) and global (n=2757) cohorts. Cumulative probabilities of 24-week confirmed disability worsening and improvement will be presented subsequently.

Results

ARR decreased in UK patients from 2.21 in the year before initiation to 0.15 on natalizumab (P<0.0001), consistent with a global decrease from 2.00 to 0.18 (P<0.0001). In patients with one prior DMT, ARR decreased in UK patients from 2.13 in the year before initiation to 0.15 on natalizumab (P<0.0001), similar to the global decrease from 2.03 to 0.16 (P<0.0001).

Conclusions

The reduction in ARR on natalizumab was similar in the TOP UK and global cohorts, including in the subset of patients with one prior DMT. These findings support the real-world effectiveness of natalizumab.

Support

Biogen. Disclosures on poster.
141 Cognitive processing speed predicts disease progression in SPMS: post hoc analysis from the EXPAND study
Authors: Penner Iris-Katharina , Giovannoni Gavin , Chitnis Tanuja , Vermesch Patrick , Arnould Sophie , DeLasHeras Virginia , Karlsson Goeril , Piani-Meier Daniela , Kappos Ludwig , Benedict Ralph
Published: August 2022

Objective

Assess the predictive value of cognitive processing speed (CPS), using the Symbol Digit Modali- ties Test (SDMT) score, on disability progression in secondary progressive multiple sclerosis (SPMS).

Design/Methods

SPMS patients from the Phase 3 EXPAND study (core part [CP] and core+extension part [CP+EP]) were categorised into quartiles of baseline SDMT score (worst-WQ [Q1], intermediate [Q2-Q3], and best-BQ [Q4] quartile). The predictive value of baseline SDMT quartiles for time-to-wheelchair (T2W; i.e., Expanded Disability Status Scale [EDSS] score ≥7) sustained until end of follow-up, or 6-month confirmed disability progression (6mCDP) by EDSS, were assessed at the end of the CP (up to 37-months) and CP+EP (up to 5-years) by Cox regression (adjusted for treatment, age, gender, baseline EDSS, baseline SDMT quartile, and treatment-by-baseline SDMT quartile interaction).

Results

Analyses included 1628/1651 patients (98.6%) randomised in EXPAND (baseline SDMT: WQ, n=435; intermediate, n=808; BQ, n=385). Risk of T2W (WQ vs BQ) was higher in the CP (HRWQ/BQ=1.31, 95% CI:0.72–2.38; p=0.37) and increased with long-term follow-up (HRWQ/BQ=1.81; 1.17–2.78; p=0.01). Baseline SDMT was not predictive of 6mCDP. The predictive value of on-study SDMT score change will be presented.

Conclusions

The results support the predictive value of CPS for long-term physical disability progression in SPMS. Funding: Novartis Pharma AG, Basel, Switzerland.
144 Long-term efficacy of ofatumumab in patients with relapsing multiple sclerosis
Authors: Hauser Stephen , Fox Edward , Aungst Angela , Su Wendy , Zielman Ronald , Gupta Ayan Das , Stoneman Dee , Robertson Derrick , Cohen Jeffrey , Kappos Ludwig
Published: August 2022

Objective

To assess the long-term efficacy of ofatumumab treatment for up to ~4 years in patients with relapsing multiple sclerosis (RMS).

Methods

This analysis (data cut-off: 25-Sep-2021) will include cumulative data from patients randomised to ofatumumab/teriflunomide in the ASCLEPIOS I/II trials (core study) and the ongoing, open-label, ALITHIOS extension study. Patients will be analyzed in two groups: those randomised to ofatumumab in the core (continuous group) and those randomised to teriflunomide in the core with potential switch to ofatumumab in the extension (switch group). Annualised relapse rate (ARR), disability worsening (time- to-3-month/6-month confirmed disability worsening), disability improvement (time-to-6-month confirmed disability improvement), and brain MRI outcomes (number of Gd+T1 lesions and annualised T2 lesion rate) will be assessed.

Results

Overall, 1882 patients who were randomised in the ASCLEPIOS I/II trials (ofatumumab/terifluno- mide: 946/936) will be included in the analysis. In total, 690/946 patients treated with ofatumumab and 677/936 patients treated with teriflunomide entered ALITHIOS. Updated efficacy results for up to ~4 years will be presented at the congress.

Conclusions

These analyses will provide insights on the sustained efficacy of continuous ofatumumab treatment for up to 4 years in patients with RMS, and on ofatumumab efficacy in patients newly switched from teriflunomide. Funding: Novartis Pharma AG, Basel, Switzerland.
157 Natalizumab treatment satisfaction in the TONiC-MS study: study design
Authors: James Bethan , Mills Roger , Vonsy Jean , Langdon Dawn , Ando Hikari , Young Carolyn
Published: August 2022

Background

The Trajectories of Outcome in Neurological Conditions-MS (TONiC-MS) is an ongoing observational study of people with MS in the UK, collecting patient reported outcome measures. In 2021, natalizumab became available in s.c. formulation in addition to the i.v. formulation first licensed in UK in 2006. There are currently no data on patient preference between the two formulations.

Methods

This is a prospective, observational, open-label questionnaire study nested in the TONiC-MS study. Following informed consent, participants on natalizumab-i.v. in TONiC-MS receive a baseline question- naire pack covering: treatment duration, frequency of administration, cannulation experience; adverse events; Neurological Fatigue Index-MS; Hospital Anxiety and Depression Scale; Stigma Scale for Chronic Illness; WHOQol-BREF; MSIS 29 Psychological; Warwick-Edinburgh Mental Well-being Scale. If the subject switches to natalizumab-s.c., one and three months later they will complete a follow-on pack repeating the above alongside the Patient Preference Questionnaire.

Results

Enrolment of participants on natalizumab-i.v. started in August 2021. Study design and interim data will be presented.

Discussion

This study will provide real-world data on experience with natalizumab-i.v. and natalizumab-s.c. in the UK. The data collected will allow examination of quality of life, MS psychological impact, well-being and adverse events on the different formulations of natalizumab.
177 An unusual presentation in motor neurone disease
Authors: Terry Robyn , Tanti Matthew , Jung Agam , Mavroudis Ioannis , Devinuwara Kanch , Sivakumar Gnanamurthy
Published: August 2022

Motor Neurone Disease (MND) is a life limiting neurodegenerative condition. Spasticity in MND is usually managed with oral medications. Intrathecal baclofen (ITB) is occasionally used. While there is some expe- rience of ITB in Primary Lateral Sclerosis (PLS) there are few reports of ITB in the context of Amyotrophic Lateral Sclerosis (ALS). Paroxysmal sympathetic hyperactivity (PSH) is known to occur with central nervous system (CNS) insults, but there is only one prior reported case of MND with PSH in the literature.

We report a patient with an eight-year history of PLS, sleep apnoea, recent immobility and conversion to ALS who developed PSH after ITB pump insertion. His spasticity was severe despite oral medications and the ITB insertion resulted in dramatic improvement. Two months post procedure he developed recurrent episodes of facial flushing, hypertension, tachycardia and headache, typical of PSH, which seemed to follow episodes of sleep apnoea. Other somatovisceral triggers were not found. Imaging of the neuraxis revealed peri-rolandic atrophy in keeping with ALS but no new CNS lesions.

PSH in our patient seemed to follow ITB insertion despite ITB being a treatment for PSH. More studies are required to assess efficacy and complications of ITB for patients with MND.
179 Impact inventory development in neurological pathways
Authors: Chappell Rachel , Fearn Sarah , Raftery James , Kipps Christopher
Published: August 2022

Background

Quantification of the economic burden within long-term neurological conditions pathways is difficult, and little evidence is available on how best to approach this. With the ambition to deliver care differently through digital mechanisms, and enhanced provision of self-management support, it is impera- tive that we develop mechanisms that can help measure the economic impact of pathway interventions in long-term neurological conditions. An impact inventory is a recognised initial step in defining the costs of an intervention from a range of perspectives including health/non-health and known/unknown cost items

Methods

We used thematic analysis to analyse survey data on events causing an increase in care needs, grouped these as health- or care-related, calculated reported event frequencies and then applied NHS (National Tariff workbook) and social care reference costs (PSSRU, 2020) to them.

Results

We identified 728 events comprising 35 event types across 5 long-term neurological conditions. Six events were common across conditions, and 13 were condition-specific. Post-event care costs were significantly greater than health-related costs (mean 7.9 times), and total pathway event costs varied nearly five-fold across conditions (£5,395 vs £23,258).

Conclusion

Costs can be quantified in neurological pathways using an impact inventory to characterise events that change care requirements.
182 Pooled safety data from the risdiplam clinical development programme
Authors: Baranello Giovanni , Servais Laurent , Chiriboga Claudia , Darras Basil , Bader-Weder Silvia , Gorni Ksenija , Jaber Birgit , McIver Tammy , Scalco Renata , Mercuri Eugenio
Published: August 2022

Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) premRNA splicing modifier approved by the EMA and MHRA for the treatment of patients aged ≥2 months, with a clinical diagnosis of Type 1, 2 or 3 spinal muscular atrophy (SMA) or 1–4 copies of SMN2.

Safety data were pooled from three studies within the risdiplam clinical development programme:

FIREFISH (NCT02913482) assesses safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of risdiplam in infants with Type 1 SMA

SUNFISH (NCT02908685) assesses safety, tolerability, PK, PD and efficacy of risdiplam in patients with Types 2/3 SMA

JEWELFISH (NCT03032172) assesses safety, tolerability, PK and PD of risdiplam in patients who previously received RG7800 (RO6885247), nusinersen (SPINRAZA®), olesoxime or onasemnogene abeparvovec (ZOLGENSMA®).

Pooled analyses from FIREFISH, SUNFISH and JEWELFISH showed no treatment-related safety findings leading to withdrawal from risdiplam in 465 patients treated for up to 38.9 months (data-cut-offs: 14 November 2019, 15 January 2020 and 31 January 2020, respectively). The differences in adverse event profiles between Type 1 and Types 2/3 SMA populations appeared to be driven by the severity of the underlying disease. Here we will present updated pooled safety analyses for the risdiplam studies.
183 Lumbar ports to deliver nusinersen in SMA: first adult and paediatric patients in the UK
Authors: Hewamadduma Channa , Childs Annemarie , Lacy Patricia de , Sivakumar Gnanamurthy , Nevin Katie , Ahmad Faizan , Khan Almas , Ali Ayesha , Marley Fiona , McMullan John
Published: August 2022

5q- Spinal muscular atrophy (SMA) is a progressive inherited disorder of the motor neurons due to bi allelic mutations in SMN1 gene responsible for a high mortality in infancy, and significant morbidity in childhood, adolescence and into adult life. Advent of SMN1 gene splice modifiers have revolutionised the therapeutic landscape in SMA. Nusinersen is the first such treatment in SMA and is delivered intrathecally via lumbar puncture (LP). Nusinersen is currently accessible to the UK SMA patients via a managed access agreement.

LPs are difficult in some patients due to previous spinal fusion surgery (especially in Type 2 SMA), obesity, and other anatomical challenges. Some patients and families find repeat LPs intolerable. A proportion of SMA patients therefore have not been able to access nusinersen for the above reasons, although they would otherwise choose nusinersen as the treatment of first-choice. Nusinersen delivery via a lumbar port and catheter system is not licensed. However it has been successfully attempted in other European and US centres before.

Here we report the details and protocols of the first UK adult and paediatric SMA patients who underwent lumbar port and catheter insertion to successfully deliver nusinersen treatment, thereby maintaining the choice of a therapeutic option for a proportion of SMA patients.
207 Bayesian revolution in stroke research – a four-arm hypothetical study for neuro- protection in the hyperacute stage
Authors: Das Abhijit , Chatterjee Somenath , Sekhar Alakendu
Published: August 2022

Background and Aims

The treatment of acute ischemic stroke (AIS) still has multiple equipoises and the current time-consuming and inefficient process of clinical translation is a major hindrance. Bayesian approaches offer an alternative method that can accelerate the development of novel treatments. These designs allow multiple treatment options to be tested simultaneously and these features significantly reduce sample size and allow for faster and more efficient clinical translation. Unfortunately, unlike other fields, Stroke researchers are yet to adopt these methodologies.

Methods

We propose the “leapfrog design” to evaluate multiple treatments simultaneously. This allows continual treatment improvement and finding one or more treatments that are better than the current ‘gold standard’ which is accomplished by allowing replacement of the comparison arm (the arm against which all other arms are compared) by new treatment arms that achieve a prespecified threshold for demonstrating superiority. For the hypothetical study we simulated a 4-arm study involving – a) Nerinetide b) TRPM7 c) SRC-ND2 and d) uric acid in patients undergoing thrombectomy. We used the BFDA – an R package for Bayes factor (BF) design analysis.

Results

We chose Cohen’s d = 0.4, as in early stage of development, with a BFfail of 1/4, and BFsuccess of 5. The Nmin and Nmax were found much smaller than traditional RCT numbers.

Conclusions

This will be a much-needed paradigm shift for further progress in stroke research beyond current equipoises.
Evaluating the feasibility of a real world pharmacovigilance study (OPTIMISE:MS)
Authors: Dobson Ruth , Craner Matthew , Waddingham Ed , Miller Aleisha , Pindoria Jayant , Cavey Ana , Matthews Paul M ,   on behalf of all OPTIMISE:MS investigators
Published: August 2022

Background

Clinical trial populations do not fully reflect routine practice. The power of routinely collected data is increasingly recognised.

Methods

The OPTIMISE:MS pharmacovigilance study is a prospective, pragmatic observational study, conducted across 13 UK MS centres. Data were collected at the time of routine clinical visits. The first participant was recruited on 24th May 2019; data were extracted on 11th November 2021.

Results

2112 participants were included (median age 44.0 years; 1570 (72%) female; 1981 (94%) relapsing- remitting MS). 639 (30%) were untreated at study entry, 205 (10%) taking interferon beta/copaxone, 1004 (47%) were taking second/third generation DMT first line (including dimethyl fumarate, oral cladribine, natalizumab, ocrelizumab), and 264 (13%) had escalated from either interferon beta or copaxone. 342 clinical events were reported, of which 108 were infections. There was an increased risk of adverse events in people taking second/third generation DMT (RR 3.45, 95%CI 1.57-7.60, p<0.01 vs no DMT). Unadjusted Poisson regression demonstrated increased incident adverse events in people taking natalizumab (IRR 5.28, 95%CI 1.41-19.74, p<0.05), ocrelizumab (IRR 3.24, 95%CI 1.22-8.62, p<0.05), and GA biosimilar (Brabio) (IRR 4.89, 95%CI 1.31-18.21, p<0.05) vs no DMT.

Conclusions

Routinely collected healthcare data can be used to evaluate DMT safety in people with MS. These data highlight the potential of pragmatic studies to guide understanding of risks and benefits associated with DMT.
Network changes predicting language decline following anterior temporal lobe resection
Authors: Binding Lawrence , Taylor Peter , Baxendale Sallie , McEvoy Andrew , Miserocchi Anna , Duncan John , Vos Sjoerd
Published: August 2022

Anterior temporal lobe resection (ATLR), while successful can result in lasting impairment of language function. White matter bundles have been shown to explain some of the variance seen in language decline after ATLR. Network analysis of the structural connectome has been shown superior in predicting preoperative language ability but remains unexplored in predicting postoperative ability.

Diffusion MRI-based tractography was used to generate the preoperative connectome on 54 left-lat- eralised (as determined by functional MRI), left-hemisphere ATLR. Postoperative connectomes were estimated via manually drawn resection masks. Graded naming test (GNT), semantic, and letter fluency were binarised into significant decline or not (via their reliable change indices). Strength (sum of connec- tions) and betweenness centrality (interconnectivity) network changes were generated using pre- and postoperative connectomes as predictor variables. Each model was entered into a linear support vector machine incorporating synthetic minority over-sampling technique for class imbalances.

Strength changes alone accurately predicted 81.6% of patients who had GNT decline. Betweenness centrality changes accurately predicted 73.3% of patients who had letter fluency decline. Patients with semantic decline were predicted equally as well by strength and betweenness centrality changes (accuracy=71.1%).

These findings demonstrate the usefulness of the structural network in predicting and potentially prevent- ing postoperative language decline.
Attenuated heart-brain integration predicts functional non-epileptic seizures
Authors: Elkommos Samia , Martin-Lopez David , Koreki Akihiro , Jolliffe Claire , Mula Marco , Critch-ley Hugo , Edwards Mark , Garfinkel Sarah , Richardson Mark P , Yogarajah Mahinda
Published: August 2022

Background

Patients with functional seizures (FS) can experience dissociation (depersonalisation) before their seizures. Depersonalisation encompasses a feeling of disembodiment, putatively caused by reduced afferent visceral mapping, that is, changes in interoceptive processing. The heartbeat-evoked potential (HEP) is an electroencephalographic (EEG) index of synchronised neural responses to individual heart- beats, and a marker of interoceptive representation. HEP amplitude is reported to be reduced in dep- ersonalisation-derealisation disorder.

Purpose

To assess whether alterations in interoceptive processing indexed by the HEP occur prior to FSs, and compare this with epileptic seizures (ES).

Methods

HEP amplitudes were calculated from EEG during video-EEG monitoring in 25 patients with FS and 19 patients with ES, and compared between interictal and preictal states.

Results

The FS group demonstrated a significant reduction in HEP amplitude between interictal and preictal states at F8 (rB=0.612, p=0.006) and C4 (rB=0.600, p=0.007). No differences in HEP amplitude were found between interictal and preictal states in the ES group. Findings were not related to heart rate, mean ECG or QRS amplitudes, which did not differ between states or groups.

Conclusion

Our data support the notion that aberrant interoception underpins disembodiment prior to dissociative FS. Changes in HEP amplitude may reflect a neurophysiological biomarker of FS.
Future approaches to seizure source localisation using optically pumped magnetoencephalography and electrical impedance tomography
Authors: Vivekananda U , Mellor S , Tierney T , Aristovich K , Barnes G , Walker M
Published: August 2022

A third of patients with epilepsy are drug resistant, and epilepsy surgery (i.e. removal of the brain epilepsy focus) may present a powerful alternative in achieving seizure freedom. Magnetoencephalography (MEG) has been increasingly used in identifying the epilepsy focus due to its inherent properties of high spatial resolution and relative immunity to muscle artefact. However current MEG systems are cumbersome and restrictive for the patient, meaning that recording sessions are usually brief (1-2 hours). Here we demon- strate the first use of Optically Pumped Magnetoencephalography (OP-MEG) worldwide in three epilepsy patients with unrestricted head movement. We use a different type of sensor, which operates at room temperature and can be placed directly on the patient’s scalp, permitting free head movement. We show that OP-MEG could reliably identify abnormal epileptiform activity, even in cases where EEG could not, and localise this activity to the abnormal brain region.

In patients who undergo intracranial EEG i.e. electrodes surgically placed within the brain, we have also demonstrated the first use of Electrical Impedance Tomography (EIT), a method for producing images of the internal electrical impedance of a subject due to nerve cell swelling. This method can produce images of seizure propagation similar to fMRI, but can be recorded continuously at any time during presurgical video-telemetry. Both methods have the potential to revolutionise how functional imaging is performed in epilepsy.
A novel neurodegenerative disease with multi-system features
Authors: Holm-Mercer Leah , Rudge Peter , Coysh Thomas , Brandner Sebastian , Jaunmuktane Zane , Ramadan Haw- raman , Ostler Jo , Smith Colin , Reisz Zita
Published: August 2022

Inherited prion diseases (IPD) are caused by mutations in the prion protein gene (PRNP) leading to accu- mulation of misfolded prion protein (PrP). Here we describe three novelPRNPmutations.

A patient with gradually progressive cognitive decline, peripheral neuropathy, diarrhoea and autonomic dysfunction, starting in the 6th decade, whose father suffered a similar illness with neuropathology showing PrP-cerebral amyloid angiopathy, PrP-amyloid plaques and abundant tau disease with co-localising TDP-43, had a truncation mutation at codon 157.

A missense mutation at codon 107 ofPRNPcausing an amino acid change from threonine to isoleucine was observed in a patient with a 9-year illness starting with cognitive decline followed by gait disturbance. Neuropathology shows multi-centric PrP-amyloid plaques.

Substitution of proline to serine at codon 105 has previously been reported in one patient, however our case exhibited a different phenotype: dysphasia in the absence of neurological signs, with subsequent rapid cognitive then motor decline with myoclonus. Neuropathology showed predominantly synaptic deposition of PrP and sparse cerebellar plaques.

These cases highlight the remarkable heterogeneity which can be seen within IPD, and the importance of genetic screening ofPRNPin cases where there is an unexplained phenotype, particularly when there is a family history.
Multi-centre audit of myotonic dystrophy care in UK: is it the time for national recommendations?
Authors: Litesh Mohit , Campbell Paul R , Mehboob Sadaf , Vonberg Frederick , Koh Woon Senn , Kelly Phillip , Shanmugarajah Priya , Viegas Stuart , Lilleker James B , Hewamadduma Channa
Published: August 2022

Myotonic Dystrophy Type 1 (DM1) is the most common muscular dystrophy in adults. Structured multi- disciplinary care is required to manage the multi-system involvement, to improve patient safety, and to reduce mortality and morbidity. Previous audits based on the 2018 consensus-based care recommenda- tions have been conducted at individual UK centres. In this study a standardised audit tool was created and deployed to 3 tertiary UK neuroscience centres.

In total, data regarding 375 patients (197 (53%) female, mean age 47 years (range 1-84)) with DM1 were analysed. 62% had adult-onset disease. Neurology teams reviewed 64% of patients at least once a year. Key findings included: Cardiology review was performed annually for only 30%; of patients with respiratory needs, only 12% were reviewed six-monthly by specialist teams; Swallowing function was assessed in only 44% of those required; Clinical assessment for cognitive impairment was conducted in 12%.

In conclusion, this multi-centre UK audit identifies several significant areas of care that need to be optimised in DM1, even within dedicated neuromuscular clinics. This highlights the need for a national initiative to establish minimum care standards. Such initiative can help drive resource allocation resulting in positive change.
Changing phenotypes, a spectrum over 10 years
Authors: Moe Aye , Schaefer Andrew , Gorman Gráinne , Ng Yi Shiau
Published: August 2022

Our patient first presented with progressive unsteadiness and slurred speech at the age of 67 years. The initial working diagnosis was progressive ataxia. There were minimal cerebellar changes on MRI head and extensive laboratory tests including common spinocerebellar ataxia screen was negative. He sub- sequently developed distal muscle wasting and weakness, and pathologically brisk reflexes, with normal CK levels. Motor neuron disease (MND) was then clinically suspected, however, further neurophysiologi- cal studies and a nerve biopsy revealed changes consistent with an axonal neuropathy. Generalised muscle wasting, bilateral scapular winging, eyelid ptosis and complex ophthalmoplegia were identified eight years after initial clinic review. The complex evolving neurological phenotype prompted a muscle biopsy to investigate for mitochondrial disease. Whilst some evidence of mitochondrial dysfunction was identified, the mitochondrial DNA maintenance nuclear gene panel was negative. He was enrolled to the 100k genome project which revealed a heterozygous KIF5A pathogenic variant. Mutations in KIF5A are associated with a wide phenotypic spectrum including CMT neuropathy, hereditary spastic paraplegia and MND-like syndrome. Our case highlights the diagnostic conundrum of evolving neurological mani- festations of KIF5A disease that demonstrates overlapping cardinal features with mitochondrial disease.
007 Functional neurological disorders and sociodemographic factors: a review
Authors: Vidot Micha , Wu Kit , Mitchell James , Nitkunan Arani , Carr Georgina
Published: August 2022

Background

To improve equity of service, in line with the aspirations of public policy across the UK, it is imperative that we understand how sociodemographic factors affect the management and care of functional neurological disorders (FND).

Aims

To describe the relationship between sociodemographic factors and the epidemiology, clinical factors, diagnosis, treatment, patient experience and outcomes for people with FND.

Methods

We conducted a focused review of published literature from 2000 to 2021 investigating the rela- tionship between FND and each of the patient protected characteristics, as outlined in the Equality Act 2010, with additional factors such as socioeconomic status, education and employment also included.

Results

There is limited but some published data looking at age, disability, marriage/civil partnership, race, sex and gender, education and employment. However, minimal data is found discussing gender reassignment, pregnancy and maternity, religion and beliefs, sexual orientation, geographical variation, socioeconomic status and settlement status/immigrants.

Discussion

FND is a relatively new term used to describe a condition that has had many aliases in the past, therefore leading to a lack of consistency in terminology and research methodology. Further research is needed to explore FND in relation to patient protected characteristics, and the effect on patient outcomes.
011 A case of a neurological immune-related adverse event associated with ipilimumab/nivolumab
Authors: Walker Josh , Farag Mena , Josephs Debra , Williams Victoria , Holmes Paul
Published: August 2022

We present an unusual movement disorder due to immune checkpoint inhibitors which responded rapidly to prednisolone.

Background

Immune checkpoint inhibitors (ICIs) have revolutionised the scope of cancer therapy but can induce autoimmune effects on healthy organs, termed immune-related adverse events (irAEs). Their pathophysiology relies on the same mechanisms that confer anti-tumour activity and can affect any organ in the body. Neurological irAEs (n-irAEs) although rare, are potentially fatal. Differentiating n-irAEs from paraneoplastic syndromes and other neurological disorders can be challenging.

Case

We present a case of n-irAE in a patient with metastatic renal cell carcinoma treated with two cycles of ipilimumab/nivolumab. Following the second cycle, the patient developed subacute onset of postural and rest tremor, predominantly affecting her upper limbs, head and tongue, of variable amplitude, with bradykinesia of foot tapping. Her gait was broad-based. MRI brain was unremarkable. CSF was lymphocytic (WBC 103 cells, 90% lymphocytes) with elevated protein (1.30g/L), normal CSF:serum glucose ratio, negative CSF culture and viral PCR. She was treated for ICI-associated neurotoxicity and responded rapidly to high-dose steroids.

Conclusion

Physicians should be aware of the diverse presentations of n-irAEs, including unusual movement disorders. Close collaboration between neurologists and oncologists is imperative in the management of these patients.
017 Neurology virtual clinic: quality improvement project
Authors: Ashjaei Shayan , Varmpompiti Kyriakoula , Alexandratou Anna , Wu Kit , Stanton Biba , Theochari Evangelia , Weeks Robert
Published: August 2022

Background

Neurology patients with complex diagnoses in a busy tertiary centre can undergo multiple investigations to reach a diagnosis and are usually discharged with pending results, as tests can take a considerable amount of time to be processed (and released).

Aim

We set up a Virtual Clinic to follow-up patients’ results post discharge to avoid loss to follow up and improve safety of patient care.

Methods

We identified a significant proportion of neurology inpatients who were not followed-up efficiently (30.8% over 3-month-period) and addressed this issue by initiating a Virtual Clinic. The clinic was run weekly by neurology junior doctors, with protected clinic hours. The outcome of the clinic was communicated to the referring neurology consultant. We compared the follow up rates in the three months pre-clinic (October to December 2019) to the three months after setting up the clinic (January to March 2020).

Results

Using the PDSA methodology, we successfully managed to increase the follow-up for outstanding investigations to 68.8% from 30.8% (pre-clinic setup), via the implementation of the Neurology Virtual Clinic. We re-audited for another three-month period using the same methodology. For the period September to November 2020, this percentage increased further to 73.68%.

Conclusion

This new service was effective at improving test result monitoring and decreased the number of investigations that were not followed up promptly. Most importantly improved the safety of our patients’ care.
022 Preliminary results from a consultant-led acute neurology service based in the emergency department
Authors: Alim-Marvasti Ali , See Isaiah , Kandasamy Rohan , Hutchinson Joseph , Lane Charlie , Baruah Tim , Balaratnam Michelle , Chandratheva Arvind , Simister Robert , Haider Salman
Published: August 2022

Background and aim

5-10% of emergency department (ED) presentations are primarily neurological. We investigated the impact of the introduction of an acute neurology service to the ED, using the same day emergency care (SDEC) model.

Methods

We performed a retrospective review of consecutive referrals to a consultant-led service at University College London Hospital during weekday afternoons from 5th May 2021 to 20th Jan 2022.

Results

Of 664 Neurology referrals, female sex was more common than male (60% vs 35.8%, p<0.0001, Fig. 1).

Most referrals were from ED Majors (30%, Fig. 2). The most common presenting complaints were headache(n=187), weakness(n=34), dizziness(n=28), and numbness(n=26). Referrers’ working diagnoses included no diagnosis (n=69), unspecified headaches(n=62), migraines(n=42), and stroke(n=23) (Fig. 3). The most common diagnoses after Neurology review were migraines(n=160), vascular events(n=21), functional(n=16), and seizures(n=12) (Fig 4).

Following review, working diagnosis changed in 307(46.2%), and the following planned actions were cancelled: hospital admission in 204(30.7%); stroke referral in 190(28.6%); imaging in 45 and lumbar puncture in 33. 170(25%) cases were fully managed in SDEC which would otherwise have followed the urgent 2-week-wait pathway.

Conclusions

Acute Neurology input in the ED had major impacts on working diagnoses, hospital admis- sions, urgent outpatient referrals, and emergency investigations.
027 Patient reported experience of acute neurology telephone clinics during COVID-19 pandemic
Authors: Wu Kit , Alexandratou Anna , Beyrouti Rahma , Amarasena Pubudu , King Rachel , Weeks Rob
Published: August 2022

Background

The COVID-19 pandemic has changed delivery of care worldwide where face to face clinics had to adapt to telephone consultations. Management of neurological symptoms have traditionally relied on detailed physical assessments which poses challenges for remote consultations.

Aim

To evaluate patient-reported experience of acute neurology telephone clinics to better understand areas for improvement of this ongoing service.

Method

We formulated a voluntary, confidential, thirteen-question survey on patient experience. The questionnaire was devised based on the previously published King’s Patient Experience Measure in Neuro- oncology Questionnaire (Ashkan et al, 2021). Four domains were measured: clinic environment, patients’ questions/queries, follow-up and feedback.

Results

Our data showed that telephone clinics can achieve a high-degree of satisfaction, efficiency in communication and engagement (100%), addressing patients’ concerns (100%) with clear clinical outcomes (100%) and over 95% of patients feeling satisfied with the care they have received. Despite this, over 35% of patients would prefer a face to face consultation. Feedback suggested patients would be open to a blended model of face to face and telephone consultations.

Discussion

Incorporating telephone consultations as part of a new model of care can improve equity of access for patients, in line with the NHS Long Term Plan. It is an efficient way of bringing care closer to the patient, which would be well suited in the new Integrated Care System.
034 Revolutionary cancer treatment a pyrrhic victory?
Authors: Saeed Iman , Warner Graham
Published: August 2022

Innovative immunotherapy in the form of Immune Checkpoint Inhibitors (ICIs) has significantly improved outcomes for patients with numerous metastatic cancers. A double-edged sword, we are increasingly learning about the immune-related adverse events (irAEs) associated with use of these novel therapeu- tic agents.

Here we present the case of a 53 years old woman with background of malignant melanoma of the leg and metastatic lesions to the lung and brain. She commenced treatment with dual immunotherapy with Nivolumab/Ipilimumab with subsequent resolution of both metastatic lesions.

Two years following the completion of immunotherapy, she developed left sided arm and leg weakness, hemianopia, left sided Epilepsia Partialis Continua (EPC) and cognitive decline. MRI showed diffusion res- triction along the active cortex during the period of EPC that settled as AEDs suppressed clinical seizure activity. However, while there was no tumour recurrence with interval oncology MRI, there was progressive asymmetrical atrophy of the right cerebral hemisphere with associated white matter signal abnormality in keeping with Rasmussen’s encephalitis scan changes.

We propose that this represents a late delayed reaction to immunotherapy, beyond the recognised encephalitis that was the likely cause of EPC. Increasing use of ICIs will likely reveal more cases.
045 Survival in frontotemporal lobar degeneration: identifying blood, brain and behavioural predictors of survival
Authors: Stockton Katherine , Naessens Michelle , Murley Alexander , Coyle-Gilchrist Ian , Lansdall Claire , Rowe James
Published: August 2022

My ABN fellowship focusses on the syndromes caused by frontotemporal lobar degeneration. Despite distinctive pathological causes, these highly heterogeneous syndromes overlap in clinical manifesta- tions and pathophysiology. This is both a challenge and an opportunity for future trials aimed at slowing the diseases or treating their symptoms. By modelling phenotypic data and long-term outcomes, I will determine the features of blood, brain and behaviour that predict survival. The “PIck’s disease and Pro- gressive supranuclear palsy Prevalence and INcidence” study (PiPPIN), has 440 participants from previous recruitment phases, of whom 318 have died. I have recruited 91 from an expected 220-250 patients in this 3rd phase. My initial analysis of existing samples will test the hypothesis that metabolic signatures dif- ferentiate disorders (PSP, FTD, controls). Preliminary results from N=269 samples confirm multiple metabolic differences between patients and controls, focussing within the lipid pathways. This will be analysed in relation to clinical severity, phenotype, and survival outcomes. Subsequent analysis will integrate cognitive/behavioural profiles, magnetic resonance imaging and spectroscopy, and blood biomarkers (including metabolites) in multivariate models of survival. Prediction of survival does not indicate causation but will generate hypotheses of promising targets for intervention and tools for risk-based stratification.
046 Sporadic Creutzfeldt-Jakob disease in the young: a 10 year review of United Kingdom national surveillance
Authors: Tam Johnny , Centola John , Kurudzhu Hatice , Watson Neil , MacKenzie Janet , Leitch Margaret , Green Alison , Summers David , Barria Marcelo ,   et al
Published: August 2022

Introduction

Sporadic Creutzfeldt-Jakob Disease (sCJD) is the commonest human prion disease, with a median age of onset of 68 years. We aimed to characterise the clinical, investigation, and neuropatho- logical features in young individuals with sCJD using data derived from national CJD surveillance.

Methods

We interrogated the NCJDRSU database for individuals diagnosed with definite (post-mortem confirmed) or probable sCJD assessed from 2011-2021. We extracted data on clinical features, MRI, EEG, RT-QuIC, 14-3-3, and PRNP sequencing. Neuropathological findings were also studied where available. This data was compared in young individuals (≤50y) compared to all others.

Results

47 young individuals (4%) were identified (age at onset 25-50) from a total of 1178 cases. 14 (29.8%) were autopsy-confirmed. Psychiatric disturbance at presentation (36.2% vs 22%, p = 0.03) and longer disease duration (by 46 days, 95% CI 15-88, p < 0.01) were commoner in this group. CSF RT-QuIC showed lower sensitivity (81% vs 94%, p=0.01) in younger individuals. There was no difference in the sensi- tivity of MR brain, CSF 14-3-3, or EEG. There were no significant neuropathological differences in autopsy confirmed cases.

Conclusions

Younger individuals with sCJD are more likely to present with neuropsychiatric symptoms, longer disease duration, and lower sensitivity of RT-QuIC.
054 Baseline characteristics of the Phase III GRADUATE studies: investigating subcu- taneous gantenerumab in early AD
Authors: Lane Christopher , Bullain Szofia , Thanasopoulou Angeliki , Delmar Paul , Boada Mercè , Grim-Mer Timo , Kerwin Diana , Baudler-Klein Monika , Kerchner Geoffrey A , Doody Rachelle S
Published: August 2022

Gantenerumab is a fully human anti-amyloid beta (Aβ) monoclonal immunoglobulin G1 antibody in devel- opment for the treatment of Alzheimer’s disease (AD). Two ongoing multicentre, randomised, double-blind, placebo-controlled, Phase III studies, GRADUATE I (NCT03444870) and GRADUATE II (NCT03443973), are assessing the efficacy and safety of subcutaneous gantenerumab in early AD for 27 months.

Eligible participants had prodromal AD or probable AD dementia; demonstrated abnormal memory using the Free and Cued Selective Recall Test; met criteria for the Mini-Mental State Examination (≥22) and Clinical Dementia Rating – Global Score (0.5-1); and had confirmed Aβ pathology. Participants were randomised 1:1 to receive subcutaneous gantenerumab or placebo, administered at study site or via home nursing. The study drug is titrated in three up-titration steps (120 mg, 225 mg, 510 mg monthly) over 9-months to the target 1,020 mg monthly dosage. All participants receive the same titration and target dose, regardless of apolipoprotein E β4 status.

The GRADUATE primary endpoint is change from baseline to Week 116 in Clinical Dementia Rating scale – Sum of Boxes. Secondary efficacy measures, fluid and imaging biomarkers, and safety are also being assessed.

Recruitment is complete. Participants were enrolled from 32 countries across 5 continents. Detailed baseline characteristics will be presented.
Parametrized black holes: scattering investigation
Authors: Magalhães Renan B. , Leite Luiz C. S. , Crispino Luís C. B.
Published: August 2022

We study the scattering of light-like geodesics and massless scalar waves by a static Konoplya–Zhidenko black hole, considering the case that the parametrized black hole solution contains a single deformation parameter. By performing a geodesic analysis, we compute the classical differential scattering cross section and probe the influence of the deformation parameter on null trajectories. Moreover, we investigate the propagation of a massless scalar field in the vicinity of the static Konoplya–Zhidenko black hole and use the plane waves formalism to compute the differential scattering cross section. We confront our numerical results in the backward direction with the glory approximation, finding excellent agreement. We compare the results for the deformed black hole with the Schwarzschild case, finding that the additional parameter has an important role in the behavior of the scattering process for moderate-to-high scattering angles.