bluuebunny/crossref_metadata_2025 huggingface dataset:
140  How can we maximise discovery potential from sparse clinical information?
Authors: Lewis-Smith David , Galer Peter D , Ganesan Shiva , Ellis Colin A , Thomas Rhys H , Helbig Ingo
Published: May 2022

Collaborative studies exploit large data sets to discover new associations with diseases. However, analyses of clinical features struggle with big data. Beyond sheer volume, the challenge is in harmonisation of terminology and the level of detail of information provided for analysis by different sources; in epilepsy this is most pertinent to seizures.

We applied two ontologies (representations of the relationship between different types of seizure) to the same sparse details from 82 individuals. We compared the amount of information imputed using the Human Phenotype Ontology (HPO, a reference of clinical phenotypes widely used by geneticists) and an ontology of seizures created by the Epilepsiome Task Force of the International League Against Epilepsy Genetics Commission (based upon ILAE classifications).

We translated each individual’s seizure descriptions into 2 terms (median) from each ontology. Imputa- tion generated 2 additional terms per individual using the HPO and 4 using the Epilepsiome ontology. The Epilepsiome ontology was able to increase the amount of information available for analysis by two- thirds compared to the HPO.

Well-designed ontologies can be used to impute descriptions of complex clinical features at multiple less specific levels of precision, addressing a major limiting step in harmonisation of data for collabora- tion or re-use.

rhys.thomas@ncl.ac.uk
150  PROVE study 506: Perampanel as adjunctive therapy or monotherapy in real- world care of epilepsy patients
Authors: Kuzniecky Ruben , Wechsler Robert T , Patten Anna , Malhotra Manoj
Published: May 2022

Background

We report an analysis of PROVE Study 506 (NCT03208660) in epilepsy patients who received perampanel (adjunctive or monotherapy) during routine care.

Methods

Data were from patients initiating perampanel after 01-Jan-2014 (cut-off: 15-Mar-2019). Retention rate (primary endpoint; patients remaining on perampanel at 3/6/12/18/24 months following initiation [Safety Analysis Set (SAS)]), dosing and safety were assessed. Patients received adjunctive perampanel (with concomitant anti-seizure medications [ASMs]) or perampanel monotherapy (primary=without con- comitant ASMs; secondary=conversion to monotherapy).

Results

SAS included 1676 (98.4%) patients receiving adjunctive perampanel and 47 (2.8%) receiving monotherapy. Patients receiving adjunctive perampanel and perampanel monotherapy (primary, n=33/secondary, n=14) are in each relevant group. Most patients on adjunctive perampanel received 1–3 baseline ASMs (77.6%).

Overall, 816 (47.9%) patients discontinued (monotherapy, n=23 [48.9%]); most commonly due to adverse event (overall, 22.8%; monotherapy, 14.9%) and inadequate therapeutic effect (overall, 13.2%; mono- therapy, 25.5%).

Retention rates (24 months) were: 47.6% (adjunctive); 31.3% (primary monotherapy); 83.3% (secondary monotherapy). Mean (standard deviation) maximum perampanel doses (mg) were: adjunctive, 6.6 (3.2); monotherapy, 7.2 (2.7). Treatment-emergent adverse events occurred in 696 (adjunctive; 41.5%) and 17 (monotherapy; 36.2%) patients; dizziness was most common.

Conclusion

Retention on perampanel (adjunctive/monotherapy) was favourable for ≤2 years, with similar safety between groups.

Funding

Eisai Inc.

manoj_malhotra@eisai.com
155  Long-term efficacy of adjunctive cenobamate in patients with uncontrolled focal seizures
Authors: Steinhoff Bernhard , Brodie Martin , Sanchez-Alvarez Juan , Milanov Ivan , Finlan Lee , Brandt Christian
Published: May 2022

Purpose

The results of the double-blind (DB), placebo-controlled trial C017 demonstrated that ceno- bamate achieved highly significant rates of seizure freedom vs placebo in patients with uncontrolled FOS. Here we assess the long-term efficacy of cenobamate during the open-label extension (OLE) of the 017 study.

Methods

Subjects who completed the 12-weeks DB maintenance phase were eligible to continue in an optional OLE phase. The OLE started with a 2-week blinded conversion period, where all subjects converted to cenobamate at a target dose of 300mg. 360 patients completed the maintenance phase of the DB study, 98.3% (354/360) and entered the OLE study (OLE safety population, N=355; OLE ITT population, n=354). Of these 355 patients, 265 were originally randomized to Cenobamate (CNB/CNB) and 90 were originally randomized to PBO and transitioned to CNB (PBO/CNB).

Results

As of July 2019, 58.9% (209/355) of patients were continuing in the OLE, median exposure time 4.2 (0.01–5.7) years. Overall responder rate (≥ 50% seizure frequency reduction) was 63.8%. Yearly responder rates were 65.5% (232/354), 73.8% (206/279), 73.2% (175/239) 77.4% (171/221), 80.8% (168/208) for years

1 to 5 respectively. 25.5% (53/208) of evaluable patients were seizure free (100% reduction) during the 5th year of study.

Conclusions

Long-term adjunctive cenobamate in adults with FOS was effective and generally well tolerated (up to 5.7 years). Responder and seizure freedom rates were consistent with those shown during the double-blind studies.

lee.finlan@arvelletx.com
156  Long-term effects of perampanel on cognition, growth/development in paediatric patients with epilepsy study 311
Authors: Ben Renfroe J , Patten Anna , Malhotra Manoj , Ngo Leock Y
Published: May 2022

Background

The long-term (≤1-year) effects of adjunctive perampanel on cognition, behaviour and growth/development were assessed in paediatric patients aged 4–<12 years with partial-onset seizures (POS) (with/without secondarily generalised seizures [SGS]) or primary generalised tonic-clonic seizures (PGTCS) during Study 311 (NCT02849626).

Methods

Core Study (4-week pretreatment/23-week treatment) completers could enter the Extension (29-week maintenance/4-week follow-up). Assessments included: change from baseline at Week 52 for cognition (Aldenkamp-Baker Neuropsychological Assessment Schedule [ABNAS]), behavioural/emotional problems (Child Behaviour Checklist [CBCL]), visuomotor skills (Lafayette Grooved Pegboard Test [LGPT]) and growth/development.

Results

Mean standard deviation (SD) change from baseline to Week 52 in total ABNAS score was -3.3 (16.6) (n=112). Mean (SD) change from baseline at Week 52 in CBCL total problems was -6.0 (14.0) and

-1.6 (14.7) for patients aged 1.5–5 (n=17) and 6–18 years (n=102), respectively; for time to complete the LGPT, this was 5.3 (48.0) seconds for patients aged ≤8 years (n=33) and 0.4 (23.2) for patients aged >8 years (n=51). No significant impact on growth/development observed.

Conclusion

No clinically significant changes were observed in cognition, behaviour or growth/devel- opment parameters following long-term (≤1 year) adjunctive perampanel in paediatric patients (aged 4–<12 years) with POS, SGS or PGTCS. Funding: Eisai Inc.

manoj_malhotra@eisai.com
160  Long-term cognitive effects of perampanel in paediatric patients with epilepsy by responder status and dose
Authors: Gidal Barry , Meador Kimford J , Patten Anna , Malhotra Manoj , Ngo Leock Y
Published: May 2022

Background

The long-term (≤1-year) effects of adjunctive perampanel on cognition by responder status and modal dose were assessed in paediatric patients (aged 4–<12 years) with partial-onset seizures (with/without secondarily generalised seizures) or primary generalised tonic-clonic seizures during Study 311 (NCT02849626).

Methods

Core Study (4-week pretreatment/23-week treatment) completers could enter the Extension (29-week maintenance/4-week follow-up). The Aldenkamp-Baker Neuropsychological Assessment Schedule [ABNAS] was used to assess cognition (change from baseline, Weeks 23/52) by total seizure response category (<50%/≥50%/≥75%/100% responder) and modal dose (mg/day).

Results

Mean (standard deviation) change from baseline in total ABNAS for Weeks 23 and 52 by response category was: <50%, 3.7 (11.5) and -3.2 (16.8); ≥50%, -4.7 (13.8) and -3.7 (18.4); ≥75%, -2.1 (11.4) and -4.2

(14.8); 100%, -1.6 (18.3) and -0.6 (20.6), respectively; and by modal dose was: <4 mg/day, -5.8 (7.3) and

-2.0 (7.2); 4 mg/day, -4.8 (22.4) and -10.4 (25.6); >4–6 mg/day, 1.3 (8.3) and -1.3 (10.2); >6–8 mg/day, -0.5

(10.7) and 1.9 (9.4); >8–12 mg/day, -0.1 (12.8) and -7.4 (20.2); >12–16 mg/day, 2.2 (12.4) and 1.1 (14.8), respectively.

Conclusion

Adjunctive perampanel had few long-term effects on cognition in paediatric patients, regard- less of responder status and modal dose.

Funding

Eisai Inc.

11m2anoj_malhotra@eisai.com
163  Long-term safety of adjunctive cenobamate in patients with uncontrolled focal seizures
Authors: Morales Irene Garcia , Brodie Martin J , Milanov Ivan , Czlonkowska Anna , Brandt Christian , lan Lee Fin- , Alvarez-Baron Elena , Steinhoff Bernhard J
Published: May 2022

Purpose

Results from two double-blind, placebo-controlled studies demonstrated that adjunctive ceno- bamate significantly reduced the frequency of seizures vs placebo. Cenobamate 200mg/day achieved seizure freedom in 28.3% vs 8.8% placebo (P<0.0003; 013 study maintenance phase) and 21.1%, 11.2% for cenobamate 400mg/d and 200mg/d, respectively, vs 1% in placebo (P<0.002; 017 maintenance phase). Cenobamate also showed a favorable safety and tolerability profile. Here, we report the combined long-term safety and tolerability outcomes from the ongoing open-label extensions (OLEs) of C013 and C017.

Methods

Adults with uncontrolled FOS were enrolled in two double-blind, placebo-controlled studies. Patients completing both double-blinded phases were invited to participate in OLE studies (n=504).

Results

As of July 2019, 58.3% of the patients who entered the OLEs, continued; at baseline, median age was 38 years, and 86.5% were taking ≥2 concomitant AEDs. Median (range) length of exposure was 237 weeks (1–407). The most frequent TEAEs (≥10%) were dizziness (33.9%), somnolence (23.6%), headache (18.7%), fatigue (14.3%), diplopia (12.9%) and upper respiratory tract infections (12.3%). Most TEAEs were mild or moderate (78%). 22% experienced SAEs of which only seizure exceeded 1% (n=11). Discontinu- ations were due to TEAE (8%), withdrawal by patient (12%), lack of efficacy (12%), other (4%). No cases of DRESS were reported.

Conclusions

Long-term adjunctive cenobamate treatment (up to 94 months) is generally well tolerated. Most TEAEs were CNS-related and consistent with those shown in the two double-blind studies.

lee.finlan@arvelletx.com
164  Progressive multifocal leukoencephalopathy (PML) following autologous periph- eral blood stem cell transplantation for multiple myeloma
Authors: Fernandes Peter , Bennett Karina , Storrar Neill , Johnson Peter
Published: May 2022

A 67-year-old man presented with unilateral weakness and reduced dexterity four months after autolo- gous peripheral blood stem cell transplantation for multiple myeloma. The weakness progressed over the following months, with accompanying cognitive and sensory symptoms. Brain MRI showed numerous hyper- intense T2 lesions within the subcortical white matter of both cerebral hemispheres suggestive of demy- elination, progressing rapidly on interval imaging. His CSF tested positive for JC virus, diagnostic of PML.

This diagnosis was unexpected as the patient did not appear to be significantly immunocompromised and PML is extremely rare in patients with multiple myeloma. Treatment for progressive multifocal leukoen- cephalopathy is via restoring immune function; in our patient no reversible cause of immuno-suppression was present. At the time of our patient’s diagnosis no treatments had been shown to be effective against PML in clinical trials. However, in the last year both pembrolizumab and BK virus specific T-cell therapy have demonstrated efficacy against PML in published clinical trials, offering new hope for patients.

Clinicians should consider a diagnosis of PML when assessing patients with neurological symptoms and signs following treatment for multiple myeloma and in other haematological conditions, particularly as efficacious treatments can now be given if PML is diagnosed early.

peter.fernandes@ed.ac.uk
Multimodal MRI demonstrates task-related cortical hyper-activation and neuro- chemical alteration in amyotrophic lateral sclerosis
Authors: Edmond Evan C , Dharmadasa Thanuja , Clarke William , Talbot Kevin , Stagg Charlotte J , Turner Martin R
Published: May 2022

Background

There is a paucity of reliable markers of disease activity and progression in ALS. Better biomarkers would also reduce clinical trial duration and cost by providing more sensitive measures of target engagement. Cortical hyperexcitability with transcranial magnetic stimulation, while promising, has not yet been clinically translatable. Multimodal correlation of cortical hyperexcitability could yield more robust composite biomarkers.

Methods

This project applies multimodal non-invasive neuroimaging (MRI, MEG) and neurophysiol- ogy (TMS) to explore cortical hyperexcitability in ALS. 11 affected ALS patients, 9 age matched healthy controls and 13 asymptomatic relatives at-risk of inheriting the disease-causing C9orf72 hexanucleotide repeat expansion were studied. MRI findings are reported here (diffusion-tensor imaging [DTI], functional MRI and MR spectroscopy).

Results

Right cortical activation with contralateral finger movement was significantly increased in patients (p = 0.04), while right cortical de-activation with ipsilateral movement was lost (p = 0.01). N-acetyl-aspar- tate (p=0.04) and glutamate (p = 0.01) are significantly reduced in patients. At-risk relatives occupy an intermediate profile.

Discussion

Bilateral motor cortex hyperexcitability was found in ALS. Asymmetry in task-related activa- tion is consistent with previously reported loss of cortical inhibition in early ALS. Integration of multimodal imaging and neurophysiological data could explain variable phenotype and disease mechanisms in ALS.

eedmond@gmail.com
176  Clinical research participation in neurology
Authors: Jacob Carmen , Copson Ellen , Galea Ian
Published: May 2022

The benefits of clinical research for patients are well recognised. The Royal College of Physicians’ recent strategy document ‘Benefiting from the research effect’ highlights the role of NHS trusts in supporting research activity. Anecdotal evidence suggests that higher recruitment of patients to research studies in oncology compared to neurology is partly driven by a more pro-active approach by oncologists in dis- cussing clinical research participation with their patients. In an ongoing evaluation across NHS neurology and oncology services in a large teaching hospital, we are gathering views from clinical staff regarding their experience, attitudes, training, and barriers in recruiting patients to clinical studies, comparing the two specialities. To gather the patient perspective, hospital attenders from the neurology research setting (specifically the multiple sclerosis Phase III trial MS-STAT2), and from the multiple sclerosis clinical service in the same hospital are being surveyed. Preliminary results suggest that in 23/40 trial neurology patients (57.5%), there was at least one occasion where additional clinical care unrelated to the study was delivered as a result of engagement with research pathway. Comparing neurology to oncology, and neurology research with service settings, will deliver objective data to inform improvements in clinical research participation in neurology.

carmen.jacob@uhs.nhs.uk
189  Association of British Neurology trainees: biennial national census
Authors: Ahmad Hena , Zarkali Angeliki , Kemp Michael J , Banerjee Gargi , Rees Richard N , Shribman Samuel , Grote Helen , Ross Russell Amy L
Published: May 2022

Background

The Association of British Neurology Trainees (ABNT) conducts a biennial census of neurology trainees.

This acquires data on training, education, research, out of program experiences and trainees’ future plans, which are invaluable in shaping the future workforce. This is particularly important given the introduction and implementation of Shape of Training in 2022.

Aim

To review trainee perspectives on neurology specialist training in 2020.

Methods

Online questionnaire, designed by the ABNT committee, sent by email to all specialist neurology trainees and associate ABN members.

Results

Results will be reviewed and compared with previous data by members of the ABNT committee. We hope to present these results to an audience of aspiring neurologists, trainees and consultant neurologists.

Conclusion

The results of this census, in combination with those conducted in 2015 and 2017, will influence Shape of Training discussions and new curriculum design. We hope the information it provides will facili- tate communication and collaboration between the ABN, Specialty Advisory Committee, Joint Royal College of Physicians Training Board and other external bodies. This will inform future workforce planning and guide the transition through curriculum reforms.

hena.ahmad2@nhs.net
195  Delayed transfer of care (DToC) in neuroscience across South London: an insight through patient journeys
Authors: Wu Kit , Liu Yan , King Rachel , Ellis Cathy , Nirmalananthan Niran , Weeks Rob , Isaacs Jeremy , Dilley Michael
Published: May 2022

Introduction

Patients with complex neurological problems often require admission to a regional neuro- science centre to undergo further investigations and treatments not available in their local hospitals. A ‘delayed transfer of care’ (DToC) occurs when a patient is ready to be discharged but is still occupying a bed. Financially, this cost £104 million in London alone where 18% of all occupied beds are due to DToC [NHSE 2016].

Objectives

To investigate causes of DToC for Neuroscience patients between regional Neuroscience units [King’s College and St George’s Hospitals (KCH and SGH respectively)] and DGHs in the South London region.

Method

We reviewed notes of 28 neurological patients admitted to KCH from surrounding DGHs between March 2018 to June 2019. Key events of the repatriation process in relation to the patient’s hospital journey were analysed.

Results

Sixteen male and twelve female patients [mean age 58.5 years (29–89)] were admitted to KCH with a median length of stay of 21.5 days, of which 8.5 days were due to delays in the internal repatriation process and 3.5 days to time waiting for an available bed at their corresponding DGH.

Conclusion

In addition to traditional DToC data, we found further internal delays not previously captured. Cause analysis showed this to be a bidirectional problem. Collection of further datasets, facilitated by ODN, will help to determine variation in DToC for hospitals within a network and guide solutions.

kitwu@doctors.org.uk
202  Placebo-controlled intravenous nitroglycerin phenotyping of acute attacks of cluster headache
Authors: Wei Diana Y , Goadsby Peter J
Published: May 2022

Introduction

Cluster headache (CH) is characterised by attacks of excruciating unilateral headache, ipsilateral cranial autonomic symptoms (CAS) and/or agitation. Nitroglycerin (NTG) is known to induce CH. This study is the first single-blind placebo-controlled study using intravenous NTG in CH to characterise comprehensively NTG induced CH attacks.

Methods

CH patients attended three study visits in total, first visit CH patients were unblinded and received intravenous NTG 0.5mcg/kg/min over 20 minutes, if successful they were asked to return for blinded visits either receiving NTG or placebo. The clinical phenotype was recorded. The study was approved by the NHS Research Ethics Committee.

Results

Thirty-three patients participated, 24 completed all study visits. Nineteen episodic cluster headache (58%) and 14 chronic cluster headache (42%). NTG brought on CH attacks (n= 26, 79%), agitation (n= 24, 73%) and CAS (n= 31, 94%) in the unblinded NTG visit. NTG brought on CH attacks (n= 19, 76%), agitation (n= 20, 80%) and CAS (n= 21, 84%) in the blinded NTG visit. Only one participant had a spontaneous CH attack (4%) in the placebo visits, four participants reported unilateral CAS symptoms, and none had agitation.

Conclusion

We demonstrate that intravenous NTG effectively triggers CH attacks.

diana.wei@kcl.ac.uk
204  Idiopathic intracranial hypertension in Wales: population characterisation, epidemiological trends and healthcare utilisation
Authors: Miah Latif , Strafford Huw , Fonferko-Shadrach Beata , Hollinghurst Joe , Rees Mark I , Sawhney Inder , Hadjikoutis Savvas , Powell Rob , Lacey Arron , Owen Pickrell W
Published: May 2022

Objective

To characterise the Welsh idiopathic intracranial hypertension (IIH) population, epidemiologi- cal trends and healthcare outcomes using routinely collected healthcare data.

Methods

We used primary and secondary care healthcare diagnostic codes within the Secure Anonymised Information Linkage databank to ascertain IIH cases and controls in a retrospective cohort study between 2003–2017. We validated IIH diagnosis codes using anonymised secondary care lists of IIH cases.

Results

We analysed 35 million patient years of data (2003–2017). There were 1765 cases of IIH in 2017 (85% female). The prevalence and incidence of IIH in 2017 was 76/100,000 and 7.8/100,000, significantly increased from 2003 (prevalence=12/100,000, incidence=2.3/100,000). IIH prevalence is associated with socio-economic deprivation and increasing body mass index (BMI). 9% of people with IIH had CSF shunts with less than 0.2% having bariatric surgery. Unscheduled hospital admissions were significantly higher in the IIH cohort compared to controls; and also in IIH patients with CSF shunts compared to those without.

Conclusions

IIH incidence and prevalence is increasing significantly, corresponding to population increases in BMI. This has important implications for healthcare professionals and policy makers given the comor- bidities, complications and increased healthcare utilisation and economic burden associated with IIH.

lotif_miah@hotmail.com
208  Long-term efficacy of erenumab in patients with chronic migraine who failed ≥3 prior prophylactic treatments
Authors: Weatherall Mark , Gantenbein Andreas , Ritter Shannon , Snellman Josefin , Klatt Jan Klatt , Mikol Daniel
Published: May 2022

Objective

Erenumab is a fully human monoclonal antibody. Following a 12-wk double-blind (DB), placebo- controlled chronic migraine (CM) study, a 52-wk open-label extension (OLE) study assessed long-term efficacy and safety of erenumab. We report the long-term efficacy of erenumab in a subgroup of patients in the OLE who failed ≥3 prior prophylactic treatments due to lack of efficacy and/or poor tolerability before enrolment in the parent study.

Methods

During the 52-wk OLE patients received erenumab every 4wks. Following a protocol amendment, patients who had not reached wk28, had a dose increase to 140mg to allow them to receive the higher dose for ≥6 months; patients completing wk28 visit remained on 70mg throughout OLE. OLE treatment phase data were summarised by visit for all pts (combined treatment groups).

Results

Of 605 pts enrolled in the OLE, 226 had ≥3 prior prophylactic TFs. Mean(SD) MMD at baseline for the TF subgroup was 18.95(4.2);overall,18.11(4.5). At wk52, erenumab treatment resulted in a sustained reduction in MMD from baseline(TF,−7.94[6.5];overall,−9.29[6.6]) and 47% of pts in the ≥3 TF subgroup achieved ≥50% response.

Conclusion

Erenumab treatment resulted in sustained efficacy in pts with ≥3 TF, a difficult-to-treat popula- tion, with greater efficacy for 140mg vs 70mg.

13m6ark.weatherall1@nhs.net
209  Increased burden of headache in patients with migraine complicated by MOH: sub-group analysis BECOME study
Authors: Panesar Pritpal , Watson David , Pozo-Rosich Patricia , Lucas Christian , Gaul Charly , Ramsden Emma , Ritter Shannon , Martelletti Paolo , Snellman Josefin
Published: May 2022

Objective

To evaluate the burden of headache in patients with chronic migraine complicated by medi- cation overuse headache (CM+MO) using patient-reported outcomes (PRO) and healthcare resource utilisation (HRU) questionnaires.

Methods

BECOME was a prospective, non-interventional study conducted in 2 concurrent parts over 3 months across Europe and Israel. Part 1 assessed clinical characteristics of all patients with migraine visiting headache specialist centres over 3 months. Part 2 examined burden of disease in patients with

≥1 prior prophylactic treatment failure (PPTF), ≥4 monthly migraine days (MMD). We assessed quality of life (QoL) in patients in Part 2 using PRO questionnaires.

Results

Of the 2419 patients (86.9% females; mean[SD] age 43.0[11.56] years) analysed in Part 2, 571 (23.6%) reported CM+MO. Patients with CM+MO reported lower functioning (mean[SD] EQ-5D utility scores 0.67[0.24] vs 0.78[0.21]), lower health status (EQ VAS scores 59.3[20.94] vs 69.8[19.48]), higher dis- ability (mMIDAS score 35.5[21.98] vs 21.9[17.39]) and greater proportion had grade IV disability (88.1% vs 80.1%) than those without MO.

Conclusions

Patients with ≥1 PPTF reported severe burden of migraine irrespective of MO, but patients with MO had lower functioning and health status, greater severity in disability, and greater use of HRU than those without MO.

pritpal.panesar@novartis.com
212  Preventing blindness for patients with optic disc swelling: improving care using transformative new technology
Authors: Braithwaite Tasanee , Wu Kit , Saunders Katherine , Teo James , Yorke Richard , Moosai Shivir , Brex Peter , O’Sullivan Eoin
Published: May 2022

Introduction

Optic disc swelling (ODS) is a non-specific sign with clinical consequences ranging from benign to irreversible blindness. It is often a challenge to manage: patients present to different specialities and there is no unifying clinical pathway.

Objectives/Aims

1. to identify all patients presenting to King’s College Hospital with ODS using a translational informatics digital platform (Cogstack); 2. to develop an electronic care pathway with an integrated decision support tool.

Method

We used a digital translational informatics platform called Cogstack, developed in-house by King’s College London, to search 1.4billion EPR data files during a 12-week period. We engaged an MDT team to developed a clinical decision support tool, containing ‘red flag’ symptoms and signs for patients presenting with ODS.

Results

Cogstack identified 407 patients with ODS in a 12-week period. Of these, 15% were new cases, 24% were not seen or referred to (neuro)/ophthalmology.

The care pathway ensured that patients received timely investigation and initial management facilitated by transformative new technology. This translated into saving time, standardising care and enhanced patient safety.

Conclusion

This technology-facilitated care pathway provides a proof of concept for other institutions. Its development supports the topical agenda of NHS improvement, to ‘Get it Right First Time’, and the aim to deliver a value-based healthcare.

kitwu@doctors.org.uk
214  DCE-MRI in neurological disease: how to do it
Authors: Varatharaj Aravinthan , Darekar Angela , Cramer Stig P , Larsson Henrik BW , Galea Ian
Published: May 2022

MRI with gadolinium-based contrast agent is widely used in clinical practice and is a key tool for the diagnosis and monitoring of diseases such as multiple sclerosis. Dynamic contrast-enhanced MRI (DCE-MRI) is an advanced technique which maps the time course of T1 signal enhancement. Quantitative informa- tion regarding tissue properties can be extracted, providing additional utility compared to conventional contrast MRI. No further contrast injection is required, and the impact on total scan time can be minimal. Maps of blood-brain barrier permeability can be produced, with an ability to detect leakage well below the threshold of conventional MRI. This practical poster outlines a step-by-step protocol for setting up brain DCE-MRI, analysing the data with minimal user input, and incorporating it into research and future clinical practice. Common pitfalls and their solutions are addressed. The information is not vendor-specific so can easily be applied to any MR hardware.

a.varatharaj@soton.ac.uk
215  Interstitial fluid drainage along cranial nerves in humans
Authors: Varatharaj Aravinthan , Gawne-Cain Mary , Galea Ian
Published: May 2022

Brain interstitial fluid (ISF) drainage plays an important role in neurological disease. A complete picture of ISF drainage pathways is still being pieced together. Most current data are from animals not humans. ISF may enter the cerebrospinal fluid (CSF), which then leaves via arachnoid granulations, dural lymphatics, the cribriform plate, and cranial and spinal nerve root sleeves. CSF-independent routes of ISF drainage are less clear, and include the peri-arterial pathway, a controversial peri-venous route, and possibly brain- to-blood efflux across capillary endothelium. We present an exploratory study of the cranial nerve ISF outflow in humans, using high-resolution magnetic resonance imaging pre- and post- administration of gadolinium-based contrast agent, in a healthy volunteer and in a person with a large enhancing multiple sclerosis (MS) brainstem lesion. We reasoned that the high contrast concentration in the restricted interstitial space of the lesioned brainstem would highlight drainage pathways. While cranial nerve enhancement was present in both cases, it was most marked in the MS case. Through analysis of the spatial and temporal kinetics of enhancement we explore ISF drainage along cranial nerves and its dependence on transfer to CSF. These findings have implications for our understanding of brain ISF movement in health and disease.

a.varatharaj@soton.ac.uk
221  Adhesive spinal arachnoiditis following subarachnoid haemorrhage mimicking a multiple sclerosis relapse
Authors: Farag Mena , Younus Osman , Hampton Timothy , Walsh Daniel , Silber Eli
Published: May 2022

We present a case of adhesive spinal arachnoiditis, as a complication of a fall with traumatic subarach- noid haemorrhage, in a patient with progressive multiple sclerosis (MS).

A 68 year-old woman with MS and spasticity, on Baclofen, Pregabalin and Nabiximols, was admitted following a fall. CT scanning demonstrated traumatic subarachnoid haemorrhage. She was admitted to the ITU initially and managed conservatively. Four months later, while undergoing inpatient rehabilitation, her condition deteriorated over six weeks with worsening paraparesis, neurogenic bladder and bowel dys- function with a C5–6 sensory level. She received steroids and underwent MRI of her neuroaxis. Imaging of her brain showed unchanged demyelinating lesions. Spinal imaging identified distortion with considerable T2 signal change in the cervical and thoracic regions, extending from the C5/6 to the T8/9 level, radiologi- cally consistent with a syrinx and myelopathy. It was felt her deterioration was not due to demyelination but secondary to cervicothoracic adhesions ventral to the cord as sequelae of cerebral haemorrhage. Following neurosurgical review, the patient underwent C4-T1 laminoplasty, adhesionolysis and expansion duraplasty with histopathology showing calcified connective tissue but the clinical outcome has thus far been poor. It is important to consider all the causes of deterioration in patients with progressive MS.

menafarag@doctors.org.uk
Epilepsy-related causes of mortality in people with epilepsy: a systematic review of systematic reviews
Authors: Mbizvo Gashirai K , Bennett Kyle , Simpson Colin R , Duncan Susan E , Chin Richard FM
Published: May 2022

Purpose

This systematic review of epilepsy mortality systematic reviews evaluates comparative risks, causes, and risk factors for all-cause mortality in people with epilepsy (PWE) to specifically establish the burden of epilepsy-related deaths.

Method

MEDLINE and Embase were searched from conception to 26/12/2018 for systematic reviews evaluating all-cause mortality in PWE of any age. Two authors performed independent study selection, data extraction and quality assessment. Deaths were separated into epilepsy-related and unrelated using a recently published classification system. Outcomes included standardised mortality ratio (SMR) and mortality rate (MR) in a primary analysis of comparative risks, causes, and risk factors for all-cause and epilepsy-related mortality. A narrative synthesis of review findings was used to present results.

Results

Six moderate- or high-quality systematic reviews were included, evaluating 103 observational studies. All-cause mortality remained similarly high between 1950 and present (median SMR range 2.2–3.4). Africa had the highest SMR (median 5.4, range 2.6–7.2). SMRs were also higher for children < 18 years (median 7.5, range 3.1–22.4) than adults (median 2.6, range 1.3–8.7), and for epilepsy-related (median 3.8, range 0.0–82.4) than unrelated causes (median 1.7, range 0.7–17.6). Structural brain disease conferred the greatest risk for all-cause mortality (SMR range 24.0–41.5). Common epilepsy-related death causes included SUDEP, alcohol, drowning, pneumonia, and suicide.

Conclusion

Premature all-cause mortality remains a major problem in PWE globally, particularly in children and young adults, with most being epilepsy-related and potentially preventable.

mbizvogkm@gmail.com
231  A Phase2 study evaluating safety and efficacy of prasinezumab in early Parkinson’s disease (PASADENA)
Authors: Pagno A , Anzures-Cabrera J , I Taylor K , Nikolcheva T , Zago W , Svoboda H , Doody R , Fontoura P , Umbricht D , Bonni A
Published: May 2022

Aims

To describe the design and baseline data of the PASADENA study

Methods

Prasinezumab is a humanized IgG1 monoclonal antibody, which selectively binds aggregated α-synuclein, potentially reducing neuronal toxicity and slowing disease progression. This Phase 2 multicentre, randomised, double-blind, placebo-controlled study evaluated safety and efficacy of 4 weekly intravenous prasinezumab, at high dose (4500 mg/3500 mg body weight ≥65 kg/<65 kg) or low dose (1500 mg), versus placebo in patients with early Parkinson’s disease (NCT03100149). The study has two parts: a 52-week, double-blind, placebo-controlled treatment period (Part 1) followed by all-participants-on-active-treat- ment blinded extension for 52 weeks (Part 2). Primary endpoint is change in MDS-UPDRS total score from baseline at 52-weeks. Secondary endpoints include time to disease progression/disability and ipsilateral putamen DaT-SPECT uptakes. Skin biopsies determine the presence of pathological alpha-synuclein.

Results

316 patients enrolled in Austria, France, Germany, Spain and US (June 2017 - November 2018). Participant baseline data, including demographic characteristics, motor and non-motor symptoms, imaging and non-imaging biomarkers will be presented.

Conclusions

PASADENA will provide an initial evaluation of prasinezumab’s effects on clinical progres- sion and loss of dopaminergic terminals in patients with early Parkinson’s disease, to inform future patient selection and Phase 3 study design. This study was funded by F. Hoffmann-La Roche Ltd. These data will be presented at Advances in Alzheimer’s and Parkinson’s Therapies gennaro.pagano@roche.com
241  Intrathecal antisense oligonucleotide delivery in HD: experience from RG6042 programme and best practice considerations
Authors: Leavitt Blair , Wild Edward , Bang Jee , Smith Anne , Schlegel Valerie , Schobel Scott , Nicotra Alessia , Landwehrmeyer Bernhard , Tabrizi Sarah ,   Mark Guttman on behalf of the OLE Investigator Network
Published: May 2022

Intrathecal administration involves the introduction of a drug substance into the subarachnoid space of the spinal column through a needle inserted into the lower back via lumbar puncture (LP) or via a special device. This procedure is used when drugs cannot cross the blood-brain barrier. Once injected, drugs are distributed within the cerebrospinal fluid from which they can access target tissues in spinal cord and brain.

We use the intrathecal route to deliver RG6042 (previously HTTRx), an investigational, huntingtin mRNA- targeting antisense oligonucleotide to patients with Huntington’s disease (HD). Experience on intrathe- cal administration via LP has been gained in the RG6042 clinical development programme, including the double-blind, placebo-controlled, multiple ascending dose, Phase I/IIa study (NCT02519036) in 46 patients with early manifest HD and an open-label extension (NCT03342053) where patients received 120 mg RG6042 monthly or every other month in a 62-week treatment period (total procedures ≥400 in the programme to date).

We will report on the experience with intrathecal drug delivery across these two studies and present information on suggested best practices in HD. Procedure-related videos will be shared, including use of spinal ultrasound. Finally, we will describe real-world considerations of implementing intrathecally delivered therapies in the clinical interface.

alessia.nicotra@roche.com
242  A systematic review on the benefit of multidisciplinary care for patients with atypical parkinsonian syndromes
Authors: Niaz Usman , Ghosh Boyd , Donnelly Jade
Published: May 2022

Background

Atypical Parkinsonian Syndromes (APS) are a rare group of neurodegenerative diseases comprising of Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA) and Corticobasal Syndrome (CBS). There are current guidelines recommending Multidisciplinary team care in APS, but there have been no systematic reviews investigating this.

Methods

Systematic searches of Medline, EMBASE, CINAHL and Open Grey were conducted and litera- ture which met the inclusion criteria were further screened.

Results

887 results were found across the 4 databases of which 192 remained after title screening and 70 after abstract screening. Of these 70 papers, 9 were included in the final review; data was synthesised from them along with the case studies and conference abstracts. The MDT papers demonstrated benefits of a multifaceted approach in the patients’ physical symptoms, along with an improved quality of life and reduced caregiver burden. However, the papers generally lacked methodological rigour, with a common deficiency being the absence of a control group and small sample sizes.

Conclusion

MDT care and its various facets seem to have benefits for patients suffering from APS, however the lack of statistical power in the current literature makes this conclusion difficult to draw. Further research of higher quality is recommended.

un1g16@soton.ac.uk
247  Unusual presentation to an emergency department
Authors: Yoganathan Katie , Shah Apeksha , Marta Monica
Published: May 2022

24-year-old man presented with drowsiness, worsening cognitive impairment and a mixed movement disorder. He was adopted as a child and was reported to be independent and working one year before admission, but progressively slow and unable to self-care since. On examination, he was cognitively impaired on all domains. He had increased tone, brisk reflexes and extensor plantars. There were dysto- nia-parkinsonian features of dystonic tremor and bradykinesia, slow saccades and oculomotor apraxia, along with motor impersistence. After exclusion of chronic infections, the working diagnosis was of a neurodegenerative movement disorder. Whilst there was no overt chorea, the differentials for juvenile Huntingdon’s disease (HD) were explored, and HD ultimately confirmed on genetic testing.

Learning Points

Juvenile HD patients may not have chorea but may be rigid or parkinsonian.

Slow saccades are most prominent in juvenile HD patients, even early.

Involuntary movements are often partially suppressible, and mild chorea is easily overlooked. Look for involuntary head turns, fidgety movements of the fingers and toes, frequent blinking and odd facial expressions.

Test for motor impersistence in these individuals.

Gait may appear normal but tandem walk may bring out chorea, imbalance, or other problems.

katieyoganathan@gmail.com
248  Tremor frequency can be measured using smartphone video
Authors: Williams Stefan , Fang Hui , Wong David C , Relton Samuel D , Alam Taimour , Alty Jane E
Published: May 2022

Textbook descriptions of tremulous disorders typically mention the tremor frequencies characteristic of particular conditions, and determination of frequency can aid diagnosis. However, current clinical practice does not involve routine accelerometry or EMG for most tremulous patients, or use of smartphone accel- erometer, and the human eye cannot accurately measure tremor frequency.

37 hand videos were recorded with smartphone camera from 5 essential tremor participants, 10 Parkin- son’s participants and 1 functional tremor participant, either showing a hand resting or held in posture. Tremor was simiultaneously measured using a commercially available accelerometer for clinical use (‘Natus Neurology’). The computing technique of ‘optical flow’ was applied to the smartphone video to measure pixel movement over time in two directions perpendicular to the long axis of the hand. Dominant frequencies were extracted from smartphone video optical flow and from clinic accelerometer data using fast Fourier transform.

Bland-Altman analysis showed a mean of the difference in measurements between smartphone video (pixel optical flow) and accelerometer of 0.05 Hz (SD 0.16 Hz) with 95% confidence intervals for this mean difference of -0.26 Hz to +0.36 Hz.

We demonstrate excellent agreement between our computing method for smartphone video tremor measurement and the gold standard of accelerometry. Our computing technique suggests that neu- rologists already have ‘point and press’ contactless equipment in their pocket that has the potential to augment routine clinical assessment by measuring tremor frequency.

stefanwilliams@doctors.org.uk
249  Slow motion analysis of repetitive tapping (SMART) test: a new measurement of bradykinesia
Authors: Simonet Cristina , Lambert Christian , Rees Richard , Galmes Miquel Angel , Schrag Anette , Noyce Alastair
Published: May 2022

Objectives

To develop a quantitative and objective tool to track repetitive tapping movements (RTM) using a slow motion capture and and compare patients with Parkinson’s disease (PD), REM-sleep behaviour disorder (RBD) and healthy controls (HC).

Methods

We assessed 48 participants (PD=20, RBD=5, HC=23). For each participant, RTM was recorded during 20s by a smartphone at 240 frames/s and then analysed using novel Python scripts. Two kinetic parameters were extracted: amplitude between fingers and frequency (number of taps/s). Linear regres- sion was used to determine the trend of movement over time.

Results

Although HC and RBD group (64.8±8.7yo and 68.4±8.2yo respectively) were older than PD group (58.1±12.8yo), the PD group performed the task significantly slower (p=0.0003) and with greater, but not significant, amplitude decrement than HC (p=0.5). RBD group was similar to PD group with significant slower RTM (p<0.0001) and non-significant amplitude decrement (p=0.3). SMART test was able to differentiate between all three groups, with a positive goodness of fit between PD and HC. The frequency parameter displayed 92.8% and 100% of sensibility (for 60.8% and 13% specificity with respective AUC=0.84 and 0.92) when comparing PD vs HC and RBD vs HC respectively.

Conclusions

We present an accurate way to quantify motor dysfunction in PD. Despite the small number of subjects, the fact that RBD group presented objective motor impairment could help with the early diagnosis at the prodromal phase of PD.

15c6.simonet@qmul.ac.uk
256  FIREFISH part 2: risdiplam efficacy and safety in type 1 SMA
Authors: Baranello Giovanni , Servais Laurent , Masson Riccardo , Mazurkiewicz-Bełdzińska Maria , Khairi Muna El- , Fuerst-Recktenwald Sabine , Gerber Marianne , Gorni Ksenija , Darras Basil T ,   on behalf of the FIREFISH Study Group
Published: May 2022

FIREFISH (NCT02913482) is an ongoing, multicentre, open-label study of risdiplam in infants aged 1–7 months with Type 1 spinal muscular atrophy (SMA) and two SMN2 gene copies. FIREFISH aims to determine the efficacy and safety of risdiplam, an orally administered, centrally and peripherally distributed SMN2 pre-mRNA splicing modifier.

FIREFISH Part 1 (n=21) assesses the safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels. In FIREFISH Part 1 there have been no drug-related safety findings leading to withdrawal from the study following ≤30 (median 19) months of treatment (data-cut: 2nd July 2019). The confirmatory Part 2 (n=41) investigates the efficacy of risdiplam at the dose selected in Part 1. The primary efficacy endpoint is the proportion of infants sitting without support after 12 months on treatment, as assessed by Item 22 of the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development, third edition.

Here we report efficacy and safety data from the confirmatory Part 2 of the FIREFISH study in participants who have received treatment with risdiplam for a minimum of 12 months. FIREFISH Part 2 will provide important data on the efficacy and safety of risdiplam in infants with Type 1 SMA.

g.baranello@ucl.ac.uk
262  Limb-shaking linked to haemodynamic cerebrovascular disease
Authors: Cleaver Jonathan , Pope Laura , Mayo Thomas , Gbadamoshi Lukuman
Published: May 2022

Limb-shaking transient ischaemic attacks (TIAs) are under-recognised in neurology and typically consists of involuntary movements resembling focal seizure-like activity. This form of TIA suggests severe carotid occlusive disease and is a warning for future strokes. Awareness can help avoid unnecessary medication, lifestyle measures and driving implications.

We present a case of a 61-year-old patient who developed transient but persistent right upper limb shaking and syncope on turning to the left. He suffered a recent NSTEMI causing severe left ventricular dysfunction and associated anaemia. His ictal EEG was unremarkable. CT angiography and doppler ultrasound revealed severe left internal carotid artery stenosis. This suggested an underlying low-flow TIA and symptoms resolved with blood pressure optimisation and blood transfusions.

Cerebrovascular events typically present with acute negative symptoms including loss of power, sensation, vision or speech. Alternatively, focal movement abnormalities would generally make the physician think of a non-cerebrovascular disorder. This stresses the need to raise awareness of limb-shaking TIAs to expedite diagnosis and instigate management strategies to lower future stroke risk.

Along with secondary stroke prevention, attacks can be abolished by improving blood supply through optimisation of blood pressure, cardiac function and treating anaemia. Failing this, surgical revasculari- sation procedures should be considered.

jkcleaver88@gmail.com