bluuebunny/crossref_metadata_2025 huggingface dataset:
210  Erenumab for the treatment of chronic migraine with idiopathic intracranial hypertension in ocular remission
Authors: Yiangou Andreas , Mitchell James , Vijay Vivek , Thomas Pravin , Fisher Claire , Edwards Julie , Alimajstorovic Zerin , Grech Olivia , Mollan Susan P , Sinclair Alexandra J
Published: May 2022

Headache therapy is an unmet need in idiopathic intracranial hypertension (IIH).

This was a prospective, real world, open-label cohort study over 9 months in the UK. Adult females with confirmed diagnosis of IIH now in ocular remission with chronic migraine (CM)-like headaches and failure of ≥3 preventative medications received Erenumab 70mg monthly. Clinical assessment was 3-monthly and primary endpoint was mean change in monthly migraine days (MMD) from baseline (30-day pre- treatment period) compared to 6 months.

Study included 55 patients with mean(SD) age 35.3(9) years. Mean(SD) baseline monthly migraine days (MMD) was 16.1(4.7) and monthly headache days (MHD) was 29(2.3). MMD reduced significantly at 6 months by 10.3(4.8) (P<.001) and MHD reduced by 10.6 (8.7) (P<.001). Crystal clear days increased by 10.5(9) (P<.001) and monthly analgesic days reduced by 3.9(8.3) (P=.001). Significant improvements were also noted in patient reported outcomes. Results were consistent at 3 and 9 months.

This prospective real world open-label study provides evidence for the efficacy of Erenumab for the treatment of headache in this population. It provides important mechanistic insights suggesting that CGRP is likely a key modulator driving headache in patients with IIH in ocular remission and worthy of evaluation in a future randomised trial.

a.yiangou@bham.ac.uk

137
213  Improving the investigation and management of papilloedema in an acute medical setting
Authors: Hornby Catherine , Auger Stephen , Jacobs Ben , Turner Ben
Published: May 2022

Aim

To streamline and improve the investigation of patients with papilloedema presenting to the acute medical take in a large teaching hospital.

Methods

Patients seen on the acute medical take at the Royal London Hospital with suspected papil- loedema were identified retrospectively. A total of 19 patients were seen between April and November 2019. A number of modifiable delays to initial investigations and areas for improvement were identified from these data. A simple flowchart explaining key points in investigation and initial management of patients with papilloedema was devised and distributed to those involved in the acute take.

Results

The identified areas for improvement included delays to lumbar puncture, failure to discuss management with neurologists after identification of raised intracranial pressure, and ensuring initial management was started in those with suspected idiopathic intracranial hypertension. There were also a number of instances in which papilloedema was not confirmed by an ophthalmologist prior to inap- propriate invasive investigations. Education and provision of better information to acute medics improved many of these outcomes.

Conclusion

A clear and easy to use flowchart for those involved in the acute take minimised errors identified and improved the initial investigation and management of papilloedema presenting to the acute medical take.

catherine.hornby2@nhs.net
216  Lesion distribution and substrate in type 1 myotonic dystrophy: comparison with multiple sclerosis
Authors: Leddy Sara , Serra Laura , Esposito Davide , Vizzotto Camilla , Silvestri Gabriella , Petrucci Antonio , Meola Giovanni , Cercignani Mara , Bozzali Marco
Published: May 2022

Introduction

This study compares the white matter lesion distribution and substrate between patients with type one myotonic dystrophy (DM1) and patients with Multiple Sclerosis (MS).

Methods

Twenty-eight patients with DM1, 29 patients with relapsing remitting MS, and 15 healthy controls had an MRI scan, including FLAIR, quantitative magnetization transfer (qMT) imaging. qMT data were processed to compute the pool size ratio (F), correlating with myelin content. The average F was computed within lesions and normal appearing white matter (NAWM) for every participant. Lesion masks were warped into MNI space and lesion probability maps were obtained for each patient group.

Results

Mean lesion volume was higher in MS than DM1. DM1 presented higher prevalence of anterior temporal lobe lesions, but none in the cerebellum and brainstem. In both patient groups the mean F of lesions was lower than the NAWM (p<0.01, CI 0.06–0.07), but it was lower in MS than DM1 (p<0.01, CI 0.01–0.04).

Conclusions

DM1 show a greater lesion distribution in the temporal lobe regions compared to MS. Using qMT, we demonstrated reduced F values within DM1 lesions, suggesting a loss of myelin density. The mean F is lower in MS lesions than DM1 lesions, indicating a lesser degree of demyelination in the former.

sara.leddy1@nhs.net
219  MRI monitoring in MS patients prescribed disease monitoring treatments in Kings College Hospital
Authors: Raftopoulos Rhian , Teo James , Jarosz Jozef , Brex Peter
Published: May 2022

To date the MRI monitoring of MS patients on disease modifying treatments at KCH has gone unquanti- fied. This audit aimed to quantify and evaluate our current use of MRI in monitoring treatment response and safety in patients prescribed disease modifying treatments(DMTS)

A list of patients prescribed DMTs between April 2016 and July 2019 was obtained via the Blueteq system. We used Cogstack to extract all MRI scan reports available for these patients (excluding pre-treatment scans). Every scan report was reviewed manually and the presence of new or enlarging T2 lesions and contrast enhancing lesions were documented for each of the different disease modifying treatments.

2072 scan reports were reviewed for 1250 patients prescribed DMTs. The largest number of monitoring scans were performed on patients prescribed Natalizumab (average 5.2 per scan per patient, compared to 1.04 scans per patient for alemtuzimab, 1.63 per patient for fingolimod). Patients prescribed higher efficacy drugs had the greatest proportion of stable MRI scans (93% + 85% of natalizumab and alem- tuzimab monitoring scans versus 66 and 70% of glatiramer acetate and B interferon monitoring scans, respectively). 3 of 2072 scans demonstrated imaging findings suspicious for PML (all patients prescribed natalizumab), 1 case was subsequently confirmed.

r.raftopoulos@ucl.ac.uk
222  DECISIve – DiagnosE using the Central veIn SIgn. A study comparing T2* MRI and lumbar puncture
Authors: Allen Christopher Martin , Morgan Paul , Craner Matthew , Tallantyre Emma , Schmierer Klaus , Dineen Robert , Fitzsimmons Deborah , DasNair Roshan , Partlett Christopher , Evangelou Nikos
Published: May 2022

Can a brain T2* MRI scan replace lumbar puncture in the diagnostic pathway of MS? We will present the preliminary data from DECISIve, a National Institute for Health Research – Research for Patient Benefit funded multicentre study. Clinical Trials reference:NCT04024969

Due to the revised 2017 McDonald diagnostic criteria, many more people are undergoing lumbar punctures, resulting in discomfort and additional costs to the NHS. Brain lesions with a central vein, detected with T2* MRI are thought to be characteristic of MS. Using a single group superiority diagnostic accuracy study, our primary research question is: Is T2* MRI a more sensitive diagnostic test than lumbar puncture with oligoclonal band examination, amongst people at first clinical presentation with possible MS?

Recruitment is now open across four neuroscience centres for a year and clinical follow up will last 18 months to establish the diagnosis. We will compare the accuracy, speed, costs and acceptability of the different tests needed to make a diagnosis of MS and establish if most lumbar punctures can be replaced by a slightly longer MRI scan.

christopher.allen@nottingham.ac.uk
223  Functional neurological symptom disorder & autistic spectrum disorders: a litera- ture review of co-incidence and shared mechanisms
Authors: Roelofs Jacob , Petrochilos Panayiota , Selai Caroline
Published: May 2022

Functional Neurological Symptom Disorder (FNSD) and Autistic Spectrum Disorders (ASD) are both complex and incompletely understood conditions. This review investigates the literature for evidence of associa- tion between them.

A literature search produced nineResultsthree case reports and six epidemiological studies. The case reports describe the conditions co-occurring, providing anecdotal evidence of an association. Nimmo- Smith and Lever reported 2.5-fold and three-fold higher prevalence of ‘somatoform disorders’ in ASD samples compared to the general population (Lever 2016; Nimmo-Smith 2020). Jester and Schendel published studies which both suggest higher rates of functional symptoms in ASD patients, are limited by methodological issues (Jester 2016; Schendel 2019). Only the study by Roy reported no difference; 8% prevalence compared to 7.5% (Roy 2015). McWilliams et al reported a case series showing a much higher rate of ASDs in 59 young people with non-epileptic seizures; 16.9%, compared to 1.3–1.5% in the general population (McWilliam 2019).

The range of terminology and methodology used makes integrating the results difficult, but overall there is evidence of an association between ASD and FNSD. Potential mechanisms linking the two such as emotional dysregulation and alexithymia are highlighted, as well as brain regions including the amygdala and anterior cingulate cortex (ACC).

jacob.john.roelofs@gmail.com
227  Reduced drift rate: a biomarker of impaired information processing in functional movement disorders
Authors: Sadnicka Anna , Daum Corinna , Meppelink Anne-Marthe , Edwards Mark , Manohar Sanjay
Published: May 2022

Recently the similarity of neuropsychiatric profiles across a range of functional syndromes has been high- lighted. This is suggestive of a common underlying mechanism with a theoretical deficit of information processing proposed. In this study, we took the temporal discrimination threshold, as a paradigm that can be used to model sensory processing in functional movement disorders. Our hypothesis was that we would be able to delineate markers of slowed information processing in this paradigm removed from the phenomenological presentation with a movement disorder. We recorded both response accuracy and reaction time in a two choice temporal resolution/discrimination task in 36 patients with functional movement disorders and 36 controls. We used a well-established model for decision-making (the drift diffusion model) to estimate mechanistic physiological dimensions of decision-making and sensory pro- cessing. This revealed pathologically reduced drift rate in the patient group, a parameter that quantifies the quality and rate of information accumulation within this sensory task (p=0.002). We discuss how the deficits we observed in patients with functional movement disorders are likely to stem from abnormal allocation of attention that impairs the quality of sensory information available. Within a predictive coding framework sensory information could be down-weighted in favour of predictions encoded by the prior. Our results therefore offer a parsimonious account for a range of experimental and clinical findings.

asadnick@sgul.ac.uk
229  Developing novel smell test for Parkinson’s disease using microencapsulation of essential oils in alginate
Authors: Li Haoxuan , Ismail Ahmed , Azevedo Helena , Castrejon-Pita Rafa , Giovannoni Gavin , Noyce Alastair
Published: May 2022

Background

Olfactory dysfunction is an early, non-motor feature of Parkinson’s disease. The UPSIT is one of the most commonly used smell tests. However, newer methods to encapsulate smells might offer better performance and longer ‘shelf life’. We developed a prototype of a novel smell test involving microen- capsulation of essential oils (EO) in alginate gel.

Methods

A dual infusion pump system with a stainless-steel nozzle needle, containing an inner and outer needle, emitted EO and alginate respectively. The alginate beads expelled from the needle were solidified in calcium chloride (CaCl2) solution (1M). Various alginate viscosities were investigated. Microcapsules were separated into 3 storage conditions: open, closed and loosely sealed (LS). Their size, weight and scent retention were monitored over six months.

Results

98% of LS microcapsules remained functional at six months. The average weight of microcap- sules decreased by 15.9%, reaching 0.0024g by six months. However, microcapsules made using medium viscosity (>2000cP) alginate and those kept in LS conditions, remained relatively constant in weight. Mor- phological analysis revealed the average diameter of microcapsules to be 2mm.

Conclusion

This pilot project has provided insight into the microencapsulation process, indicating that medium viscosity alginate and LS storage are favourable for future development of a cheap and widely applicable smell test.

ha15632@qmul.ac.uk
230  Sydenham’s chorea in an elderly patient
Authors: Diyab Mohamed , Bose Sumanjeet , Awad Ezzat , Zukos Ioannis , Dasari Ravi
Published: May 2022

79 year old gentleman presented with multiple involuntary limb movements, initially referred to the acute medical unit as a seizure. After initial triage, he was managed as a dystonia. Patient was seen by ITU, and neurology opinion was requested. On consultant review, the ‘dancing type’ involuntary movements in limbs and in the face pointed towards a generalised chorea with mild athetosis of the left side, with expulsive speech. Patient also reported severe dental pain, and on examination, bloody ulcers and poor oral hygiene and dentition were noted. MRI showed acute small stroke of the left occipital area. Inflam- matory markers were raised, and anticardiolipin antibodies were increased. Blood cultures were positive for streptococcal bacteraemia. CT-CAP ruled out malignancy or large bleed, trans-oesophageal echo was negative for infective endocarditis, antibasal ganglia antibodies were negative, and paraneoplastic antibodies were negative. Patient was ultimately treated for Sydenham’s chorea secondary to strepto- coccal infection, after ruling out all other likely causes and in light of positive streptococcal bacteraemia. Symptoms resolved significantly on olanzapine, amoxicillin, and gentamycin.

d.mosh666@yahoo.com
234  Using functional status to aid interpretation of cUHDRS scores in patients with Huntington’s disease
Authors: Trundell Dylan , Palermo Giuseppe , Long Jeffery D , Leavitt Blair R , Schobel Scott A , Blair Rachel , Tabrizi Sarah J
Published: May 2022

The composite Unified Huntington’s Disease Rating Scale (cUHDRS) is a scoring algorithm that combines Total Functional Capacity (TFC), Total Motor Score, Symbol Digit Modalities Test and Stroop Word Reading measures. Our aim was to enhance understanding of cUHDRS scoring by linking to established measures of meaningful daily function and independence in individuals with early-to-moderate-manifest Hunting- ton’s disease (HD).

Data from Enroll-HD were evaluated. For patients meeting the reference population for the cUHDRS (manifest HD, TFC 5–13, ≥20 years; N=3,490), cUHDRS score ranges were calculated. Patients were divided into groups around each integer score; for each grouping, the mean HD stage, Independence Scale (IS) score, mean Functional Assessment (FA) score and number of FA items that ≥50% of individuals achieved were calculated.

cUHDRS score groupings ranged 3–18 (N=3,484). For patients in the 14–18 cUHDRS score groupings, ≥50% achieved 25 FA items and had a mean IS=95. For patients in the lowest cUHDRS score group, cUHDRS=3, only 12 FA items were achievable by ≥50% and mean IS=65.

cUHDRS scores reflect the differing levels of function in individuals with early-to-moderate-manifest HD. The cUHDRS can better differentiate between individuals with Stage 1 HD than commonly used measures of function.

rachel.blair@roche.com
235  Assessing coding of diagnosis for atypical parkinsonian syndromes
Authors: Zhong G , Massey L , Thomas S , Ghosh B
Published: May 2022

Background

Atypical Parkinsonian syndromes, including Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA) and Corticobasal Syndrome (CBS), are rare neurodegenerative diseases. Reports showed that the use of the health services for patients with these diseases is underestimated. The NHS uses International Classification of Disease revision 10 (ICD-10) to code health use which has led to error in patient data for these diseases, as they are relatively new entries to this system and there were changes in coding practice in 2016.

Aims

To retrospectively investigate the scale of miscoding of PSP, MSA and CBS in England since the introduction of ICD-10.

Methods

Freedom of information requests were issued to 150 NHS trusts in England to investigate their method of coding and determine the coding error rate.

Results

The coding error rates prior to, and after 2016 respectively were: 29.5%, 0% (PSP); 3.8%, 2.3% (MSA); 24.2%, 24.2% (CBS). The indexing for CBS is difficult as no specific coding exists for CBS in ICD-10.

Conclusion

The high error rate for PSP is contributed by miscoding of PSP (G23.1) as MND (G12.2), due to the coding techniques employed. These errors have largely been rectified in later versions of ICD-10 with the exception of CBS.

ggz1g17@soton.ac.uk
237  Designing and implementing a home based care pathway for people with Parkinson’s disease
Authors: Edwards Emma , Triscott Kevin , Ankeny Ursula , Langley Joseph , Partridge Rebecca , Swabey Matthew , Rideout Jane , Whipps Sue , Whipps John , Carroll Camille
Published: May 2022

Healthcare for people with Parkinson’s (PwP) can vary across the UK. With the prediction that numbers will increase by a fifth by 2025, the Parkinson’s specialist team in Plymouth recognised an opportunity to meet the challenge with a service re-design that incorporated patient initiated contact and digital technology.

Following a series of workshops facilitated by healthcare design engineers, and attended by PwP, their family, Parkinson’s practitioners, and digital health representatives, various supportive and educational materials were devised to support patient self-management supported by home based monitoring.

The main structure and associated materials of the pathway incorporated 3 main themes:

Education and support (which includes an initial teaching session, information booklets, symptom tracking cards, and an online social media group for peer support);

Clear information on how to initiate a healthcare contact via a dedicated email and telephone hotline;

Motor and non-motor symptoms monitored from home via the Parkinson’s KinetigraphTM (PKG) watch and regular completion of validated questionnaires.

The first phase of this Health Foundation Innovation project was implemented in Oct 2019 with 10 PwP from Plymouth taking part. A wider roll out of the pathway involving people in East Cornwall, West Devon and Plymouth is taking place in 2020, involving 150 patients. Embedded processes for evaluation and feedback inform continued development and refinement of the pathway.

camille.carroll@plymouth.ac.uk
239  New de novo mutation in CACNA1a gene leading to episodic ataxia type 2
Authors: Coulden Amy , Wu Kit , Joe Dorothy , Watkins Susanne , Chaudhuri Kallol Ray , Sztriha Laszlo
Published: May 2022

Introduction andAim

Episodic ataxia (EA) is a group of inherited ion channel disorders affecting the cer- ebellum characterised by sporadic episodes of ataxia (Riant et al, 2011; Tomlinson et al, 2013). At least 7 different types have been identified, type 2 being the most common. We describe a patient present- ing with recurrent episodes of dizziness and gait disturbance with a novel mutation in CACNA1a gene (c.586del) leading to episodic ataxia type 2.

Clinical presentation

A 65-year old male presented with recurrent episodes of dizziness and gait distur- bance, which had been present since childhood but increased in severity over last 2 years and leading to hospitalisation. He also reported mild cognitive impairment. Examination showed bilateral horizontal jerky nyastagmus with an otherwise normal neurological examination.

Investigations

Neuroimaging studies showed mild small vessel disease. Genetic sequencing revealed a heterogenicity for the c.586del likely pathogenic frameshift mutation in exon 4 of the CACNA1A gene, resulting in targeting of the mRNA for nonsense- mediated decay or the production of a truncated protein leading to the diagnosis of autosomal dominant episodic ataxic type 2 in this patient.

We report a new de novo mutation in CACNA1a gene leading to episodic ataxia type 2. The patient was given acetazolamide (250mg/day) which improved his symptoms. Episodic ataxia should be considered in patients presenting with a history of intermittent dizziness.

kitwu@doctors.org.uk
244  Idiopathic anosmia with motor impairment – a unique prodrome of Parkinson’s?
Authors: Rees Richard N , Simonet Cristina , Noyce Alastair J , Schrag Anette
Published: May 2022

Introduction

Anosmia is a recognised risk factor for Parkinson’s disease (PD), however, many of the causes are not neurodegenerative. We hypothesise that the prodromal phase of PD associated with idiopathic anosmia is predominantly motor and does not have other significant non-motor features.

Methods

We recruited individuals with idiopathic anosmia (IA) (confirmed by specialist ENT assessment) from across England. Participants from the PREDICT-PD study who were deemed to be low risk of future PD on the basis of scoring with an evidence-based algorithm were used as healthy-aging controls (HA). Patients with established PD were recruited from clinic. All participants had a comprehensive in-person assessment.

Results

We assessed 75 participants (HA=21, IA=40, PD=14), who were well balanced in terms of age and education. There were more men in the PD group than in the other two groups.

There was no difference in motor scores between the HA and IA groups in MDS-UPDRS-III scores (p=0.83), MOCA (p=0.06), RBDsq (p=0.39) or autonomic scores (p=0.20). When dividing IA into those with and without mild motor impairment (MMI; MDS-UPDRS-III ≥7), the IA-MMI group did not show overt non-motor differences compared to the HA group.

Discussion

Some patients with IA present with motor dysfunction that is not associated with non-motor features. This has significance for understanding the variation in the prodromal phase of PD and poten- tially selecting patients for disease modifying trials.

richard.n.rees@ucl.ac.uk
245  Cognitive function in patients with a long-standing diagnosis of SWEDD
Authors: Jesuthasan Aaron , Pavese Nicola
Published: May 2022

Introduction

Patients with clinical features of Parkinson’s Disease (PD), but scans without evidence of dopaminergic deficit are termed SWEDDs. Only a portion of these patients retain their SWEDDs diagnosis later in life and are here regarded as ‘true SWEDDs’. Cognitive symptoms of ‘true SWEDDs’ remain unclear yet important to optimise their management. We used data from the Parkinson’s Progression Markers Initiative to investigate these further.

Methodology

Baseline cognitive data of 25 SWEDDs, who retained diagnoses after 2 years of follow up (confirmed by normal 123I-FP-CIT SPECT scans), were compared with that of 62 de novo PD and 195 healthy control (HC) subjects. Data was analysed using SPSS Statistics.

Results

No significant difference was found when comparing ‘true SWEDDs’ to de novo PD patients and HCs in tests of global cognition, visuospatial function, executive function and attention. However, Hopkins Verbal Learning Test-Revised (HVLT-R) showed a significant difference between the three groups (P=0.004), maintained when specifically analysing ‘true SWEDDs’ versus HCs (P=0.009).

Conclusion

Our data suggest a significant difference in memory function between ‘true SWEDDs’ and HCs, as demonstrated by the HVLT-R test. This suggests memory-stimulating therapies are important for managing ‘true SWEDDs’, however further work is required to validate these findings.

aaronjesuthasan@gmail.com
250  Is primary writing tremor a forme fruste of dystonia?
Authors: Latorre Anna , Rocchi Lorenzo , Rothwell John , Bhatia Kailash
Published: May 2022

Objective

To investigate whether primary writing tremor (PWT) and dystonia share a common pathophysiology.

Background

PWT is probably the most common form of task-specific tremor. Its pathophysiology is still debated and there is controversy about it being a type of focal dystonia, a variant of essential tremor or a separate entity.

Methods

We recruited 7 patients with PWT, who underwent the following neurophysiological tests: blink recovery cycle (BRC), eye-blink classical conditioning (EBCC), short and long-intracortical inhibition (SICI-LICI). Moreover, motor-evoked potentials (MEP), SICI and LICI were measured pre and post paired associative stimulation (PAS) plasticity paradigm. Data were compared with those obtained in 7 dystonic patients (DYT).

Results

Data analysis for BRC showed a similar inhibition between DYT and PWT. There was no differ- ence between DYT and PWT in the number of conditioned response (CR) during. Baseline SICI and LICI were similar in the two patients’ group, but whereas they were unchanged in PWT after PAS, they were reduced in DYT.

Conclusions

The present results suggest that PWT and DYT have similar brainstem excitability and associa- tive learning. Cortical plasticity induced by PAS had a different effect on SICI and LICI in the two groups. Overall this data suggests that PWT and DYT share some pathophysiological mechanisms.

a.latorre@ucl.ac.uk
251  The mendelian calculator
Authors: McAuley John
Published: May 2022

Monogenetic disorders are a common differential in Neurological clinical practice. While it is relatively easy to counsel patients with a known genetic disease on the probability of passing the condition to their offspring, calculating the probability of disease of an as yet unknown inheritance pattern from a known family history is much less straightforward.

The Mendelian Calculator is a freely-available Web-based application that uses the input family history and estimated penetrance and relative population frequencies of inheritance patterns to calculate the probability that a patient’s clinical presentation is sporadic or inherited in a particular Mendelian fashion.

The App also provides predictive values, sensitivities, specificities, likelihood ratios, and Matthews cor- relation coefficients to help the user determine the likelihood of finding inherited disease of a particular pattern when the family history of affected members is as yet unestablished. This can be especially helpful when there are both sporadic and genetic variants of a certain disease phenotype in deciding on the utility of further genetic investigation.

In a short survey scoring the usefulness of the App in clinical practice, most Neurologists felt it was very useful. Comments included the suggestion to provide baseline data on relative frequencies and pen- etrances for common neurological phenotypes.

john_m_30@hotmail.com
255  SUNFISH part 2: risdiplam in type 2 and type 3 SMA
Authors: Servais Laurent , Mercuri Eugenio , Barisic Nina , Boespflug-Tanguy Odile , Deconinck Nicolas , Fuerst-Recktenwald Sabine , Fuhrer Sibylle , Gerber Marianne , Gorni Ksenija , Day John W
Published: May 2022

SUNFISH (NCT02908685) is a multicentre, two-part, randomised (2:1, risdiplam:placebo), placebo-con- trolled, double-blind study in patients, aged 2–25 years, with Type 2 or Type 3 spinal muscular atrophy (SMA). SUNFISH investigates the safety and efficacy of risdiplam, an orally administered, centrally and peripherally distributed SMN2 pre-mRNA splicing modifier.

SUNFISH is comprised of two parts: Part 1 (n=51) is a dose-selection study assessing the safety, tolerability and pharmacokinetics/pharmacodynamics of different risdiplam doses in patients with Type 2/3 SMA; confirmatory Part 2 (n=180) assesses the safety and efficacy of the risdiplam dose selected from Part 1 compared with placebo in patients with Type 2 and non-ambulant Type 3 SMA. The primary objective of Part 2 is to evaluate the efficacy of risdiplam compared with placebo in terms of motor function as assessed by the change from baseline in the 32-item Motor Function Measure total score at Month 12.

In SUNFISH Part 1, no drug-related safety findings led to withdrawals from the study following 1 year of treatment with risdiplam (data-cut: 28th June 2019). Here we report data from Part 2 of the SUNFISH study including baseline demographics, safety and efficacy data in participants who have received treatment with risdiplam or placebo for 12 months.

laurent.servais@paediatrics.ox.ac.uk
258  A case of two brothers: should we look beyond a diagnosis of cerebral palsy?
Authors: Ndukwe Ihedinachi , O’Riordan Sean , Hutchinson Michael
Published: May 2022

Background

Pelizaeus-Merzbacher Disease (PMD) is an X-linked leukodystrophy with variable phenotypes often overlapping with cerebral palsy (CP).

Case Descriptions

We describe 2 brothers, presenting at the same time.

Case1: 34 years old with a 2-year history of hand tremor, cognitive decline and deteriorating mobility. He required neonatal ICU following a prolonged delivery, was slow to walk and subsequently misdiagnosed at age 4. Examination revealed a left torticollis, intention tremor and spastic paraparesis.

Case 2: 29 years old with progressive hand tremor and cognitive decline. He had nystagmus, titubation and late crawling and was diagnosed with CP within his first year of life; becoming wheelchair-bound by age 9. Examination revealed titubation, action tremor, nystagmus and spastic quadriparesis.

There were no other family history of similar symptoms or genetic disorder prior to their births.

Results of Investigations

MRI Brain suggested leukodystrophy in both cases. Genetic analysis revealed pathogenic mutation in the PLP1 gene(c454–322G>A;P?) confiriming a diagnosis of Pelizaeus Merzbacher Disease.

Conclusion

The phenotypic similarities between PMD and CP especially in early childhood and the delayed progression of symptoms contributed to their misdiagnosis. We should look beyond Cerebral Palsy and consider PLP-related diseases in males with cerebral-palsy-like features regardless of a lack of family history.

ihedinachindukwe@gmail.com
259  A novel mutation of protein kinase C gamma associated with spinocerebellar ataxia type 14
Authors: Leddy Sara , Ridha Basil
Published: May 2022

Background

Spinocerebellar ataxia (SCA) type 14 (SCA14) is an autosomal dominant neurodegenerative disorder caused by mutations in the protein kinase Cγ gene (PRKCG). It is a very rare form of autosomal dominant cerebellar ataxia (ADCA), accounting for approximately 1–4% of all cases.

Case

We present a patient with a typical SCA14 phenotype, who was found to have a novel mutation in the PRKCG gene (heterozygous for C.344A> T p. (ASP115VAL)), a 74 year old man who presented with a one year history of poor balance. Neurological examination revealed dysarthric speech in a cerebellar pattern, slight bilateral finger-nose dysmetria, dysdiadochokinesis, and significant heel-shin incoordina- tion. He walked with a wide-based gait and could not attempt tandem gait. Blood tests to exclude an underlying secondary cause for his ataxia were non-diagnostic. MRI brain revealed selective cerebellar atrophy with a minor degree of small vessel disease.

Initial genetic testing did not reveal abnormality. An extended ataxia genetic panel testing of 98 genes known to cause ataxia revealed a novel mutation.

Discussion

This case adds to the number of novel missense mutations leading to a SCA14 phenotype. While current management of spinocerebellar ataxias is supportive, the importance of accurate diagnosis has become pertinent in recent years with emerging gene therapies.

sara.leddy1@nhs.net
260  Gene transfer with rAAVrh74.MHCK7.SGCB increased β-sarcoglycan expression in LGMD type 2E patients
Authors: Richardson James , Rodino-Klapac Louise , Pozsgai Eric , Lewis Sarah , Griffin Danielle , Lehman Kelly , Church Kathleen , Miller Natalie , Iammarino Megan , Lowes Linda , Mendell Jerry
Published: May 2022

These are initial findings of ongoing, phase 1 multiple ascending-dose gene transfer trial of ≤9 LGMD2E patients who received rAAVrh74.MHCK7.SGCB (NCT03652259). Participants: patients 4–15y, confirmed β-sarcoglycan (SGCB) mutation (both alleles), negative for rAAVrh74 antibodies, >40%n on 100-meter timed test. Patients received single IV infusion of 5x1013 vg/kg rAAVrh74.MHCK7.SGCB. Prednisone 1 mg/kg/day was initiated 1d before gene delivery, tapering after 30d. Primary endpoints: ≥20% SGCB-positive fibers (Day-60 muscle biopsy) and safety (Day 270). Secondary endpoints: CK decrease and functional endpoints (Day 270). First 3 patients enrolled (age 13[n=2]; age 4[n=1]): robust SGCB expression observed by immunohistochemistry (IHC), with a mean of 51% SGCB positive fibers (range 42–63%) expressing a mean 47% intensity (range 38–57%). Co-localization of β-sarcoglycan observed (IHC). Western blot showed a mean 36.1% SGCB expression vs normal (range 34–39%). Mean CK levels reduced by 82%, suggesting slowed muscle destruction. Two patients had elevated liver enzymes (1 serious) and 1 had elevated bilirubin following oral steroid taper, which returned to baseline. Two patients had transient mild nausea, corresponding with increased steroid dosing. No other clinically significant lab findings. Gene transfer in LGMD2E patients following rAAVrh74.MHCK7.SGCB infusion was positive for defined endpoints, demon- strating potential benefits of a rationally designed delivery system.

jrichardson@sarepta.com
The clinical features and prognosis of scan negative uro-neurological disorders
Authors: Hoeritzauer Ingrid , Carson Alan , Statham Patrick , Panicker Jalesh , Granitsiotis Voula , Eugenicos Maria , Summers David , Demetriades Andreas , Stone Jon
Published: May 2022

Background

More than 50% of patients presenting with cauda equina syndrome (CES) have normal imaging. These patients require phenotyping to ascertain symptom aetiology and mechanism.

Prospective Study Results

198 patients presented with suspected CES over 28 months. 47 were diagnosed with ‘scan-positive’ CES (mean age 48yrs, 43% female). 76 patients had evidence of nerve root compres- sion or displacement and were placed into a ‘mixed’ category (mean age 46yrs, 71% female) and 61 patients had normal scans ‘scan-negative’ CES (mean age 40yrs, 77% female). Fourteen patients had a neurological diagnosis explaining their clinical CES symptoms during admission.

Patients with ‘scan-positive’ CES were more likely to have reduced or lost bilateral ankle jerks (78% vs. 30% and 12%, p≤0.0001). Patients with ‘scan-negative’ CES were found to have positive signs of a functional neurological disorder on examination (11% v. 34% and 68%, p≤0.0001) as well as high rates of panic, medication usage and psychopathology. Four patients out of 151 (4%, mixed group n=3, ‘scan-negative’ group n=1) had a neurological diagnosis after discharged which potentially explained their clinical CES presentation.

Conclusions

This is the first well phenotyped, prospective study of patients with ‘scan-negative’ CES dem- onstrating a pain, medication and functional mechanism of symptom production.

ingrid.hoeritzauer@ed.ac.uk
265  Use of support vector machine to predict discharge destination on an acute stroke ward
Authors: Berker Henry de , Berker Archy de , Aung Htin , Duarte Pedro , Shetty Hamsaraj , Hughes Tom
Published: May 2022

Background

Predicting the discharge destination of stroke patients at admission is important for stream- lining of services, management of patient and carer expectations, and the planning and facilitating of discharge to appropriate destinations.

Methods

We reviewed data from the Sentinel Stroke National Audit Programme (SSNAP) from a single acute stroke ward in South Wales. We analysed age, modified Rankin Scale (mRS) and National Institute of Health Stroke Scale (NIHSS) data using a multi-class Support Vector Machine (SVM) to train and test a model to predict discharge destination.

Results

Data was extracted from 1131 patients with acute and subacute stroke admitted to an acute stroke unit between January 1st, 2015, and December 31st, 2016. Per-class sensitivity of the model for final destination or outcome was 0.89 for home, 0.6 community hospital, 0.75 inpatient rehabilitation, 0.45 death. Per-class positive predictive value (PPV) was 0.84 for home, 0.62 community hospital, 0.72 inpatient rehabilitation, 0.55 death.

Conclusion

From data that is available from simple assessments done in routine clinical pratice it is possible to identify patients with acute stroke for whom discharge home or inpatient rehabilitation is highly likely. Collaborations between clinicians and data scientists may help to maximise the value of clinical assessment tools that are already in widespread use.

Tom.Hughes2@wales.nhs.uk
266  A drowsy patient: beyond the familiar territory
Authors: Oo Aung , Khine Ngu
Published: May 2022

A 72-year-old man was brought to the hospital after he was found unresponsive at home by his wife who reported that he has been sleepy in the last few days.

He has a background of hypertension, myocardial infarct, and osteoarthritis. His medications include anti-hypertensive and morphine sulphate.

On examination, he was drowsy with GCS fluctuating between 9–11 but maintaining his airways. He was moving all four limbs; pupils were small and unequal but reactive to light. Planter reflexes were downgoing.

Opioid toxicity was suspected and treated with naloxone without any response.

The CT head scan showed no acute pathology. He was subsequently started on IV ceftriaxone and acyclovir for possible meningitis and encephalitis.

He later had an MRI, which showed restricted diffusion in bilateral paramedian thalami.

Artery of Percheron is a rare anatomic variant where a single branch of posterior cerebral artery supplies blood to paramedian thalami and part of rostral midbrain bilaterally. AOP stroke accounts only 0.1% to 2% of all ischemic strokes. The presentation is variable due to the numerous functions relayed through the thalamus. MRI is diagnostic.

Due to the non-classic stroke signs/symptoms and the lack of clinical awareness, timely diagnosis of AOP infarct is quite challenging.

daniel.jiang77@gmail.com
Speech-in-noise perception is a marker of preclinical Alzheimer’s disease
Authors: Watson Cameron J , Waters Sheena , Jacobs Benjamin M , Foote Isabelle F , Dey Sumit , Noyce Alastair J , Hardy Christopher J D , Marshall Charles R ,   equal contribution
Published: May 2022

Background

Central auditory function is affected early in the course of Alzheimer’s disease, and may be useful as a prodromal disease marker. Speech-in-noise perception is a simple test of central auditory function.

Methods

We used Speech Reception Threshold (SRT) as a measure of speech-in-noise perception in 160,905 healthy subjects in UK Biobank. We assessed odds ratios for incident Alzheimer’s disease by SRT quintile at a mean follow up of 10 years. In a subgroup of 37,082 healthy subjects with contemporaneous cognitive testing and brain imaging we assessed the relationships of SRT with cognitive performance and structural neuroanatomy (using voxel based morphometry (VBM)).

Results

Poorer SRT was associated with greater odds of incident Alzheimer’s disease (odds ratio for quintile 5 relative to quintile 1: 2.91 (95%CI 1.92–4.57) p=0.000001). Poorer SRT was associated with poorer cognitive performance in multiple domains. VBM revealed symmetrical grey matter correlates of SRT in a distributed network of auditory and speech perception areas, as well as medial temporal lobe structures.

Conclusion

Speech-in-noise perception is a simple non-invasive assay of cognition, brain structure and risk of incident Alzheimer’s disease, and as such may be readily translatable as a cost-effective tool for dementia risk stratification at scale.

cameron..watson@qmul.ac.uk
Deep phenotyping of frontal lobe epilepsy compared to other epilepsy syndromes
Authors: Wee Ryan , Nash Adina , Angus-Leppan Heather
Published: May 2022

Background

Epilepsy syndromes differ in their demography, clinical manifestations and investigation findings. Frontal lobe epilepsy (FLE), a focal epilepsy syndrome with a heterogeneous presentation, is understudied and often misdiagnosed. We sought to phenotype the diagnostic features of FLE and to differentiate FLE from other epilepsy syndromes.

Methods

1481 prospective cases of epilepsy, diagnosed based on International League against Epilepsy criteria, were identified from a neurology centre in London.

Results

166 patients had FLE based on clinical findings and investigations. 97 had electroencephalogra- phy (EEG) foci in frontal areas (definite FLE) while 69 patients with FLE had no frontal EEG foci (probable FLE). Definite and probable FLE did not differ in any other features. Systematic comparisons of FLE and other epilepsy syndromes revealed demographic, clinical and investigation features that differentiated FLE from the other syndromes; these features included an underlying structural or metabolic aetiology, abnormalities on MRI and the absence of intellectual disability.

Conclusions

FLE is a varied clinical syndrome characterised by dyscognitive symptoms and a predomi- nantly structural or metabolic aetiology usually identified with MRI. There was no difference in the clinical features of definite and probable FLE. This large case series provides further insights into the hallmark features of FLE.

ryan.wee.13@ucl.ac.uk
Review of neurological complications following treatment with immune check- point inhibitors
Authors: Bose Smriti , Sumangala Salini , Steven Neil , Jacob Saiju
Published: May 2022

Objective

Immunotherapy with cytotoxic T lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 and ligand-1 (PD-1 and PD-L1) inhibitors are the most promising development in oncology. Neurological complications are reportedly seen in 2–4 % of patients treated with immune checkpoint inhibitors (CPI).

Method

This was an observational study which included all oncology and haematology patients who received the most common CPI (Ipilimumab, Nivolumab, and Pembrolizumab), either as monotherapy, in combination or sequentially between the periods of January 2017 to April 2019.

Results

Total of 375 patients received CPI during this period. The most common cancer was malignant melanoma, lung, head and neck and renal cancers. 199 patients had neurological complications, the vast majority due to metastasis or vascular complications related to the cancer. One hundred patients were identified as having neurological symptoms related to Immune therapy. 67 of these patients who were symptomatic received some sort of intervention for the neurological IRAE, which included change in immunotherapy, temporary or permanent suspension of treatment or steroids.

Conclusion

This is one of the largest series of cancer patients studied so far for neurological IRAEs following CPI therapy. Early diagnosis of these events is highly vital for effective treatment and cure of symptoms. Steroids hold the mainstay of treatment followed by IVIG/PLEX, possibly in a graded fashion based on severity. Long term studies are needed to establish a clear pathway and identify prognostic indicators.

saiju.jacob@uhb.nhs.uk
Biomarkers for brain injury and copper toxicity in Wilson’s disease: a diffusion tensor imaging study
Authors: Shribman Samuel , Bocchetta Martina , Burrows Maggie , Gillett Godfrey T , Tsochatzis Emmanuel , Bandmann Oliver , Rohrer Jonathan D , Warner Thomas T
Published: May 2022

Introduction

Chelation therapy is used to ‘de-copper’ patients with Wilson’s disease but neurological outcomes are unpredictable and biomarkers of end-organ damage are needed.

Methods

We prospectively performed clinical assessments, venepuncture and 3T MRI in 40 patients with Wilson’s disease. Using tract-based spatial statistics, we compared diffusion tensor imaging parameters across white matter tracts between patients with neurological (n=23) and hepatic (n=17) presentations and active (n=5) and stable (n=35) disease. We also tested associations with neurological examination scores and serum free copper concentrations in stable patients.

Results

There were no differences in DTI parameters between patients with neurological and hepatic presentations, however examination scores were negatively associated with axial diffusivity in subcortical tracts in stable patients. Patients with active disease had widespread increases in mean, axial and, to a lesser extent, radial diffusivity. In contrast, increasing serum copper concentrations in stable patients were associated with widespread increases in mean, radial and, to a lesser extent, axial diffusivity.

Conclusions

We demonstrate that distinct patterns of abnormal white matter diffusivity are associated with brain injury and copper toxicity in Wilson’s disease. Decreases in axial diffusivity in chronically-treated patients likely reflect axonal loss. Increases in axial and radial diffusivity are a promising biomarker for monitoring treatment response.

s.shribman@ucl.ac.uk
Lower lymphocyte count is associated with increased risk of Parkinson’s disease
Authors: Jensen Melanie , Jacobs Benjamin , Dobson Ruth , Bandres-Ciga Sara , Blauwendraat Cornelis , Schrag Anette , Noyce Alastair
Published: May 2022

Objectives

Patients with established Parkinson’s disease (PD) display differences in blood biomarkers of immune function, including leukocyte differentials, compared to controls. These may be useful biomarkers to predict PD and inform pathogenesis. We sought to identify whether peripheral immune dysregulation was associated with risk of subsequent PD.

Methods

We examined the relationship between incident PD and baseline leukocyte differential count in UK Biobank, a longitudinal cohort with >500,000 participants. We used a range of sensitivity analyses and Mendelian randomization (MR) to further explore the nature of associations.

Results

After excluding individuals with comorbidities which could influence inflammation biomarkers, 465 incident PD cases and 312,125 controls remained. Lower lymphocyte count was associated with increased risk of PD diagnosis (per 1-SD decrease in count OR 1.18, 95% CI 1.07–1.32, padjusted=0.01). The association between lower lymphocyte count and increased PD risk remained robust to sensitivity analyses. MR suggested that the effect of lower lymphocyte count on PD risk may be causal (per 1-SD decrease in lymphocyte count; ORMR 1.09, 95% CI 1.01–1.18, p=0.02).

Conclusions

We provide converging evidence from observational analyses in UKB and MR that lower lymphocyte count is associated with an increased risk of subsequent PD.

m.jensen@cantab.net