bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

BackgroundPelizaeus-Merzbacher Disease (PMD) is an X-linked leukodystrophy with variable phenotypes often overlapping with cerebral palsy (CP).Case DescriptionsWe 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 InvestigationsMRI 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.ConclusionThe 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

BackgroundSpinocerebellar 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.CaseWe 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.DiscussionThis 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

BackgroundMore 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 Results198 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.ConclusionsThis 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

BackgroundPredicting 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.MethodsWe 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.ResultsData 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.ConclusionFrom 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

BackgroundCentral 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.MethodsWe 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)).ResultsPoorer 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.ConclusionSpeech-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

BackgroundEpilepsy 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.Methods1481 prospective cases of epilepsy, diagnosed based on International League against Epilepsy criteria, were identified from a neurology centre in London.Results166 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.ConclusionsFLE 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

ObjectiveImmunotherapy 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).MethodThis 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.ResultsTotal 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.ConclusionThis 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

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

ObjectivesPatients 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.MethodsWe 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.ResultsAfter 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).ConclusionsWe 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
Visual dysfunction predicts cognitive impairment and white matter degenera- tion in Parkinson’s disease
Authors: Zarkali Angeliki , McColgan Peter , Leyland Louise-Ann , Lees Andrew , Weil Rimona 
Published: May 2022

IntroductionVisual dysfunction predicts Parkinson’s dementia but whether this translates to structural change is not known. We aimed to identify longitudinal white matter changes in Parkinson’s with low visual function and those who developed mild cognitive impairment(MCI).MethodsWe used fixel-based analysis to examine longitudinal white matter change in Parkinson’s. Diffusion MRI and clinical assessments were performed in 77 patients (22 low/55 high visual performers; and 13 MCI/51 normal cognition) and 25 controls at baseline and after 18 months. We compared micro-structural changes in fibre density, macro-structural changes in fibre cross-section and combined fibre density and cross-section across white matter, adjusting for age, gender and intracranial volume.ResultsParkinson’s with low visual performance showed worse cognition at follow-up (r=-0.386, p-0.024) and were more likely to develop MCI than those with normal vision (p=0.008). Parkinson’s with poor visual function showed diffuse micro-structural and macro-structural changes at baseline, whereas those with MCI showed fewer baseline changes. At follow-up, Parkinson’s with low visual function showed wide- spread macrostructural changes with up to 22% further reductions in fibre cross-section, involving the fronto-occipital fasciculi, external capsules, and middle cerebellar peduncles bilaterally. No longitudinal change was seen in baseline MCI or in MCI converters, even when combining the two groups.ConclusionsParkinson’s with poor visual function show increased white matter damage over time, providing further evidence for visual function as a marker of imminent cognitive decline.a.zarkali@ucl.ac.uk