Delays in Multiple Sclerosis diagnosis (DIMES): protocol for a multicentre, observational study of multiple sclerosis diagnostic pathways in the United Kingdom and Republic of Ireland.

BACKGROUND: Multiple sclerosis (MS) is a leading cause of non-traumatic disability in young adults. Accumulating evidence indicates early diagnosis and early treatment improves long-term outcomes. However, the MS diagnostic pathway is increasingly complex, and delays may occur at several stages. Factors causing delays remain understudied. We aim to quantify the time taken for MS to be diagnosed, and characterise the diagnostic pathway and initial care provided, in the United Kingdom (UK) and Republic of Ireland (ROI). METHODS: Delays In MultiplE Sclerosis diagnosis (DIMES) in the UK and ROI is a multicentre, observational, retrospective study that will be conducted via the Neurology and Neurosurgery Interest Group (NANSIG) collaborative network. Any hospital in the UK and ROI providing an MS diagnostic service is eligible to participate. Data on consecutive individuals newly diagnosed with MS between 1st July 2022 and 31st December 2022 will be collected. The primary outcomes are 1) time from symptoms/signs prompting referral to neurology, to MS diagnosis; and 2) time from referral to neurology for suspected MS, to MS diagnosis. Secondary outcomes include: MS symptoms, referring specialties, investigations performed, neurology appointments, functional status, use of disease modifying treatments, and support at diagnosis including physical activity, and follow up. Demographic characteristics of people newly diagnosed with MS will be summarised, adherence to quality standards summarised as percentages, and time-to-event variables presented with survival curves. Multivariable models will be used to investigate the association of demographic and clinical factors with time to MS diagnosis, as defined in our primary outcomes. DISCUSSION: DIMES aims to be the largest multicentre study of the MS diagnostic pathway in the UK and ROI. The proposed data collection provides insights that cannot be provided from contemporary registries, and the findings will inform approaches to MS services nationally in the future.

Care and three-year outcomes of children with Benign Epilepsy with Centro-Temporal Spikes in England.

PURPOSE: Benign Epilepsy with Centro-Temporal Spikes (BECTS) is a pediatric epilepsy with typically good seizure control. Although BECTS may increase patients' risk of developing neurological comorbidities, their clinical care and short-term outcomes are poorly quantified. METHODS: We retrospectively assessed adherence to National Institute for Health and Care Excellence (NICE) guidelines relating to specialist referral, electroencephalogram (EEG) conduct and annual review in the care of patients with BECTS, and measured their seizure, neurodevelopmental and learning outcomes at three years post-diagnosis. RESULTS: Across ten centers in England, we identified 124 patients (74 male) diagnosed with BECTS between 2015 and 2017. Patients had a mean age at diagnosis of 8.0 (95% CI = 7.6-8.4) years. 24/95 (25%) patients were seen by a specialist within two weeks of presentation; 59/100 (59%) received an EEG within two weeks of request; and 59/114 (52%) were reviewed annually. At three years post-diagnosis, 32/114 (28%) experienced ongoing seizures; 26/114 (23%) had reported poor school progress; 15/114 (13%) were diagnosed with a neurodevelopmental disorder (six autism spectrum disorder, six attention-deficit/hyperactivity disorder); and 10/114 (8.8%) were diagnosed with a learning difficulty (three processing deficit, three dyslexia). Center-level random effects models estimated neurodevelopmental diagnoses in 9% (95% CI: 2-16%) of patients and learning difficulty diagnoses in 7% (95% CI: 2-12%). CONCLUSIONS: In this multicenter work, we found variable adherence to NICE guidelines in the care of patients with BECTS and identified a notable level of neurological comorbidity. Patients with BECTS may benefit from enhanced cognitive and behavioral assessment and monitoring.

Postoperative Diabetes Insipidus Mimicking Radiological Findings and Symptoms of Intracranial Hypotension: A Case Report.

Endocrine disturbances such as diabetes insipidus (DI) and syndrome of inappropriate antidiuretic hormone secretion (SIADH) are recognized complications of craniopharyngioma surgery, which occur due to damage to structures that produce or store antidiuretic hormone (ADH). Intracranial hypotension is a clinical syndrome that presents with headache and typical radiological features and can occur due to a leak of cerebral spinal fluid (CSF) in operations that involve the opening of the arachnoid (e.g., craniopharyngioma surgery). We describe a patient presenting with headache, radiological evidence of intracranial hypotension, and chronic DI after craniopharyngioma surgery. This occurred in the absence of evidence of a CSF leak. The headache and radiological findings resolved after the identification and treatment of DI. Intracranial hypotension may have occurred secondary to dehydration in chronic DI. A 48-year-old woman presented with progressive visual field loss due to cystic recurrence of a craniopharyngioma. She underwent redo (second) extended endoscopic transsphenoidal surgery, having previously undergone an uncomplicated debulking procedure two years prior. Her redo operation was uneventful, and her vision improved postoperatively. A lumbar drain was placed preoperatively to protect the skull base repair and was removed after 48 hours. In the initial postoperative period, she developed a clinical (polyuria) and biochemical picture consistent with DI, subsequently reverting to a SIADH, after which fluid and sodium homeostasis appeared to normalize, and she was discharged. Two months after discharge, she re-presented with new headaches eased by lying flat. Magnetic resonance imaging (MRI) brain showed bilateral convexity subdural effusions and diffuse pachymeningeal enhancement, suggesting intracranial hypotension and raising concern for postoperative CSF leak. MRI spine did not show a CSF fistula at the site of the previous lumbar drain. Transsphenoidal examination under anesthesia showed a well-healed skull base repair and no evidence of CSF leak. She concurrently reported polyuria and polydipsia. A formal water deprivation test confirmed central DI. Treatment with desmopressin improved her headache, and a follow-up MRI brain showed resolution of the previous stigmata of intracranial hypotension. This case report reminds physicians and neurosurgeons that systemic disorders (such as dehydration) can cause intracranial hypotension.

Systematic Review of Cerebral Phenotypes Associated With Monogenic Cerebral Small-Vessel Disease.

Background Cerebral small-vessel disease (cSVD) is an important cause of stroke and vascular dementia. Most cases are multifactorial, but an emerging minority have a monogenic cause. While NOTCH3 is the best-known gene, several others have been reported. We aimed to summarize the cerebral phenotypes associated with these more recent cSVD genes. Methods and Results We performed a systematic review (PROSPERO [International Prospective Register of Systematic Reviews]: CRD42020196720), searching Medline/Embase (conception to July 2020) for any language publications describing COL4A1/2, TREX1, HTRA1, ADA2, or CTSA pathogenic variant carriers. We extracted data about individuals' characteristics and clinical and vascular radiological cerebral phenotypes. We summarized phenotype frequencies per gene, comparing patterns across genes. We screened 6485 publications including 402, and extracted data on 390 individuals with COL4A1, 123 with TREX1, 44 with HTRA1 homozygous, 41 with COL4A2, 346 with ADA2, 82 with HTRA1 heterozygous, and 14 with CTSA. Mean age ranged from 15 (ADA2) to 59 years (HTRA1 heterozygotes). Clinical phenotype frequencies varied widely: stroke, 9% (TREX1) to 52% (HTRA1 heterozygotes); cognitive features, 0% (ADA2) to 64% (HTRA1 homozygotes); and psychiatric features, 0% (COL4A2; ADA2) to 57% (CTSA). Among individuals with neuroimaging, vascular radiological phenotypes appeared common, ranging from 62% (ADA2) to 100% (HTRA1 homozygotes; CTSA). White matter lesions were the most common pathology, except in ADA2 and COL4A2 cases, where ischemic and hemorrhagic lesions dominated, respectively. Conclusions There appear to be differences in cerebral manifestations across cSVD genes. Vascular radiological changes were more common than clinical neurological phenotypes, and present in the majority of individuals with reported neuroimaging. However, these results may be affected by age and biases inherent to case reports. In the future, better characterization of associated phenotypes, as well as insights from population-based studies, should improve our understanding of monogenic cSVD to inform genetic testing, guide clinical management, and help unravel underlying disease mechanisms.

Socioeconomic deprivation is associated with reduced efficacy of an insulin adjustment education program for people with type 1 diabetes.

BACKGROUND: The Dose Adjustment for Normal Eating (DAFNE) course teaches insulin dose adjustment to match dietary carbohydrates and improve glycaemic control in participants with type 1 diabetes mellitus (T1DM). We investigated the association between socioeconomic deprivation and reduction in HbA1c as a marker of sustained glycaemic control, after attending DAFNE education. METHODS: This retrospective observational study identified adults with T1DM who attended DAFNE training in NHS Lothian, South East Scotland. We extracted age, sex, postcode-based Scottish Index of Multiple Deprivation (SIMD) quintiles and annual HbA1c measurements available four years before and after course attendance. We calculated mean HbA1c before (baseline) and after attendance at DAFNE, across four annual measurements. Change in mean HbA1c (mmol/mol) was categorised into three groups: decrease (≥ - 2.5), no change (<±2.5), increase (≥ + 2.5). We used multivariable ordinal logistic regression, with baseline mean HbA1c as a covariate, to investigate the association of SIMD quintile with reduction in mean HbA1c. RESULTS: 335 participants were included. Age and sex distribution were similar across SIMD quintiles (Mean age = 45, range 21-91, 59% women). Lower SIMD quintiles (greater deprivation) had higher baseline mean HbA1c (SIMD 1: 76.0, SIMD 5: 69.0). Higher SIMD quintiles (lower deprivation) were associated with lower odds of no change/increase in mean HbA1c (SIMD 5, odds ratio = 0.25, 95% confidence interval 0.10, 0.58, p = 0.001, multivariable analysis). CONCLUSION: Socioeconomic deprivation was associated with higher baseline mean HbA1c and lower reduction in HbA1c following DAFNE education. Future research could explore causes and how best to support participants from deprived areas. PREVIOUS SUBMISSIONS: This work has not been previously submitted to a journal. This work was presented as a poster at The ABCD Conference 2021 and the abstract (of no more than 300 words) from the meeting has been published: Innes CWD, Henshall DE, Wilson B, Poon M, Morley SD, Ritchie SA. Socioeconomic deprivation is associated with reduced efficacy of an insulin adjustment education programme for people with type 1 diabetes. Br J Diabetes. 2021; 21: 293-296.

Comparing quality of reporting between preprints and peer-reviewed articles in the biomedical literature.

BACKGROUND: Preprint usage is growing rapidly in the life sciences; however, questions remain on the relative quality of preprints when compared to published articles. An objective dimension of quality that is readily measurable is completeness of reporting, as transparency can improve the reader's ability to independently interpret data and reproduce findings. METHODS: In this observational study, we initially compared independent samples of articles published in bioRxiv and in PubMed-indexed journals in 2016 using a quality of reporting questionnaire. After that, we performed paired comparisons between preprints from bioRxiv to their own peer-reviewed versions in journals. RESULTS: Peer-reviewed articles had, on average, higher quality of reporting than preprints, although the difference was small, with absolute differences of 5.0% [95% CI 1.4, 8.6] and 4.7% [95% CI 2.4, 7.0] of reported items in the independent samples and paired sample comparison, respectively. There were larger differences favoring peer-reviewed articles in subjective ratings of how clearly titles and abstracts presented the main findings and how easy it was to locate relevant reporting information. Changes in reporting from preprints to peer-reviewed versions did not correlate with the impact factor of the publication venue or with the time lag from bioRxiv to journal publication. CONCLUSIONS: Our results suggest that, on average, publication in a peer-reviewed journal is associated with improvement in quality of reporting. They also show that quality of reporting in preprints in the life sciences is within a similar range as that of peer-reviewed articles, albeit slightly lower on average, supporting the idea that preprints should be considered valid scientific contributions.

Beyond the Brain: Systematic Review of Extracerebral Phenotypes Associated With Monogenic Cerebral Small Vessel Disease.

BACKGROUND AND PURPOSE: An important minority of cerebral small vessel disease (cSVD) is monogenic. Many monogenic cSVD genes are recognized to be associated with extracerebral phenotypes. We assessed the frequency of these phenotypes in existing literature. METHODS: We performed a systematic review following the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), searching Medline/Embase for publications describing individuals with pathogenic variants in COL4A1/2, TREX1, HTRA1, ADA2, and CTSA genes (PROSPERO 74804). We included any publication reporting on ≥1 individual with a pathogenic variant and their clinically relevant phenotype. We extracted individuals' characteristics and information about associated extracerebral phenotypes and stroke/transient ischemic attack. We noted any novel extracerebral phenotypes and looked for shared phenotypes between monogenic cSVDs. RESULTS: After screening 6048 publications, we included 96 COL4A1 (350 individuals), 32 TREX1 (115 individuals), 43 HTRA1 (38 homozygous/61 heterozygous individuals), 16 COL4A2 (37 individuals), 119 ADA2 (209 individuals), and 3 CTSA (14 individuals) publications. The majority of individuals originated from Europe/North America, except for HTRA1, where most were from Asia. Age varied widely, ADA2 individuals being youngest and heterozygous HTRA1/CTSA individuals oldest. Sex distribution appeared equal. Extracerebral phenotypes were common: 14% to 100% of individuals with a pathogenic variant manifested at least one extracerebral phenotype (14% COL4A2, 43% HTRA1 heterozygotes, 47% COL4A1, 57% TREX1, 91% ADA2, 94% HTRA1 homozygotes, and 100% CTSA individuals). Indeed, for 4 of 7 genes, an extracerebral phenotype was observed more frequently than stroke/transient ischemic attack. Ocular, renal, hepatic, muscle, and hematologic systems were each involved in more than one monogenic cSVD. CONCLUSIONS: Extracerebral phenotypes are common in monogenic cSVD with extracerebral system involvement shared between genes. However, inherent biases in the existing literature mean that further data from large-scale population-based longitudinal studies collecting health outcomes in a systematic unbiased way is warranted. The emerging knowledge will help to select patients for testing, inform clinical management, and provide further insights into the underlying mechanisms of cSVD.

Accuracy of identifying incident stroke cases from linked health care data in UK Biobank.

OBJECTIVE: In UK Biobank (UKB), a large population-based prospective study, cases of many diseases are ascertained through linkage to routinely collected, coded national health datasets. We assessed the accuracy of these for identifying incident strokes. METHODS: In a regional UKB subpopulation (n = 17,249), we identified all participants with ≥1 code signifying a first stroke after recruitment (incident stroke-coded cases) in linked hospital admission, primary care, or death record data. Stroke physicians reviewed their full electronic patient records (EPRs) and generated reference standard diagnoses. We evaluated the number and proportion of cases that were true-positives (i.e., positive predictive value [PPV]) for all codes combined and by code source and type. RESULTS: Of 232 incident stroke-coded cases, 97% had EPR information available. Data sources were 30% hospital admission only, 39% primary care only, 28% hospital and primary care, and 3% death records only. While 42% of cases were coded as unspecified stroke type, review of EPRs enabled a pathologic type to be assigned in >99%. PPVs (95% confidence intervals) were 79% (73%-84%) for any stroke (89% for hospital admission codes, 80% for primary care codes) and 83% (74%-90%) for ischemic stroke. PPVs for small numbers of death record and hemorrhagic stroke codes were low but imprecise. CONCLUSIONS: Stroke and ischemic stroke cases in UKB can be ascertained through linked health datasets with sufficient accuracy for many research studies. Further work is needed to understand the accuracy of death record and hemorrhagic stroke codes and to develop scalable approaches for better identifying stroke types.

Global Assessment of Mendelian Stroke Genetic Prevalence in 101 635 Individuals From 7 Ethnic Groups.

Background and Purpose- Mendelian stroke confers a high lifetime risk for mutation carriers; however, ethnicity-specific prevalence estimates have been difficult to establish. Methods- Eighteen genes responsible for Mendelian stroke were investigated using the Genome Aggregation Database. Genome Aggregation Database participants belonged to 1 of 7 populations: African/African-American, Latino/Admixed American, Ashkenazi Jewish, East Asian, Finnish European, non-Finnish European, and South Asian. Rare nonsynonymous variants from 101 635 participants free of neurological disease were examined for each ethnicity. Mutations were categorized according to 3 nested classes: pathogenic clinical variants, likely damaging variants based on in silico prediction, and all nonsynonymous variants. Results- ABCC6, KRIT1, CECR1, COL3A1, COL4A1, COL4A2, COLGALT1, GLA, HTRA1, NOTCH3, RNF213, and TREX1 harbored pathogenic clinical variants in Genome Aggregation Database. Across all 18 genes, total nonsynonymous carrier frequency was found to be high in 5 ethnicities (African/African-American, Latino/Admixed American, East Asian, non-Finnish European, and South Asian; 28.5%-37.5%) while lower total frequencies were estimated for in silico-predicted likely damaging variants (14.9%-19.7%) and pathogenic clinical variants (0.7%-2.8%). Overall, East Asian exhibited the highest total pathogenic clinical mutation carrier frequency (2.8%). ABCC6 pathogenic clinical variants were most prevalent among East Asian (0.8%). Pathogenic NOTCH3 variants, causal for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, were most frequent among East Asian (1.1%) and South Asian (1.2%). East Asian also demonstrated the highest carrier rate for RNF213 (0.8%). Finnish European exhibited the greatest HTRA1 frequency (0.2%), while COL4A1 pathogenic variants were most prevalent in African/African-American (0.3%). Conclusions- Especially, among pathogenic clinical variants, Mendelian stroke genetic prevalence differed significantly between populations. These prevalence estimates may serve as guides for screening and risk profiling in patients worldwide, particularly for understudied non-European populations.

Identifying dementia outcomes in UK Biobank: a validation study of primary care, hospital admissions and mortality data.

Prospective, population-based studies that recruit participants in mid-life are valuable resources for dementia research. Follow-up in these studies is often through linkage to routinely-collected healthcare datasets. We investigated the accuracy of these datasets for dementia case ascertainment in a validation study using data from UK Biobank-an open access, population-based study of > 500,000 adults aged 40-69 years at recruitment in 2006-2010. From 17,198 UK Biobank participants recruited in Edinburgh, we identified those with ≥ 1 dementia code in their linked primary care, hospital admissions or mortality data and compared their coded diagnoses to clinical expert adjudication of their full-text medical record. We calculated the positive predictive value (PPV, the proportion of cases identified that were true positives) for all-cause dementia, Alzheimer's disease and vascular dementia for each dataset alone and in combination, and explored algorithmic code combinations to improve PPV. Among 120 participants, PPVs for all-cause dementia were 86.8%, 87.3% and 80.0% for primary care, hospital admissions and mortality data respectively and 82.5% across all datasets. We identified three algorithms that balanced a high PPV with reasonable case ascertainment. For Alzheimer's disease, PPVs were 74.1% for primary care, 68.2% for hospital admissions, 50.0% for mortality data and 71.4% in combination. PPV for vascular dementia was 43.8% across all sources. UK routinely-collected healthcare data can be used to identify all-cause dementia in prospective studies. PPVs for Alzheimer's disease and vascular dementia are lower. Further research is required to explore the geographic generalisability of these findings.

A prospective observational study of emergency department presentations following novel psychoactive substance use.

Background and aims Novel psychoactive substances are compounds intended to mimic the effects of illicit drugs. They provide a unique challenge to healthcare, as complications of their use and their impact on services are relatively unknown. This study aims to determine nature of presentations, patient demographics and impact on healthcare. Methods Novel psychoactive substances users who presented to a large urban emergency department over 4 weeks were prospectively identified and followed for 1 year. Patients over 13 years old were eligible for inclusion. Information regarding patient demographics and presentations was collected. Results During the study period, 53 patients (39 male), mean age 32.6 ± 8.9 (±standard deviation), presented 148 times with complaints relating to novel psychoactive substances use. Study population characteristics included history of illicit drug use (83.0%), intravenous drug use (64.2%), psychiatric diagnosis or symptoms (56.6%), methadone prescription (52.8%) and having no fixed abode (37.7%). Injection was the most common method of use (72.3%), Burst the most commonly named agent (19.6%) and behavioural change the most common presenting complaint (31.1%). Patients collectively spent 10,620 h in hospital over 1 year. Conclusion This study highlights differences between the young population targeted by government campaigns regarding novel psychoactive substances use and the presenting population to hospital, and the associated burden on the National Health Service.