European Journal of Neurology

Objective To estimate the prevalence of epilepsy-associated malformations of cortical development (MCDs) in Eastern Denmark, and to validate whether epilepsy prevalence in the same population is consistent with national estimates. Methods A retrospective cohort study of people registered with ICD-10 code DG40* and/or DZ033A from 1998 up to 1 July 2023 was conducted. The study population was defined as all living residents in Eastern Denmark with at least one recorded hospital-patient contact within the year preceding 1 July 2023. Magnetic resonance imaging (MRI) availability was required to assess presence of any MCD. MRI radiology reports were manually reviewed or evaluated using a language model to identify MCDs, including encephalocele, focal cortical dysplasia (FCD), hemimegalencephaly, heterotopia, hypothalamic hamartoma, lissencephaly, polymicrogyria and schizencephaly. Prevalence estimates were calculated for each MCD subtype and for epilepsy overall, and compared with the available literature. Results On 1 July 2023, 28,739 people met inclusion criteria, and 14,434 had an available brain MRI, including radiological description of possible MCDs. The prevalence per 100,000 population was 1044.6 (95\% CI 1032.6 to 1056.6) for epilepsy and 32.1 (95\% CI 30.1 to 34.3) for any MCD associated with seizures. Reported MCD prevalence in the literature, when existent, was derived from pediatric age-ranged selected cohorts, except for FCD. No prevalence estimates for hemimegalencephaly and heterotopia were identified. Signifiance We presented the first population-based estimates of seizure-associated MCD prevalence in a large all-age cohort. Direct comparison with prior literature was prevented due to differences in study design and population structure, but epilepsy prevalence was consistent with previously reported national estimates.

Background The time trend in long-term survival after a stroke is to some extent unknow due to (relatively) short follow up periods in available data. The objective of this study is to identify and quantify differences in long-term stroke survival in Sweden between men and women and patients with different attained educational levels, comparing two time-periods, 2000-2009 and 2010-2022. Methods This study employs total population Swedish register data pertaining to hospital-based care and mortality due to stroke for the period 2000-2022 in order to estimate survival (all-cause mortality) after ischaemic and haemorrhagic stroke, respectively, and pertaining to attained educational level. Kaplan-Meier survival functions are estimated stratifying for time-period, sex and educational level. Cox regressions are employed to quantify mortality hazard ratios between the strata. Age is taken into account in complementary analyses (supplement). Results Taking only time-period (2000-2009 vs 2010-2022) into account resulted in significantly higher survival in the second period for ischaemic stroke patients (HR: 0.84; 95% CI: 0.83-0.84), while no significant difference could be detected for haemorrhagic stroke. Stratifying for sex showed that men gained more than women in terms of reduced mortality hazard rate between the periods. Further stratifying by educational level and estimating survival separately for men and women showed that, for both men and women, patients with the lowest education were relatively worse off (compared to patients with higher education) in the second period. Further analyses, taking age into account, reversed the relative hazard ratio between men and women, but corroborated the result that low education is associated with poorer outcome than high education. Conclusions The results suggest that there are considerable differences in expected long-term survival after stroke between the sexes, but that this may be due to differences in age between the sexes at the time of stroke. Moreover, lower educational level is significantly associated with lower long-time survival.

Objective: Cognitive impairment is a common comorbidity among people with epilepsy (PWE) and is associated with disability and reduced quality of life. We characterized the burden of cognitive impairment and identified factors associated with cognitive performance in a large, population-based cohort of PWE living in Northern Peru, a region highly endemic for Taenia solium where neurocysticercosis (NCC) is a common cause of acquired epilepsy. Methods: PWE enrolled in a population-based cohort in Northern Peru between 2007 and 2020 completed the Mini-Mental State Examination (MMSE) at enrollment. Cognitive impairment was defined as an MMSE score <24. Demographic and clinical data, including epilepsy characteristics and NCC status, were collected. Negative binomial regression was used to identify factors associated with the number of MMSE errors. Results: Among 764 participants, the mean MMSE score was 26.4 (SD 4.2), and 16.4% met criteria for cognitive impairment. Memory and attention were the most affected domains. In multivariable analysis, older age and lower educational attainment were independently associated with poorer cognitive performance. Conclusion: In this large, community-based cohort from Northern Peru, approximately 1 in 6 PWE had abnormal global cognition on the MMSE, with memory and attention most affected. These findings underscore the importance of incorporating cognitive evaluation and management into comprehensive epilepsy care, particularly in resource-limited settings where cognitive morbidity may be underrecognized. Given the potential for cognitive difficulties to compound disability and adversely affect quality of life, identifying and addressing cognitive morbidity may be especially important in populations already facing substantial barriers to epilepsy care.

Objective: In KCNQ2-related disorders (KCNQ2-RD), neurodevelopmental outcome remains variable despite established genotype-phenotype correlations. Our aim is to improve counselling, by developing and internally validating models predicting neurodevelopmental outcomes based on early clinical and genetic features, universally available to clinicians. Methods: We conducted a multicentric retrospective cohort study including 277 individuals carrying a (likely) pathogenic variant in the KCNQ2 gene, with a minimum follow-up age of three years. Mosaic variants were excluded. The cohort was randomly split into training (70%) and validation (30%) sets. Ten expert selected parameters with minimal missing data were used to train random forest models to predict (i) dichotomous outcomes and (ii) three-category outcomes for cognition, language, and gross motor milestones. Results: Models incorporated seven clinical (neonatal hypotonia, EEG characteristics, age at seizure onset, seizure type, and seizure frequency at onset, prematurity, and sex) and three genetic variables (de novo status, exon localisation, and position within known KCNQ2-developmental and epileptic encephalopathy (DEE) hotspot regions). Dichotomous models showed the highest predictive performance, with accuracies of 0.83 for normal vs. mild-profound intellectual disability (ID), 0.83 for achievement of first words, and 0.86 for achievement of independent walking. Three category models remained clinically informative: accuracies were 0.79 for normal vs. mild vs. moderate-profound ID, 0.70 for first words [&le;]16 months vs. >16 months vs. never, and 0.71 for independent walking [&le;]18 months vs. >18 months vs. never. The strongest predictors for adverse neurodevelopmental outcomes were presence of hypotonia at birth, seizure onset within the first day of life, multiple seizures per day at onset, tonic seizures at onset, a burst-suppression pattern on EEG at onset, the presence of a de novo variant, and variant location within exons 6-7. Significance: These prediction models demonstrate the feasibility of early prognostication in KCNQ2-RD and support future prospective external validation. They enable more accurate individualised counselling by integrating clinical and genetic information readily available at time of genetic diagnosis and provide an objective foundation for early intervention planning and future precision medicine trial stratification.

Introduction Post stroke dysphagia is common, associated with poor functional outcome and lacks treatment strategies beyond behaviour therapies delivered by speech & language therapists. Here, we present the statistical analysis plan for the ongoing pharyngeal electrical stimulation for acute stroke dysphagia trial (PhEAST). PES is a candidate treatment for dysphagia present in non-ventilated stroke patients. Methods PhEAST is an investigator-initiated international prospective randomised open-label blinded-endpoint phase-4 superiority trial involving 650 participants with tube-dependent post-stroke dysphagia. Consenting patients are randomised to PES versus no PES given on top of standard care with PES given daily for 6 days. The primary outcome is the dysphagia severity rating scale (DSRS), a measure of swallowing impairment, made at days 14 and 90 and analysed using repeated measures regression. Conclusion We present the statistical analysis plan for the main analyses based on data up to day 90 along with planned secondary analyses including presentation of baseline data, health economics, cognition and extended follow-up to 12 months.

INTRODUCTION: Biomarkers for monitoring disease activity and treatment response in peripheral neuropathies remain limited. Big tau, a high-molecular-weight isoform of tau, is predominantly expressed in the peripheral nervous system (PNS). We investigated serum levels of big tau, brain-derived tau (BD-tau), and neurofilament light chain (NfL) in peripheral neuropathies, multiple sclerosis (MS), Alzheimer disease (AD), and healthy controls (HC). METHODS: Ultra-sensitive blood-based assays run on an HD-X Single Molecule Array analyser (Quanterix) were used to measure big tau and BD-tau in serum from patients with Guillain-Barr&eacute syndrome (GBS, n=81), Miller Fisher syndrome (MFS, n=20), Charcot-Marie-Tooth disease (CMT, n=102), chronic inflammatory demyelinating polyneuropathy (CIDP, n=43), MS (n=159), AD (n=20), and HC (n=41). NfL was measured in patients with neuropathies using an SR-X Single Molecule Array analyser (Quanterix). RESULTS: Serum big tau levels were higher in GBS than in AD (11.4 vs 2.4 pg/mL, p<0.0001) and MS (11.4 vs 9.0 pg/mL, p=0.01), and similar to CIDP and CMT. Contrarily, serum BD-tau levels in GBS were higher than in CIDP (3.0 vs 2.3 pg/mL, p=0.006) and MS (3.0 vs 1.7 pg/mL, p<0.0001), but similar to CMT, and lower than in AD (3.0 vs 9.8 pg/mL, p<0.0001). Serum NfL levels were higher in GBS than in CIDP (32.5 vs 13.0 pg/mL, p=0.0002), CMT (32.5 vs 12.3 pg/mL, p<0.0001), and HC (32.5 vs 7.6 pg/mL, p<0.0001). Compared with GBS, MFS patients showed higher BD-tau (12.7 vs 3.0 pg/mL, p=0.003), lower big tau (5.4 vs 11.4 pg/mL, p=0.002), and higher NfL levels, although the latter did not reach statistical significance (118.3 vs 32.5 pg/mL, p=0.16). The NfL/big tau ratio was significantly higher in MFS than in GBS, CIDP, and CMT. In GBS, BD-tau correlated with early clinical severity (MRC at 1 week; I-RODS at 4 weeks; maximum GBS-DS and GBS-DS at 4 weeks), whereas neither tau biomarker showed long-term clinical correlations. Higher BD-tau and big tau levels were associated with the need for mechanical ventilation (BD-tau: 8.6 vs 2.9 pg/mL, p=0.019; big tau: 19.7 vs 10.7 pg/mL, p=0.007), while higher BD-tau levels were associated with mortality (10.9 vs 2.9 pg/mL, p=0.003). CONCLUSIONS: Higher big tau levels in peripheral neuropathies than in CNS diseases support its role as a PNS-specific biomarker. In MFS, increased serum BD-tau, reduced big tau, and an elevated NfL/big tau ratio suggest CNS involvement with relative preservation of the PNS.

Background: Evidence regarding delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) remains sparse. We aimed to identify its predictors and occurrence and evaluate its role in ischemic stroke and functional outcome under treatment with interventional rescue therapy (IRT). Methods: This retrospective single-center study included 628 adults with aSAH from 2014?2023. The primary endpoint was occurrence of refractory DCI (= refractory despite induced hypertension) treated with at least one IRT. Multivariable models evaluated refractory DCI, new ischemic stroke, and poor functional outcome (mRS 3?6) at 6?12 months. Results: Among 628 included patients, 61 who died within 3 days were excluded from DCI analysis; 166/567 (29%) developed refractory DCI. Younger age (OR = 0.98; P<0.001), female sex (OR = 0.57; P=0.007), and higher WFNS grade (OR = 1.18; P=0.011) were independently associated with refractory DCI. Earlier first IRT was associated with longer DCI duration (IRR = 0.88; P<0.001) and more required IRTs (IRR = 0.91; P<0.001). IRT was performed later than day 14 in 29/166 patients (17.5%); none was older than 70 years. Refractory DCI was associated with new ischemic stroke (OR = 4.68; P<0.001) and poor functional outcome (OR = 2.37; P<0.001); earlier first IRT was associated with poor outcome within the refractory DCI subgroup (OR = 0.86; P=0.03). Outcomes after 1?2 IRTs did not differ from those without refractory DCI (P=0.4), whereas ?3 IRTs were associated with poor outcome (P=0.04). Conclusions: Refractory DCI affected 29% of aSAH patients, predominantly younger women and patients with poorer initial neurological status, and extended beyond day 14 in nearly 20% of affected patients, none of whom was older than 70 years. Refractory DCI and earlier onset were associated with poorer radiological and functional outcomes. The absence of a detected outcome difference after 1?2 IRTs suggests that favorable outcomes may remain achievable despite refractory DCI.

Background and Objectives. Prion disease is an untreatable, typically rapidly progressive dementia. New drug candidates designed to lower prion protein are now entering clinical trials. To support future pivotal trials, we sought to assemble and analyze a public dataset of natural history data characterizing the symptomatic course of prion disease in order to provide a quantitative basis for modelling and rational trial design. Methods. We extracted data from medical publications between 2000 and 2024 reporting on n[&ge;]5 prion disease patients. Information about demographics, ascertainment, and clinical milestones, such as time from onset to death, akinetic mutism, diagnostic testing and outcomes, were extracted for aggregate cohorts of [&ge;]2 patients and individual patient-level data (PLD). We computed summary statistics of cohorts and PLD, visualized survival through forest plots and Kaplan-Meier curves, analyzed covariates regarding survival, and identified biases and heterogeneity within the literature. Results. From 245 included publications we extracted 418 aggregate cohort medians and 1,400 rows of individual PLD. 90% of cohorts and 91% of individual patients had symptom-to-death milestones, while only 7% and 11% had a time interval from a clinical presentation milestone to death, respectively. Symptom-to-death intervals varied as much as 3.2-fold even between cohorts of the same histopathologic subtype, and akinetic mutism occurred 73% sooner than death when both endpoints were reported (N=53). Indicators of disease severity, such as a cognitive test, were rarely present in either aggregate data (11%) or PLD (6%). Discussion. Data routinely reported in publications can quantify diagnostic delay and covariates affecting survival time, but are limited in ability to inform pivotal trial design because most such data are aggregated, cross-sectional, lack indicators of disease severity, and present timelines beginning with onset rather than more relevant clinical milestones, such as diagnosis, that may better reflect the moment of potential for trial enrollment. There is a need for clinical data to report milestones such as intervals from diagnosis to death, for longitudinal cognitive and functional scores, and for deposition of publicly accessible PLD.

Background: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with no known cure. Disease progression in people living with ALS is heterogeneous, hindering personalized treatment development. The current gold standard for measuring disease progression in ALS, the ALS Functional Rating Scale - Revised (ALSFRS-R), is widely used but based on subjective measurements. Blood-based neurofilament light (NfL) has been studied as a diagnostic and prognostic biomarker but less information exists on its utility as a disease progression biomarker. Methods: We present results from blood draws of 300 participants in the FDA-funded Clinic-Based Multi-Site ALS Natural History and Biofluid study of the ALS Natural History Consortium (NHC). Plasma NfL levels were measured and analyzed against different disease progression metrics based on the ALSFRS-R. Results: NfL levels were found to be correlated with the ALSFRS-R average rate of change (r=-0.53, 95% CI -0.62 to -0.42). This association differed at a cutoff value of 61 pg/mL, with stronger correlations below this cutoff (r=-0.51 vs r=-0.18). Survival differed stratifying by this cutoff value, with participants under the cutoff having higher survival probabilities. The predictive value of NfL when predicting time to death was higher compared with the first ALSFRS-R across different event horizons. A model including both was better when predicting events up to 2 years after diagnosis. Conclusions: These results highlight the utility of NfL as a disease progression biomarker in ALS alongside ALSFRS-R based disease progression metrics. The cutoff value can aid in clinical trial stratification, pragmatic trial planning, and clinical care.

Background: Telestroke evaluation and treatment programs are a promising option for geographically underserved populations. Adherence to guideline-based secondary prevention measures among telestroke programs remains understudied, particularly for patients with symptomatic intracranial atherosclerosis. The primary objective of this study was to evaluate whether routine telestroke consultation provides guideline-concordant management comparable to on-site vascular neurology consultation. Methods: This retrospective cohort review identified patients with stroke due to intracranial atherosclerosis within a single healthcare system comprising nine hospitals, including two comprehensive stroke centers with on-site stroke coverage and seven sites with remote telestroke coverage. Data was collected from January 2019 to December 2023. Adherence to guideline-based quality indicators was determined using four primary outcome measures including rates of permissive hypertension, high-intensity statin prescription at discharge, time to initiation of first antiplatelet medications, and appropriate antithrombotic therapy at discharge. Results: A total of 132 patients were included in the final analysis (median age, 69 years; 65 female [49.2], 67 male [50.8%]), with 87 patients evaluated and managed on-site and 45 via telestroke. Guideline adherence was similar between groups for permissive hypertension and discharge antithrombotic therapy. Patients managed via telestroke were more likely to receive high-intensity statins at discharge (absolute difference 27.1% (95% CI 11.4, 42.8)) and received antiplatelet therapy earlier than patients managed on-site. Conclusion: In this multisite, single-system cohort, routine telestroke consultation was associated with similar or greater adherence to selected guideline-based management measures compared with on-site vascular neurology consultation.

Background: Atrial fibrillation detected after stroke (AFDAS) is frequently diagnosed after embolic stroke of undetermined source (ESUS) and has important implications for secondary stroke prevention. Although prediction scores have been proposed to identify patients at increased risk of AFDAS, prospective evidence supporting their implementation to guide rhythm monitoring in routine clinical practice is limited. Methods: In this prospective, population-based implementation cohort study, adults with ESUS were enrolled between January 2022 and December 2024 across all stroke centers in Styria, Austria. The Graz AF Risk Score was prospectively implemented as part of a risk-adapted diagnostic pathway for cardiac rhythm monitoring. Patients with a score [&ge;]4 were recommended for implantable loop recorder monitoring, whereas monitoring in those with scores <4 remained at the treating physician's discretion. The primary outcome was AFDAS detection; recurrent ischemic stroke and recurrent stroke etiology were secondary outcomes. Results: Among 784 patients (median age 73 years [IQR 64-80], 45.7% women), AFDAS was detected in 166 patients (21.2%) during a median follow-up of 26.3 months (IQR 20-34). AFDAS detection was substantially higher in patients with a Graz AF Risk Score [&ge;]4 than <4 (38.1% vs. 3.9%; p<0.001). After adjustment for age, sex and ILR monitoring, a score [&ge;]4 independently predicted AFDAS (HR 6.3, 95% CI 3.5-11.2; p<0.001) and recurrent ischemic stroke (HR 2.2, 95% CI 1.1-4.1; p=0.023). Only one recurrent stroke in patients with a score <4 was attributable to atrial fibrillation (AF) (1/18, 5.6%). Conclusions: Prospective implementation of the Graz AF Risk Score identified patients with ESUS at markedly different risks of AFDAS. A Graz AF Risk Score [&ge;]4 was also independently associated with recurrent ischemic stroke. These findings support a risk-adapted approach to cardiac rhythm monitoring after ESUS.

BACKGROUND Recruitment in stroke neurorehabilitation trials is often difficult, particularly in studies requiring MRI and repeated laboratory visits. The recruitment efficiency was analyzed to identify the major barriers to enrollment in a stroke neurorehabilitation trial. METHODS In this observational screening study, 1201 patients were screened at a neurological rehabilitation center in Germany between October 2023 and February 2026. Recruitment barriers were analyzed using a stepwise recruitment flow approach. RESULTS Of 678 patients with ischemic stroke, 13 were ultimately enrolled (1.9%; 1.1% of all 1201 screened rehabilitation patients). The most common exclusion reasons were strict clinical eligibility criteria (52.2%), travel distance to the study center (23.9%), and predefined age restrictions (17.9%). Recruitment losses occurred across multiple stages of the screening process. CONCLUSION Recruitment in stroke neurorehabilitation trials is strongly limited by restrictive study criteria and logistical barriers. More pragmatic and inclusive study designs may improve recruitment efficiency and better reflect real-world stroke populations.

Background The global increase in autism spectrum disorder (ASD) diagnoses is expected to substantially increase demand for long-term rehabilitation services. However, little is known about how this increase affects rehabilitation service utilization and capacity in low- and middle-income countries. Methods We conducted a retrospective longitudinal study of children receiving developmental care at a tertiary rehabilitation center in Salvador, Brazil (2017-2026). Patients were classified into Childhood Autism, Other ASD, and non-ASD diagnostic groups according to ICD-10 diagnoses. Temporal trends in admissions and patients under follow-up were analyzed using generalized additive models and segmented Poisson regression. Factors associated with follow-up duration were evaluated using multivariable Cox proportional hazards models. Results Among 2,123 eligible children, 833 (39.2%) had Childhood Autism, 462 (21.8%) had Other ASD, and 828 (39.0%) had non-ASD diagnoses. Compared with children with non-ASD diagnoses, those with Childhood Autism entered care at younger ages, were predominantly male (77.9% vs. 57.2%), attended more visits, and remained under follow-up longer (all P<0.001). Admissions of children with Childhood Autism increased by 30.2% annually before 2023 but declined thereafter (-19.6% annually; P<0.001). Despite this decline, the number of children with Childhood Autism receiving ongoing rehabilitation continued to increase, reflecting prolonged follow-up. In adjusted analyses, Childhood Autism was associated with a substantially lower hazard of reaching the last recorded follow-up visit than non-ASD diagnoses (adjusted hazard ratio, 0.35; 95% CI, 0.30-0.40; P<0.001). Conclusions The rapid increase in ASD admissions fundamentally reshaped rehabilitation service utilization. Because children with ASD remained under follow-up substantially longer than those with other developmental conditions, they accounted for an increasing share of the rehabilitation caseload, even after new admissions began to decline. These findings highlight the importance of planning rehabilitation services according to both new admissions and the cumulative demand generated by long-term follow-up.

Background: Therapy development in ultra-rare, progressive and fatal diseases like vanishing white matter (VWM) is hampered by very low patient numbers and ethical constraints regarding placebo-controlled studies. Under such conditions, standard randomized controlled trials may not be feasible. The use of historical control information could be part of a solution, but would require extra considerations regarding selection of patients and choice of endpoints. We used the VWM registry as a case study to outline key methodological considerations for informing trial design in ultra-rare disease. Methods: The study included 462 patients, available in the VWM registry. Prospective clinical data were collected since 2004 using VWM-specific questionnaire and Health Utility Index (HUI) assessments, while retrospective data from clinical charts were available from 1988 on. We evaluated methodological aspects relevant to trial design, including patient selection, drift in the disease course over time, endpoint selection, and clinically relevant stratification into subgroups. Results: Regarding patient selection, patients with comorbidities impacting disease course, and pre-symptomatic individuals without clinical onset were considered not suitable as historical controls. After excluding patients before 1991, we found no evidence of drift in the disease course from 1991 onwards. Regarding choice of endpoints, episodes of rapid decline were relatively infrequent and occurred mostly at disease onset, limiting their usefulness as trial endpoint. Multi-state modelling and clinical evaluation showed ambulation as preferable endpoint over survival. For longitudinal HUI multiscores, baseline imputation allowed modelling of early disease. The scores showed a distinct ordering, reflecting the association between multi-domain function and disease progression. Regarding stratification, the combination of data-driven analyses and clinical expertise informed revised age of onset groups. Females showed later onset and milder disease; adjustment for age of onset eliminated the effect of sex. Conclusion: This case study provides key considerations for evaluating registry data as historical control and demonstrates how these considerations can inform clinical trial design in ultra-rare diseases.

Objective: Whether a scheduled antiseizure medication (ASM) continues on schedule across the ICU-to-floor transfer has not been characterized. We quantified ASM administration-gap frequency across this transfer and compared it with gap frequency during matched non-transfer intervals in the same patient and drug. Methods: In this retrospective MIMIC-IV (version 3.1) cohort study, we identified epilepsy and status-epilepticus admissions with an ICU stay followed by floor transfer and a scheduled ASM order active at ICU departure. A gap was defined as an interval exceeding 1.5 times the expected dosing interval between the last ICU dose and first floor dose, or no further dose before discharge, and compared with a matched non-transfer control interval in the same patient and drug (paired McNemar test). A multivariable model evaluated six prespecified clinical predictors; sociodemographic variables were summarized descriptively. Results: Among 2,469 ASM transition-by-drug observations (1,583 admissions, 1,335 patients), an administration gap occurred in 251 (10.2%; 95% CI, 8.7%-11.7%). Gap frequency across the transfer exceeded frequency during matched non-transfer control intervals in the same patient and drug: a paired rate difference of 5.8 percentage points (95% CI, 4.4-7.1; 7.5% vs 1.7%; P = 7.3 x 10^-22) before the transfer and 6.4 percentage points (95% CI, 4.9-7.9; 8.9% vs 2.5%; P = 1.9 x 10^-23) after. Gap rates were similar for intravenous-available (9.9%) and oral-only (11.4%) drugs (rate difference, 1.5 percentage points; 95% CI, -1.6 to 4.5; P = .34). None of six prespecified predictors reached significance after correction. Significance: An antiseizure medication administration gap occurred in approximately 1 of every 10 drug-transition observations at the ICU-to-floor transfer, exceeding matched non-transfer gap rates by 5.8 to 6.4 percentage points. This transfer-associated excess, rather than any single medication or patient characteristic, supports a structured medication-continuity check.

Background: The Boston Criteria v2.0 represent the gold standard for diagnosing Cerebral Amyloid Angiopathy (CAA), but their application is currently precluded in mixed small vessel disease (SVD), where deep and lobar hemorrhages coexist. The aims of this study are: (i) to determine which cerebrospinal fluid (CSF) biomarker (A{beta}42, A{beta}40, A{beta}42/40 ratio) is the best candidate to support the CAA diagnosis; (ii) to define a data-driven cut-off, and (iii) to explore if a biomarker-integrated classification significantly improves the phenotypical concordance with the suspected predominant SVD (CAA vs. arteriosclerosis). Methods: We analyzed data from a retrospective multicenter cohort of patients with suspected CAA, defined as probable CAA (Boston criteria v2.0) but allowing deep hemorrhagic lesions, and with available CSF biomarkers. We visually quantified MRI-visible SVD markers (e.g., cerebral microbleeds [CMB], cortical superficial siderosis [cSS], lacunes) and their association with MRI-visible SVD features. We employed a Gaussian Mixture Model (GMM) to identify a data-driven threshold for amyloid positivity (A+). Then, we compared the prevalence of MRI-visible manifestations of SVD between subgroups applying different frameworks, namely the current MRI-based classification (probable CAA vs. mixed SVD) and a CSF biomarker-integrated classification (A+ vs. A-). Results: We enrolled 121 patients (age: 72 [66-77] years; 60% probable CAA, 40% mixed SVD with suspected CAA). The CSF A{beta}42/40 ratio showed a bimodal distribution and consistent associations with all CAA-specific radiological features. The CSF biomarker-integrated reclassification, particularly using the GMM cut-off, significantly improved the distinction between subgroups regarding CAA- and arteriosclerosis-related MRI features (e.g., cSS presence: probable CAA vs. mixed SVD: aOR=2.84 [95%CI 1.27-6.39], p=0.011; A+ vs. A-: aOR=12.68 [95%CI 4.31-37.32], p<0.001; deep lacunes presence: probable CAA vs. mixed SVD: aOR=0.20 [95%CI 0.08-0.50], p<0.001; A+ vs. A-: aOR=0.04 [95%CI 0.01-0.11], p<0.001). Notably, patients classified as A+ never demonstrated more than four deep CMBs. Discussion: A CSF biomarker-integrated classification may improve the classification of CAA compared with the current MRI-based framework. These findings are cohort-specific and would benefit from further validation, especially with a neuropathological reference. Still, these results support a future transition toward an integrated biological-radiological framework, which may refine in vivo CAA diagnosis, particularly in mixed SVD.

Background: On-call clinicians frequently report the anecdotal impression of 'theme shifts' during which specific acute neurological diagnoses appear to cluster. Whether such clustering reflects a statistically true and reproducible phenomenon has not been systematically investigated; the present paper examines seasonality and temporal clustering within six different acute neurological conditions. Methods: In this retrospective, single-center cohort study, we identified all patients admitted to a tertiary neurological department between July 2016 and June 2026 with acute unilateral vestibulopathy, cerebral artery dissection, generalized epileptic seizures, primary intracerebral hemorrhage, peripheral facial nerve palsy, or transient global amnesia (TGA) (n = 2,140). Monthly and seasonal distributions were assessed using chi-squared goodness-of-fit and cosinor analysis. Short-term temporal clustering was tested by Monte Carlo permutation across time windows from 24 hours to 90 days, and endogenous cluster dynamics were characterized using Hawkes self-exciting point process modeling. Results: Admissions for generalized epileptic seizures showed a statistically significant deviation from a uniform monthly distribution with a winter distribution (p<0.001 and q = 0.002), and a significant temporal clustering across time windows from 72 hours to 90 days (all q < 0.05). Peripheral facial nerve palsy presented significant clustering at the 90-day window (q = 0.029) and TGA at 60-day time window (q = 0.041) without seasonality; the diagnostic groups of acute unilateral vestibulopathy, cerebral artery dissection and primary intracerebral hemorrhage showed neither seasonality nor clustering after correction for multiple comparison. No diagnostic group showed clustering within a 24-hour window, statistically significant self-excitation in Hawkes process modelling, or a significant linear trend in monthly case counts over the study period. Conclusion: The anecdotal impression of diagnostic 'theme shifts' among on-call neurologists appears to have a measurable basis, although clustering is confined to specific conditions and rather on a time scale of weeks to months. Generalized epileptic seizures were the only diagnostic group that uniquely combined seasonality with temporal clustering, suggesting a shared trigger, while facial palsy and TGA showed episodic, yet non-seasonal clustering.

The Dementia Trials Accelerator (DTA) is a UK-wide programme designed to improve the feasibility, efficiency, and inclusiveness of recruitment into clinical trials of dementia and related brain-health conditions. Dementia trials are frequently constrained by the difficulty and cost of identifying eligible participants, which often requires cognitive assessments and measurement of blood-based biomarkers. The DTA addresses these barriers with two linked services. First, the DTA provides a federated platform to improve findability of potential participants across existing UK-based cohorts with consent to recontact. A single point of contact across multiple cohorts would allow increased efficiency of search for participants for studies. Second, the DTA provides a community-centred pre-screening service with information relevant to trial eligibility and a linked plasma and DNA tissue bank, with participant consent for recontact. Participants aged 65-75 years are approached via existing cohorts and registries. Consenting participants complete an online questionnaire and digital cognitive assessment, attend an in-person assessment for physical measures and face-to-face cognitive testing, and provide venous blood samples which are processed to plasma and whole blood for long-term storage and biomarker measurement. The initial programme target is to recruit at least 10,000 participants into the DTA pre-screening service. The DTA is designed to support approved academic and industry studies by enabling the DTA team to approach eligible participants for specific studies, without transferring identifiable information without consent. In parallel with its immediate trial-readiness purpose, the DTA is positioned to interoperate with emerging national approaches to biomarker-led recruitment by generating high-quality, recontactable cohorts with standardised cognitive characterisation and scalable biosampling suitable for blood-based biomarkers.

Background Blood biomarkers are increasingly used to support the diagnosis and monitoring of neurodegenerative diseases. However, their interpretation is complicated by physiological determinants, including age, sex, body-mass index, and renal function, and by differences in absolute concentrations between analytical methods. We aimed to develop population-based reference equations allowing individualized interpretation of the main blood biomarkers used in neurology. Methods In this cross-sectional study, we analysed plasma samples from cognitively unimpaired participants selected from the French CONSTANCES and Three-City population-based cohorts. Generalized additive models for location, scale, and shape were used to model neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), phosphorylated tau 181 (p-tau181), amyloid-{beta}40, amyloid-{beta}42, and their ratios according to age, sex, body-mass index, and renal function. The resulting equations provided individualized expected concentrations, percentiles, and Z-scores. Previously established disease-specific concentrations were converted into Z-score. Cross-calibration equations were developed for NfL measurements across analytical methods and sample matrices. Findings The final reference populations comprised 5123 participants for amyloid biomarkers and p-tau181 and 5122 for NfL and GFAP; median age was 52.3 years and half were women. Between ages 40 and 80 years, expected NfL and GFAP concentrations increased by an average of 2.6% and 2.2% per year, respectively. Renal function, body-mass index, and sex had additional biomarker-specific effects. Application of the equations to clinical cohorts preserved distinct disease-associated profiles: NfL Z-scores were increased across disorders characterised by neuroaxonal injury, whereas p-tau181 and GFAP showed its greatest increase in Alzheimer disease. NfL cross-calibration equations showed excellent agreement between methods and matrices, with intraclass correlation coefficients greater than 0.90. Interpretation This population-based multibiomarker framework enables blood biomarker concentrations to be interpreted relative to individuals with similar physiological characteristics. Publicly available equations, reference curves, and standardized Z-scores could improve individualized interpretation and comparability across biomarkers, laboratories, and clinical populations.

Objective: To determine whether paradoxical relief, feeling unusually better after a seizure compared to before it, is more common after functional/dissociative seizures (FDS) than epileptic seizures (ES), quantify its diagnostic accuracy, and explore its relationship with preictal symptoms. Methods: Consecutive patients admitted to a tertiary epilepsy unit for prolonged inpatient EEG monitoring underwent a structured clinical interview on admission, before final multidisciplinary diagnostic classification. Preictal dissociative and autonomic/somatic symptom burden was assessed using items adapted from established questionnaires. Diagnostic classification incorporated clinical history, seizure semiology, video electroencephalography findings, and collateral information. Patients with dual or indeterminate diagnoses were excluded. Associations with paradoxical relief were examined using logistic regression, followed by an exploratory mediation analysis. Results: Of 176 patients assessed, 66 with FDS and 65 with ES were included. Paradoxical relief was reported by 46/66 patients with FDS (69.7%) and 10/65 with ES (15.4%; unadjusted odds ratio [OR] 12.65, 95% confidence interval [CI] 5.57 to 31.09). As a diagnostic signal for FDS, paradoxical relief had 69.7% sensitivity (95% CI 57.1 to 80.4), 84.6% specificity (95% CI 73.5 to 92.4), a positive likelihood ratio of 4.53 (2.51 to 8.19), and a negative likelihood ratio of 0.36 (0.24 to 0.52). FDS diagnosis remained independently associated with paradoxical relief after adjustment (OR 10.59, 95% CI 3.42 to 38.06). In a parallel mediation analysis, dissociative symptom burden showed a significant indirect effect, accounting for 19.5% of the association between diagnostic group and relief, whereas the indirect effect through somatic/autonomic symptom burden was not significant. Significance: Paradoxical relief is substantially more common after FDS than ES and may provide a simple, clinically useful diagnostic signal. Its absence does not exclude FDS, and the finding requires external validation. The association with dissociative symptoms is exploratory and supports prospective investigation of whether relief reflects transient resolution of a disturbed, disembodied preictal state.