Introduction:Diagnosing Parkinson's disease (PD) and related synucleinopathies in patients with early or atypical features remains challenging. Dopamine transporter single-photon emission CT (DaT SPECT) imaging and phosphorylated alpha-synuclein (p-Syn) skin biopsy are increasingly used, but their concordance and combined value in diagnostically uncertain, real-world patients are unknown. We evaluated whether these two biomarkers provide complementary rather than redundant diagnostic information. Methods:We retrospectively analysed patients evaluated at a tertiary movement disorders centre (January 2022-March 2025) who presented with parkinsonism or tremor not meeting established criteria for PD, multiple system atrophy or dementia with Lewy bodies. 86 patients underwent p-Syn skin biopsy; 52 also underwent DaT SPECT. Using the treating neurologist's final clinical diagnosis as the reference standard, we calculated sensitivity, specificity, predictive values and concordance for each test and for combined ('either-positive') testing and compared clinical features between concordant and discordant groups. Results:DaT SPECT and p-Syn biopsy showed similar sensitivity (79.0% and 79.0%) and specificity (74.0% and 81.0%) for synucleinopathy. Combined testing increased sensitivity to 95.6% but reduced specificity to 59.9%. Results were discordant in 30.8% of dual-tested patients; +DaT/-p-Syn patients more often reported hyposmia, whereas -DaT/+p Syn patients more often reported REM sleep behaviour disorder. Almost half of discordant cases ultimately met criteria for idiopathic PD. Conclusions:DaT SPECT and p-Syn skin biopsy provide complementary, not redundant, diagnostic information. The high discordance, with eventual PD diagnosis in many cases, is consistent with the dual-origin (brain-first vs body-first) model of alpha-synuclein propagation. Both are best used as rule-in tests in early or diagnostically uncertain disease, where a negative result does not exclude a synucleinopathy; in advanced disease meeting full clinical criteria, they may have greater rule-out value. Combined testing improves early detection at a cost to specificity, with implications for trial enrolment and for interpreting biomarkers alongside symptom evolution.
Introduction:Timely and accurate identification of stroke subtypes, particularly intracerebral haemorrhage (ICH) and large vessel occlusion (LVO), is essential for improving stroke outcomes. Biomarkers have shown potential in identifying these subtypes. Glial fibrillary acidic protein (GFAP), which is elevated in ICH, and D-dimer, which is associated with LVO, are promising for rapid, point-of-care identification. This study evaluates whether combining GFAP and D-dimer with clinical features improves the diagnostic accuracy for ICH and LVO. Methods and analysis:This is a multicentre, observational diagnostic accuracy study recruiting a minimum of 257 patients with suspected stroke within 6 hours of symptom onset from two UK hyperacute stroke centres. The study will integrate clinical features and point-of-care biomarker results using the LVOne test (GFAP and D-dimer) to develop diagnostic models that differentiate ICH and LVO from other stroke presentations. Patients will be identified on hospital arrival, and clinical variables and blood samples collected immediately, with the final diagnosis recorded prior to discharge. Statistical analyses will assess discrimination, calibration and clinical utility, with sensitivity, specificity and predictive values reported. Model development and reporting will follow the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis+Artificial Intelligence and the Standards for Reporting of Diagnostic Accuracy Studies guidelines. Ethics and dissemination:The study is registered with ISRCTN (ISRCTN35174477). Ethical approval has been obtained from the Yorkshire & The Humber - Leeds West Research Ethics Committee (25/YH/0102) and the Health Research Authority. Results will be disseminated via open-access peer-reviewed journals, presentations at national and international conferences and summaries for patient and public contributors.
Background:Postoperative delirium (POD) is a common complication of deep brain stimulation (DBS) in patients with Parkinson's disease, leading to worsened outcomes. However, predictive factors remain unclear. This study aimed to identify predictors of POD following subthalamic nucleus (STN) DBS, with a focus on preoperative radiographic assessment and caudate nucleus (CN) transgression. Methods:We retrospectively reviewed 122 patients who underwent awake STN DBS from June 2017 to August 2024. Clinical, laboratory and imaging variables were assessed including postoperative classification of CN transgression. Two Firth logistic regression models were constructed for analysis, with model 1 including and model 2 excluding the Movement Disorder Society Non-Motor Rating Scale. Results:POD occurred in 16.4% of the patients. Model 2 (n=62, area under the curve (AUC)=0.904) showed superior performance to model 1 (n=122, AUC=0.884). History of lumbar TPS (trans-pedicle screw fixation) surgery (OR 6.21) and higher preoperative score of Unified Parkinson's Disease Rating Scale (UPDRS) part II (off-medication) (OR 1.13) were independent predictors. A higher medial temporal lobe atrophy (MTA) score (OR 3.481) showed marginal significance (p=0.054). CN transgression by the electrode or postoperative perilead oedema (PLE) was not associated with an increased risk. Conclusions:In this study, a higher preoperative UPDRS II score (off-medication) and history of lumbar TPS surgery are independent predictors of POD following STN DBS. A higher MTA score is marginally significant in predicting POD. In contrast, CN transgression or postoperative PLE appears to be unrelated. These findings may aid in risk stratification and surgical planning.
Background:The use of wearable technology results in objective and reliable monitoring of motor activity in Parkinson's disease (PD) but its utility as a diagnostic aid has not been assessed. Objectives:To assess whether a Personal KinetiGraph (PKG) performed at baseline and again following a long-form levodopa (LD) challenge (increasing to 300 mg daily over a minimum of 6 weeks) is a useful discriminator in those with parkinsonism but diagnostic uncertainty. Methods:Over a 10-year period, 26 patients with parkinsonism in whom there was diagnostic uncertainty due to clinical complexity or conflicting evidence were tested with a PKG, recording bradykinesia and tremor before and after formalised treatment with LD. Patients were followed for a median of 46.5 months (mean 49.8) to establish a 'final' clinical diagnosis. Results:Of the 15/26 diagnostically uncertain patients with a 'final' diagnosis of PD, the PKG demonstrated bradykinesia (mean bradykinesia score ≥25) at baseline in 14/15; in 12/15, bradykinesia improved with LD and, when present, tremor was similarly reduced. In the 11/26 patients who had a final diagnosis other than PD, the PKG recorded bradykinesia in 3/11 with improved bradykinesia and reduced tremor in only 1/11. PKG-defined bradykinesia coupled with LD responsiveness was 88% sensitive (95% CI 57% to 98%) and 89% specific (95% CI 52% to 99%) for a 'final' PD diagnosis in this select group. Additionally, PKG-defined tremor and LD responsiveness had a sensitivity of 85% (95% CI 55% to 98%) and specificity of 89% (95% CI 52% to 99%). Conclusion:PKG-defined bradykinesia and tremor coupled with LD responsiveness appear to be predictive of an eventual PD diagnosis in diagnostically challenging cases. Larger studies are required to verify these conclusions.
Introduction:Childhood stroke leads to long-term neurological impairment, impacts on quality of life and has substantial economic costs. Coordinated systems of care are required to streamline rapid diagnosis and treatment of stroke. The primary aim is to investigate the effect of Code Stroke protocols on increasing the proportion of children with stroke diagnosed within the 4.5-hour time window for reperfusion therapies. Methods and analysis:Prospective, multicentre, quasi-experimental interventional study in nine Australian and New Zealand children's hospitals from 2020 to 2026. Children aged 1 month to <18 years with stroke symptoms are eligible for inclusion. A staged pre-implementation and post implementation study design will investigate effects of (1) Code Stroke protocols to streamline diagnosis and treatment, (2) decision support tools to improve diagnostic accuracy and (3) perfusion imaging to quantify brain at risk of infarction. Presenting characteristics, timelines of care, treatments, functional and health economic outcomes will be collected. The primary outcome is the proportion of children with stroke diagnosed within 4.5 hours, estimated using a mixed-effect logistic regression model, with the dichotomous variable time to diagnosis as the dependent variable, implementation phase as the independent fixed effect and hospitals as random effects. Sample size calculation estimates that 98 patients with radiologically confirmed stroke per phase will yield 80% power to detect change from 15% to 40% in the proportion of children diagnosed within 4.5 hours.
Introduction Achieving seizure control remains a primary objective of epilepsy surgery but other important patient-centred outcomes should not be overlooked. Despite the need for more holistic approaches supporting well-being over and above seizure control, scant empirical research has identified effective interventions aimed at improving adults’ cognitive, psychological, and/or social outcomes following epilepsy surgery. This novel scoping review will be the first to map the evidence in this landscape.Methods and analysis The review will be conducted with reference to the Joanna Briggs Institute Manual for Evidence Synthesis and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. Databases searched will include MEDLINE, Embase, and CINAHL. Interventions of interest may be delivered preoperatively and/or postoperatively, and primary outcomes will be specific to cognitive, psychological, and social functioning after either resective or ablative epilepsy surgery conducted in adulthood. No limitations will be imposed on publication date, language, or country/region of origin. Selection will be based on title and abstract examination followed by full-text review. Data will be charted in duplicate and the results of descriptive and qualitative analyses will be presented using tabular and graphical formats, along with a narrative summary of the findings.Ethics and dissemination Ethics approval is not required for this review. The final review will be submitted for peer review in a medical journal and considered for dissemination via the International League Against Epilepsy (ILAE). This review is intended as a first step towards informing the development of ILAE consensus-based recommendations on enhancing cognitive, psychological, and social outcomes after epilepsy surgery in adulthood.
Background Spinal dural arteriovenous fistula (sdAVF) is treatable but may be overlooked when MRI shows a longitudinally extensive T2-hyperintense lesion without clear flow voids. We assessed whether mismatch between MRI lesion extent and bedside sensory mapping could prompt reconsideration of sdAVF.Methods We retrospectively analysed eight confirmed sdAVF cases from a consecutive single-centre cohort of 10 patients with spinal AVF between January 2013 and December 2024. Pretreatment MRI lesion and sensory deficit ranges were converted to myelomeres, and strength in selected bilateral lower limb muscles was summarised descriptively.Results MRI lesion range exceeded sensory deficit range in six of eight patients. Median MRI lesion length was 12.0 myelomeres (IQR 9.75–15.5) vs 6.0 myelomeres (IQR 3.5–8.5) for sensory deficit length; the median paired difference was 7.0 myelomeres (range −4 to 13). Despite long lesions, five of eight patients had total Medical Research Council scores of 26/30 or higher across selected bilateral lower limb muscles.Conclusions We observed clinicoradiological range dissociation in sdAVF. This finding may prompt reconsideration of sdAVF when the initial evaluation is inconclusive.
Introduction:Posterior circulation stroke (PCS) in the vertebrobasilar system carries high morbidity and mortality. While mechanical thrombectomy (MT) is effective in selected patients, functional recovery after MT for PCS remains variable and may be influenced by clinical, imaging and procedural factors. Objectives:To summarise clinical, imaging and procedural factors associated with functional recovery, defined as modified Rankin Scale 0-2 at 90 days, after MT in PCS. Methods:This systematic review and meta-analysis searched EMBASE, MEDLINE, PubMed, EBSCO, Scopus, CNKI, SSRN, bioRxiv and medRxiv from inception until 31 December 2025. Inclusion criteria were adult patients with PCS who underwent MT in clinical trials or observational studies. Risk Of Bias In Non-randomised Studies-of-Exposure was assessed. Meta-analysis used a random-effects model to pool ORs with 95% CIs, assessing heterogeneity via I2 and Cochran's Q test (PROSPERO: CRD42024626263). Results:We analysed 12 094 patients from 75 studies. Predictors of favourable outcomes included higher posterior circulation-Alberta Stroke Programme Early CT Score (OR=1.80, 95% CI 1.59 to 2.03, p<0.001, I2=0.0%), intravenous thrombolysis (OR=1.66, 95% CI 1.31 to 2.1, p<0.001, I2=21.7%), first-pass effect (OR=2.36, 95% CI 1.84 to 3.03, p<0.001, I2=9.28%) and modified thrombolysis in cerebral infarction 2b/3 (OR=3.58, 95% CI 2.31 to 5.55, p<0.001, I2=58.43%). Poor outcomes were associated with higher baseline National Institutes of Health Stroke Scale (OR=0.92, 95% CI 0.89 to 0.95, p<0.001, I2=85.09%), diabetes mellitus (OR=0.56, 95% CI 0.43 to 0.72, p<0.001, I2=24.63%), hypertension (OR=0.73, 95% CI 0.59 to 0.91, p=0.010, I2=0.0%) and general anaesthesia use (OR=0.56, 95% CI 0.36 to 0.89, p=0.010, I2=64.53%). Conclusions:Stroke severity, imaging scores and procedural success are factors consistently reported to be associated with functional outcomes in PCS after MT. Although the independence of these factors cannot be determined from this analysis, these findings may help summarise current evidence on reported prognostic factors and support future prospective validation using standardised protocols.
Rationale:Postictal psychosis (PIP) is a transient psychiatric phenomenon characterised by psychotic symptoms following a seizure. While its immediate manifestations have been well documented, there is limited understanding of its long-term implications, particularly its relationship with subsequent primary psychotic disorders. Methods:We conducted a retrospective cohort study using de-identified patient data from the TriNetX database (2006-2026). Individuals aged 18-65 years with a diagnosis of probable PIP (International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM): F06.0, F06.2) or brief psychotic disorder within 7 days of the epileptic disorder diagnosis (ICD-10-CM: F23) were propensity-score matched 1:1 with controls without PIP based on age, sex, race, ethnicity and relevant psychiatric and chronic physical comorbidities. We excluded individuals with prior psychotic disorders or delirium. The primary outcome was any psychotic disorder diagnosis within a 5-year follow-up period. Kaplan-Meier survival analyses and HRs were calculated to assess the differences in survival probabilities. Results:A total of 1275 individuals were identified and matched for analysis. Patients with probable PIP were at significantly higher risk for subsequent psychotic disorders (HR=10.78, 95% CI 6.21 to 18.70, p=0.002). The 5-year survival probability for developing any psychotic disorder was 85.79% in the probable PIP group compared with 98.21% in controls (log-rank test, χ2=112.25; p<0.0001). Conclusions:Probable PIP is associated with a heightened risk of subsequent primary psychotic disorders, including interictal forms, within 5 years.
Background:The McDonald criteria (MC) are fundamental in diagnosing multiple sclerosis (MS). Despite advancements in diagnosis, misdiagnosis remains a persistent challenge. The 2024 MC revisions incorporate new radiological features (central vein sign (CVS), paramagnetic rim lesions (PRLs)) and biomarkers (kappa free light chain (KFLC)) to enhance diagnostic specificity, even in asymptomatic individuals. Objective:To explore Egyptian neurologists' understanding of and readiness to implement the updated 2024 MC for multiple sclerosis diagnosis. Methods:An exploratory cross-sectional, open online survey was conducted among 143 neurologists in Egypt. A 16-item questionnaire assessed their professional background, MS exposure, attitudes towards the updated MC and access to relevant diagnostic and imaging resources. Domain scores for clinical confidence and knowledge/familiarity were computed, and associations with demographic factors were analysed. Results:Most neurologists (98%) actively managed MS cases, and 83% reported familiarity with the updated MC. Clinical confidence scores were moderate overall, whereas knowledge/familiarity scores were generally higher; the two measures were positively correlated (Spearman ρ = 0.24, p=0.02). Knowledge gaps remained: nearly 62% were unfamiliar with PRLs, and 38% were unaware of the CVS. Resource limitations were notable, with 83% lacking access to KFLC testing and 75% limited to 1.5 T MRI machines. Conclusion:Egyptian neurologists demonstrate strong engagement with the updated MC; however, limited awareness of novel markers and restricted access to essential diagnostic resources (3 T MRI, KFLC) present barriers to their optimal application.
Background The effect of early high-efficacy therapy initiation versus escalation from moderate-efficacy therapy on progression independent of relapse activity (PIRA) in multiple sclerosis remains unclear. This study aimed to compare the treatment strategies on effectiveness against PIRA. Methods From the Danish MS Registry, treatment-naïve adult patients with multiple sclerosis started on high-efficacy therapies or moderate-efficacy therapies between 2012 and 2022 were included in this nationwide cohort study. Stabilised inverse probability of treatment weights, derived from propensity scores, were applied to balance confounders and to perform weighted Cox and negative binomial regression models. Patients were followed under an intention-to-treat framework until the latest clinical visit before the data extraction date (2 June 2025). The primary outcome was time to first PIRA; the secondary outcome was annualised relapse rate (ARR). Results Among 3316 patients (594 high-efficacy, 2722 moderate-efficacy) with a median follow-up time of 7.4 years (min–max: 1.5–13.4), we found no statistical difference in time to first progression independent of relapse activity with a HR of 0.89, 95% CI 0.59 to 1.36, p=0.60. Early high-efficacy therapy initiation was associated with a 40% reduction in ARR (incidence rate ratio of 0.60, 95% CI 0.46 to 0.77, p<0.001). Conclusions In this nationwide cohort study, we found a reduction in relapse activity associated with early initiation of high-efficacy therapies but no statistically significant difference when investigating time to first PIRA. Our findings indicate a therapeutic gap in the current treatment landscape with respect to mitigating PIRA.
Background Malignant hemispheric infarction (MHI) is associated with high early mortality when managed conservatively. Decompressive hemicraniectomy (DHC) improves survival, but long-term functional outcomes and caregiver burden in low-resource settings remain poorly characterised, particularly in India. This study aimed to evaluate long-term outcomes and caregiver burden among MHI survivors undergoing DHC at a tertiary care centre in South India. Methods We conducted an ambispective study of adult patients who underwent DHC for MHI between 2018 and 2023 and had at least 6 months of follow-up. Functional outcome was assessed using the modified Rankin Scale (mRS) and caregiver burden was evaluated using the Zarit Burden Interview. Subgroup analyses were performed based on infarct lateralisation and timing of surgery. Logistic regression was used to identify predictors of a favourable functional outcome. Results 66 patients (mean age 44±12.8 years; 80% male) were included, with a median follow-up of 2 years (IQR: 1–4). Overall mortality was 24.2% (n=16). Among the 50 survivors, 26 (52.0%) achieved a good functional outcome (mRS ≤3) and 13 (26.0%) achieved an excellent outcome (mRS ≤2). Infarct lateralisation did not significantly influence mortality or functional recovery. Although early surgery and higher admission Glasgow Coma Scale scores were associated with better outcomes in univariate analysis, these factors were not significant in multivariate models. Caregivers of patients with mRS >2 reported significantly higher burden, particularly in emotional, physical and social domains. Conclusions DHC for MHI results in meaningful long-term survival and functional recovery in selected patients, regardless of hemisphere involvement. However, residual disability imposes a substantial caregiver burden. Stroke care pathways in resource-limited settings should incorporate comprehensive rehabilitation and long-term caregiver support.
Background Phase 3 trials of the anti-amyloid monoclonal antibodies lecanemab and donanemab in Alzheimer’s disease demonstrated modest slowing of cognitive decline over 18 months. Subsequent open-label extensions (OLE) suggested greater long-term benefit based on comparisons with historical untreated cohorts, which are vulnerable to selection and attrition bias. Methods We simulated longitudinal Clinical Dementia Rating–Sum of Boxes trajectories using mixed-effects models calibrated to reproduce published means, variances and attrition patterns from the Clarity-AD and TRAILBLAZER-ALZ 2 trials, separately for early- and delayed-start cohorts and in combined analyses. Observed annualised slopes were also directly compared between double-blind (DB) and OLE phases. Placebo effects were estimated by comparing DB placebo arms with matched untreated historical cohorts derived from published natural history data. Results Simulations closely reproduced reported trajectories. In both trials, the early-start cohorts showed significantly faster annualised decline during OLE than during DB treatment (lecanemab ∆=0.53; 95% CI 0.40 to 0.66; donanemab ∆=0.66; 95% CI 0.41 to 0.91), whereas delayed-start cohorts showed no meaningful phase-related differences. OLE decline rates approximated those observed in DB placebo groups. In the lecanemab trial, DB placebo participants declined more slowly than matched untreated controls; decline in the donanemab trial varied by baseline severity. Conclusions Despite selective retention favouring slower progressors, both lecanemab and donanemab accelerated cognitive decline during OLE phases and paralleled placebo-level declines.
Objectives:In patients living with advanced dementia, the intensity of care during life-threatening infections remains controversial and marked by wide variation in practice. This international survey investigated physicians' and physicians-in-training's management choices for individuals with advanced dementia and the factors associated with those choices. Design:Vignette-based survey. Setting:Twelve countries across five continents. Methods:We administered our vignette-based survey to medical students, residents and physicians. The survey elicited participants' views on whether antibiotics should be administered to an elderly patient with advanced dementia and very poor quality of life, presenting with bacterial pneumonia. We explored factors associated with treatment choices using univariable analysis and multiple logistic regression models. Results:Of the 785 participants (age, mean (SD): 31.1 (11.5) years), one-third (31.2%) resided in the Region of the Americas, 21.9% in Europe, 16.2% in the Eastern Mediterranean region and 17.1% in China. In the univariable analysis, choice to treat was associated with younger age, country/WHO region (African region highest overall, European region lowest overall), stage of medical training (medical student most inclined to treat) and absence of medical assistance in dying (MAiD) legislation. Multivariable analyses provided evidence that country was the variable most strongly associated with the choice to treat with antibiotics (Cameroon, China, Saudi Arabia highest; Norway, Switzerland, Spain lowest), with the presence of MAiD legislation also strongly associated (OR 0.35, 95% CI 0.23 to 0.51). Age (OR 0.82, 95% CI 0.66 to 1.00) and religiosity level (OR 0.93, 95% CI 0.87 to 0.99) showed weaker associations with treatment decisions. Conclusion:Inclination to treat individuals with advanced dementia who develop pneumonia varies greatly between and within jurisdictions. Social factors (in particular country but also presence of MAiD legislation) proved the most prominent associations, with individual characteristics much less influential. These findings underscore the importance of contextual and cultural factors in value-sensitive clinical decisions. Registration:We registered the protocol at Open Science Framework (osf.io/6kfbt).
Background:Timely recognition of immune checkpoint immune-related neurological adverse events (irNAEs) is critical given their potential severity, yet remains challenging due to limited clinical experience. This study investigates clinical presentation and management of irNAEs from a neurological perspective. Methods:We retrospectively identified all patients treated with immune checkpoint inhibitors (ICIs) at Erasmus MC Cancer Institute, Rotterdam, The Netherlands between 2017 and 2024. Patient records were analysed by a neurologist for clinical and treatment of irNAE post-ICI initiation. Results:Of 3176 ICI-treated patients, irNAE was diagnosed in 76 cases (2.4%). Peripheral syndromes occurred in 55 (70%), central in 21 (30%) patients. Classification into distinct disease entities was challenging due to remarkable overlap in affected neurological structures. Median onset of irNAE was 8 weeks after ICI initiation (range 1-104 weeks); 70% developed within 18 weeks. IrNAE-related mortality was 13%, observed only in the first 18 weeks. Fewer non-small cell lung cancer patients developed irNAE (OR, 0.36; 95% CI 0.16 to 0.8; p=0.012) compared with other tumour types. Males (OR, 1.78; 95% CI 1.1 to 2.90; p=0.019) and PD1/CTLA4 combination therapy (OR 2.1, 95% CI 1.28 to 3.46, p=0.004) were associated with increased irNAE incidence. Glucocorticoids were given in 64% of patients; 14% received immunosuppressive therapy beyond steroids. Treatment response varied widely, both clinically and temporally. Conclusion:This retrospective single-centre study confirms irNAEs are infrequent complications of ICI. The distinct symptom profile, with substantial overlap within affected neurological structures, underscores the need for neurological expertise in irNAE care. While most develop within 18 weeks of treatment, late-onset cases occur. Mortality occurred only in early-onset cases.
Introduction Epilepsy affects 1% of the US population, imposing a significant burden through seizures, distress and medication side effects. Many adverse outcomes can be reduced with patient education and an acute seizure action plan. Electronic health record clinical templates can support this care but are often seen as burdensome. This study will develop a clinical template embedding an acute seizure action plan into routine neurology visits and examine its effect on care quality and healthcare use, as well as barriers and facilitators to adoption. Methods and analysis This study is a single-site, prospective, quality improvement, hybrid type 1 effectiveness-implementation study, sequential mixed-method design. Providers are randomised to either the acute seizure action plan plus general health education, or general health education alone control group, with 10 patients per provider enrolled over 12–15 months and followed for 1 year. Phase 1 will collect baseline interviews and pre-enrolment seizure outcomes. Phase 2 will implement the intervention with quantitative data along with provider interviews at 6 months. Phase 3 will include 12-month interviews to assess real-world use of the acute seizure action plan. The primary outcome is change in epilepsy quality measure scores before and after implementation between groups. Secondary outcomes include changes in individual quality measures, seizure metrics and healthcare utilisation. Implementation processes will be assessed by the Unified Theory of Acceptance and Use of Technology and Theoretical Domains Framework. Ethics and dissemination The study was approved by the Yale Institutional Review Board (Protocol ID: 2000032913). Findings will be disseminated through peer-reviewed publications and conference presentations.
Background Germline pathogenic variants in the Additional Sex Combs-Like 1 (ASXL1) gene are associated with the neurodevelopmental Bohring-Opitz syndrome and cancers like Wilms’ tumours. Bohring-Opitz syndrome is a phenotypically heterogeneous condition characterised by feeding difficulties, syndromic facial abnormalities, abnormal posturing and developmental delays, and it has only been reported in infant/adolescent patients. There are no reported neuromuscular phenotypes associated with ASXL1.Case presentation A 71-year-old male proband exhibited congenital facial, extraocular, proximal upper limb and generalised/distal lower limb muscle weakness/wasting. This was associated with dysphagia, childhood motor developmental delay, bilateral upper limb tremor and bilateral pes cavus. He demonstrated some features of Bohring-Opitz syndrome including feeding difficulties, microcephaly, micrognathia and anteverted nares but lacked the characteristic posturing. Muscle imaging demonstrated symmetrical lower limb atrophy. His adult age diagnosis is unique among ASXL1-associated conditions. A genetic diagnosis of the ASXL1 variant (c.1210C>T; p.Arg404Ter) was achieved through phenotype-driven genetic neurodevelopmental panel testing given some overlap with neurodevelopmental patients following unsuccessful initial genetic sequencing.Conclusions This expands the phenotype of ASXL1 pathogenic variants with a novel and distinct neuromuscular presentation. This case demonstrates the importance of thorough and accurate phenotype for unusual presentations, as this diagnosis was missed through routine genetic testing.
Background: Aicardi-Goutières syndrome (AGS) is a neurogenetic leukoencephalopathy that typically manifests within the first 6 months of life. Classically, AGS presents with an early encephalopathic episode characterised by feeding difficulties, irritability and psychomotor regression or delay. Cutaneous lesions affecting the extremities and epilepsy are common, with symptoms usually evolving over weeks to months before stabilising. Milder phenotypes have been described, often demonstrating relative preservation of language and cognitive function. Case presentation: Here, we report a case of a 31-year-old woman with compound heterozygous variants in the ADAR gene: (GRCh38) NM_001111.4:c.577C>G p.(Pro193Ala) and (GRCh38) NM_001111.4:c.1111_1112del p.(Ser371Cysfs*3), consistent with AGS. The developmental history revealed normal early motor milestones. At age 3, she developed progressive ataxia and hypotonia. Over time, she exhibited spasticity, dystonia and learning difficulties, along with significant cardiac valvular calcification. Conclusions: The patient was recently referred for consideration of treatment with baricitinib, a selective JAK1/JAK2 inhibitor. This case underscores the importance of considering AGS in individuals with non-classical presentations, particularly when extracerebral calcification is a notable feature.
Moyamoya disease (MMD) is a rare cerebrovascular disease characterised by gradual progressive stenosis and occlusion of the terminal internal carotid arteries, anterior cerebral arteries and proximal middle cerebral arteries bilaterally. This pathology leads to the formation of a compensatory and fragile collateral vascular network at the brain’s base. With disease progression, MMD may result in ischaemic or haemorrhagic stroke. However, the lack of reliable and effective methods to assess disease progression leaves many patients at high risk of stroke without timely clinical intervention. Therefore, determining the disease course and assessing stroke risk are critical. Cerebrovascular reserve (CVR) reflects the ability of brain tissue to increase blood flow under stress. CVR evaluation assists clinicians in understanding MMD severity, guiding therapeutic decisions and determining prognosis. This narrative review analyses recent literature, highlights the advantages and disadvantages of various CVR assessment techniques, and discusses the interplay between CVR and MMD. In addition, it examines the role of CVR in evaluating disease progression and associated treatments.
Introduction Following a cerebrovascular event, the associated risks for further major adverse cerebro- and cardiovascular events and death (MACE) and important aspects of cognitive, mental and patient-reported outcomes are currently not understood, particularly long-term. Here, we present the study design of the ongoing Berlin Long-term Observation of Vascular Events (BeLOVE) stroke stratum and report data of the first study phase.Methods and analysis BeLOVE is a prospective, longitudinal, observational, hospital-based cohort study. Its stroke stratum enrols adult patients with acute ischaemic stroke, transient ischaemic attack (TIA) or non-traumatic intracerebral haemorrhage. Patients undergo deep phenotyping including cerebral and cardiac MRI, ECG, echocardiography and bio-sampling including multi-omics analyses. Regular, standardised follow-ups take place annually over a period of up to 10 years and record the frequency of MACE as the primary outcome.Secondary outcomes include the frequency, progression and interactions of functional impairments, namely post-stroke cognition, pain, depression, seizures and their relationship to quality of life.The first study phase included 758 patients (median 69 years, 37% female). At 2-year follow-up, the cumulative incidence (95% CI) of the composite primary endpoint MACE was 0.107 (0.085 to 0.132) and that of first ischaemic stroke, first myocardial infarction and death were 0.066 (0.049 to 0.086), 0.015 (0.008 to 0.026) and 0.040 (0.027 to 0.056), respectively.Ethics and dissemination Each participant will provide informed written consent during the acute in-hospital phase. Data will be available for research purposes via a written request to the data use and access committee.Trial registration number German Clinical Trials Register: http://www.drks.de/DRKS00023323 on 4 November 2020.
