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Background: Observational studies have demonstrated improved outcomes with the adjunctive use of balloon guide catheters (BGC) during endovascular thrombectomy (EVT) for anterior circulation acute ischaemic stroke (AIS). However, the lack of high-level evidence and global practice heterogeneity justifies a randomised controlled trial (RCT) to investigate the effect of transient proximal blood flow arrest on the procedural and clinical outcomes of patients with AIS following EVT. Hypothesis: Proximal blood flow arrest in the cervical internal carotid artery during EVT for proximal large vessel occlusion is superior to no flow arrest in achieving complete vessel recanalisation. Methods: ProFATE is an investigator-initiated, pragmatic, multicentre RCT with blinding of participants and outcome assessment. An estimated 124 participants with an anterior circulation AIS due to large vessel occlusion, an NIHSS of ⩾2, ASPECTS ⩾ 5 and eligible for EVT using a first-line combined technique (contact aspiration and stent retriever) or contact aspiration only will be randomised (1:1) to receive BGC balloon inflation or no inflation during EVT. Outcomes: The primary outcome is the proportion of patients achieving near-complete/complete vessel recanalisation (eTICI 2c-3) at the end of the EVT procedure. Secondary outcomes include the functional outcome (modified Rankin Scale at 90 days), new or distal vascular territory clot embolisation rate, near-complete/complete recanalisation after the first pass, symptomatic intracranial haemorrhage, procedure-related complications and death at 90 days. Discussion: This is the first RCT to investigate the effect of proximal blood flow arrest during EVT using a BGC on the procedural and clinical outcomes of patients with AIS due to large vessel occlusion.

Ataxia-Telangiectasia (A-T) is a very rare autosomal recessive disease characterised by cerebellar ataxia, extrapyramidal movements and cancer predisposition. Delayed diagnosis is common due to clinical heterogeneity. The development of clinical trials in A-T is limited by a lack of suitable biomarkers. Abnormal hypointensity of the dentate nuclei (DN) has been demonstrated in some genetic ataxias. We assess the degree of hypointensity of the DN in paediatric and adult A-T patients using the Gupta visual ranking score and report a novel observation of a lack of hypointensity of the DN in adults. Adult A-T patients had significantly lower visual rating scores than paediatric patients (0.07 versus 0.55 respectively). Our findings demonstrate that the normal process leading to hypointensity of the DN is initiated in children with A-T, but the physiological DN hypointensity is lost by adulthood.

IMPORTANCE: Hyperintense foci on diffusion-weighted imaging (DWI) that are spatially remote from the acute hematoma occur in 20% of people with acute spontaneous intracerebral hemorrhage (ICH). Tranexamic acid, a hemostatic agent that is under investigation for treating acute ICH, might increase DWI hyperintense lesions (DWIHLs). OBJECTIVE: To establish whether tranexamic acid compared with placebo increased the prevalence or number of remote cerebral DWIHLs within 2 weeks of ICH onset. DESIGN, SETTING, AND PARTICIPANTS: This prospective nested magnetic resonance imaging (MRI) substudy of a randomized clinical trial (RCT) recruited participants from the multicenter, double-blind, placebo-controlled, phase 3 RCT (Tranexamic Acid for Hyperacute Primary Intracerebral Hemorrhage [TICH-2]) from July 1, 2015, to September 30, 2017, and conducted follow-up to 90 days after participants were randomized to either the tranexamic acid or placebo group. Participants had acute spontaneous ICH and included TICH-2 participants who provided consent to undergo additional MRI scans for the MRI substudy and those who had clinical MRI data that were compatible with the brain MRI protocol of the substudy. Data analyses were performed on an intention-to-treat basis on January 20, 2020. INTERVENTIONS: The tranexamic acid group received 1 g in 100-mL intravenous bolus loading dose, followed by 1 g in 250-mL infusion within 8 hours of ICH onset. The placebo group received 0.9% saline within 8 hours of ICH onset. Brain MRI scans, including DWI, were performed within 2 weeks. MAIN OUTCOMES AND MEASURES: Prevalence and number of remote DWIHLs were compared between the treatment groups using binary logistic regression adjusted for baseline covariates. RESULTS: A total of 219 participants (mean [SD] age, 65.1 [13.8] years; 126 men [57.5%]) who had brain MRI data were included. Of these participants, 96 (43.8%) were randomized to receive tranexamic acid and 123 (56.2%) were randomized to receive placebo. No baseline differences in demographic characteristics and clinical or imaging features were found between the groups. There was no increase for the tranexamic acid group compared with the placebo group in DWIHL prevalence (20 of 96 [20.8%] vs 28 of 123 [22.8%]; odds ratio [OR], 0.71; 95% CI, 0.33-1.53; P = .39) or mean (SD) number of DWIHLs (1.75 [1.45] vs 1.81 [1.71]; mean difference [MD], −0.08; 95% CI, −0.36 to 0.20; P = .59). In an exploratory analysis, participants who were randomized within 3 hours of ICH onset or those with chronic infarcts appeared less likely to have DWIHLs if they received tranexamic acid. Participants with probable cerebral amyloid angiopathy appeared more likely to have DWIHLs if they received tranexamic acid. CONCLUSIONS AND RELEVANCE: This substudy of an RCT found no evidence of increased prevalence or number of remote DWIHLs after tranexamic acid treatment in acute ICH. These findings provide reassurance for ongoing and future trials that tranexamic acid for acute ICH is unlikely to induce cerebral ischemic events. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN93732214

Introduction The efficacy and safety of endovascular thrombectomy (EVT) beyond 6 hours from acute ischaemic stroke (AIS) onset for patients with proximal large vessel occlusion (LVO) selected without CT perfusion or MR imaging is undetermined in routine clinical practice. Methods In this single centre study, we identified consecutive AIS patients with an ICA or M1 MCA segment occlusion who were eligible for EVT based on non‐contrast CT/CT angiography (without CT perfusion or MR imaging) using an Alberta Stroke Program Early CT Score (ASPECTS) of ≥ 6, and an NIHSS score of≥ 6, presenting beyond 6 hours from stroke onset, between January 2018 and March 2022. During the study period, EVT capacity limitations meant EVT‐eligible patients presenting out of regular working hours (between 18.00 and 08.00 on weekdays) or on weekends, consistently received best medical management (BMM). This systemic unavailability of EVT, allows a comparison of EVT and BMM in patients who meet the same inclusion criteria, in which selection based on physician‐related bias is significantly reduced. Functional outcomes (modified Rankin Scale (mRS) at 90 days), symptomatic intracranial haemorrhage (sICH) and mortality at 90 days were compared between patients receiving EVT or BMM following multivariable adjustment for age, sex, baseline stroke severity, ASPECTS, onset‐to‐neuroimaging time, IV thrombolysis, and clot location.Pre‐specified subgroup analyses were performed. Results Among 4802 AIS patients, 150 patients (3.1%) presenting beyond 6‐hours of onset were eligible for EVT: 74 (49%) treated with EVT and 76 (51%) with BMM. Compared to the BMM group, patients treated with EVT had significantly improved functional outcome (mRS) (adjusted common OR = 2.23, 95%CI 1.18‐4.22, p = 0.013), and higher rates of functional independence (mRS≤2; 39.2.% vs 9.2%; aOR = 4.73, 95%CI 1.64‐13.63, p = 0.004). No significant difference was observed between the EVT and BMM groups in the sICH (5.4% vs 2.6%, p = 0.94) or mortality (20.2% vs 47.3%, p = 0.16) rates, respectively. EVT remained effective within the 6–12 hour and >12 hour time window subgroups. No significant treatment interaction was observed in all subgroups. Conclusions In routine clinical practice, of the 3.1% of patients in our AIS population presenting after 6 hours from stroke onset who were deemed eligible for EVT by NCCT/CTA alone, those treated with EVT achieved significantly improved functional outcome, compared to patients treated with BMM only. No significant differences were noted between the two groups with respect to sICH and mortality. While confirmatory randomised trials are awaited, these findings suggest that EVT is effective and safe when performed in AIS patients selected without CTP or MRI beyond 6 hours from stroke onset.

BackgroundThere is a paucity of data on anesthesia-related outcomes for endovascular treatment (EVT) in the extended window (>6 hours from ischemic stroke onset). We compared functional and safety outcomes between local anesthesia (LA) without sedation, conscious sedation (CS) and general anesthesia (GA).MethodsPatients who underwent EVT in the early (ResultsA total of 4337 patients were included, 3193 in the early window (1135 LA, 446 CS, 1612 GA) and 1144 in the extended window (357 LA, 134 CS, 653 GA). Compared with GA, patients treated under LA alone had increased odds of an improved modified Rankin Scale (mRS) score at discharge (early: adjusted common (ac) OR=1.50, 95% CI 1.29 to 1.74, p=0.001; extended: acOR=1.29, 95% CI 1.01 to 1.66, p=0.043). Similar mRS scores at discharge were found in the LA and CS cohorts in the early and extended windows (p=0.21). Compared with CS, use of GA was associated with a worse mRS score at discharge in the early window (acOR=0.73, 95% CI 0.45 to 0.96, p=0.017) but not in the extended window (p=0.55). There were no significant differences in the rates of symptomatic intracranial hemorrhage or in-hospital mortality across the anesthesia modalities in the extended window.ConclusionLA without sedation during EVT was associated with improved functional outcomes compared with GA, but not CS, within and beyond 6 hours from stroke onset. Prospective studies assessing anesthesia-related outcomes in the extended time window are warranted.

BackgroundThe safety and functional outcome of endovascular thrombectomy (EVT) in the very late (VL; >24 hours) time window from ischemic stroke onset remains undetermined.MethodsUsing data from a national stroke registry, we used propensity score matched (PSM) individual level data of patients who underwent EVT, selected with CT perfusion or non-contrast CT/CT angiography, between October 2015 and March 2020. Functional and safety outcomes were assessed in both late (6–24 hours) and VL time windows. Subgroup analysis was performed of imaging selection modality in the VL time window.ResultsWe included 1150 patients (late window: 1046 (208 after PSM); VL window: 104 (104 after PSM)). Compared with EVT treatment initiation between 6 and 24 hours, patients treated in the VL window had similar modified Rankin Scale (mRS) scores at discharge (ordinal shift; common OR=1.08, 95% CI 0.69 to 1.47, p=0.70). No significant differences in achieving good functional outcome (mRS ≤2 at discharge; 28.8% (VL) vs 29.3% (late), OR=0.97, 95% CI 0.58 to 1.64, p=0.93), successful reperfusion (modified Thrombolysis in Cerebral Infarction score of 2b–3) (p=0.77), or safety outcomes of symptomatic intracranial hemorrhage (p=0.43) and inhospital mortality (p=0.23) were demonstrated. In the VL window, there was no significant difference in functional outcome among patients selected with perfusion versus those selected without perfusion imaging (common OR=1.38, 95% CI 0.81 to 1.76, p=0.18).ConclusionIn this real world study, EVT beyond 24 hours from stroke onset or last known well appeared to be feasible, with comparable safety and functional outcomes to EVT initiation between 6 and 24 hours. Randomized trials assessing the efficacy of EVT in the VL window are warranted, but may only be feasible with a large international collaborative approach.

Background SIOP Ependymoma I was a non-randomised trial assessing event free and overall survival (EFS/OS) of non-metastatic intracranial ependymoma in children aged 3–21 years treated with a staged management strategy. A further aim was to assess the response rate (RR) of subtotally resected (STR) ependymoma to vincristine, etoposide, and cyclophosphamide (VEC). We report final results with 12-year follow-up and post hoc analyses of recently described biomarkers. Methods Seventy-four participants were eligible. Children with gross total resection (GTR) received radiotherapy, whilst those with STR received VEC before radiotherapy. DNA methylation, 1q, hTERT, ReLA, Tenascin-C, H3K27me3, and pAKT status were evaluated. Results Five- and ten-year EFS was 49.5% and 46.7%, OS was 69.3% and 60.5%. GTR was achieved in 33/74 (44.6%) and associated with improved EFS (P = .003, HR = 2.6, 95% confidence interval (CI) 1.4–5.1). Grade 3 tumours were associated with worse OS (P = .005, HR = 2.8, 95%CI 1.3–5.8). 1q gain and hTERT expression were associated with poorer EFS (P = .003, HR = 2.70, 95%CI 1.49–6.10 and P = .014, HR = 5.8, 95%CI 1.2–28) and H3K27me3 loss with worse OS (P = .003, HR = 4.6, 95%CI 1.5–13.2). Methylation profiles showed expected patterns. 12 participants with STR did not receive chemotherapy; a protocol violation. However, best chemotherapy RR was 65.5% (19/29, 95%CI 45.7–82.1), exceeding the prespecified 45%. Conclusions Participants with totally resected ependymoma had the best outcomes. RR of STR to VEC exceeded the pre-specified efficacy criterion. However, cases of inaccurate stratification highlighted the need for rapid central review. 1q gain, H3K27me3 loss, and hTERT expression were all associated with poorer survival outcomes.

This study evaluated deep learning algorithms for semantic segmentation and quantification of intracerebral hemorrhage (ICH), perihematomal edema (PHE), and intraventricular hemorrhage (IVH) on noncontrast CT scans of patients with spontaneous ICH. Models were assessed on 1732 annotated baseline noncontrast CT scans obtained from the Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage (ie, TICH-2) international multicenter trial (ISRCTN93732214), and different loss functions using a three-dimensional no-new-U-Net (nnU-Net) were examined to address class imbalance (30% of participants with IVH in dataset). On the test cohort (n = 174, 10% of dataset), the top-performing models achieved median Dice similarity coefficients of 0.92 (IQR, 0.89–0.94), 0.66 (0.58–0.71), and 1.00 (0.87–1.00), respectively, for ICH, PHE, and IVH segmentation. U-Net–based networks showed comparable, satisfactory performances on ICH and PHE segmentations (P > .05), but all nnU-Net variants achieved higher accuracy than the Brain Lesion Analysis and Segmentation Tool for CT (BLAST-CT) and DeepLabv3+ for all labels (P < .05). The Focal model showed improved performance in IVH segmentation compared with the Tversky, two-dimensional nnU-Net, U-Net, BLAST-CT, and DeepLabv3+ models (P < .05). Focal achieved concordance values of 0.98, 0.88, and 0.99 for ICH, PHE, and ICH volumes, respectively. The mean volumetric differences between the ground truth and prediction were 0.32 mL (95% CI: −8.35, 9.00), 1.14 mL (−9.53, 11.8), and 0.06 mL (−1.71, 1.84), respectively. In conclusion, U-Net–based networks provide accurate segmentation on CT images of spontaneous ICH, and Focal loss can address class imbalance. International Clinical Trials Registry Platform (ICTRP) no. ISRCTN93732214 Supplemental material is available for this article. © RSNA, 2022 Keywords: Head/Neck, Brain/Brain Stem, Hemorrhage, Segmentation, Quantification, Convolutional Neural Network (CNN), Deep Learning Algorithms, Machine Learning Algorithms

Background Diffuse midline gliomas (DMG) are characterized by a high incidence of H3 K27 mutations and poorer outcome. The HERBY trial has provided one of the largest cohorts of pediatric DMGs with available radiologic, histologic-genotypic, and survival data. Purpose To define MRI and molecular characteristics of DMG. Materials and Methods This study is a secondary analysis of a prospective trial (HERBY; ClinicalTrials.gov identifier, NCT01390948) undertaken between October 2011 and February 2016. Among 121 HERBY participants, 50 had midline nonpontine-based tumors. Midline high-grade gliomas were reclassified into DMG H3 K27 mutant, H3 wild type with enhancer of zest homologs inhibitory protein overexpression, epidermal growth factor receptormutant, or not otherwise stated. The epicenter of each tumor and other radiologic characteristics were ascertained from MRI and correlated with the new subtype classification, histopathologic characteristics, surgical extent, and outcome parameters. Kaplan-Meier curves and log-rank tests were applied to determine and describe survival differences between groups. Results There were 42 participants (mean age, 12 years ± 4 [SD]; 23 girls) with radiologically evaluable thalamic-based DMG. Eighteen had partial thalamic involvement (12 thalamopulvinar, six anteromedial), 10 involved a whole thalamus, nine had unithalamic tumors with diffuse contiguous extension, and five had bithalamic tumors (two symmetric, three partial). Twenty-eight participants had DMG H3 K27 mutant tumors; there were no differences in outcome compared with other DMGs (n = 4). Participants who underwent major debulking or total or near-total resection had longer overall survival (OS): 18.5 months vs 11.4 months (P = .02). Enrolled participants who developed leptomeningeal metastatic dissemination before starting treatment had worse outcomes (event-free survival, 2.9 months vs 8.0 months [P = .02]; OS, 11.4 months vs 18.5 months [P = .004]). Conclusion Thalamic involvement of diffuse midline gliomas ranged from localized partial thalamic to holo- or bithalamic with diffuse contiguous spread and had poor outcomes, irrespective of H3 K27 subtype alterations. Leptomeningeal dissemination and less than 50% surgical resection were adverse risk factors for survival. Clinical trial registration no. NCT01390948 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Widjaja in this issue.

BACKGROUND AND PURPOSE: SWI hypointense cerebral lesions have been reported in adults with the inherited cerebellar neurodegenerative disorder ataxia telangiectasia. This study aims to establish the prevalence, age-dependency, and spatial distribution of these lesions in children and young people with ataxia telangiectasia. MATERIALS AND METHODS: Participants with classic ataxia telangiectasia and matched controls underwent SWI acquisition at 3T at 1 or 2 time points. SWI hypointense lesions were manually labeled according to the Microbleed Anatomical Rating Scale. Differences in prevalence of lesion number between groups with ataxia telangiectasia and without ataxia telangiectasia were tested with the Fisher exact test, and differences in age between participants with ataxia telangiectasia with and without lesions were tested using independent samples from the Mann-Whitney U test. The relationship between age and lesion number was modeled as an exponential function. RESULTS: Analyzable SWI datasets from 17 participants with ataxia telangiectasia (with median age at first scan of 12.4 years; range, 4.6–20.2 years; 8 [47%] were female) and 22 matched healthy controls showed prevalence of SWI hypointense lesions in 41% of participants with ataxia telangiectasia and 0% in controls (P = .001, the Fisher exact test). Lesions were exclusively supratentorial and predominantly lobar. Participants with ataxia telangiectasia with SWI hypointense lesions were older than those without (median age was 15.2 years versus 9.3 years, U = 10.5, P = .014). An exponential curve described the relationship between age and lesion number (R2 = 0.67). CONCLUSIONS: SWI hypointense lesions are common in children and young people with ataxia telangiectasia, accumulating from 12 years of age onward. In contrast to cerebellar-dominant neurodegeneration in ataxia telangiectasia, SWI hypointense lesions were exclusively supratentorial. Further investigation is needed to establish the clinical relevance of these imaging-detected lesions.

Objectives To test radiomics-based features extracted from noncontrast CT of patients with spontaneous intracerebral haemorrhage for prediction of haematoma expansion and poor functional outcome and compare them with radiological signs and clinical factors. Materials and methods Seven hundred fifty-four radiomics-based features were extracted from 1732 scans derived from the TICH-2 multicentre clinical trial. Features were harmonised and a correlation-based feature selection was applied. Different elastic-net parameterisations were tested to assess the predictive performance of the selected radiomics-based features using grid optimisation. For comparison, the same procedure was run using radiological signs and clinical factors separately. Models trained with radiomics-based features combined with radiological signs or clinical factors were tested. Predictive performance was evaluated using the area under the receiver operating characteristic curve (AUC) score. Results The optimal radiomics-based model showed an AUC of 0.693 for haematoma expansion and an AUC of 0.783 for poor functional outcome. Models with radiological signs alone yielded substantial reductions in sensitivity. Combining radiomics-based features and radiological signs did not provide any improvement over radiomics-based features alone. Models with clinical factors had similar performance compared to using radiomics-based features, albeit with low sensitivity for haematoma expansion. Performance of radiomics-based features was boosted by incorporating clinical factors, with time from onset to scan and age being the most important contributors for haematoma expansion and poor functional outcome prediction, respectively. Conclusion Radiomics-based features perform better than radiological signs and similarly to clinical factors on the prediction of haematoma expansion and poor functional outcome. Moreover, combining radiomics-based features with clinical factors improves their performance. Key Points • Linear models based on CT radiomics-based features perform better than radiological signs on the prediction of haematoma expansion and poor functional outcome in the context of intracerebral haemorrhage. • Linear models based on CT radiomics-based features perform similarly to clinical factors known to be good predictors. However, combining these clinical factors with radiomics-based features increases their predictive performance.

Background: The impact on clinical outcomes of patient selection using perfusion imaging for endovascular thrombectomy (EVT) in patients with acute ischemic stroke presenting beyond 6 hours from onset remains undetermined in routine clinical practice. Methods: Patients from a national stroke registry that underwent EVT selected with or without perfusion imaging (noncontrast computed tomography/computed tomography angiography) in the early ( Results: We included 4249 patients, 3203 in the early window (593 with perfusion versus 2610 without perfusion) and 1046 in the late window (378 with perfusion versus 668 without perfusion). Within the late window, patients with perfusion imaging had a shift towards better functional outcome at discharge compared with those without perfusion imaging (adjusted common odds ratio [OR], 1.45 [95% CI, 1.16–1.83]; P =0.001). There was no significant difference in functional independence (29.3% with perfusion versus 24.8% without; P =0.210) or in the safety outcome measures of symptomatic intracerebral hemorrhage ( P =0.53) and in-hospital mortality (10.6% with perfusion versus 14.3% without; P =0.053). In the early time window, patients with perfusion imaging had significantly improved odds of functional outcome (adjusted common OR, 1.51 [95% CI, 1.28–1.78]; P =0.0001) and functional independence (41.6% versus 33.6%, adjusted OR, 1.31 [95% CI, 1.08–1.59]; P =0.006). Perfusion imaging was associated with lower odds of futile recanalization in both time windows (late: adjusted OR, 0.70 [95% CI, 0.50–0.97]; P =0.034; early: adjusted OR, 0.80 [95% CI, 0.65–0.99]; P =0.047). Conclusions: In this real-world study, acquisition of perfusion imaging for EVT was associated with improvement in functional disability in the early and late time windows compared with nonperfusion neuroimaging. These indirect comparisons should be interpreted with caution while awaiting confirmatory data from prospective randomized trials.

Neonatal stroke is a devastating condition that causes brain injury in babies and often leads to lifelong neurological impairment. Recent prospective population studies of neonatal stroke are lacking. Neonatal strokes are different from those in older children and adults. A better understanding of its aetiology, current management, and outcomes could reduce the burden of this rare condition. The study aims to explore the incidence and 2 year outcomes of neonatal stroke across an entire population in the UK and Republic of Ireland. This is an active national surveillance study using a purpose-built integrated case notification-data collection online platform. Over a 13 month period, with a potential 6 month extension, clinicians will notify neonatal stroke cases presenting in the first 90 days of life electronically via the online platform monthly. Clinicians will complete a primary questionnaire via the platform detailing clinical information, including neuroimaging, for analysis and classification. An outcome questionnaire will be sent at 2 years of age via the platform. Appropriate ethics and regulatory approvals have been received. The neonatal stroke study represents the first multinational population surveillance study delivered via a purpose-built integrated case notification-data collection online platform and data safe haven, overcoming the challenges of setting up the study.

BackgroundNeonatal stroke is a devastating condition that causes brain injury in babies and often leads to lifelong neurological impairment. Recent, prospective whole population studies of neonatal stroke are lacking. Neonatal strokes are different from those seen in older children and adults. A better understanding of the aetiology, current management and outcomes of neonatal stroke could reduce the burden of this rare condition. Most healthcare professionals see only a few cases of neonatal stroke in their careers, so population-based prospective studies are needed.ObjectivesTo explore the incidence and two-year outcomes of neonatal stroke across an entire population in the UK and the Republic of Ireland.PopulationAny infant presenting with neonatal stroke in the first 90 days of life.DesignActive national surveillance study using a purpose-built integrated case notification-data collection online platform.MethodsOver a 13-month period, British and Irish clinicians will notify any cases of neonatal stroke electronically via the online platform monthly. Clinicians will complete a primary questionnaire via the platform detailing clinical information, demographic details and investigations, including neuroimaging for detailed analysis and classification. An outcome questionnaire will be sent at two years of age via the platform. Appropriate ethical and regulatory approvals have been received from England, Wales, Scotland, Northern Ireland and the Republic of Ireland.ConclusionThe neonatal stroke study represents the first multinational population surveillance study delivered via a purpose-built integrated case notification-data collection online platform and data safe haven, overcoming the challenges of setting up the study.SynopsisStudy questionThe neonatal stroke active surveillance study aims to explore the incidence and two-year outcome of neonatal stroke in the UK and Ireland.What is already known?Neonatal stroke is a rare but often devastating condition with lifelong consequences including cerebral palsy, epilepsy and cognitive delay. There are no contemporary, prospective multinational population studies on the presentation and outcomes of neonatal stroke. Whilst often the aetiology is multifactorial further information on underlying aetiology may help to identify potential future preventative treatments leading to improved outcomes.What does this study add?International collaboration is required to understand the epidemiology, management and outcomes of rare diseases or conditions. This is the first multinational surveillance study delivered via a purpose-built integrated case notification-data collection online platform and data safe haven, presenting practical and ethical challenges. The study will describe the burden of neonatal stroke while providing parents/carers and healthcare professionals with up-to-date information about the condition including the two-year outcomes.

BackgroundThe effectiveness and safety of endovascular thrombectomy (EVT) in the late window (6–24 hours) for acute ischemic stroke (AIS) patients selected without advanced imaging is undetermined. We aimed to assess clinical outcomes and the relationship with time-to-EVT treatment beyond 6 hours of stroke onset without advanced neuroimaging.MethodsPatients who underwent EVT selected with non-contrast CT/CT angiography (without CT perfusion or MR imaging), between October 2015 and March 2020, were included from a national stroke registry. Functional and safety outcomes were assessed in both early (ResultsAmong 3278 patients, 2610 (79.6%) and 668 (20.4%) patients were included in the early and late windows, respectively. In the late window, for every hour delay, there was no significant association with shift towards poorer functional outcome (modified Rankin Scale (mRS)) at discharge (adjusted common OR 0.98, 95% CI 0.94 to 1.01, p=0.27) or change in predicted functional independence (mRS ≤2) (24.5% to 23.3% from 6 to 24 hours; aOR 0.99, 95% CI0.94 to 1.04, p=0.85). In contrast, predicted functional independence was time sensitive in the early window: 5.2% reduction per-hour delay (49.4% to 23.5% from 1 to 6 hours, p=0.0001). There were similar rates of symptomatic intracranial hemorrhage (sICH) (3.4% vs 4.6%, p=0.54) and in-hospital mortality (12.9% vs 14.6%, p=0.33) in the early and late windows, respectively, without a significant association with time.ConclusionIn this real-world study, there was minimal change in functional disability, sICH and in-hospital mortality within and across the late window. While confirmatory randomized trials are needed, these findings suggest that EVT remains feasible and safe when performed in AIS patients selected without advanced neuroimaging between 6–24 hours from stroke onset.

Research suggests that disruption of brain networks might explain cognitive deficits in multiple sclerosis (MS). The reliability and effectiveness of graph theoretic network metrics as measures of cognitive performance were tested in 37 people with MS and 23 controls. Specifically, relationships with cognitive performance (linear regression against the paced auditory serial addition test-3 seconds [PASAT-3], symbol digit modalities test [SDMT], and attention network test) and 1-month reliability (using the intraclass correlation coefficient [ICC]) of network metrics were measured using both resting-state functional and diffusion magnetic resonance imaging data. Cognitive impairment was directly related to measures of brain network segregation and inversely related to network integration (prediction of PASAT-3 by small worldness, modularity, characteristic path length, R2 = 0.55; prediction of SDMT by small worldness, global efficiency, and characteristic path length, R2 = 0.60). Reliability of the measures for 1 month in a subset of nine participants was mostly rated as good (ICC >0.6) for both controls and MS patients in both functional and diffusion data, but was highly dependent on the chosen parcellation and graph density, with the 0.2–0.5 density range being the most reliable. This suggests that disrupted network organization predicts cognitive impairment in MS and its measurement is reliable for a 1-month period. These new findings support the hypothesis of network disruption as a major determinant of cognitive deficits in MS and the future possibility of the application of derived metrics as surrogate outcomes in trials of therapies for cognitive impairment.

Optic Pathway Glioma (OPG) is a relatively common brain tumour in childhood; however, there is scarce understanding of neuropsychological sequelae in these survivors. In this study, 12 children with diagnosis of OPG before 6 years of age received a comprehensive standardised assessment of visual perception, general intelligence and academic achievement, using adjustments to visual materials of the tests, to examine the extent of concurrent impairment in these functional domains. Information about vision, clinical and socio-demographic factors were extracted from medical records to assess the associations of neuropsychological outcomes with clinical and socio-demographic factors. Children with OPG exhibited high within-patient variability and moderate group-level impairment compared to test norms. Visual perception was the most impaired domain, while scholastic progression was age-appropriate overall. For cognition, core verbal and visuo-spatial reasoning skills were intact, whereas deficits were found in working memory and processing speed. Visual function was associated with tasks that rely on visual input. Children with OPG are at moderate risk of neuropsychological impairment, especially for visual perception and cognitive proficiency. Future research should elucidate further the relative contribution of vision loss and neurofibromatosis type 1 co-diagnosis within a large sample.

ObjectiveTo assess the association of baseline imaging markers of cerebral small vessel disease (SVD) and brain frailty with clinical outcome after acute stroke in the Efficacy of Nitric Oxide in Stroke (ENOS) trial.MethodsENOS randomized 4,011 patients with acute stroke (ResultsIn all participants and those with lacunar syndrome (LACS; 1,397, 34.8%), baseline CT imaging features of SVD and brain frailty were common and independently associated with unfavorable shifts in mRS score at day 90 (all participants: SVD score odds ratio [OR] 1.15, 95% confidence interval [CI] 1.07–1.24; brain frailty score OR 1.25, 95% CI 1.17–1.34; those with LACS: SVD score OR 1.30, 95% CI 1.15–1.47, brain frailty score OR 1.28, 95% CI 1.14–1.44). Brain frailty was associated with worse cognitive scores at 90 days in all participants and in those with LACS.ConclusionsBaseline imaging features of SVD and brain frailty were common in lacunar stroke and all stroke, predicted worse prognosis after all acute stroke with a stronger effect in lacunar stroke, and may aid future clinical decision-making.IdentifierISRCTN99414122.

Background: Seeking consent rapidly in acute stroke trials is crucial as interventions are time sensitive. We explored the association between consent pathways and time to enrollment in the TICH-2 (Tranexamic Acid in Intracerebral Haemorrhage-2) randomized controlled trial. Methods: Consent was provided by patients or by a relative or an independent doctor in incapacitated patients, using a 1-stage (full written consent) or 2-stage (initial brief consent followed by full written consent post-randomization) approach. The computed tomography-to-randomization time according to consent pathways was compared using the Kruskal-Wallis test. Multivariable logistic regression was performed to identify variables associated with onset-to-randomization time of ≤3 hours. Results: Of 2325 patients, 817 (35%) gave self-consent using 1-stage (557; 68%) or 2-stage consent (260; 32%). For 1507 (65%), consent was provided by a relative (1 stage, 996 [66%]; 2 stage, 323 [21%]) or a doctor (all 2-stage, 188 [12%]). One patient did not record prerandomization consent, with written consent obtained subsequently. The median (interquartile range) computed tomography-to-randomization time was 55 (38–93) minutes for doctor consent, 55 (37–95) minutes for 2-stage patient, 69 (43–110) minutes for 2-stage relative, 75 (48–124) minutes for 1-stage patient, and 90 (56–155) minutes for 1-stage relative consents ( P Conclusions: The use of initial brief consent was associated with shorter times to enrollment, while maintaining good participant retention. Seeking written consent from relatives was associated with significant delays. Registration: URL: https://www.isrctn.com ; Unique identifier: ISRCTN93732214.

Cerebral microbleeds (CMBs) are associated with white matter damage, various neu-rodegenerative and cerebrovascular diseases. CMBs occur as small, circular hypointense lesions on T2*-weighted gradient recalled echo (GRE) and susceptibility weighted imaging (SWI) images, and hyperintense on quantitative susceptibility mapping (QSM) images due to their paramagnetic nature. Accurate detection of CMBs would help to determine the CMB lesion count and distribution, which would be further useful to understand the clinical impact of CMBs and to obtain quantitative imaging biomarkers. In this work, we propose a fully automated, deep learning-based, 2-step algorithm, using structural and anatomical properties of CMBs from any single input image modality (e.g. GRE / SWI / QSM) for their accurate detection. Our method consists of an initial candidate detection step, that detects CMBs with high sensitivity and a candidate discrimination step using a knowledge distillation framework to classify CMB and non-CMB instances, followed by a morphological clean-up step. We used 4 datasets consisting of different modalities specified above, acquired using various protocols and with a variety of pathological and demographic characteristics. On cross-validation within datasets, our method achieved a cluster-wise true positive rate (TPR) over 90% with an average of less than 2 false positives per subject. Our method is flexible in terms of the input modality and provides comparable cluster-wise TPR and a better cluster-wise precision compared to existing state-of-the-art methods. When evaluated across different datasets, our method showed good generalisability with a cluster-wise TPR greater than 80% with different modalities.

BACKGROUND Medulloblastoma, ependymoma, and pilocytic astrocytoma are common pediatric posterior fossa tumors. These tumors show overlapping characteristics on conventional MRI scans, making diagnosis difficult. PURPOSE To investigate whether apparent diffusion coefficient (ADC) values differ between tumor types and to identify optimum cut-off values to accurately classify the tumors using different performance metrics. STUDY TYPE Systematic review and meta-analysis. SUBJECTS Seven studies reporting ADC in pediatric posterior fossa tumors (115 medulloblastoma, 68 ependymoma, and 86 pilocytic astrocytoma) were included following PubMed and ScienceDirect searches. SEQUENCE AND FIELD STRENGTH Diffusion weighted imaging (DWI) was performed on 1.5 and 3 T across multiple institution and vendors. ASSESSMENT The combined mean and standard deviation of ADC were calculated for each tumor type using a random-effects model, and the effect size was calculated using Hedge's g. STATISTICAL TESTS Sensitivity/specificity, weighted classification accuracy, balanced classification accuracy. A P value 1.2 was considered to represent a large difference. RESULTS The mean (± standard deviation) ADCs of medulloblastoma, ependymoma, and pilocytic astrocytoma were 0.76 ± 0.16, 1.10 ± 0.10, and 1.49 ± 0.16 mm2 /sec × 10-3 . To maximize sensitivity and specificity using the mean ADC, the cut-off was found to be 0.96 mm2 /sec × 10-3 for medulloblastoma and ependymoma and 1.26 mm2 /sec × 10-3 for ependymoma and pilocytic astrocytoma. The meta-analysis showed significantly different ADC distributions for the three posterior fossa tumors. The cut-off values changed markedly (up to 7%) based on the performance metric used and the prevalence of the tumor types. DATA CONCLUSION There were significant differences in ADC between tumor types. However, it should be noted that only summary statistics from each study were analyzed and there were differences in how regions of interest were defined between studies. EVIDENCE LEVEL 1 TECHNICAL EFFICACY: Stage 3.

Rate and severity of radiological features of physical abuse in children during the first UK-wide COVID-19 enforced national lockdown.ObjectiveTo assess the number, type and outcome of radiological investigations for children presenting to hospital with suspected physical abuse (SPA; including abusive head trauma) during the first national COVID-19 enforced lockdown compared with the prelockdown period.DesignMulticentre, retrospective, observational, interrupted time series analysis.SettingEight secondary/tertiary paediatric centres between January 2018 and July 2020 inclusive.Participants1587 hospital assessed children undergoing radiographic skeletal surveys (SkS) and head CT imaging performed for SPA/child protection concerns.Main outcome measuresIncidence and severity of fractures identified on SkS; head injury (composed of incidence rates and ratios of skull fracture, intracranial haemorrhage (ICH) and hypoxic ischaemic injury (HII)) on head CT imaging; and ratio of antemortem and postmortem SkS.Results1587 SkS were performed: 1282 (81%) antemortem, 762 (48%) male, and positive findings in 582 (37%). Median patient age was 6 months. There were 1.7 fractures/child prelockdown versus 1.1 fractures/child during lockdown. There was no difference between positive/negative SkS rates, the absolute ratio of antemortem/postmortem SkS or absolute numbers of head injury occurring between January 2018 and February 2020 and the lockdown period April–July 2020. Likewise, prelockdown incidence and rates of skull fracture 30/244 (12%), ICH 28/220 (13%) and HIE 10/205 (5%) were similar to lockdown, 142/1304 (11%), 171/1152 (15%) and 68/1089 (6%), respectively.ConclusionThe first UK COVID-19 lockdown did not lead to an increase in either the number of antemortem or postmortem radiological investigations performed for SPA, or the number or severity of fractures and intracranial injuries identified by these investigations.

Cerebral microbleeds (CMBs) appear as small, circular, well defined hypointense lesions of a few mm in size on T2*-weighted gradient recalled echo (T2*-GRE) images and appear enhanced on susceptibility weighted images (SWI). Due to their small size, contrast variations and other mimics (e.g. blood vessels), CMBs are highly challenging to detect automatically. In large datasets (e.g. the UK Biobank dataset), exhaustively labelling CMBs manually is difficult and time consuming. Hence it would be useful to preselect candidate CMB subjects in order to focus on those for manual labelling, which is essential for training and testing automated CMB detection tools on these datasets. In this work, we aim to detect CMB candidate subjects from a larger dataset, UK Biobank, using a machine learning-based, computationally light pipeline. For our evaluation, we used 3 different datasets, with different intensity characteristics, acquired with different scanners. They include the UK Biobank dataset and two clinical datasets with different pathological conditions. We developed and evaluated our pipelines on different types of images, consisting of SWI or GRE images. We also used the UK Biobank dataset to compare our approach with alternative CMB preselection methods using non-imaging factors and/or imaging data. Finally, we evaluated the pipeline’s generalisability across datasets. Our method provided subject-level detection accuracy > 80% on all the datasets (withindataset results), and showed good generalisability across datasets, providing a consistent accuracy of over 80%, even when evaluated across different modalities.

BackgroundSIOP Ependymoma I was a non-randomised trial assessing event free and overall survival (EFS/OS) from non-metastatic intracranial ependymoma in children aged 3 to 21 years, treated with a staged management strategy. Chemotherapy efficacy in ependymoma is debated and therefore the response rate (RR) of subtotally resected (STR) ependymoma to vincristine, etoposide and cyclophosphamide (VEC) was an additional primary outcome. We report final results with 12-year follow-up and post hoc analyses of recently described biomarkers.Methods74 participants were eligible. Children with gross total resection (GTR) received radiotherapy, whilst those with STR received VEC before radiotherapy. DNA methylation and 1q status were evaluated, alongside hTERT, ReLA, Tenascin-C, H3K27me3 and pAKT expression.ResultsFive- and ten-year EFS was 49.5% and 46.7%, OS was 69.3% and 60.5%. GTR was achieved in 33/74 (44.6%) and associated with improved EFS (p=0.003, HR=2.6, 95% confidence interval (CI) 1.4-5.1). Grade 3 tumours were associated with worse OS (p=0.005, HR=2.8, 95%CI 1.3-5.8). 1q gain and hTERT expression were associated with poorer EFS (p=0.003, HR=2.70, 95%CI 1.49-6.10 and p=0.014, HR=5.8, 95%CI 1.2-28 respectively) and H3K27me3 loss with worse OS (p=0.003, HR=4.6, 95%CI 1.5-13.2). DNA methylation profiles showed expected patterns. 12 participants with STR did not receive chemotherapy; a protocol violation. However, chemotherapy RR was 65.5% (19/29, 95%CI 45.7-82.1), exceeding a prespecified 45% RR.ConclusionsRR of STR to VEC exceeded the pre-specified criterion for efficacy. However, cases of inaccurate treatment stratification highlighted the need for rapid central review. Prognostic associations for 1q gain, H3K27me3 and hTERT were confirmed.

Multiple sclerosis (MS) is characterised by widespread damage of the central nervous system that includes alterations in normal-appearing white matter (NAWM) and demyelinating white matter (WM) lesions. Neurite orientation dispersion and density imaging (NODDI) has been proposed to provide a precise characterisation of WM microstructures. NODDI maps can be calculated for the Neurite Density Index (NDI) and Orientation Dispersion Index (ODI), which estimate orientation dispersion and neurite density. Although NODDI has not been widely applied in MS, this technique is promising in investigating the complexity of MS pathology, as it is more specific than diffusion tensor imaging (DTI) in capturing microstructural alterations. We conducted a meta-analysis of studies using NODDI metrics to assess brain microstructural changes and neuroaxonal pathology in WM lesions and NAWM in patients with MS. Three reviewers conducted a literature search of four electronic databases. We performed a random-effect meta-analysis and the extent of between-study heterogeneity was assessed with the I2 statistic. Funnel plots and Egger’s tests were used to assess publication bias. We identified seven studies analysing 374 participants (202 MS and 172 controls). The NDI in WM lesions and NAWM were significantly reduced compared to healthy WM and the standardised mean difference of each was −3.08 (95%CI −4.22 to (−1.95), p ≤ 0.00001, I2 = 88%) and −0.70 (95%CI −0.99 to (−0.40), p ≤ 0.00001, I2 = 35%), respectively. There was no statistically significant difference of the ODI in MS WM lesions and NAWM compared to healthy controls. This systematic review and meta-analysis confirmed that the NDI is significantly reduced in MS lesions and NAWM than in WM from healthy participants, corresponding to reduced intracellular signal fraction, which may reflect underlying damage or loss of neurites.

Background and Purpose: The computed tomography angiography or contrast-enhanced computed tomography based spot sign has been proposed as a biomarker for identifying on-going hematoma expansion in patients with acute intracerebral hemorrhage. We investigated, if spot-sign positive participants benefit more from tranexamic acid versus placebo as compared to spot-sign negative participants. Methods: TICH-2 trial (Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage) was a randomized, placebo-controlled clinical trial recruiting acutely hospitalized participants with intracerebral hemorrhage within 8 hours after symptom onset. Local investigators randomized participants to 2 grams of intravenous tranexamic acid or matching placebo (1:1). All participants underwent computed tomography scan on admission and on day 2 (24±12 hours) after randomization. In this sub group analysis, we included all participants from the main trial population with imaging allowing adjudication of spot sign status. Results: Of the 2325 TICH-2 participants, 254 (10.9%) had imaging allowing for spot-sign adjudication. Of these participants, 64 (25.2%) were spot-sign positive. Median (interquartile range) time from symptom onset to administration of the intervention was 225.0 (169.0 to 310.0) minutes. The adjusted percent difference in absolute day-2 hematoma volume between participants allocated to tranexamic versus placebo was 3.7% (95% CI, −12.8% to 23.4%) for spot-sign positive and 1.7% (95% CI, −8.4% to 12.8%) for spot-sign negative participants ( P heterogenity =0.85). No difference was observed in significant hematoma progression (dichotomous composite outcome) between participants allocated to tranexamic versus placebo among spot-sign positive (odds ratio, 0.85 [95% CI, 0.29 to 2.46]) and negative (odds ratio, 0.77 [95% CI, 0.41 to 1.45]) participants ( P heterogenity =0.88). Conclusions: Data from the TICH-2 trial do not support that admission spot sign status modifies the treatment effect of tranexamic acid versus placebo in patients with acute intracerebral hemorrhage. The results might have been affected by low statistical power as well as treatment delay. Registration: URL: http://www.controlled-trials.com ; Unique identifier: ISRCTN93732214.

Background: Misdiagnosis is common in multiple sclerosis (MS) as a proportion of patients present with atypical clinical/magnetic resonance imaging (MRI) findings. The central vein sign has the potential to be a non-invasive, MS-specific biomarker. Objective: To test the accuracy of the central vein sign in predicting a diagnosis of MS in patients with diagnostic uncertainty at disease presentation using T2*-weighted, 3 T MRI. Methods: In this prospective pilot study, we recruited individuals with symptoms unusual for MS but with brain MRI consistent with the disease, and those with a typical clinical presentation of MS whose MRI did not suggest MS. We calculated the proportion of lesions with central veins for each patient and compared the results to the eventual clinical diagnoses. The optimal central vein threshold for diagnosis was established. Results: Thirty-eight patients were scanned, 35 of whom have received a clinical diagnosis. Median percentage of lesions with central veins was 51% in MS and 28% in non-MS. A threshold of 40.7% lesions with central veins resulted in 100% sensitivity and 73.9% specificity. Conclusion: The central vein sign assessed with a clinically available T2* scan can successfully diagnose MS in cases of diagnostic uncertainty. The central vein sign should be considered as a diagnostic biomarker in MS.

Background and purpose The interrelation of cognitive performance, cerebrovascular damage and brain functional connectivity (FC) in advanced arteriosclerosis remains unclear. Our aim was to investigate the associations between FC, white matter damage and cognitive impairment in carotid artery disease. Methods Seventy-one participants with a recent cerebrovascular event and with written informed consent underwent resting-state functional magnetic resonance imaging and the Addenbrooke's Cognitive Examination - Revised (ACE-R). Network and inter-hemispheric FC metrics were compared between cognitively normal and impaired subjects, and interrelated with cognition. In order to explore the nature of FC changes, their associations with microstructural damage of related white matter tracts and cognitive performance were investigated, followed by mediation analysis. Results Participants with global cognitive impairment showed reduced FC compared to the cognitively intact subjects within the central executive network (CEN), and between hemispheres. Patients with executive dysfunction had decreased CEN FC whilst patients with memory loss demonstrated low FC in both the CEN and the default mode network (DMN). Global performance correlated with connectivity metrics of the CEN hub with DMN nodes, and between hemispheres. Cingulum mean diffusivity (MD) was negatively correlated with ACE-R and CEN-DMN FC. The cingulum MD-cognition association was partially mediated by CEN-DMN FC. Conclusions Long-range functional disconnection of the CEN with DMN nodes is the main feature of cognitive impairment in elderly subjects with symptomatic carotid artery disease. Our findings provide further support for the connectional diaschisis concept of vascular cognitive disorder, and highlight a mediation role of functional disconnection to explain associations between microstructural white matter tract damage and cognitive impairment.

BACKGROUND Studies have shown signal intensity (SI) changes in the brains of children exposed to repeated doses of a gadolinium-based contrast agent (GBCA). HYPOTHESIS The trajectory of changes in relative dentate nucleus (DN) and globus pallidus (GP) SI in children receiving multiple doses of GBCA will alter when switched from linear to macrocyclic agents. STUDY TYPE Retrospective longitudinal. POPULATION Thirty-five children, age range 0.5-17.0 years, undergoing brain tumor follow-up between 2006 and 2017. FIELD STRENGTH/SEQUENCE Unenhanced T1 WI, serial scans at both 1.5T and 3T. ASSESSMENT Regions of interest were drawn on DN, GP, and SIs normalized to middle cerebellar peduncle (DN/MCP) and cerebral white matter (GP/CWM), respectively. A change in SI ratios as a function of dose (slope gradient) calculated according to the type of contrast agent received: linear only, macrocyclic only, or switchover from linear to macrocyclic. For the latter, gradients were compared before and after switchover. The effect of anticancer treatment on slope gradient was tested. STATISTICAL TESTS One-sample t-test or Mann-Whitney U-test for slope gradients differing from zero. Independent samples t-tests to compare slope gradient groups. Paired sample t-tests to compare slope gradients before and after switchover. RESULTS A significant (P < 0.05) increase in SI ratio was observed following multiple doses of linear but not macrocyclic agents: mean percentage increase per dose in SI was 0.063% vs. -0.034% for DN/MCP, and 0.078% vs. 0.004% for GP/CWM ratios. A significant (P < 0.05) change of SI trajectory in the DN/MCP ratio was demonstrated when switching from a linear to macrocyclic agent. There was no difference in SI trajectory between patients who had anticancer therapies and those who did not, DN/MCP P = 0.740; GP/BWM P = 0.694. DATA CONCLUSION Switching from linear to macrocyclic gadolinium-based contrast agents seems to halt the relative T1 signal increase in deep gray matter in children. Anticancer treatments appeared to have no impact on the trajectory of T1 SI. LEVEL OF EVIDENCE 4 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:288-295.

Summary Background The CNS manifestations of COVID-19 in children have primarily been described in case reports, which limit the ability to appreciate the full spectrum of the disease in paediatric patients. We aimed to identify enough cases that could be evaluated in aggregate to better understand the neuroimaging manifestations of COVID-19 in the paediatric population. Methods An international call for cases of children with encephalopathy related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and abnormal neuroimaging findings was made. Clinical history and associated plasma and cerebrospinal fluid data were requested. These data were reviewed by a central neuroradiology panel, a child neurologist, and a paediatric infectious diseases expert. The children were categorised on the basis of their time of probable exposure to SARS-CoV-2. In addition, cases were excluded when a direct link to SARS-CoV-2 infection could not be established or an established alternate diagnostic cause could be hypothesised. The accepted referral centre imaging data, from ten countries, were remotely reviewed by a central panel of five paediatric neuroradiologists and a consensus opinion obtained on the imaging findings. Findings 38 children with neurological disease related to SARS-CoV-2 infection were identified from France (n=13), the UK (n=8), the USA (n=5), Brazil (n=4), Argentina (n=4), India (n=2), Peru (n=1), and Saudi Arabia (n=1). Recurring patterns of disease were identified, with neuroimaging abnormalities ranging from mild to severe. The most common imaging patterns were postinfectious immune-mediated acute disseminated encephalomyelitis-like changes of the brain (16 patients), myelitis (eight patients), and neural enhancement (13 patients). Cranial nerve enhancement could occur in the absence of corresponding neurological symptoms. Splenial lesions (seven patients) and myositis (four patients) were predominantly observed in children with multisystem inflammatory syndrome. Cerebrovascular complications in children were less common than in adults. Significant pre-existing conditions were absent and most children had favourable outcomes. However, fatal atypical CNS co-infections developed in four previously healthy children infected with SARS-CoV-2. Interpretation Acute-phase and delayed-phase SARS-CoV-2-related CNS abnormalities are seen in children. Recurring patterns of disease and atypical neuroimaging manifestations can be found and should be recognised being as potentially due to SARS-CoV-2 infection as an underlying aetiological factor. Studies of paediatric specific cohorts are needed to better understand the effects of SARS-CoV-2 infection on the CNS at presentation and on long-term follow-up in children. Funding American Society of Pediatric Neuroradiology, University of Manchester (Manchester, UK). Video Abstract Neuroimaging manifestations in children with SARS-CoV-2 infection

Background Antiplatelet therapy increases the risk of hematoma expansion in intracerebral hemorrhage (ICH) while the effect on functional outcome is uncertain. Methods and Results This is an exploratory analysis of the TICH‐2 (Tranexamic Acid in Intracerebral Hemorrhage‐2) double‐blind, randomized, placebo‐controlled trial, which studied the efficacy of tranexamic acid in patients with spontaneous ICH within 8 hours of onset. Multivariable logistic regression and ordinal regression were performed to explore the relationship between pre‐ICH antiplatelet therapy, and 24‐hour hematoma expansion and day 90 modified Rankin Scale score, as well as the effect of tranexamic acid. Of 2325 patients, 611 (26.3%) had pre‐ICH antiplatelet therapy. They were older (mean age, 75.7 versus 66.5 years), more likely to have ischemic heart disease (25.4% versus 2.7%), ischemic stroke (36.2% versus 6.3%), intraventricular hemorrhage (40.2% versus 27.5%), and larger baseline hematoma volume (mean, 28.1 versus 22.6 mL) than the no‐antiplatelet group. Pre‐ICH antiplatelet therapy was associated with a significantly increased risk of hematoma expansion (adjusted odds ratio [OR], 1.28; 95% CI, 1.01–1.63), a shift toward unfavorable outcome in modified Rankin Scale (adjusted common OR, 1.58; 95% CI, 1.32–1.91) and a higher risk of death at day 90 (adjusted OR, 1.63; 95% CI, 1.25–2.11). Tranexamic acid reduced the risk of hematoma expansion in the overall patients with ICH (adjusted OR, 0.76; 95% CI, 0.62–0.93) and antiplatelet subgroup (adjusted OR, 0.61; 95% CI, 0.41–0.91) with no significant interaction between pre‐ICH antiplatelet therapy and tranexamic acid (P interaction=0.248). Conclusions Antiplatelet therapy is independently associated with hematoma expansion and unfavorable functional outcome. Tranexamic acid reduced hematoma expansion regardless of prior antiplatelet therapy use. Registration URL: https://www.isrctn.com ; Unique identifier: ISRCTN93732214.

Cerebral microbleeds (CMBs) appear as small, circular, well defined hypointense lesions of a few mm in size on T2*-weighted gradient recalled echo (T2*-GRE) images and appear enhanced on susceptibility weighted images (SWI). Due to their small size, contrast variations and other mimics (e.g., blood vessels), CMBs are highly challenging to detect automatically. In large datasets (e.g., the UK Biobank dataset), exhaustively labelling CMBs manually is difficult and time consuming. Hence it would be useful to preselect candidate CMB subjects in order to focus on those for manual labelling, which is essential for training and testing automated CMB detection tools on these datasets. In this work, we aim to detect CMB candidate subjects from a larger dataset, UK Biobank, using a machine learning-based, computationally light pipeline. For our evaluation, we used 3 different datasets, with different intensity characteristics, acquired with different scanners. They include the UK Biobank dataset and two clinical datasets with different pathological conditions. We developed and evaluated our pipelines on different types of images, consisting of SWI or GRE images. We also used the UK Biobank dataset to compare our approach with alternative CMB preselection methods using non-imaging factors and/or imaging data. Finally, we evaluated the pipeline's generalisability across datasets. Our method provided subject-level detection accuracy > 80% on all the datasets (within-dataset results), and showed good generalisability across datasets, providing a consistent accuracy of over 80%, even when evaluated across different modalities.

BackgroundEarly reports have detailed a range of neurological symptoms in patients with the SARS-CoV-2 infection. However, there is a lack of detailed description and incidence of the neurological disorders amongst hospitalized COVID-19 patients. We describe a range of neurological disorders (other than non-specific neurological symptoms), including their clinical, radiological and laboratory findings, encountered in our cohort of COVID-19 patients admitted to a large tertiary institution.MethodsWe reviewed our prospectively collated database of all adult Neurology referrals, Neurology and Stroke admissions and Neurological multi-disciplinary team meetings for all hospitalized patients with suspected or proven COVID-19 from 17 March 2020 to 31 August 2020.ResultsTwenty-nine of 1243 COVID-19 inpatients (2.3%) presented with COVID-19-related neurological disorders. The mean age was 68.9 +/- 13.5(SD) years, age range of 34-97 years, and there were 16 males. 22 patients had confirmed, 5 were probable and 2 had suspected COVID-19 infection according to the WHO case classification. Eight patients (27%) required critical care admission. Neurological symptoms at presentation included acute confusion and delirium, seizures, and new focal neurological deficits. Based on the pre-defined neurological phenotype, COVID-19 patients were grouped into four main categories. 16 patients had cerebrovascular events (13 with acute ischaemic stroke and 3 had haemorrhagic features), 7 patients were found to have inflammatory, non-inflammatory and autoimmune encephalopathy (including 2 with known Multiple Sclerosis), whilst disorders of movement and peripheral nervous system were diagnosed in 3 patients each.ConclusionAlthough the exact prevalence and aetiology remain unclear, new onset of neurological disorders, in addition to anosmia, is non-sporadic during the acute COVID-19-infection. Longitudinal follow-up of these patients is required to determine the clinical and functional outcome, treatment response and long-term effects of the SARS-CoV-2 infection.

IntroductionIntracerebral haemorrhage (ICH) can be devastating and is a common cause of death and disability worldwide. Pre-ICH antiplatelet drug use is associated with a 27% relative increase in 1 month case fatality compared with patients not using antithrombotic drugs. We aim to assess the feasibility of conducting a randomised controlled testing the safety and efficacy of desmopressin for patients with antiplatelet-associated ICH.Methods and analysisWe aim to include 50 patients within 24 hours of spontaneous ICH onset, associated with oral antiplatelet drug(s) use in at least the preceding 7 days. Patients will be randomised (1:1) to receive intravenous desmopressin 20 µg in 50 mL sodium chloride 0.9% infused over 20 min or matching placebo. We will mask participants, relatives and outcome assessors to treatment allocation. Feasibility outcomes include proportion of patients approached being randomised, number of patients receiving allocated treatment, rate of recruitment and adherence to treatment and follow-up. Secondary outcomes include change in ICH volume at 24 hours; hyponatraemia at 24 hours, length of hospital stay, discharge destination, early death less than 28 days, death or dependency at day 90, death up to day 90, serious adverse events (including thromboembolic events) up to day 90; disability (Barthel index, day 90), quality of life (EuroQol 5D (EQ-5D), day 90), cognition (telephone mini-mental state examination day 90) and health economic assessment (EQ-5D).Ethics and disseminationThe Desmopressin for reversal of Antiplatelet drugs in Stroke due to Haemorrhage (DASH) trial received ethical approval from the East Midlands—Nottingham 2 research ethics committee (18/EM/0184). The DASH trial is funded by National Institute for Health and Care Research RfPB grant: PB-PG-0816-20011. Trial results will be published in a peer reviewed academic journal and disseminated through academic conferences and through patient stroke support groups. Reporting will be in compliance with Consolidated Standards of Reporting Trials recommendations.Trial registration numbersNCT03696121;NCT67038373; EudraCT 2018-001904-12.

Three decades ago a series of parallel circuits were described involving the frontal cortex and deep grey matter structures, with putative roles in control of motor and oculomotor function, cognition, behaviour and emotion. The circuit comprising the dorsolateral prefrontal cortex, caudate, globus pallidus and thalamus has a putative role in regulating executive functions. The aim of this study is to investigate effective connectivity (EC) of the dorsolateral‐prefrontal circuit and its association with PASAT‐3 performance in people with multiple sclerosis(MS). We use Granger causality analysis of resting‐state functional MRI from 52 people with MS and 36 healthy people to infer that reduced EC in the afferent limb of the dorsolateral prefrontal circuit occurs in the people with MS with cognitive dysfunction (left: p = .006; right: p = .029), with bilateral EC reductions in this circuit resulting in more severe cognitive dysfunction than unilateral reductions alone (p = .002). We show that reduced EC in the afferent limb of the dorsolateral prefrontal circuit mediates the relationship between cognitive performance and macrostrucutral and microstructural alterations of white matter tracts in components of the circuit. Specificity is shown by the absence of any relationship between cognition and EC in the analogous and anatomically proximal motor circuit. We demonstrate good stability of the EC measures in people with MS over an interval averaging 8‐months. Key positive and negative results are replicated in an independent cohort of people with MS. Our findings identify the dorsolateral prefrontal circuit as a potential target for therapeutic strategies aimed at improving cognition in people with MS., Multimodal neuroimaging studies allow testing of biologically plausible models of multiple sclerosis‐related cognitive dysfunction. We used multimodal MRI to demonstrate reduced effective connectivity in the dorsolateral prefrontal circuit correlates with cognitive performance in people with multiple sclerosis and mediates the relationship between structural alterations in the circuit and cognition.

Neurological deterioration is common after intracerebral hemorrhage (ICH). We aimed to identify the predictors and effects of neurological deterioration and whether tranexamic acid reduced the risk of neurological deterioration. Data from the Tranexamic acid in IntraCerebral Hemorrhage-2 (TICH-2) randomized controlled trial were analyzed. Neurological deterioration was defined as an increase in National Institutes of Health Stroke Scale (NIHSS) of ≥ 4 or a decline in Glasgow Coma Scale of ≥ 2. Neurological deterioration was considered to be early if it started ≤ 48 h and late if commenced between 48 h and 7 days after onset. Logistic regression was used to identify predictors and effects of neurological deterioration and the effect of tranexamic acid on neurological deterioration. Of 2325 patients, 735 (31.7%) had neurological deterioration: 590 (80.3%) occurred early and 145 (19.7%) late. Predictors of early neurological deterioration included recruitment from the UK, previous ICH, higher admission systolic blood pressure, higher NIHSS, shorter onset-to-CT time, larger baseline hematoma, intraventricular hemorrhage, subarachnoid extension and antiplatelet therapy. Older age, male sex, higher NIHSS, previous ICH and larger baseline hematoma predicted late neurological deterioration. Neurological deterioration was independently associated with a modified Rankin Scale of > 3 (aOR 4.98, 3.70–6.70; p p = 0.041) but not late neurological deterioration (aOR 0.76, 0.52–1.11; p = 0.15). Larger hematoma size, intraventricular and subarachnoid extension increased the risk of neurological deterioration. Neurological deterioration increased the risk of death and dependency at day 90. Tranexamic acid reduced the risk of early neurological deterioration and warrants further investigation in ICH. URL:https://www.isrctn.com Unique identifier: ISRCTN93732214