Publications by authors named "David J Werring"

235 Publications

Antithrombotic dilemmas in stroke medicine: new data, unsolved challenges.

J Neurol Neurosurg Psychiatry 2022 Jun 21. Epub 2022 Jun 21.

Stroke Research Centre, UCL Queen Square Institute of Neurology, London, UK

Antithrombotic therapy is a key element of secondary prevention in patients who have had an ischaemic stroke or transient ischaemic attack. However, its use in clinical practice is not always straightforward. This review provides an update on certain difficult scenarios in antithrombotic management, with a focus on recent clinical trials and large observational studies. We discuss the approach to patients with an indication for antithrombotic treatment who also have clinical or radiological evidence of previous intracranial bleeding, patients with indications for both anticoagulant and antiplatelet treatment, and patients in whom antithrombotic treatment fails to prevent stroke. We also review the timing of anticoagulation initiation after cardioembolic stroke, and the use of antithrombotics in patients with asymptomatic cerebrovascular disease. Despite a wealth of new evidence, numerous uncertainties remain and we highlight ongoing trials addressing these.
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http://dx.doi.org/10.1136/jnnp-2020-325249DOI Listing
June 2022

Targeted detection and repair of a spinal dural defect associated with successful biochemical resolution of subarachnoid bleeding in classical infratentorial superficial siderosis.

Neurol Sci 2022 Jun 13. Epub 2022 Jun 13.

Department of Neurology, National Hospital for Neurology and Neurosurgery, London, UK.

BACKGROUND AND IMPORTANCE  : Classical infratentorial superficial siderosis (iSS) is characterised by repeated insidious bleeding into the subarachnoid space, leading to haemosiderin deposition within the subpial layers of the brainstem, cerebellum and spinal cord, sometimes with supratentorial involvement. Although nearly always associated with a dural defect (usually from previous trauma or neurosurgery) there is little evidence to support definitive investigation and management strategies. Here, we present a novel investigation strategy to identify a dural defect and subsequent successful surgical repair with biochemical resolution of subarachnoid bleeding. CLINICAL PRESENTATION: A 55-year-old gentleman presented with a 15-year progressive history of sensorineural deafness, followed by a slowly worsening gait ataxia. He had previously sustained cranio-spinal trauma. On examination there were features of myelopathy and ataxia. MRI demonstrated classical iSS, affecting cerebellum and cerebral cortices, with a cervicothoracic epidural CSF collection. Lumbar puncture (LP) revealed elevated ferritin 413 ng/mL and red cell count of 4160. Reverse CT myelography, a novel technique involving contrast injection into the collection, delineated a dural defect at the T9/T10 level that was not present on conventional myelography. Following surgical repair, repeat LP twelve months later demonstrated biochemical improvement (ferritin 18 ng/mL, red cells < 1). There was no further neurological deterioration in symptoms during eighteen months follow-up. CONCLUSION: We show the value of a rational targeted investigation pathway in identifying a surgically reparable dural defect underlying classical iSS. We also provide proof of concept that surgical repair can facilitate biochemical resolution of subarachnoid bleeding and might prevent progression of neurological disability.
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http://dx.doi.org/10.1007/s10072-022-06181-xDOI Listing
June 2022

Cerebral small vessel disease and intracranial bleeding risk: Prognostic and practical significance.

Int J Stroke 2022 Jun 24:17474930221106014. Epub 2022 Jun 24.

Stroke Research Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.

Balancing the risks of recurrent ischemia and antithrombotic-associated bleeding, particularly intracranial hemorrhage (ICH), is a key challenge in the secondary prevention of ischemic stroke and transient ischemic attack. In hyperacute ischemic stroke, the use of acute reperfusion therapies is determined by the balance of anticipated benefit and the risk of ICH. Cerebral small vessel disease (CSVD) causes most spontaneous ICH. Here, we review the evidence linking neuroimaging markers of CSVD to antithrombotic and thrombolytic-associated ICH, with emphasis on cerebral microbleeds (CMB). We discuss their role in the prediction of ICH, and practical implications for clinical decision making. Although current observational data suggest CMB presence should not preclude antithrombotic therapy in patients with ischemic stroke or TIA, they are useful for improving ICH risk prediction with potential relevance for determining the optimal secondary prevention strategy, including the use of left atrial appendage occlusion. Following ICH, recommencing antiplatelets is probably safe in most patients, while the inconclusive results of recent randomized controlled trials of anticoagulant use makes recruitment to ongoing trials (including those testing left atrial appendage occlusion) in this area a high priority. Concern regarding CSVD and ICH risk after hyperacute stroke treatment appears to be unjustified in most patients, though some uncertainty remains regarding patients with very high CMB burden and other risk factors for ICH. We encourage careful phenotyping for underlying CSVD in future trials, with the potential to enhance precision medicine in stroke.
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http://dx.doi.org/10.1177/17474930221106014DOI Listing
June 2022

Prognostic indicators and outcomes of hospitalised COVID-19 patients with neurological disease: An individual patient data meta-analysis.

PLoS One 2022 2;17(6):e0263595. Epub 2022 Jun 2.

Barts Health NHS Trust, London, United Kingdom of Great Britain and Northern Ireland.

Background: Neurological COVID-19 disease has been reported widely, but published studies often lack information on neurological outcomes and prognostic risk factors. We aimed to describe the spectrum of neurological disease in hospitalised COVID-19 patients; characterise clinical outcomes; and investigate factors associated with a poor outcome.

Methods: We conducted an individual patient data (IPD) meta-analysis of hospitalised patients with neurological COVID-19 disease, using standard case definitions. We invited authors of studies from the first pandemic wave, plus clinicians in the Global COVID-Neuro Network with unpublished data, to contribute. We analysed features associated with poor outcome (moderate to severe disability or death, 3 to 6 on the modified Rankin Scale) using multivariable models.

Results: We included 83 studies (31 unpublished) providing IPD for 1979 patients with COVID-19 and acute new-onset neurological disease. Encephalopathy (978 [49%] patients) and cerebrovascular events (506 [26%]) were the most common diagnoses. Respiratory and systemic symptoms preceded neurological features in 93% of patients; one third developed neurological disease after hospital admission. A poor outcome was more common in patients with cerebrovascular events (76% [95% CI 67-82]), than encephalopathy (54% [42-65]). Intensive care use was high (38% [35-41]) overall, and also greater in the cerebrovascular patients. In the cerebrovascular, but not encephalopathic patients, risk factors for poor outcome included breathlessness on admission and elevated D-dimer. Overall, 30-day mortality was 30% [27-32]. The hazard of death was comparatively lower for patients in the WHO European region.

Interpretation: Neurological COVID-19 disease poses a considerable burden in terms of disease outcomes and use of hospital resources from prolonged intensive care and inpatient admission; preliminary data suggest these may differ according to WHO regions and country income levels. The different risk factors for encephalopathy and stroke suggest different disease mechanisms which may be amenable to intervention, especially in those who develop neurological symptoms after hospital admission.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0263595PLOS
June 2022

Statistical analysis plan for the randomized controlled trial Tenecteplase in Wake-up Ischaemic Stroke Trial (TWIST).

Trials 2022 May 19;23(1):421. Epub 2022 May 19.

Department of Neurology, University Hospital of North Norway, Tromsø, Norway.

Background: Patients with wake-up ischemic stroke are frequently excluded from thrombolytic treatment due to unknown symptom onset time and limited availability of advanced imaging modalities. The Tenecteplase in Wake-up Ischaemic Stroke Trial (TWIST) is a randomized controlled trial of intravenous tenecteplase 0.25 mg/kg and standard care versus standard care alone (no thrombolysis) in patients who wake up with acute ischemic stroke and can be treated within 4.5 h of wakening based on non-contrast CT findings.

Objective: To publish the detailed statistical analysis plan for TWIST prior to unblinding.

Methods: The TWIST statistical analysis plan is consistent with the Consolidating Standard of Reporting Trials (CONSORT) statement and provides clear and open reporting.

Discussion: Publication of the statistical analysis plan serves to reduce potential trial reporting bias and clearly outlines the pre-specified analyses.

Trial Registration: ClinicalTrials.gov NCT03181360 . EudraCT Number 2014-000096-80 . WHO ICRTP registry number ISRCTN10601890 .
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http://dx.doi.org/10.1186/s13063-022-06301-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9118782PMC
May 2022

Iatrogenic cerebral amyloid angiopathy: an emerging clinical phenomenon.

J Neurol Neurosurg Psychiatry 2022 May 16. Epub 2022 May 16.

Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, University College London Hospitals NHS Foundation Trust, London, UK.

In the last 6 years, following the first pathological description of presumed amyloid-beta (Aβ) transmission in humans (in 2015) and subsequent experimental confirmation (in 2018), clinical cases of iatrogenic cerebral amyloid angiopathy (CAA)-attributed to the transmission of Aβ seeds-have been increasingly recognised and reported. This newly described form of CAA is associated with early disease onset (typically in the third to fifth decade), and often presents with intracerebral haemorrhage, but also seizures and cognitive impairment. Although assumed to be rare, it is important that clinicians remain vigilant for potential cases, particularly as the optimal management, prognosis, true incidence and public health implications remain unknown. This review summarises our current understanding of the clinical spectrum of iatrogenic CAA and provides a diagnostic framework for clinicians. We provide clinical details for three patients with pathological evidence of iatrogenic CAA and present a summary of the published cases to date (n=20), identified following a systematic review. Our aims are: (1) To describe the clinical features of iatrogenic CAA, highlighting important similarities and differences between iatrogenic and sporadic CAA; and (2) To discuss potential approaches for investigation and diagnosis, including suggested diagnostic criteria for iatrogenic CAA.
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http://dx.doi.org/10.1136/jnnp-2022-328792DOI Listing
May 2022

Network impact score is an independent predictor of post-stroke cognitive impairment: A multicenter cohort study in 2341 patients with acute ischemic stroke.

Neuroimage Clin 2022 27;34:103018. Epub 2022 Apr 27.

Université Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, F-59000 Lille, France.

Background: Post-stroke cognitive impairment (PSCI) is a common consequence of stroke. Accurate prediction of PSCI risk is challenging. The recently developed network impact score, which integrates information on infarct location and size with brain network topology, may improve PSCI risk prediction.

Aims: To determine if the network impact score is an independent predictor of PSCI, and of cognitive recovery or decline.

Methods: We pooled data from patients with acute ischemic stroke from 12 cohorts through the Meta VCI Map consortium. PSCI was defined as impairment in ≥ 1 cognitive domain on neuropsychological examination, or abnormal Montreal Cognitive Assessment. Cognitive recovery was defined as conversion from PSCI < 3 months post-stroke to no PSCI at follow-up, and cognitive decline as conversion from no PSCI to PSCI. The network impact score was related to serial measures of PSCI using Generalized Estimating Equations (GEE) models, and to PSCI stratified according to post-stroke interval (<3, 3-12, 12-24, >24 months) and cognitive recovery or decline using logistic regression. Models were adjusted for age, sex, education, prior stroke, infarct volume, and study site.

Results: We included 2341 patients with 4657 cognitive assessments. PSCI was present in 398/844 patients (47%) <3 months, 709/1640 (43%) at 3-12 months, 243/853 (28%) at 12-24 months, and 208/522 (40%) >24 months. Cognitive recovery occurred in 64/181 (35%) patients and cognitive decline in 26/287 (9%). The network impact score predicted PSCI in the univariable (OR 1.50, 95%CI 1.34-1.68) and multivariable (OR 1.27, 95%CI 1.10-1.46) GEE model, with similar ORs in the logistic regression models for specified post-stroke intervals. The network impact score was not associated with cognitive recovery or decline.

Conclusions: The network impact score is an independent predictor of PSCI. As such, the network impact score may contribute to a more precise and individualized cognitive prognostication in patients with ischemic stroke. Future studies should address if multimodal prediction models, combining the network impact score with demographics, clinical characteristics and other advanced brain imaging biomarkers, will provide accurate individualized prediction of PSCI. A tool for calculating the network impact score is freely available at https://metavcimap.org/features/software-tools/lsm-viewer/.
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http://dx.doi.org/10.1016/j.nicl.2022.103018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9079101PMC
April 2022

Total Cerebral Small Vessel Disease Score and Cerebral Bleeding Risk in Patients With Acute Stroke Treated With Intravenous Thrombolysis.

Front Aging Neurosci 2022 11;14:790262. Epub 2022 Apr 11.

Department of Neurology, Stroke Research Center, Fujian Medical University Union Hospital, Fuzhou, China.

Objective: The aim of this study was to investigate the association of total cerebral small vessel disease (cSVD) score with the risk of intracerebral hemorrhage (ICH) in patients with acute ischemic stroke who received intravenous thrombolysis (IVT) using recombinant tissue-plasminogen activator (rt-PA).

Methods: We retrospectively reviewed clinical data from two stroke registries of patients with acute ischemic stroke treated with IVT. We assessed the baseline magnetic resonance (MR) visible cSVD markers and total cSVD score (ranging from 0 to 4) between patients with and without ICH after IVT. Logistic regression analysis was used to determine the association of total cSVD score with the risk of ICH after IVT, adjusted for cofounders selected by least absolute shrinkage and selection operator (LASSO). We additionally performed an -value analysis to fully explain away a specific exposure-outcome association. Receiver operating characteristic (ROC) curve analysis was used to quantify the predictive potential of the total cSVD score for any ICH after IVT.

Results: Among 271 eligible patients, 55 (20.3%) patients experienced any ICH, 16 (5.9%) patients experienced a symptomatic ICH (sICH), and 5 (1.85%) patients had remote intracranial parenchymal hemorrhage (rPH). Logistic regression analysis showed that the risk of any ICH increased with increasing cSVD score [per unit increase, adjusted odds ratio (OR) 2.03, 95% CI 1.22-3.41, = 0.007]. Sensitivity analyses using -value revealed that it would need moderately robust unobserved confounding to render the exposure-outcome (cSVD-any ICH) association null. ROC analysis showed that compared with the National Institutes of Health Stroke Scale (NIHSS) score alone, a combination of cSVD and NIHSS score had a larger area under the curve for any ICH (0.811, 95% CI 0.756-0.866 vs. 0.784, 95% CI 0.723-0.846, = 0.0004).

Conclusion: The total cSVD score is associated with an increased risk of any ICH after IVT and improves prediction for any ICH compared with NIHSS alone.
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http://dx.doi.org/10.3389/fnagi.2022.790262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9037754PMC
April 2022

Effect of Tranexamic Acid Administration on Remote Cerebral Ischemic Lesions in Acute Spontaneous Intracerebral Hemorrhage: A Substudy of a Randomized Clinical Trial.

JAMA Neurol 2022 05;79(5):468-477

Radiological Sciences, Mental Health and Clinical Neuroscience, University of Nottingham, Nottingham, United Kingdom.

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.
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http://dx.doi.org/10.1001/jamaneurol.2022.0217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8938900PMC
May 2022

Prevalence of Clinical and Neuroimaging Markers in Cerebral Amyloid Angiopathy: A Systematic Review and Meta-Analysis.

Stroke 2022 Jun 10;53(6):1944-1953. Epub 2022 Mar 10.

Second Department of Neurology (A.T., A.H.K., C.Z., G.P.P., G.T.), National and Kapodistrian University of Athens, "Attikon" University Hospital, Greece.

Background: Limited data exist regarding the prevalence of clinical and neuroimaging manifestations among patients diagnosed with cerebral amyloid angiopathy (CAA). We sought to determine the prevalence of clinical phenotypes and radiological markers in patients with CAA.

Methods: Systematic review and meta-analysis of studies including patients with CAA was conducted to primarily assess the prevalence of clinical phenotypes and neuroimaging markers as available in the included studies. Sensitivity analyses were performed based on the (1) retrospective or prospective study design and (2) probable or unspecified CAA status. We pooled the prevalence rates using random-effects models and assessed the heterogeneity using the Cochran and statistics.

Results: We identified 12 prospective and 34 retrospective studies including 7159 patients with CAA. The pooled prevalence rates were cerebral microbleeds (52% [95% CI, 43%-60%]; I=93%), cortical superficial siderosis (49% [95% CI, 38%-59%]; I=95%), dementia or mild cognitive impairment (50% [95% CI, 35%-65%]; I=97%), intracerebral hemorrhage (ICH; 44% [95% CI, 27%-61%]; I=98%), transient focal neurological episodes (48%; 10 studies [95% CI, 29%-67%]; I=97%), lacunar infarcts (30% [95% CI, 25%-36%]; I=78%), high grades of perivascular spaces located in centrum semiovale (56% [95% CI, 44%-67%]; I=88%) and basal ganglia (21% [95% CI, 2%-51%]; I=98%), and white matter hyperintensities with moderate or severe Fazekas score (53% [95% CI, 40%-65%]; I=91%). The only neuroimaging marker that was associated with higher odds of recurrent ICH was cortical superficial siderosis (odds ratio, 1.57 [95% CI, 1.01-2.46]; I=47%). Sensitivity analyses demonstrated a higher prevalence of ICH (53% versus 16%; =0.03) and transient focal neurological episodes (57% versus 17%; =0.03) among retrospective studies compared with prospective studies. No difference was documented between the prevalence rates based on the CAA status.

Conclusions: Approximately one-half of hospital-based cohort of CAA patients was observed to have cerebral microbleeds, cortical superficial siderosis, mild cognitive impairment, dementia, ICH, or transient focal neurological episodes. Cortical superficial siderosis was the only neuroimaging marker that was associated with higher odds of ICH recurrence. Future population-based studies among well-defined CAA cohorts are warranted to corroborate our findings.
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http://dx.doi.org/10.1161/STROKEAHA.121.035836DOI Listing
June 2022

New Insights Into Cerebrovascular Pathophysiology and Hypertension.

Stroke 2022 04 8;53(4):1054-1064. Epub 2022 Mar 8.

Stroke Research Centre, UCL Queen Square Institute of Neurology, London, United Kingdom (D.J.W.).

Despite advances in acute management and prevention of cerebrovascular disease, stroke and vascular cognitive impairment together remain the world's leading cause of death and neurological disability. Hypertension and its consequences are associated with over 50% of ischemic and 70% of hemorrhagic strokes but despite good control of blood pressure (BP), there remains a 10% risk of recurrent cerebrovascular events, and there is no proven strategy to prevent vascular cognitive impairment. Hypertension evolves over the lifespan, from predominant sympathetically driven hypertension with elevated mean BP in early and mid-life to a late-life phenotype of increasing systolic and falling diastolic pressures, associated with increased arterial stiffness and aortic pulsatility. This pattern may partially explain both the increasing incidence of stroke in younger adults as well as late-onset, chronic cerebrovascular injury associated with concurrent systolic hypertension and historic mid-life diastolic hypertension. With increasing arterial stiffness and autonomic dysfunction, BP variability increases, independently predicting the risk of ischemic and intracerebral hemorrhage, and is potentially modifiable beyond control of mean BP. However, the interaction between hypertension and control of cerebral blood flow remains poorly understood. Cerebral small vessel disease is associated with increased pulsatility in large cerebral vessels and reduced reactivity to carbon dioxide, both of which are being targeted in early phase clinical trials. Cerebral arterial pulsatility is mainly dependent upon increased transmission of aortic pulsatility via stiff vessels to the brain, while cerebrovascular reactivity reflects endothelial dysfunction. In contrast, although cerebral autoregulation is critical to adapt cerebral tone to BP fluctuations to maintain cerebral blood flow, its role as a modifiable risk factor for cerebrovascular disease is uncertain. New insights into hypertension-associated cerebrovascular pathophysiology may provide key targets to prevent chronic cerebrovascular disease, acute events, and vascular cognitive impairment.
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http://dx.doi.org/10.1161/STROKEAHA.121.035850DOI Listing
April 2022

Magnetic resonance imaging-based scores of small vessel diseases: Associations with intracerebral haemorrhage location.

J Neurol Sci 2022 Mar 24;434:120165. Epub 2022 Jan 24.

Department of Neurology and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Centre, Maastricht, the Netherlands. Electronic address:

Introduction: Total small vessel disease (SVD) score and cerebral amyloid angiopathy (CAA) score are magnetic resonance imaging-based composite scores built to preferentially capture deep perforator arteriopathy-related and CAA-related SVD burden, respectively. Non-lobar intracerebral haemorrhage (ICH) is related to deep perforator arteriopathy, while lobar ICH can be associated with deep perforator arteriopathy or CAA; however, the associations between ICH location and these scores are not established.

Methods: In this post-hoc analysis from a prospective cohort study, we included 153 spontaneous non-cerebellar ICH patients. Wald test, univariable and multivariable logistic regression analysis were performed to investigate the association between each score (and individual score components) and ICH location.

Results: Total SVD score was associated with non-lobar ICH location (Wald test: unadjusted, p = 0.017; adjusted, p = 0.003); however, no individual component of total SVD score was significantly associated with non-lobar ICH. CAA score was not significantly associated with lobar location (Wald test: unadjusted, p = 0.056; adjusted, p = 0.126); cortical superficial siderosis (OR 8.85 [95%CI 1.23-63.65], p = 0.030) and ≥ 2 strictly lobar microbleeds (OR 1.63 [95%CI 1.04-2.55], p = 0.035) were related with lobar ICH location, while white matter hyperintensities showed an inverse relation (OR 0.53 [95%CI 0.26-1.08; p = 0.081]).

Conclusions: Total SVD score was associated with non-lobar ICH location. The lack of significant association between CAA score and lobar ICH may in part be due to the mixed aetiology of lobar ICH, and to the inclusion of white matter hyperintensities, a non-specific marker of SVD type, in the CAA score.
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http://dx.doi.org/10.1016/j.jns.2022.120165DOI Listing
March 2022

Practical "1-2-3-4-Day" Rule for Starting Direct Oral Anticoagulants After Ischemic Stroke With Atrial Fibrillation: Combined Hospital-Based Cohort Study.

Stroke 2022 05 2;53(5):1540-1549. Epub 2022 Feb 2.

Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan (S.K., K.T., Sohei Yoshimura, T.C., M.S., M.K.).

Background: The "1-3-6-12-day rule" for starting direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation after acute ischemic stroke or transient ischemic attack recommends timings that may be later than used in clinical practice. We investigated more practical optimal timing of DOAC initiation according to stroke severity.

Methods: The combined data of prospective registries in Japan, Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-nonvalvular atrial fibrillation (September 2011 to March 2014) and RELAXED (February 2014 to April 2016) were used. Patients were divided into transient ischemic attack and 3 stroke subgroups by the National Institutes of Health Stroke Scale score: mild (0-7), moderate (8-15), and severe (≥16). The early treatment group was defined as patients starting DOACs earlier than the median initiation day in each subgroup. Outcomes included a composite of recurrent stroke or systemic embolism, ischemic stroke, and severe bleeding within 90 days. Six European prospective registries were used for validation.

Results: In the 1797 derivation cohort patients, DOACs were started at median 2 days after transient ischemic attack and 3, 4, and 5 days after mild, moderate, and severe strokes, respectively. Stroke or systemic embolism was less common in Early Group (n=785)-initiating DOACS within 1, 2, 3, and 4 days, respectively-than Late Group (n=1012) (1.9% versus 3.9%; adjusted hazard ratio, 0.50 [95% CI, 0.27-0.89]), as was ischemic stroke (1.7% versus 3.2%, 0.54 [0.27-0.999]). Major bleeding was similarly common in the 2 groups (0.8% versus 1.0%). On validation, both ischemic stroke (2.4% versus 2.2%) and intracranial hemorrhage (0.2% versus 0.6%) were similarly common in Early (n=547) and Late (n=1483) Groups defined using derivation data.

Conclusions: In Japanese and European populations, early DOAC initiation within 1, 2, 3, or 4 days according to stroke severity seemed to be feasible to decrease the risk of recurrent stroke or systemic embolism and no increase in major bleeding. These findings support ongoing randomized trials to better establish the optimal timing of DOAC initiation.
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http://dx.doi.org/10.1161/STROKEAHA.121.036695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9022681PMC
May 2022

Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS): Protocol for a randomized controlled trial.

Int J Stroke 2022 Jun 12;17(5):583-589. Epub 2022 Jan 12.

Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology, London, UK.

Rationale: Atrial fibrillation causes one-fifth of ischemic strokes, with a high risk of early recurrence. Although long-term anticoagulation is highly effective for stroke prevention in atrial fibrillation, initiation after stroke is usually delayed by concerns over intracranial hemorrhage risk. Direct oral anticoagulants offer a significantly lower risk of intracranial hemorrhage than other anticoagulants, potentially allowing earlier anticoagulation and prevention of recurrence, but the safety and efficacy of this approach has not been established.

Aim: Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS) will investigate whether early treatment with a direct oral anticoagulant, within four days of stroke onset, is as effective or better than delayed initiation, 7 to 14 days from onset, in atrial fibrillation patients with acute ischemic stroke.

Methods And Design: OPTIMAS is a multicenter randomized controlled trial with blinded outcome adjudication. Participants with acute ischemic stroke and atrial fibrillation eligible for anticoagulation with a direct oral anticoagulant are randomized 1:1 to early or delayed initiation. As of December 2021, 88 centers in the United Kingdom have opened.

Study Outcomes: The primary outcome is a composite of recurrent stroke (ischemic stroke or symptomatic intracranial hemorrhage) and systemic arterial embolism within 90 days. Secondary outcomes include major bleeding, functional status, anticoagulant adherence, quality of life, health and social care resource use, and length of hospital stay.

Sample Size Target: A total of 3478 participants assuming event rates of 11.5% in the control arm and 8% in the intervention arm, 90% power and 5% alpha. We will follow a non-inferiority gatekeeper analysis approach with a non-inferiority margin of 2 percentage points.

Discussion: OPTIMAS aims to provide high-quality evidence on the safety and efficacy of early direct oral anticoagulant initiation after atrial fibrillation-associated ischemic stroke. ISRCTN: 17896007; ClinicalTrials.gov: NCT03759938.
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http://dx.doi.org/10.1177/17474930211057722DOI Listing
June 2022

Cognitive dysfunction and white matter hyperintensities in Fabry disease.

J Inherit Metab Dis 2022 Jan 7. Epub 2022 Jan 7.

Department of Neuropsychology, National Hospital for Neurology and Neurosurgery, London, UK.

Fabry disease (FD) is an X-linked lysosomal storage disorder with multi-system involvement including cerebrovascular disease. Patients with FD also have a high risk of ischaemic stroke and TIA. White matter hyperintensities are common, but their clinical impact on cognition remains uncertain. Previous studies have examined the neuropsychological profile of FD, but have been inconclusive in part due to methodological limitations including small sample sizes. We sought to address these limitations in a case-control study of 26 patients with Fabry disease with mild to moderate disease symptoms matched with 18 healthy controls for age and premorbid intellectual level. We obtained detailed neuropsychological data and MRI neuroimaging data on the severity of white matter changes. Mood was accounted for as a possible confounder. Our results showed significant compromise of executive functions and information processing speed for the FD group. Error analyses suggested that the compromise of executive functions could not be entirely accounted for by slowed information processing speed. We demonstrated significant correlations between cognitive decline and the overall volume of white matter hyperintensities in the FD group. Our results point to significant compromise of cognition in FD even without stroke or mood difficulties. This suggests that neuropsychological assessment and rehabilitation should be routinely offered to patients with FD.
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http://dx.doi.org/10.1002/jimd.12472DOI Listing
January 2022

MRI and CT imaging biomarkers of cerebral amyloid angiopathy in lobar intracerebral hemorrhage.

Int J Stroke 2022 Jan 7:17474930211062478. Epub 2022 Jan 7.

Stroke Research Centre, Institute of Neurology, UCL Queen Square Institute of Neurology and National Hospital of Neurology and Neurosurgery, London, UK.

Background: Cerebral amyloid angiopathy (CAA), a common cause of intracerebral hemorrhage (ICH), is diagnosed using the Boston criteria including magnetic resonance imaging (MRI) biomarkers (cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS). The simplified Edinburgh criteria include computed tomography (CT) biomarkers (subarachnoid extension (SAE) and finger-like projections (FLPs)). The underlying mechanisms and diagnostic accuracy of CT compared to MRI biomarkers of CAA are unknown.

Methods: We included 140 survivors of spontaneous lobar supratentorial ICH with both acute CT and MRI. We assessed associations between MRI and CT biomarkers and the diagnostic accuracy of CT- compared to MRI-based criteria.

Results: FLPs were more common in patients with strictly lobar CMB (44.7% vs 23.5%; p = 0.014) and SAE was more common in patients with cSS (61.3% vs 31.2%; p = 0.002). The high probability of the CAA category of the simplified Edinburgh criteria showed 87.2% (95% confidence interval (CI): 78.3-93.4) specificity, 29.6% (95% CI: 18.0-43.6) sensitivity, 59.3% (95% CI: 38.8-77.6) positive predictive value, and 66.4% (95%: CI 56.9-75.0) negative predictive value, 2.3 (95% CI: 1.2-4.6) positive likelihood ratio and 0.8 (95% CI 0.7-1.0) negative likelihood ratio for probable CAA (vs non-probable CAA), defined by the modified Boston criteria; the area under the receiver operating characteristic curve (AUROC) was 0.62 (95% CI: 0.54-0.71).

Conclusion: In lobar ICH survivors, we found associations between putative biomarkers of parenchymal CAA (FLP and strictly lobar CMBs) and putative biomarkers of leptomeningeal CAA (SAE and cSS). In a hospital population, CT biomarkers might help rule-in probable CAA (diagnosed using the Boston criteria), but their absence is probably not as useful to rule it out, suggesting an important continued role for MRI in ICH survivors with suspected CAA.
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http://dx.doi.org/10.1177/17474930211062478DOI Listing
January 2022

Brief Consent Methods Enable Rapid Enrollment in Acute Stroke Trial: Results From the TICH-2 Randomized Controlled Trial.

Stroke 2022 04 1;53(4):1141-1148. Epub 2021 Dec 1.

Stroke Trials Unit (Z.K.L., J.P.A., P.S., P.M.B., N.S.), University of Nottingham, United Kingdom.

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 (<0.001). Two-stage consent was associated with onset-to-randomization time of ≤3 hours compared with 1-stage consent (adjusted odds ratio, 1.9 [95% CI, 1.5-2.4]). Doctor consent increased the odds (adjusted odds ratio, 2.3 [1.5-3.5]) while relative consent reduced the odds of randomization ≤3 hours (adjusted odds ratio, 0.10 [0.03-0.34]) compared with patient consent. Only 2 of 771 patients (0.3%) in the 2-stage pathways withdrew consent when full consent was sought later. Two-stage consent process did not result in higher withdrawal rates or loss to follow-up.

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.
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http://dx.doi.org/10.1161/STROKEAHA.121.035191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612544PMC
April 2022

Intravenous Thrombolysis Before Mechanical Thrombectomy for Acute Ischemic Stroke: A Meta-Analysis.

J Am Heart Assoc 2021 12 15;10(23):e022303. Epub 2021 Nov 15.

Department of Neurology Stroke Research Center Fujian Medical University Union Hospital Fuzhou China.

Background Whether intravenous thrombolysis before mechanical thrombectomy provides additional benefit for functional outcome in acute ischemic stroke remains uncertain. We performed a meta-analysis to compare the outcomes of direct mechanical thrombectomy (dMT) to mechanical thrombectomy with bridging using intravenous thrombolysis (bridging therapy [BT]) in patients with acute ischemic stroke. Methods and Results We performed a literature search in the PubMed, Excerpta Medica database, and Cochrane Central Register of Controlled Trials from January 1, 2003, to April 26, 2021. We included randomized clinical trials and observational studies that reported the 90-day functional outcome in patients with acute ischemic stroke undergoing dMT compared with BT. The 12 included studies (3 randomized controlled trials and 9 observational studies) yielded 3924 participants (mean age, 68.0 years [SD, 13.1 years]; women, 44.2%; 1887 participants who received dMT and 2037 participants who received BT). A meta-analysis of randomized controlled trial and observational data revealed similar 90-day functional independence (odds ratio [OR], 1.04; 95% CI, 0.90-1.19), mortality (OR, 1.03; 95% CI, 0.78-1.36), and successful recanalization (OR, 0.93; 95% CI, 0.76-1.14) for patients treated with dMT or BT. Compared with those in the BT group, patients in the dMT group were less likely to experience symptomatic intracranial hemorrhage (OR, 0.68; 95% CI, 0.51-0.91; =0.008) or any intracranial hemorrhage (OR, 0.71; 95% CI, 0.61-0.84; <0.001). Conclusions In this meta-analysis of patients with acute ischemic stroke, we found no significant differences in 90-day functional outcome or mortality between dMT and BT, but a lower rate of symptomatic intracranial hemorrhage for dMT. These findings support the use of dMT without intravenous thrombolysis bridging therapy. Registration URL: https://www.crd.york.ac.uk/prospero/; Unique identifier: 42021234664.
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http://dx.doi.org/10.1161/JAHA.121.022303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9075352PMC
December 2021

Oral Anticoagulants in the Oldest Old with Recent Stroke and Atrial Fibrillation.

Ann Neurol 2022 01 29;91(1):78-88. Epub 2021 Nov 29.

Stroke Unit and Division of Cardiovascular Medicine, University of Perugia, Perugia, Italy.

Objective: To investigate the safety and effectiveness of direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA) after recent stroke in patients with atrial fibrillation (AF) aged ≥85 years.

Methods: Individual patient data analysis from seven prospective stroke cohorts. We compared DOAC versus VKA treatment among patients with AF and recent stroke (<3 months) aged ≥85 versus <85 years. Primary outcome was the composite of recurrent stroke, intracranial hemorrhage (ICH) and all-cause death. We used simple, adjusted, and weighted Cox regression to account for confounders. We calculated the net benefit of DOAC versus VKA by balancing stroke reduction against the weighted ICH risk.

Results: In total, 5,984 of 6,267 (95.5%) patients were eligible for analysis. Of those, 1,380 (23%) were aged ≥85 years and 3,688 (62%) received a DOAC. During 6,874 patient-years follow-up, the impact of anticoagulant type (DOAC versus VKA) on the hazard for the composite outcome did not differ between patients aged ≥85 (HR  = 0.65, 95%-CI [0.52, 0.81]) and < 85 years (HR  = 0.79, 95%-CI [0.66, 0.95]) in simple (p  = 0.129), adjusted (p  = 0.094) or weighted (p  = 0.512) models. Analyses on recurrent stroke, ICH and death separately were consistent with the primary analysis, as were sensitivity analyses using age dichotomized at 90 years and as a continuous variable. DOAC had a similar net clinical benefit in patients aged ≥85 (+1.73 to +2.66) and < 85 years (+1.90 to +3.36 events/100 patient-years for ICH-weights 1.5 to 3.1).

Interpretation: The favorable profile of DOAC over VKA in patients with AF and recent stroke was maintained in the oldest old. ANN NEUROL 2022;91:78-88.
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http://dx.doi.org/10.1002/ana.26267DOI Listing
January 2022

The impact of the UK COVID-19 pandemic on patient-reported health outcomes after stroke: a retrospective sequential comparison.

J Neurol 2022 Apr 15;269(4):1741-1750. Epub 2021 Oct 15.

Stroke Research Centre, Queen Square Institute of Neurology, University College London, London, UK.

Background And Purpose: The COVID-19 pandemic and related social isolation measures are likely to have adverse consequences on community healthcare provision and outcome after acute illnesses treated in hospital, including stroke. We aimed to evaluate the impact of the COVID-19 pandemic on patient-reported health outcomes after hospital admission for acute stroke.

Methods: This retrospective study included adults with acute stroke admitted to the University College Hospital NHS Foundation Trust Hyperacute Stroke Unit. We included two separate cohorts of consecutively enrolled patients from the same geographical population at two time points: 16th March-16th May 2018 (pre-COVID-19 pandemic); and 16th March-16th May 2020 (during the COVID-19 pandemic). Patients in both cohorts completed the validated Patient Reported Outcomes Measurement Information System-29 (PROMIS-29 version 2.0) at 30 days after stroke.

Results: We included 205 patients who were alive at 30 days (106 admitted before and 99 admitted during the COVID-19 pandemic), of whom 201/205 (98%) provided patient-reported health outcomes. After adjustment for confounding factors, admission with acute stroke during the COVID-19 pandemic was independently associated with increased anxiety (β = 28.0, p < 0.001), fatigue (β = 9.3, p < 0.001), depression (β = 4.5, p = 0.002), sleep disturbance (β = 2.3, p = 0.018), pain interference (β = 10.8, p < 0.001); and reduced physical function (β = 5.2, p < 0.001) and participation in social roles and activities (β = 6.9, p < 0.001).

Conclusion: Compared with the pre-pandemic cohort, patients admitted with acute stroke during the first wave of the COVID-19 pandemic reported poorer health outcomes at 30 day follow-up in all domains. Stroke service planning for any future pandemic should include measures to mitigate this major adverse impact on patient health.
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http://dx.doi.org/10.1007/s00415-021-10819-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517937PMC
April 2022

Early versus late start of direct oral anticoagulants after acute ischaemic stroke linked to atrial fibrillation: an observational study and individual patient data pooled analysis.

J Neurol Neurosurg Psychiatry 2022 02 11;93(2):119-125. Epub 2021 Oct 11.

Stroke Research Center, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.

Objective: The optimal timing to start direct oral anticoagulants (DOACs) after an acute ischaemic stroke (AIS) related to atrial fibrillation (AF) remains unclear. We aimed to compare early (≤5 days of AIS) versus late (>5 days of AIS) DOAC-start.

Methods: This is an individual patient data pooled analysis of eight prospective European and Japanese cohort studies. We included patients with AIS related to non-valvular AF where a DOAC was started within 30 days. Primary endpoints were 30-day rates of recurrent AIS and ICH.

Results: A total of 2550 patients were included. DOACs were started early in 1362 (53%) patients, late in 1188 (47%). During 212 patient-years, 37 patients had a recurrent AIS (1.5%), 16 (43%) before a DOAC was started; 6 patients (0.2%) had an ICH, all after DOAC-start. In the early DOAC-start group, 23 patients (1.7%) suffered from a recurrent AIS, while 2 patients (0.1%) had an ICH. In the late DOAC-start group, 14 patients (1.2%) suffered from a recurrent AIS; 4 patients (0.3%) suffered from ICH. In the propensity score-adjusted comparison of late versus early DOAC-start groups, there was no statistically significant difference in the hazard of recurrent AIS (aHR=1.2, 95% CI 0.5 to 2.9, p=0.69), ICH (aHR=6.0, 95% CI 0.6 to 56.3, p=0.12) or any stroke.

Conclusions: Our results do not corroborate concerns that an early DOAC-start might excessively increase the risk of ICH. The sevenfold higher risk of recurrent AIS than ICH suggests that an early DOAC-start might be reasonable, supporting enrolment into randomised trials comparing an early versus late DOAC-start.
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http://dx.doi.org/10.1136/jnnp-2021-327236DOI Listing
February 2022

The coronal plane maximum diameter of deep intracerebral hemorrhage predicts functional outcome more accurately than hematoma volume.

Int J Stroke 2021 Oct 13:17474930211050749. Epub 2021 Oct 13.

Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT, USA.

Background: Among prognostic imaging variables, the hematoma volume on admission computed tomography (CT) has long been considered the strongest predictor of outcome and mortality in intracerebral hemorrhage.

Aims: To examine whether different features of hematoma shape are associated with functional outcome in deep intracerebral hemorrhage.

Methods: We analyzed 790 patients from the ATACH-2 trial, and 14 shape features were quantified. We calculated Spearman's Rho to assess the correlation between shape features and three-month modified Rankin scale (mRS) score, and the area under the receiver operating characteristic curve (AUC) to quantify the association between shape features and poor outcome defined as mRS>2 as well as mRS > 3.

Results: Among 14 shape features, the maximum intracerebral hemorrhage diameter in the coronal plane was the strongest predictor of functional outcome, with a maximum coronal diameter >∼3.5 cm indicating higher three-month mRS scores. The maximum coronal diameter versus hematoma volume yielded a Rho of 0.40 versus 0.35 ( = 0.006), an AUC of 0.71 versus 0.68 ( = 0.004), and an AUC of 0.71 versus 0.69 ( = 0.029). In multiple regression analysis adjusted for known outcome predictors, the maximum coronal diameter was independently associated with three-month mRS (p < 0.001).

Conclusions: A coronal-plane maximum diameter measurement offers greater prognostic value in deep intracerebral hemorrhage than hematoma volume. This simple shape metric may expedite assessment of admission head CTs, offer a potential biomarker for hematoma size eligibility criteria in clinical trials, and may substitute volume in prognostic intracerebral hemorrhage scoring systems.
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http://dx.doi.org/10.1177/17474930211050749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9005571PMC
October 2021

Effects of Antiplatelet Therapy After Stroke Caused by Intracerebral Hemorrhage: Extended Follow-up of the RESTART Randomized Clinical Trial.

JAMA Neurol 2021 10;78(10):1179-1186

Department of Neuroradiology, Newcastle-upon-Tyne Hospitals National Health Service Trust, Newcastle-upon-Tyne, United Kingdom.

Importance: The Restart or Stop Antithrombotics Randomized Trial (RESTART) found that antiplatelet therapy appeared to be safe up to 5 years after intracerebral hemorrhage (ICH) that had occurred during antithrombotic (antiplatelet or anticoagulant) therapy.

Objectives: To monitor adherence, increase duration of follow-up, and improve precision of estimates of the effects of antiplatelet therapy on recurrent ICH and major vascular events.

Design, Setting And Participants: From May 22, 2013, through May 31, 2018, this prospective, open, blinded end point, parallel-group randomized clinical trial studied 537 participants at 122 hospitals in the UK. Participants were individuals 18 years or older who had taken antithrombotic therapy for the prevention of occlusive vascular disease when they developed ICH, discontinued antithrombotic therapy, and survived for 24 hours. After initial follow-up ended on November 30, 2018, annual follow-up was extended until November 30, 2020, for a median of 3.0 years (interquartile range [IQR], 2.0-5.0 years) for the trial cohort.

Interventions: Computerized randomization that incorporated minimization allocated participants (1:1) to start or avoid antiplatelet therapy.

Main Outcomes And Measures: Participants were followed up for the primary outcome (recurrent symptomatic ICH) and secondary outcomes (all major vascular events) for up to 7 years. Data from all randomized participants were analyzed using Cox proportional hazards regression, adjusted for minimization covariates.

Results: A total of 537 patients (median age, 76.0 years; IQR, 69.0-82.0 years; 360 [67.0%] male; median time after ICH onset, 76.0 days; IQR, 29.0-146.0 days) were randomly allocated to start (n = 268) or avoid (n = 269 [1 withdrew]) antiplatelet therapy. The primary outcome of recurrent ICH affected 22 of 268 participants (8.2%) allocated to antiplatelet therapy compared with 25 of 268 participants (9.3%) allocated to avoid antiplatelet therapy (adjusted hazard ratio, 0.87; 95% CI, 0.49-1.55; P = .64). A major vascular event affected 72 participants (26.8%) allocated to antiplatelet therapy compared with 87 participants (32.5%) allocated to avoid antiplatelet therapy (hazard ratio, 0.79; 95% CI, 0.58-1.08; P = .14).

Conclusions And Relevance: Among patients with ICH who had previously taken antithrombotic therapy, this study found no statistically significant effect of antiplatelet therapy on recurrent ICH or all major vascular events. These findings provide physicians with some reassurance about the use of antiplatelet therapy after ICH if indicated for secondary prevention of major vascular events.

Trial Registration: isrctn.org Identifier: ISRCTN71907627.
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http://dx.doi.org/10.1001/jamaneurol.2021.2956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417806PMC
October 2021

Antiphospholipid antibodies and neurological manifestations in acute COVID-19: A single-centre cross-sectional study.

EClinicalMedicine 2021 Sep 12;39:101070. Epub 2021 Aug 12.

Francis Crick Institute, London, UK.

Background: A high prevalence of antiphospholipid antibodies has been reported in case series of patients with neurological manifestations and COVID-19; however, the pathogenicity of antiphospholipid antibodies in COVID-19 neurology remains unclear.

Methods: This single-centre cross-sectional study included 106 adult patients: 30 hospitalised COVID-neurological cases, 47 non-neurological COVID-hospitalised controls, and 29 COVID-non-hospitalised controls, recruited between March and July 2020. We evaluated nine antiphospholipid antibodies: anticardiolipin antibodies [aCL] IgA, IgM, IgG; anti-beta-2 glycoprotein-1 [aβGPI] IgA, IgM, IgG; anti-phosphatidylserine/prothrombin [aPS/PT] IgM, IgG; and anti-domain I βGPI (aD1β2GPI) IgG.

Findings: There was a high prevalence of antiphospholipid antibodies in the COVID-neurological (73.3%) and non-neurological COVID-hospitalised controls (76.6%) in contrast to the COVID-non-hospitalised controls (48.2%). aPS/PT IgG titres were significantly higher in the COVID-neurological group compared to both control groups ( < 0.001). Moderate-high titre of aPS/PT IgG was found in 2 out of 3 (67%) patients with acute disseminated encephalomyelitis [ADEM]. aPS/PT IgG titres negatively correlated with oxygen requirement (FiO =-0.15  = 0.040) and was associated with venous thromboembolism ( = 0.043). In contrast, aCL IgA ( < 0.001) and IgG ( < 0.001) was associated with non-neurological COVID-hospitalised controls compared to the other groups and correlated positively with d-dimer and creatinine but negatively with FiO.

Interpretation: Our findings show that aPS/PT IgG is associated with COVID-19-associated ADEM. In contrast, aCL IgA and IgG are seen much more frequently in non-neurological hospitalised patients with COVID-19. Characterisation of antiphospholipid antibody persistence and potential longitudinal clinical impact are required to guide appropriate management.

Funding: This work is supported by UCL Queen Square Biomedical Research Centre (BRC) and Moorfields BRC grants (#560441 and #557595). LB is supported by a Wellcome Trust Fellowship (222102/Z/20/Z). RWP is supported by an Alzheimer's Association Clinician Scientist Fellowship (AACSF-20-685780) and the UK Dementia Research Institute. KB is supported by the Swedish Research Council (#2017-00915) and the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and theUK Dementia Research Institute at UCL. BDM is supported by grants from the MRC/UKRI (MR/V007181/1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3). MSZ, MH and RS are supported by the UCL/UCLH NIHR Biomedical Research Centre and MSZ is supported by Queen Square National Brain Appeal.
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http://dx.doi.org/10.1016/j.eclinm.2021.101070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358233PMC
September 2021

Serum and cerebrospinal fluid biomarker profiles in acute SARS-CoV-2-associated neurological syndromes.

Brain Commun 2021 12;3(3):fcab099. Epub 2021 May 12.

Advanced Pathogens Diagnostic Unit, University College London Hospitals NHS Foundation Trust, London WC1H 8NJ, UK.

Preliminary pathological and biomarker data suggest that SARS-CoV-2 infection can damage the nervous system. To understand what, where and how damage occurs, we collected serum and CSF from patients with COVID-19 and characterized neurological syndromes involving the PNS and CNS ( = 34). We measured biomarkers of neuronal damage and neuroinflammation, and compared these with non-neurological control groups, which included patients with ( = 94) and without ( = 24) COVID-19. We detected increased concentrations of neurofilament light, a dynamic biomarker of neuronal damage, in the CSF of those with CNS inflammation (encephalitis and acute disseminated encephalomyelitis) [14 800 pg/ml (400, 32 400)], compared to those with encephalopathy [1410 pg/ml (756, 1446)], peripheral syndromes (Guillain-Barré syndrome) [740 pg/ml (507, 881)] and controls [872 pg/ml (654, 1200)]. Serum neurofilament light levels were elevated across patients hospitalized with COVID-19, irrespective of neurological manifestations. There was not the usual close correlation between CSF and serum neurofilament light, suggesting serum neurofilament light elevation in the non-neurological patients may reflect peripheral nerve damage in response to severe illness. We did not find significantly elevated levels of serum neurofilament light in community cases of COVID-19 arguing against significant neurological damage. Glial fibrillary acidic protein, a marker of astrocytic activation, was not elevated in the CSF or serum of any group, suggesting astrocytic activation is not a major mediator of neuronal damage in COVID-19.
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http://dx.doi.org/10.1093/braincomms/fcab099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194666PMC
May 2021

Cerebral venous thrombosis after vaccination against COVID-19 in the UK: a multicentre cohort study.

Lancet 2021 09 6;398(10306):1147-1156. Epub 2021 Aug 6.

Stroke Service, University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, UK; Faculty of Medicine and Health Sciences, Keele University, Stoke-on-Trent, UK.

Background: A new syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) has emerged as a rare side-effect of vaccination against COVID-19. Cerebral venous thrombosis is the most common manifestation of this syndrome but, to our knowledge, has not previously been described in detail. We aimed to document the features of post-vaccination cerebral venous thrombosis with and without VITT and to assess whether VITT is associated with poorer outcomes.

Methods: For this multicentre cohort study, clinicians were asked to submit all cases in which COVID-19 vaccination preceded the onset of cerebral venous thrombosis, regardless of the type of vaccine, interval between vaccine and onset of cerebral venous thrombosis symptoms, or blood test results. We collected clinical characteristics, laboratory results (including the results of tests for anti-platelet factor 4 antibodies where available), and radiological features at hospital admission of patients with cerebral venous thrombosis after vaccination against COVID-19, with no exclusion criteria. We defined cerebral venous thrombosis cases as VITT-associated if the lowest platelet count recorded during admission was below 150 × 10 per L and, if the D-dimer was measured, the highest value recorded was greater than 2000 μg/L. We compared the VITT and non-VITT groups for the proportion of patients who had died or were dependent on others to help them with their activities of daily living (modified Rankin score 3-6) at the end of hospital admission (the primary outcome of the study). The VITT group were also compared with a large cohort of patients with cerebral venous thrombosis described in the International Study on Cerebral Vein and Dural Sinus Thrombosis.

Findings: Between April 1 and May 20, 2021, we received data on 99 patients from collaborators in 43 hospitals across the UK. Four patients were excluded because they did not have definitive evidence of cerebral venous thrombosis on imaging. Of the remaining 95 patients, 70 had VITT and 25 did not. The median age of the VITT group (47 years, IQR 32-55) was lower than in the non-VITT group (57 years; 41-62; p=0·0045). Patients with VITT-associated cerebral venous thrombosis had more intracranial veins thrombosed (median three, IQR 2-4) than non-VITT patients (two, 2-3; p=0·041) and more frequently had extracranial thrombosis (31 [44%] of 70 patients) compared with non-VITT patients (one [4%] of 25 patients; p=0·0003). The primary outcome of death or dependency occurred more frequently in patients with VITT-associated cerebral venous thrombosis (33 [47%] of 70 patients) compared with the non-VITT control group (four [16%] of 25 patients; p=0·0061). This adverse outcome was less frequent in patients with VITT who received non-heparin anticoagulants (18 [36%] of 50 patients) compared with those who did not (15 [75%] of 20 patients; p=0·0031), and in those who received intravenous immunoglobulin (22 [40%] of 55 patients) compared with those who did not (11 [73%] of 15 patients; p=0·022).

Interpretation: Cerebral venous thrombosis is more severe in the context of VITT. Non-heparin anticoagulants and immunoglobulin treatment might improve outcomes of VITT-associated cerebral venous thrombosis. Since existing criteria excluded some patients with otherwise typical VITT-associated cerebral venous thrombosis, we propose new diagnostic criteria that are more appropriate.

Funding: None.
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http://dx.doi.org/10.1016/S0140-6736(21)01608-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346241PMC
September 2021

Prevalence, Characteristics, and Outcomes of Undetermined Intracerebral Hemorrhage: A Systematic Review and Meta-Analysis.

Stroke 2021 11 4;52(11):3602-3612. Epub 2021 Aug 4.

Second Department of Neurology (C.Z., A.T., A.H.K., K.V., G.T.), National and Kapodistrian University of Athens, "Attikon" University Hospital, Greece.

Background And Purpose: There are scarce data regarding the prevalence, characteristics and outcomes of intracerebral hemorrhage (ICH) of undetermined (unknown or cryptogenic) etiology. We sought to determine the prevalence, radiological characteristics, and clinical outcomes of undetermined ICH.

Methods: Systematic review and meta-analysis of studies involving patients with spontaneous ICH was conducted to primarily assess the prevalence and clinical-radiological characteristics of undetermined ICH. Additionally, we assessed the rates for ICH secondary to hypertensive arteriopathy and cerebral amyloid angiopathy. Subgroup analyses were performed based on the use of (1) etiology-oriented ICH classification, (2) detailed neuroimaging, and (3) Boston criteria among patients with cerebral amyloid angiopathy related ICH. We pooled the prevalence rates using random-effects models, and assessed the heterogeneity using Cochran Q and I2 statistics.

Results: We identified 24 studies comprising 15 828 spontaneous ICH patients (mean age, 64.8 years; men, 60.8%). The pooled prevalences of hypertensive arteriopathy ICH, undetermined ICH, and cerebral amyloid angiopathy ICH were 50% (95% CI, 43%–58%), 18% (95% CI, 13%–23%), and 12% (95% CI, 7%–17% [P<0.001 between subgroups]). The volume of ICH was the largest in cerebral amyloid angiopathy ICH (24.7 [95% CI, 19.7–29.8] mL), followed by hypertensive arteriopathy ICH (16.2 [95% CI, 10.9–21.5] mL) and undetermined ICH (15.4 [95% CI, 6.2–24.5] mL). Among patients with undetermined ICH, the rates of short-term mortality (within 3 months) and concomitant intraventricular hemorrhage were 33% (95% CI, 25%–42%) and 38% (95% CI, 28%–48%), respectively. Subgroup analysis demonstrated a higher rate of undetermined ICH among studies that did not use an etiology-oriented classification (22% [95% CI, 15%–29%]). No difference was observed between studies based on the completion of detailed neuroimaging to assess the rates of undetermined ICH (P=0.62).

Conclusions: The etiology of spontaneous ICH remains unknown or cryptogenic among 1 in 7 patients in studies using etiology-oriented classification and among 1 in 4 patients in studies that avoid using etiology-oriented classification. The short-term mortality in undetermined ICH is high despite the relatively small ICH volume.
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http://dx.doi.org/10.1161/STROKEAHA.120.031471DOI Listing
November 2021

Cerebrospinal fluid metallomics in cerebral amyloid angiopathy: an exploratory analysis.

J Neurol 2022 Mar 22;269(3):1470-1475. Epub 2021 Jul 22.

Department of Brain Repair and Rehabilitation, Stroke Research Centre, UCL Queen Square Institute of Neurology, Russell Square House, 10-12 Russell Square, London, WC1B 5EH, UK.

Introduction: Cerebral amyloid angiopathy (CAA) is associated with symptomatic intracerebral haemorrhage. Biomarkers of clinically silent bleeding events, such as cerebrospinal fluid (CSF) ferritin and iron, might provide novel measures of disease presence and severity.

Methods: We performed an exploratory study comparing CSF iron, ferritin, and other metal levels in patients with CAA, control subjects (CS) and patients with Alzheimer's disease (AD). Ferritin was measured using a latex fixation test; metal analyses were performed using inductively coupled plasma mass spectrometry.

Results: CAA patients (n = 10) had higher levels of CSF iron than the AD (n = 20) and CS (n = 10) groups (medians 23.42, 15.48 and 17.71 μg/L, respectively, p = 0.0015); the difference between CAA and AD groups was significant in unadjusted and age-adjusted analyses. We observed a difference in CSF ferritin (medians 10.10, 7.77 and 8.01 ng/ml, for CAA, AD and CS groups, respectively, p = 0.01); the difference between the CAA and AD groups was significant in unadjusted, but not age-adjusted, analyses. We also observed differences between the CAA and AD groups in CSF nickel and cobalt (unadjusted analyses).

Conclusions: In this exploratory study, we provide preliminary evidence for a distinct CSF metallomic profile in patients with CAA. Replication and validation of these results in larger cohorts is needed.
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http://dx.doi.org/10.1007/s00415-021-10711-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8857160PMC
March 2022

Off-label use of aducanumab for cerebral amyloid angiopathy.

Lancet Neurol 2021 08 5;20(8):596-597. Epub 2021 Jul 5.

Department of Brain Repair and Rehabilitation, Stroke Research Centre, University College London Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK.

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http://dx.doi.org/10.1016/S1474-4422(21)00213-1DOI Listing
August 2021

Cerebral Amyloid Angiopathy and the Fibrinolytic System: Is Plasmin a Therapeutic Target?

Stroke 2021 08 15;52(8):2707-2714. Epub 2021 Jun 15.

Australian Centre for Blood Diseases (C.B.K., R.L.M.), Monash University, Melbourne, Australia.

Cerebral amyloid angiopathy is a devastating cause of intracerebral hemorrhage for which there is no specific secondary stroke prevention treatment. Here we review the current literature regarding cerebral amyloid angiopathy pathophysiology and treatment, as well as what is known of the fibrinolytic pathway and its interaction with amyloid. We postulate that tranexamic acid is a potential secondary stroke prevention treatment agent in sporadic cerebral amyloid angiopathy, although further research is required.
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http://dx.doi.org/10.1161/STROKEAHA.120.033107DOI Listing
August 2021
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