The epidemiology of brain arteriovenous malformations in adults

Arteriovenous malformations (AVMs) of the brain are part of the spectrum of intracranial vascular malformations (IVMs). They are the leading cause of intracerebral haemorrhage in young adults, they account for ~10% of non-traumatic subarachnoid haemorrhage, and they also cause epilepsy. Not only are affected individuals subject to the initial consequences of these events, but there are substantial risks of recurrent haemorrhage and epilepsy, and long-term disability. For a disorder discovered as long ago as the mid-nineteenth century, surprisingly little is known about it. In this thesis, I begin by systematically reviewing the sizeable medical literature about brain AVM frequency, presentation, clinical course and prognosis. I did not find a single prospective, truly population-based study, which is why I set up the Scottish Intracranial Vascular Malformation Study (SIVMS) with the multidisciplinary collaboration of the four clinical neuroscience centres in Scotland. SIVMS aspires to meet the standards of the ideal study of frequency and prognosis, by using multiple, overlapping sources of case ascertainment to prospectively recruit a population based inception cohort of adults, with explicit diagnostic criteria and outcome definitions for events which are validated by independent review. During 1999-2000, 96 adults (of whom 92 were definite) were detected with a first-in-a-lifetime diagnosis of a brain AVM in Scotland. Quality of baseline demographic, clinical and basic morphological data was excellent, although detailed variables about angioarchitecture were less complete, partly because only three-quarters of patients underwent catheter angiography. The cohort was distributed in proportion to the dispersion of the Scottish population, and standardised incidence ratios were not significantly different between healthboards. The sensitivity of ICD-10 coding of brain AVMs in hospital discharge data was 72% (95%CI 61% to 80%), and its positive predictive value was 46% (95%CI 38% to 55%). Reliance on hospital discharge data for case ascertainment or a requirement for catheter angiography to make the diagnosis would have biased the cohort. Furthermore, I found that expert neuroradiologists’ assessment of AVM angioarchitecture on catheter angiography was characterised by greater intra-observer than inter-observer agreement (which ranged from less than chance for e.g. ‘angiogenesis’ to almost perfect for e.g. nidus size). In a survey with multiple, overlapping sources of ascertainment confined to the Lothian healthboard region of Scotland, using capture-recapture analysis, I found the point prevalence of brain AVMs to be 18 (95%CI 16 to 24) per 100,000 adults. In SIVMS, the crude incidence of brain AVMs in Scotland in 1999 and 2000 was 1.1 (95%CI 0.9 to 1.4) per 100,000 adults per year. Of the incident adults, 53% were male and their median age at presentation was 45 years (range 16 to 81); one fifth were incidental discoveries and four fifths were symptomatic (presentation was with intracranial haemorrhage in 59%, one or more seizure(s) in 34%, and focal neurological deficits in 7%). 9% of cases were pure arteriovenous fistulae, 75% were lobar in location, 53% were superficial, and 22% had associated aneurysms. There appeared to be significant differences between SIVMS and well-established hospital-based cohorts. Having established brain AVM prevalence, incidence and the characteristics of presenting adults, the next stage for this work is to describe prognosis for this enlarging population-based cohort. The data are being collected, the hurdles of ethical approval have been negotiated, although the direction in which privacy legislation and confidentiality guidance are heading will make this a challenging task

Antiplatelet Agent Use After Stroke due to Intracerebral Hemorrhage

This focused update about antiplatelet agents to reduce the high risk of major adverse cardiovascular events after stroke due to spontaneous (nontraumatic) intracerebral hemorrhage (ICH) complements earlier updates about blood pressure-lowering, lipid-lowering, and oral anticoagulation or left atrial appendage occlusion for atrial fibrillation after ICH. When used for secondary prevention in people without ICH, antiplatelet agents reduce the risk of major adverse cardiovascular event (rate ratio, 0.81 [95% CI, 0.75-0.87]) and might increase the risk of ICH (rate ratio, 1.67 [95% CI, 0.97-2.90]). Before 2019, guidance for clinical decisions about antiplatelet agent use after ICH has focused on estimating patients' predicted absolute risks and severities of ischemic and hemorrhagic major adverse cardiovascular event and applying the known effects of these drugs in people without ICH to estimate whether individual ICH survivors in clinical practice might be helped or harmed by antiplatelet agents. In 2019, the main results of the RESTART (Restart or Stop Antithrombotics Randomized Trial) randomized controlled trial including 537 survivors of ICH associated with antithrombotic drug use showed, counterintuitively, that antiplatelet agents might not increase the risk of recurrent ICH compared to antiplatelet agent avoidance over 2 years of follow-up (12/268 [4%] versus 23/268 [9%]; adjusted hazard ratio, 0.51 [95% CI, 0.25-1.03]; P=0.060). Guidelines in the United States, Canada, China, and the United Kingdom and Ireland have classified the level of evidence as B and indicated that antiplatelet agents may be considered/reasonable after ICH associated with antithrombotic agent use. Three subsequent clinical trials have recruited another 174 participants with ICH, but they will not be sufficient to determine the effects of antiplatelet therapy on all major adverse cardiovascular events reliably when pooled with RESTART. Therefore, ASPIRING (Antiplatelet Secondary Prevention International Randomized Study After Intracerebral Hemorrhage) aims to recruit 4148 ICH survivors to determine the effects of antiplatelet agents after ICH definitively overall and in subgroups. </p

Using patient­identifiable data for observational research and audit

Across the world rapid changes in the law, technology, and society are reshaping the way identifiable information about patients is handled. In Britain, doctors' longstanding common law duty of confidentiality to their patients has been supplemented by restrictions on processing electronic and paper based records in the Data Protection Act 1998, which came into force on 1 March 2000. This month the United Kingdom's Medical Research Coun­ cil (MRC) is the latest of several professional organisa­ tions to respond to these developments by updating its guidance on confidentiality and the use of personal information (see table on BMJ 's website).1–4 The MRC has provided invaluable, balanced guidance but there is still a real risk that strict and selective application of the other directives could jeopardise audit, clinical govern­ ance, and observational epidemiological research. This would compromise patient care and the public interest

Imaging features of intracerebral hemorrhage with cerebral amyloid angiopathy:Systematic review and meta-analysis

BACKGROUND:We sought to summarize Computed Tomography (CT)/Magnetic Resonance Imaging (MRI) features of intracerebral hemorrhage (ICH) associated with cerebral amyloid angiopathy (CAA) in published observational radio-pathological studies. METHODS:In November 2016, two authors searched OVID Medline (1946-), Embase (1974-) and relevant bibliographies for studies of imaging features of lobar or cerebellar ICH with pathologically proven CAA ("CAA-associated ICH"). Two authors assessed studies' diagnostic test accuracy methodology and independently extracted data. RESULTS:We identified 22 studies (21 cases series and one cross-sectional study with controls) of CT features in 297 adults, two cross-sectional studies of MRI features in 81 adults and one study which reported both CT and MRI features in 22 adults. Methods of CAA assessment varied, and rating of imaging features was not masked to pathology. The most frequently reported CT features of CAA-associated ICH in 21 case series were: subarachnoid extension (pooled proportion 82%, 95% CI 69-93%, I2 = 51%, 12 studies) and an irregular ICH border (64%, 95% CI 32-91%, I2 = 85%, five studies). CAA-associated ICH was more likely to be multiple on CT than non-CAA ICH in one cross-sectional study (CAA-associated ICH 7/41 vs. non-CAA ICH 0/42; χ2 = 7.8, p = 0.005). Superficial siderosis on MRI was present in 52% of CAA-associated ICH (95% CI 39-65%, I2 = 35%, 3 studies). CONCLUSIONS:Subarachnoid extension and an irregular ICH border are common imaging features of CAA-associated ICH, but methodologically rigorous diagnostic test accuracy studies are required to determine the sensitivity and specificity of these features

Activation of Nrf2 to optimise immune responses to intracerebral haemorrhage

Haemorrhage into the brain parenchyma can be devastating. This manifests as spontaneous intracerebral haemorrhage (ICH) after head trauma, and in the context of vascular dementia. Randomised controlled trials have not reliably shown that haemostatic treatments aimed at limiting ICH haematoma expansion and surgical approaches to reducing haematoma volume are effective. Consequently, treatments to modulate the pathophysiological responses to ICH, which may cause secondary brain injury, are appealing. Following ICH, microglia and monocyte derived cells are recruited to the peri-haematomal environment where they phagocytose haematoma breakdown products and secrete inflammatory cytokines, which may trigger both protective and harmful responses. The transcription factor Nrf2, is activated by oxidative stress, is highly expressed by central nervous system microglia and macroglia. When active, Nrf2 induces a transcriptional programme characterised by increased expression of antioxidant, haem and heavy metal detoxification and proteostasis genes, as well as suppression of proinflammatory factors. Therefore, Nrf2 activation may facilitate adaptive-protective immune cell responses to ICH by boosting resistance to oxidative stress and heavy metal toxicity, whilst limiting harmful inflammatory signalling, which can contribute to further blood brain barrier dysfunction and cerebral oedema. In this review, we consider the responses of immune cells to ICH and how these might be modulated by Nrf2 activation. Finally, we propose potential therapeutic strategies to harness Nrf2 to improve the outcomes of patients with ICH

Patent Foramen Ovale, Ischemic Stroke and Migraine: Systematic Review and Stratified Meta-Analysis of Association Studies

BACKGROUND: Observational data have reported associations between patent foramen ovale (PFO), cryptogenic stroke and migraine. However, randomized trials of PFO closure do not demonstrate a clear benefit either because the underlying association is weaker than previously suggested or because the trials were underpowered. In order to resolve the apparent discrepancy between observational data and randomized trials, we investigated associations between (1) migraine and ischemic stroke, (2) PFO and ischemic stroke, and (3) PFO and migraine. METHODS: Eligibility criteria were consistent; including all studies with specifically defined exposures and outcomes unrestricted by language. We focused on studies at lowest risk of bias by stratifying analyses based on methodological design and quantified associations using fixed-effects meta-analysis models. RESULTS: We included 37 studies of 7,686 identified. Compared to reports in the literature as a whole, studies with population-based comparators showed weaker associations between migraine with aura and cryptogenic ischemic stroke in younger women (OR 1.4; 95% CI 0.9–2.0; 1 study), PFO and ischemic stroke (HR 1.6; 95 CI 1.0–2.5; 2 studies; OR 1.3; 95% CI 0.9–1.9; 3 studies), or PFO and migraine (OR 1.0; 95% CI 0.6–1.6; 1 study). It was not possible to look for interactions or effect modifiers. These results are limited by sources of bias within individual studies. CONCLUSIONS: The overall pairwise associations between PFO, cryptogenic ischemic stroke and migraine do not strongly suggest a causal role for PFO. Ongoing randomized trials of PFO closure may need larger numbers of participants to detect an overall beneficial effect

Selective outcome reporting in randomised controlled trials including participants with stroke or transient ischaemic attack:A systematic review

IntroductionThe prevalence of outcome reporting bias (ORB, i.e. selective reporting according to the results observed) across primary outcomes in randomised controlled trials (RCTs) including participants with stroke or transient ischaemic attack (TIA) is unknown.Materials and methodsWe searched the Cochrane Database of Systematic Reviews on 3 February 2021 for reviews published 2008-2020 with at least one RCT of a therapeutic intervention, for participants with stroke or TIA, and a safety or efficacy outcome. We took a random sample of these RCTs and included those with a trial registry record or protocol published before reporting results. Two reviewers assessed discrepancies in outcome reporting across the trial registry record, protocol, statistical analysis plan, and publication for each RCT, using the classification system designed by the Outcome Reporting Bias in Trials group.ResultsOf 600 RCTs, we identified a trial registry record in 120 (20%), a protocol in 28 (5%), and a statistical analysis plan in 5 (1%) with 123 (21%) distinct RCTs being eligible for assessment: 110 (89%, 95% CI 83-94) were at no risk, 7 (6%, 95% CI 3-11) RCTs were at low risk, and 6 (5%, 95% CI 2-10) were at high risk of ORB.DiscussionThe prevalence of ORB in primary outcomes was low in stroke/TIA RCTs that were included in Cochrane reviews and had an identifiable trial registry record or protocol. Concerningly, we were unable to identify a trial registry record or protocol in most of our sample.ConclusionWork is needed to further reduce ORB in stroke/TIA RCTs and explore the generalisability of these findings to RCTs outside of Cochrane reviews or without a registry record or protocol, as well as to secondary outcomes