1,721,189 research outputs found
Unruptured arteriovenous malformations of the brain
Full text linkUnruptured, asymptomatic arteriovenous malformations (AVMs) lurk in the brains of approximately one person in every thousand; their prevalence, based on four studies of magnetic resonance imaging (MRI) of 7,359 people without brain disorders, 1-4 was 0.1 % (95% confidence interval [CI] 0% to
0.2%). Some of these brain AVMs may be discovered if and when they cause intracranial haemorrhage, epileptic seizure(s), headache, or a focal neurological deficit, but many brain AVMs may potentially lie dormant from the cradle to the grave
Effects of oral anticoagulation for atrial fibrillation after spontaneous intracranial haemorrhage in the UK: a randomised, open-label, assessor-masked, pilot-phase, non-inferiority trial
No full textBackground: oral anticoagulation reduces the rate of systemic embolism for patients with atrial fibrillation by two-thirds, but its benefits for patients with previous intracranial haemorrhage are uncertain. In the Start or STop Anticoagulants Randomised Trial (SoSTART), we aimed to establish whether starting is non-inferior to avoiding oral anticoagulation for survivors of intracranial haemorrhage who have atrial fibrillation.Methods: SoSTART was a prospective, randomised, open-label, assessor-masked, parallel-group, pilot phase trial done at 67 hospitals in the UK. We recruited adults (aged ≥18 years) who had survived at least 24 h after symptomatic spontaneous intracranial haemorrhage, had atrial fibrillation, and had a CHA2DS2-VASc score of at least 2. Web-based computerised randomisation incorporating a minimisation algorithm allocated participants (1:1) to start or avoid long-term (≥1 year) full treatment dose open-label oral anticoagulation. The participants assigned to start oral anticoagulation received either a direct oral anticoagulant or vitamin K antagonist, and the group assigned to avoid oral anticoagulation received standard clinical practice (antiplatelet agent or no antithrombotic agent). The primary outcome was recurrent symptomatic spontaneous intracranial haemorrhage, and was adjudicated by an individual masked to treatment allocation. All outcomes were ascertained for at least 1 year after randomisation and assessed in the intention-to-treat population of all randomly assigned participants, using Cox proportional hazards regression adjusted for minimisation covariates. We planned a sample size of 190 participants (one-sided p=0·025, power 90%, allowing for non-adherence) based on a non-inferiority margin of 12% (or adjusted hazard ratio [HR] of 3·2). This trial is registered with ClinicalTrials.gov (NCT03153150) and is complete.Findings: between March 29, 2018, and Feb 27, 2020, consent was obtained at 61 sites for 218 participants, of whom 203 were randomly assigned at a median of 115 days (IQR 49–265) after intracranial haemorrhage onset. 101 were assigned to start and 102 to avoid oral anticoagulation. Participants were followed up for median of 1·2 years (IQR 0·97–1·95; completeness 97·2%). Starting oral anticoagulation was not non-inferior to avoiding oral anticoagulation: eight (8%) of 101 in the start group versus four (4%) of 102 in the avoid group had intracranial haemorrhage recurrences (adjusted HR 2·42 [95% CI 0·72–8·09]; p=0·152). Serious adverse events occurred in 17 (17%) participants in the start group and 15 (15%) in the avoid group. 22 (22%) patients in the start group and 11 (11%) patients in the avoid group died during the study.Interpretation: whether starting oral anticoagulation was non-inferior to avoiding it for people with atrial fibrillation after intracranial haemorrhage was inconclusive, although rates of recurrent intracranial haemorrhage were lower than expected. In view of weak evidence from analyses of three composite secondary outcomes, the possibility that oral anticoagulation might be superior for preventing symptomatic major vascular events should be investigated in adequately powered randomised trials
Understanding and manipulating the mononuclear phagocyte system after intracerebral haemorrhage
No full textIntracerebral haemorrhage (ICH) is the most fatal subtype of stroke with a 40% fatality
rate in the first month and no current treatments available to improve outcome. ICH
triggers a substantial inflammatory reaction orchestrated by both the resident
macrophages of the brain (microglia) and infiltrated monocyte-derived cells (MdCs)
that are recruited towards the site of injury.
By investigating these mononuclear phagocytes in a large cohort of human post-mortem ICH brain tissue (n=55) we have shown the density of these cells increasing
significantly over time (by IBA1 immunostaining) and displaying phagocytic capacity
(by CD68 immunostaining) before returning to control levels by day 50. We have also
shown that the microglia that accumulate at the site of the bleed lose their expression
of homeostatic markers (P2Y12) within the first week after ICH, and display phenotypic
heterogeneity as displayed by GPNMB/CD68 co-staining.
A mouse model of experimental ICH where ICH was induced by an intrastriatal
stereotactic injection of 0.045U of bacterial collagenase in C57BL6/J male mice was
characterised and validated. This mouse model was then used to investigate the effect
of CSF1R agonism on the accumulation and phenotype of microglia and MdCs by flow
cytometry, RNA sequencing and immunofluorescence.
Bulk RNA sequencing at day 3 revealed that microglia (CD11B+Ly6G-P2Y12+CD45int)
are more bioenergetic and metabolically active following ICH. However, infiltrated
MdCs (CD11B+Ly6G-P2Y12-
CD45hi
) are more immune-engaged than microglia and
also appear to be better equipped at haematoma handling with increases in
erythrocyte and haemoglobin scavenging systems, as well as haem metabolism and
iron sequestration. MdCs also have higher transcriptomic expression of key
antioxidant enzymes as well as Nrf2 and PPARg pathways.
Interestingly, administration of the CSF1R agonist CSF1-Fc specifically increased the
infiltration of MdCs without any effect on the accumulation, proliferation or
transcriptome of microglia. CSF1-Fc treatment led to an increased infiltration of Ly6Chi
monocytes in the ipsilateral hemisphere at day 3 and an increase in Ly6Clow
monocytes by day 5. CSF1 specifically induced a Ly6ClowMHC-II- population of MdCs
which importantly had no effect on haematoma volume at day 3 indicating no
aggravating acute effects.
Our data suggest that promoting the infiltration of MdCs may have beneficial effects
on haematoma resolution and that this population of cells can be specifically induced
by administering CSF1-Fc
Exploration of the outcomes and experiences of people living with cognitive impairment and intracerebral haemorrhage: a mixed methods approach
Full text linkIntroduction
Stroke due to intracerebral haemorrhage (ICH) is the most devastating and least treatable
type of stroke, where onset is sudden, often leaving the individual and family ill-prepared to
deal with the long-term consequences. Associations between cognitive impairment and
ischaemic stroke have been well described in the literature however fewer data are available
for ICH and cognitive impairment. Although some studies have investigated the prevalence
and risk factors of cognitive decline before and after ICH, very little is known about the
influence of cognitive decline on functional outcome after ICH. Furthermore, there have been
no qualitative studies designed specifically to examine the experiences of people living with
cognitive impairment after intracerebral haemorrhage.
Aims
To explore the outcomes and experiences of people living with cognitive impairment and
intracerebral haemorrhage:
(a) To study the prevalence of pre-existing dementia and cognitive impairment in patients
with ICH, and to quantify their incidence at specific time points thereafter,
(b) To investigate the demographic, clinical, radiographic and functional outcomes associated
with the occurrence of cognitive impairment following an ICH, and
(c) Evaluate the experience of life after ICH with cognitive impairment.
Methods
(a) A retrospective analysis of all patients diagnosed with ICH in one region of Scotland
between June 2010 and May 2013, who had available CT data from the time of the index ICH
(n=404), was conducted. Data were taken from the Lothian Audit of the Treatment of
Cerebral Haemorrhage, including people aged ≥ 16 years at the time of diagnosis. Data on
demographics, medical history, and medication was drawn on. In addition to determining the
prevalence and risk factors of pre-existing cognitive decline, survival analysis was used to
determine cumulative rates of patients remaining free of cognitive decline up to 5 years after
their ICH (LATCH COG).
(b) A prospective observational cohort sub-study (LINCHPIN COG) of adults with ICH (n=45)
was conducted using a detailed assessment of cognition and functional outcomes at 6 and
12-24 months after ICH. Pre-existing cognitive decline was measured using the IQCODE
informant questionnaire, whilst also collecting basic demographic data, data on vascular risk
factors, stroke severity, level of dependency, and neuroimaging features on computed
tomography and magnetic resonance imaging. The primary outcome was new-onset
cognitive impairment (defined as MoCA score <26) at 6 months, when functional outcomes
(depression, fatigue, health-related quality of life) were also measured.
(c) In an embedded qualitative study, six ICH survivors and four family members participated
in semi-structured interviews and gave details about their experiences of life after ICH. The
data collected was analysed using a thematic analysis approach.
Results
(a) Using data from LATCH COG, I found that roughly 1 in 4 (23%) patients had cognitive
decline prior to their ICH. Forty-one patients (10%) had cognitive impairment with no
dementia. Fifty-two patients met the criteria for pre-existing dementia (13%).
In univariate analysis of LATCH COG, CT neuroimaging markers of cerebral amyloid
angiopathy and small vessel disease were associated with pre-existing cognitive decline. In
logistic regression analysis, patients who had a lobar ICH were twice as likely to exhibit preexisting
cognitive decline and 3 times more likely to exhibit pre-existing dementia than those
who had a non-lobar ICH. Patients with central (deep) atrophy were over 4 times more likely
to exhibit cognitive decline and 8 times more likely to exhibit dementia before their stroke
than those without. In line with this, severity of white matter changes was associated with
pre-existing cognitive decline, suggesting a neurodegenerative process. Increasing age and
larger haemorrhage volume were also associated with an increased likelihood of patients
having cognitive decline prior to their stroke.
During the first 5 years of follow-up of LATCH COG, of the 168 patients who survived longer
than 30-days after their ICH, 47 patients developed new-onset cognitive decline (cognitive
impairment and dementia). Cumulative survival rates for patients remaining free of cognitive
decline were 82% in the first year and 65% at 5 years.
In univariate analysis of LATCH COG, presence of posterior white matter lucencies was
associated with new-onset dementia, indicating an association with markers of small vessel
disease. In Cox regression analysis, patients who had a lobar ICH were twice as likely to
exhibit new-onset cognitive decline than those who had a non-lobar ICH. In those who
survived past 30 days, the incidence of new-onset cognitive decline was 37% in patients with
lobar ICH and 20% in patients with non-lobar ICH.
(b) Cognitive impairment is frequent after ICH with 43% of participants from LINCHPIN COG
scoring <26 on the MOCA at 6 months.
In univariate analysis of LINCHPIN COG, new-onset cognitive impairment at 6 months was
associated with pre-ICH history of hypertension. I could not detect statistically significant
associations between new-onset cognitive impairment and functional outcomes at 6 months.
The small sample size may have been a significant contributory factor, making it difficult to
identify any statistically significant differences between those with and without cognitive
impairment
(c) Thematic analysis of the qualitative interviews identified four overarching themes relating
to how survivor’s and their family members experienced life after stroke: ‘the effects of
stroke on sense of self and identity’, ‘adaptions and adjustment’, ‘uncertainty’, and ‘impact
on family members’. These findings were interpreted in relation to theories of biographical
disruption and suggest the necessity for individualised assessment of needs and the planning
of services to best assist stroke survivors in coming to terms with their illness and its longterm
consequences.
Conclusion
Pre-existing cognitive decline affects more than one-fifth of patients with ICH. For survivors
of ICH without pre-existing cognitive decline, over two-fifths develop new-onset cognitive
impairment by 6 months after ICH. Neuroimaging markers of cerebral amyloid angiopathy
and small vessel disease were associated with pre-existing and new-onset cognitive decline.
New-onset cognitive impairment at 6 months was associated with pre-ICH history of
hypertension. This implies an important role of vascular processes on the pathophysiology of
post-ICH cognitive decline. The qualitative accounts in this study indicate the devastating
effect that a stroke due to haemorrhage can have on the lives of survivors and their families,
with participants often indicating that they could no longer be the person that they were
before the stroke. These data may help inform patients, their family and caregivers about the
risk of cognitive impairment after ICH and its resultant impact on the lives of survivors
Association between the Edinburgh CT and genetic diagnostic criteria for lobar intracerebral haemorrhage (ICH) associated with cerebral amyloid angiopathy and the risk of recurrent ICH: outline protocol for a population-based analysis, and external validation in a hospital-based cohort
No full textThis is an outline protocol for a study assessing the association between the Edinburgh CT and genetic diagnostic criteria for lobar intracerebral haemorrhage (ICH) associated with cerebral amyloid angiopathy and the risk of recurrent ICH.Rodrigues, Mark; Seiffge, David; Werring, David; Al-Shahi Salman, Rustam. (2018). Association between the Edinburgh CT and genetic diagnostic criteria for lobar intracerebral haemorrhage (ICH) associated with cerebral amyloid angiopathy and the risk of recurrent ICH: outline protocol for a population-based analysis, and external validation in a hospital-based cohort, [text]. https://doi.org/10.7488/ds/7479
Deposition of amyloid-beta in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy
Full text linkDeposition of amyloid beta (AB) in the walls of cerebral arteries as cerebral amyloid angiopathy (CAA) suggests an age-related failure of perivascular drainage of soluble A? from the brain. As CAA is associated with Alzheimer's disease and with intracerebral haemorrhage, the present study determines the unique sequence of changes that occur as A? accumulates in artery walls. Paraffin sections of post-mortem human occipital cortex were immunostained for collagen IV, fibronectin, nidogen 2, AB and smooth muscle actin and the immunostaining was analysed using Image J and confocal microscopy. Results showed that nidogen 2 (entactin) increases with age and decreases in CAA. Confocal microscopy revealed stages in the progression of CAA: AB initially deposits in basement membranes in the tunica media, replaces first the smooth muscle cells and then the connective tissue elements to leave artery walls completely or focally replaced by AB. The pattern of development of CAA in the human brain suggests expansion of AB from the basement membranes to progressively replace all tissue elements in the artery wall. Establishing this full picture of the development of CAA is pivotal in understanding the clinical presentation of CAA and for developing therapies to prevent accumulation of AB in artery walls. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock
The Edinburgh CT and genetic diagnostic criteria for lobar intracerebral haemorrhage associated with cerebral amyloid angiopathy: model development and diagnostic test accuracy study
Full text linkBACKGROUND: Identification of lobar spontaneous intracerebral haemorrhage associated with cerebral amyloid angiopathy (CAA) is important because it is associated with a higher risk of recurrent intracerebral haemorrhage than arteriolosclerosis-associated intracerebral haemorrhage. We aimed to develop a prediction model for the identification of CAA-associated lobar intracerebral haemorrhage using CT features and genotype.METHODS: We identified adults with first-ever intracerebral haemorrhage diagnosed by CT, who died and underwent research autopsy as part of the Lothian IntraCerebral Haemorrhage, Pathology, Imaging and Neurological Outcome (LINCHPIN) study, a prospective, population-based, inception cohort. We determined APOE genotype and radiologists rated CT imaging appearances. Radiologists were not aware of clinical, genetic, and histopathological features. A neuropathologist rated brain tissue for small vessel diseases, including CAA, and was masked to clinical, radiographic, and genetic features. We used CT and APOE genotype data in a logistic regression model, which we internally validated using bootstrapping, to predict the risk of CAA-associated lobar intracerebral haemorrhage, derive diagnostic criteria, and estimate diagnostic accuracy.FINDINGS: Among 110 adults (median age 83 years [IQR 76-87], 49 [45%] men) included in the LINCHPIN study between June 1, 2010 and Feb 10, 2016, intracerebral haemorrhage was lobar in 62 (56%) participants, deep in 41 (37%), and infratentorial in seven (6%). Of the 62 participants with lobar intracerebral haemorrhage, 36 (58%) were associated with moderate or severe CAA compared with 26 (42%) that were associated with absent or mild CAA, and were independently associated with subarachnoid haemorrhage (32 [89%] of 36 vs 11 [42%] of 26; p=0·014), intracerebral haemorrhage with finger-like projections (14 [39%] of 36 vs 0; p=0·043), and APOE ɛ4 possession (18 [50%] of 36 vs 2 [8%] of 26; p=0·0020). A prediction model for CAA-associated lobar intracerebral haemorrhage using these three variables had excellent discrimination (c statistic 0·92, 95% CI 0·86-0·98), confirmed by internal validation. For the rule-out criteria, neither subarachnoid haemorrhage nor APOE ɛ4 possession had 100% sensitivity (95% CI 88-100). For the rule-in criteria, subarachnoid haemorrhage and either APOE ɛ4 possession or finger-like projections had 96% specificity (95% CI 78-100).INTERPRETATION: The CT and APOE genotype prediction model for CAA-associated lobar intracerebral haemorrhage shows excellent discrimination in this cohort, but requires external validation. The Edinburgh rule-in and rule-out diagnostic criteria might inform prognostic and therapeutic decisions that depend on identification of CAA-associated lobar intracerebral haemorrhage.FUNDING: UK Medical Research Council, The Stroke Association, and The Wellcome Trust.</p
Antiplatelet Agent Use After Stroke due to Intracerebral Hemorrhage
Full text linkThis 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
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