Does lobar intracerebral haemorrhage differ from non-lobar intracerebral haemorrhage?

Spontaneous (non-traumatic) intracerebral haemorrhage accounts for ~10% of all strokes in Western populations. Investigations may identify intracerebral haemorrhage (ICH) as ‘secondary’ to underlying causes such as tumours or aneurysms, but ~80% of ICHs which have no apparent underlying cause (so-called ‘primary’ ICH) tend to be attributed to small vessel vasculopathies such as arteriolosclerosis or cerebral amyloid angiopathy (CAA), on the basis of an adult’s risk factors and clinical and radiographic features of the ICH. The commonly accepted hypothesis is that CAA contributes to lobar ICH and arteriolosclerosis causes non-lobar ICH. In the following thesis, I set out to explore whether (a) the baseline demographic, clinical features and apolipoprotein E genotype of adults with lobar and non-lobar ICH differ, (b) the prognosis of adults with lobar and non-lobar ICH differ and (c) the neuroimaging correlates of small vessel disease in adults with lobar and non-lobar ICH differ since this might provide clues to the vasculopathies underlying lobar and non-lobar ICH. I explored (d) the strength of the association between CAA and ICH by systematically reviewing neuropathological case control studies and (e) the radiological and pathological features of lobar ICH to examine the nature of CAA in persons with lobar ICH and whether any computed tomography (CT) features of ICH are associated with CAA-related lobar ICH. I set up a prospective, community-based inception cohort study of adults with ICH in South East Scotland. Adults with spontaneous primary definite ICH had the opportunity to consent to participate in the Lothian Study of IntraCerebral Haemorrhage, Pathology, Imaging and Neurological Outcome (LINCHPIN), an ethically-approved, prospective community-based research study examining the causes of ICH using apolipoprotein E genotyping, brain MRI and research autopsy in case of death. Of 128 adults with first-ever spontaneous primary definite ICH diagnosed during 2010- 2011, age and pre-morbid hypertension did not differ by ICH location but a history of dementia was more common in adults with lobar ICH. The proportion of adults with one or more non-lobar brain microbleed (BMB) was significantly higher in adults with non-lobar ICH but I did not find any other differences in the severity or distribution of other neuroimaging correlates of small vessel disease between lobar and non-lobar ICH. The apolipoprotein e4 allele was more common in participants with lobar ICH in comparison to those with non-lobar ICH but the frequency of the e2 allele did not differ by ICH location. Adults with lobar ICH were significantly more likely to survive one year after their ICH in comparison to those with non-lobar ICH after adjustment for other known predictors of outcome. From a systematic review of neuropathological case control studies of CAA and ICH, stratified by ICH location, I found a significant association between CAA and lobar ICH but not with ICH in other locations. I examined the radiological and pathological features of 33 adults with first-ever lobar ICH. The presence of CAA or vasculopathy and the severity of CAA in a lobe affected by ICH was concordant with that of the corresponding contralateral unaffected lobe. Capillary CAA was associated with severe CAA. Subarachnoid extension of the ICH tended to be more frequent in those with CAA-related strictly lobar ICH. Having explored the incidence, risk factors and prognosis of lobar and non-lobar ICH, in future work I would aim to establish the strength of the association between CAA and ICH in different brain locations in a neuropathological case control study. Future work should examine the radiopathological features of lobar ICH in a larger cohort and the coexistence of other small vessel diseases, in particular arteriolosclerosis in persons with ICH

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

Nrf2 activation in the human brain after stroke due to supratentorial intracerebral haemorrhage: a case–control study

AIMS: Pharmacological activation of the antioxidative transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) improves outcomes in experimental models of intracerebral haemorrhage (ICH). However, the Nrf2 pathway has not been previously studied in humans after ICH. Our study aims to address this gap. METHODS: We selected cases with fatal ICH from a prospective community-based inception cohort study and age-matched and sex-matched controls who died suddenly of non-neurological disease. We used immunohistochemistry to quantify Nrf2 (% total area stained overall and % of nuclei stained) and CD68 expression in controls and perihaematomal, ipsilateral and contralateral brain tissue from cases. We measured downstream haem oxygenase-1 (HMOX1) and NAD(P)H dehydrogenase quinone 1 [NQO1] expression using RNA in situ hybridisation. RESULTS: 26 ICH cases (median age: 82 (IQR 76–86); 13 (50%) male) and eight controls (median age: 79 (IQR 77–80); 3 (37.5%) male) were included. We found no significant differences in overall % of Nrf2 staining between ICH cases and controls. However, the mean % of nuclei staining for Nrf2 seemed higher in perihaematomal compared with contralateral regions, although this was only statistically significant >60 days after ICH (25% (95% CI 17% to 33%) vs 14% (95% CI 11% to 17%), p=0.029). The percentage of perihaematomal tissue staining for CD68 was higher >60 days after ICH (6.75%, 95% CI 2.78% to 10.73%) compared with contralateral tissue (1.45%, 95% CI 0.93% to 1.96%, p=0.027) and controls (1.08%, 95% CI 0.20% to 1.97%, p=0.0008). RNA in situ hybridisation suggested increased abundance of HMOX1 and NQO1 transcripts in perihaematomal versus distant ipsilateral brain tissue obtained <7 days from onset of ICH. CONCLUSIONS: We found evidence of Nrf2 activation in human brain tissue after ICH. Pharmacological augmentation of Nrf2 activation after ICH might be a promising therapeutic approach

The Edinburgh CT and genetic diagnostic criteria for lobar intracerebral haemorrhage with cerebral amyloid angiopathy: model development and diagnostic test accuracy study

BACKGROUND: 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

Secondary injury and inflammation after intracerebral haemorrhage: a systematic review and meta-analysis of molecular markers in patient brain tissue

BACKGROUND: Inflammatory responses to intracerebral haemorrhage (ICH) are potential therapeutic targets. We aimed to quantify molecular markers of inflammation in human brain tissue after ICH compared with controls using meta-analysis. METHODS: We searched OVID MEDLINE (1946–) and Embase (1974–) in June 2020 for studies that reported any measure of a molecular marker of inflammation in brain tissue from five or more adults after ICH. We assessed risk of bias using a modified Newcastle-Ottawa Scale (mNOS; mNOS score 0–9; 9 indicates low bias), extracted aggregate data, and used random effects meta-analysis to pool associations of molecules where more than two independent case–control studies reported the same outcome and Gene Ontology enrichment analysis to identify over-represented biological processes in pooled sets of differentially expressed molecules (International Prospective Register of Systematic Reviews ID: CRD42018110204). RESULTS: Of 7501 studies identified, 44 were included: 6 were case series and 38 were case–control studies (median mNOS score 4, IQR 3–5). We extracted data from 21 491 analyses of 20 951 molecules reported by 38 case–control studies. Only one molecule (interleukin-1β protein) was quantified in three case–control studies (127 ICH cases vs 41 ICH-free controls), which found increased abundance of interleukin-1β protein after ICH (corrected standardised mean difference 1.74, 95% CI 0.28 to 3.21, p=0.036, I(2)=46%). Processes associated with interleukin-1β signalling were enriched in sets of molecules that were more abundant after ICH. CONCLUSION: Interleukin-1β abundance is increased after ICH, but analyses of other inflammatory molecules after ICH lack replication. Interleukin-1β pathway modulators may optimise inflammatory responses to ICH and merit testing in clinical trials