Gregoire Boulouis

Dementia risk after spontaneous intracerebral haemorrhage: a prospective cohort study

BACKGROUND Dementia occurs in at least 10% of patients within 1 year after stroke. However, the risk of dementia after spontaneous intracerebral haemorrhage that accounts for about 15% of all strokes has not been investigated in prospective studies. We aimed to determine the incidence of dementia and risk factors after an intracerebral haemorrhage. METHODS We did a prospective observational cohort study in patients with spontaneous intracerebral haemorrhage from the Prognosis of Intracerebral Haemorrhage (PITCH) cohort who were admitted to Lille University Hospital, Lille, France. We included patients aged 18 years and older with parenchymal haemorrhage on the first CT scan. Exclusion criteria were pure intraventricular haemorrhage; intracerebral haemorrhage resulting from intracranial vascular malformation, intracranial venous thrombosis, head trauma, or tumour; haemorrhagic transformation within an infarct; and referral from other hospitals. Median follow-up was 6 years. We studied risk factors (clinical and neuroradiological [MRI] biomarkers) of new-onset dementia as per a prespecified subgroup analysis, according to intracerebral haemorrhage location. Dementia diagnosis was based on the National Institute on Aging-Alzheimers Association criteria for all-cause dementia. We did multivariable analyses using competing risk analyses, with death during follow-up as a competing event. FINDINGS From the 560 patients with spontaneous intracerebral haemorrhage enrolled in the PITCH cohort between Nov 3, 2004 and March 29, 2009, we included 218 patients (median age 67·5 years) without pre-existing dementia who were alive at 6 months follow-up. 63 patients developed new-onset dementia leading to an incidence rate of 14·2% (95% CI 10·0-19·3) at 1 year after intracerebral haemorrhage, and incidence reached 28·3% (22·4-34·5) at 4 years. The incidence of new-onset dementia was more than two times higher in patients with lobar intracerebral haemorrhage (incidence at 1 year 23·4%, 14·6-33·3) than for patients with non-lobar intracerebral haemorrhage (incidence at 1 year 9·2%, 5·1-14·7). Disseminated superficial siderosis (subhazard ratio [SHR] 7·45, 95% CI 4·27-12·99), cortical atrophy score (SHR per 1-point increase 2·61, 1·70-4·01), a higher number of cerebral microbleeds (SHR for >5 cerebral microbleeds 2·33, 1·38-3·94), and older age (SHR per 10-year increase 1·34, 1·00-1·79) were risk factors of new-onset dementia. INTERPRETATION There is a substantial risk of incident dementia in dementia-free survivors of spontaneous intracerebral haemorrhage; our results suggest that underlying cerebral amyloid angiopathy is a contributing factor to the occurrence of new-onset dementia. Future clinical trials including patients with intracerebral haemorrhage should assess cognitive endpoints. FUNDING French Ministry of Education, Research, and Technology, Adrinord, Inserm U1171.

Association Between Hypodensities Detected by Computed Tomography and Hematoma Expansion in Patients With Intracerebral Hemorrhage

IMPORTANCE Hematoma expansion is a potentially modifiable predictor of poor outcome following an acute intracerebral hemorrhage (ICH). The ability to identify patients with ICH who are likeliest to experience hematoma expansion and therefore likeliest to benefit from expansion-targeted treatments remains an unmet need. Hypodensities within an ICH detected by noncontrast computed tomography (NCCT) have been suggested as a predictor of hematoma expansion. OBJECTIVE To determine whether hypodense regions, irrespective of their specific patterns, are associated with hematoma expansion in patients with ICH. DESIGN, SETTING, AND PARTICIPANTS We analyzed a large cohort of 784 patients with ICH (the development cohort; 55.6% female), examined NCCT findings for any hypodensity, and replicated our findings on a different cohort of patients (the replication cohort; 52.7% female). Baseline and follow-up NCCT data from consecutive patients with ICH presenting to a tertiary care hospital between 1994 and 2015 were retrospectively analyzed. Data analyses were performed between December 2015 and January 2016. MAIN OUTCOMES AND MEASURES Hypodensities were analyzed by 2 independent blinded raters. The association between hypodensities and hematoma expansion (>6 cm3 or 33% of baseline volume) was determined by multivariable logistic regression after controlling for other variables associated with hematoma expansion in univariate analyses with P ≤ .10. RESULTS A total of 1029 patients were included in the analysis. In the development and replication cohorts, 222 of 784 patients (28.3%) and 99 of 245 patients (40.4%; 321 of 1029 patients [31.2%]), respectively, had NCCT scans that demonstrated hypodensities at baseline (κ = 0.87 for interrater reliability). In univariate analyses, hypodensities were associated with hematoma expansion (86 of 163 patients with hematoma expansion had hypodensities [52.8%], whereas 136 of 621 patients without hematoma expansion had hypodensities [21.9%]; P < .001). The association between hypodensities and hematoma expansion remained significant (odds ratio, 3.42 [95% CI, 2.21-5.31]; P < .001) in a multivariable model; other independent predictors of hematoma expansion were a CT angiography spot sign, a shorter time to CT, warfarin use, and older age. The independent predictive value of hypodensities was again demonstrated in the replication cohort (odds ratio, 4.37 [95% CI, 2.05-9.62]; P < .001). CONCLUSION AND RELEVANCE Hypodensities within an acute ICH detected on an NCCT scan may predict hematoma expansion, independent of other clinical and imaging predictors. This novel marker may help clarify the mechanism of hematoma expansion and serve as a useful addition to clinical algorithms for determining the risk of and treatment stratification for hematoma expansion.

Validation of Clinicoradiological Criteria for the Diagnosis of Cerebral Amyloid Angiopathy-Related Inflammation.

IMPORTANCE Cerebral amyloid angiopathy-related inflammation (CAA-ri) is an important diagnosis to reach in clinical practice because many patients with the disease respond to immunosuppressive therapy. Reliable noninvasive diagnostic criteria for CAA-ri would allow some patients to avoid the risk of brain biopsy. OBJECTIVE To test the sensitivity and specificity of clinical and neuroimaging-based criteria for CAA-ri. DESIGN, SETTING, AND PARTICIPANTS We modified the previously proposed clinicoradiological criteria and retrospectively analyzed clinical medical records and magnetic resonance imaging fluid-attenuated inversion recovery and gradient-echo scans obtained from individuals with CAA-ri and noninflammatory CAA. At 2 referral centers between October 1, 1995, and May 31, 2013, and between January 1, 2009, and December 31, 2011, participants included 17 individuals with pathologically confirmed CAA-ri and 37 control group members with pathologically confirmed noninflammatory CAA. The control group was further divided into those with past lobar intracerebral hemorrhage (ICH) (n = 21) and those with cerebral microbleeds only and no history of ICH (n = 16). The dates of our analysis were September 1, 2012, to August 31, 2015. MAIN OUTCOMES AND MEASURES The sensitivity and specificity of prespecified criteria for probable CAA-ri (requiring asymmetric white matter hyperintensities extending to the subcortical white matter) and possible CAA-ri (not requiring the white matter hyperintensities to be asymmetric). RESULTS The 17 patients in the CAA-ri group were a mean (SD) of 68 (8) years and 8 (47%) were women. In the CAA-ri group, 14 of 17 (82%) met the criteria for both probable and possible CAA-ri. In the control group having noninflammatory CAA with lobar ICH, 1 of 21 (5%) met the criteria for possible CAA-ri, and none met the criteria for probable CAA-ri. In the control group having noninflammatory CAA with no ICH, 11 of 16 (69%) met the criteria for possible CAA-ri, and 1 of 16 (6%) met the criteria for probable CAA-ri. These findings yielded a sensitivity and specificity of 82% and 97%, respectively, for the probable criteria and a sensitivity and specificity of 82% and 68%, respectively, for the possible criteria. CONCLUSIONS AND RELEVANCE Our data suggest that a reliable diagnosis of CAA-ri can be reached from basic clinical and magnetic resonance imaging information alone, with good sensitivity and excellent specificity.

White matter hyperintensity patterns in cerebral amyloid angiopathy and hypertensive arteriopathy

Objective: To identify different white matter hyperintensity (WMH) patterns between 2 hemorrhage-prone cerebral small vessel diseases (SVD): cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy (HA). Methods: Consecutive patients with SVD-related intracerebral hemorrhage (ICH) from a single-center prospective cohort were analyzed. Four predefined subcortical WMH patterns were compared between the CAA and HA groups. These WMH patterns were (1) multiple subcortical spots; (2) peri–basal ganglia (BG); (3) large posterior subcortical patches; and (4) anterior subcortical patches. Their associations with other imaging (cerebral microbleeds [CMBs], enlarged perivascular spaces [EPVS]) and clinical markers of SVD were investigated using multivariable logistic regression. Results: The cohort included 319 patients with CAA and 137 patients with HA. Multiple subcortical spots prevalence was higher in the CAA compared to the HA group (29.8% vs 16.8%; p = 0.004). Peri-BG WMH pattern was more common in the HA- vs the CAA-ICH group (19% vs 7.8%; p = 0.001). In multivariable logistic regression, presence of multiple subcortical spots was associated with lobar CMBs (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.01–1.50, p = 0.039) and high degree of centrum semiovale EPVS (OR 2.43; 95% CI 1.56–3.80, p < 0.0001). By contrast, age (OR 1.05; 95% CI 1.02–1.09, p = 0.002), deep CMBs (OR 2.46; 95% CI 1.44–4.20, p = 0.001), total WMH volume (OR 1.02; 95% CI 1.01–1.04, p = 0.002), and high BG EPVS degree (OR 8.81; 95% CI 3.37–23.02, p < 0.0001) were predictors of peri-BG WMH pattern. Conclusion: Different patterns of subcortical leukoaraiosis visually identified on MRI might provide insights into the dominant underlying microangiopathy type as well as mechanisms of tissue injury in patients with ICH.

Estimating Total Cerebral Microinfarct Burden From Diffusion-Weighted Imaging

Background and Purpose— Cerebral microinfarcts (CMI) are important contributors to vascular cognitive impairment. Magnetic resonance imaging diffusion-weighted imaging (DWI) hyperintensities have been suggested to represent acute CMI. We aim to describe a mathematical method for estimating total number of CMI based on the presence of incidental DWI lesions. Methods— We reviewed magnetic resonance imaging scans of subjects with cognitive decline, cognitively normal subjects and previously reported subjects with past intracerebral hemorrhage (ICH). Based on temporal and spatial characteristics of DWI lesions, we estimated the annual rate of CMI needed to explain the observed rate of DWI lesion detection in each group. To confirm our estimates, we performed extensive sampling for CMI in the brain of a deceased subject with past lobar ICH who found to have a DWI lesion during life. Results— Clinically silent DWI lesions were present in 13 of 343 (3.8%) cognitively impaired and 10 of 199 (5%) cognitively intact normal non-ICH patients, both lower than the incidence in the past ICH patients (23 of 178; 12.9%; P<0.0006). The predicted annual incidence of CMI ranges from 16 to 1566 for non-ICH and 50 to 5041 for ICH individuals. Histological sampling revealed a total of 60 lesions in 32 sections. Based on previously reported methods, this density of CMI yields an estimated total brain burden maximum likelihood estimate of 9321 CMIs (95% confidence interval, 7255–11 990). Conclusions— Detecting even a single DWI lesion suggests an annual incidence of hundreds of new CMI. The cumulative effects of these lesions may directly contribute to small-vessel–related vascular cognitive impairment.

Blood pressure reduction and noncontrast CT markers of intracerebral hemorrhage expansion

Objective: To validate various noncontrast CT (NCCT) predictors of hematoma expansion in a large international cohort of ICH patients and investigate whether intensive blood pressure (BP) treatment reduces ICH growth and improves outcome in patients with these markers. Methods: We analyzed patients enrolled in the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-II) randomized controlled trial. Participants were assigned to intensive (systolic BP <140 mm Hg) vs standard (systolic BP <180 mm Hg) treatment within 4.5 hours from onset. The following NCCT markers were identified: intrahematoma hypodensities, black hole sign, swirl sign, blend sign, heterogeneous hematoma density, and irregular shape. ICH expansion was defined as hematoma growth >33% and unfavorable outcome was defined as modified Rankin Scale score >3 at 90 days. Logistic regression was used to identify predictors of ICH expansion and explore the association between NCCT signs and clinical benefit from intensive BP treatment. Results: A total of 989 patients were included (mean age 62 years, 61.9% male), of whom 186/869 experienced hematoma expansion (21.4%) and 361/952 (37.9%) had unfavorable outcome. NCCT markers independently predicted ICH expansion (all p < 0.01) with overall accuracy ranging from 61% to 78% and good interrater reliability (k > 0.6 for all markers). There was no evidence of an interaction between NCCT markers and benefit from intensive BP reduction (all p for interaction >0.10). Conclusions: NCCT signs reliably identify ICH patients at high risk of hematoma growth. However, we found no evidence that patients with these markers specifically benefit from intensive BP reduction. Clinicaltrials.gov identifier: NCT01176565.

Intensive blood pressure lowering in patients with acute intracerebral haemorrhage: clinical outcomes and haemorrhage expansion. Systematic review and meta-analysis of randomised trials

Introduction It is unclear whether intensive lowering of blood pressure (BP) at the acute phase of intracerebral haemorrhage (ICH) is beneficial. We performed a meta-analysis of randomised controlled trials (RCTs) to assess whether intensive BP lowering in patients with acute ICH is safe and effective in improving clinical outcomes. Methods We searched PubMed, EMBASE and the Cochrane databases for relevant RCTs and calculated pooled OR for 3-month mortality (safety outcome) and 3-month death or dependency (modified Rankin Scale (mRs) ≥3;efficacy outcome), in patients with acute ICH randomised to either intensive BP-lowering or standard BP-lowering treatment protocols. We also investigated the association between treatment arm and ICH expansion at 24 hours. Random effects models with DerSimonian-Laird weights were used. Results Five eligible studies including 4360 patients with acute ICH were pooled in meta-analysis. The risk of 3-month mortality was similar between patients randomised to intensive BP-lowering treatment and standard BP-lowering treatment (OR: 0.99; 95% CI: 0.82 to 1.20, p=0.909). Intensive BP-lowering treatment showed a (non-significant) trend for an association with lower 3-month death or dependency risk compared with standard treatment (OR: 0.91; 95% CI: 0.80 to 1.02), p=0.106). Intensive BP reduction was associated with a trend for lower risk of significant ICH expansion compared with standard treatment (OR: 0.82; 95% CI: 0.68 to 1.00, p=0.056), especially in larger RCTs. Conclusions For patients with acute ICH similar to those included in RCTs and without contraindication to acute BP treatment, intensive acute BP lowering is safe, but does not seem to provide an incremental clinical benefit in terms of functional outcomes. The effect of intensive BP lowering on significant haematoma expansion at 24 hours warrants further investigation.

Noncontrast Computed Tomography Hypodensities Predict Poor Outcome in Intracerebral Hemorrhage Patients

Background and Purpose— Noncontrast computed tomographic (CT) hypodensities have been shown to be associated with hematoma expansion in intracerebral hemorrhage (ICH), but their impact on functional outcome is yet to be determined. We evaluated whether baseline noncontrast CT hypodensities are associated with poor clinical outcome. Methods— We performed a retrospective review of a prospectively collected cohort of consecutive patients with primary ICH presenting to a single academic medical center between 1994 and 2016. The presence of CT hypodensities was assessed by 2 independent raters on the baseline CT. Unfavorable outcome was defined as a modified Rankin score >3 at 90 days. The associations between CT hypodensities and unfavorable outcome were investigated using uni- and multivariable logistic regression models. Results— During the study period, 1342 patients presented with ICH and 800 met restrictive inclusion criteria (baseline CT available for review, and 90-day outcome available). Three hundred and four (38%) patients showed hypodensities on CT, and 520 (65%) patients experienced unfavorable outcome. In univariate analysis, patients with unfavorable outcome were more likely to demonstrate hypodensities (48% versus 20%; P<0.0001). After adjustment for age, admission Glasgow coma scale, warfarin use, intraventricular hemorrhage, baseline ICH volume, and location, CT hypodensities were found to be independently associated with an increase in the odds of unfavorable outcome (odds ratio 1.70, 95% confidence interval [1.10–2.65]; P=0.018). Conclusions— The presence of noncontract CT hypodensities at baseline independently predicts poor outcome and comes as a useful and widely available addition to our ability to predict ICH patients’ clinical evolution.

Prognostic Factors for Cognitive Decline After Intracerebral Hemorrhage

Background and Purpose— Stroke and dementia are closely related, but no prospective study ever focused on poststroke cognitive decline in patients with intracerebral hemorrhage (ICH). We aimed to determine prognostic factors for cognitive decline in patients with ICH. Methods— We prospectively included 167 consecutive ICH survivors without preexisting dementia from the Prognosis of Intra-Cerebral Hemorrhage (PITCH) cohort. Median follow-up was 4 years (interquartile range, 2.3–5.4). We explored factors associated with cognitive decline using linear mixed models. Cognitive decline was determined based on repeated mini-mental state examination. We investigated each prognostic factor separately in univariate models. Next, we constructed clinical and radiological multivariable models. In a sensitivity analysis, we excluded patients with preexisting cognitive impairment. Results— Median age was 64 (interquartile range, 53–75) years, 69 (41%) patients were women, and median mini-mental state examination at 6 months was 27 (interquartile range, 23–29). Overall, 37% of the patients declined during follow-up. Factors associated with cognitive decline in univariate analyses were previous stroke or transient ischemic attack, preexisting cognitive impairment, microbleed presence, severity of white matter hyperintensities, and severity of cortical atrophy. In multivariable analyses, previous stroke or transient ischemic attack (&bgr; [SE], −0.55 [0.23]; P<0.05), preexisting cognitive impairment (&bgr; [SE], −0.56 [0.25]; P<0.01), and severity of cortical atrophy (&bgr; [SE], −0.50 [0.19]; P<0.01) remained independent prognostic factors. In patients without preexisting cognitive impairment (n=139), severity of cortical atrophy (&bgr; [SE], −0.38 [0.17]; P<0.05) was the only prognostic factor for future cognitive decline. Conclusions— Prognostic factors for cognitive decline after ICH are already present when ICH occurs, suggesting a process of ongoing cognitive impairment instead of new-onset decline induced by the ICH itself.

MRI-visible perivascular spaces in cerebral amyloid angiopathy and hypertensive arteriopathy

Objective: To assess MRI-visible enlarged perivascular spaces (EPVS) burden and different topographical patterns (in the centrum semiovale [CSO] and basal ganglia [BG]) in 2 common microangiopathies: cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy (HA). Methods: Consecutive patients with spontaneous intracerebral hemorrhage (ICH) from a prospective MRI cohort were included. Small vessel disease MRI markers, including cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), and white matter hyperintensities (WMH), were rated. CSO-EPVS/BG-EPVS were assessed on a validated 4-point visual rating scale (0 = no EPVS, 1 = <10, 2 = 11–20, 3 = 21–40, and 4 = >40 EPVS). We tested associations of predefined high-degree (score >2) CSO-EPVS and BG-EPVS with other MRI markers in multivariable logistic regression. We subsequently evaluated associations with CSO-EPVS predominance (i.e., CSO-EPVS > BG-EPVS) and BG-EPVS predominance pattern (i.e., BG-EPVS > CSO-EPVS) in adjusted multinomial logistic regression (reference group, BG-EPVS = CSO-EPVS). Results: We included 315 patients with CAA-ICH and 137 with HA-ICH. High-degree CSO-EPVS prevalence was greater in CAA-related ICH vs HA-related ICH (43.8% vs 17.5%, p < 0.001). In multivariable logistic regression, high-degree CSO-EPVS was associated with lobar CMB (odds ratio [OR] 1.33, 95% confidence interval [CI] 1.10–1.61, p = 0.003) and cSS (OR 2.08, 95% CI 1.30–3.32, p = 0.002). Deep CMBs (OR 2.85, 95% CI 1.75–4.64, p < 0.0001) and higher WMH volume (OR 1.02, 95% CI 1.01–1.04, p = 0.010) were predictors of high-degree BG-EPVS. A CSO-EPVS–predominant pattern was more common in CAA-ICH than in HA-ICH (75.9% vs 39.4%, respectively, p < 0.0001). CSO-PVS predominance was associated with lobar CMB burden and cSS, while BG-EPVS predominance was associated with HA-ICH and WMH volumes. Conclusions: Different patterns of MRI-visible EPVS provide insights into the dominant underlying microangiopathy type in patients with spontaneous ICH.