Solène Moulin

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.

Higher neutrophil counts before thrombolysis for cerebral ischemia predict worse outcomes.

Objective: To determine whether higher neutrophil counts before IV recombinant tissue plasminogen activator (rtPA) administration in ischemic stroke (IS) patients are associated with symptomatic intracerebral hemorrhages (sICH) and worse outcomes at 3 months. Methods: Blood samples for leukocyte, neutrophil, and lymphocyte counts were drawn before IV rtPA administration in IS patients included in the cohorts of Lille and Helsinki. The primary endpoint was sICH (European Cooperative Acute Stroke–II definition). Secondary endpoints were death and excellent (modified Rankin Scale [mRS] score 0–1 or equal to prestroke mRS) and good (mRS score 0–2 or equal to prestroke mRS) outcomes at 3 months. Results: We included 846 patients (median age 71 years; 50.8% men). The neutrophil count and neutrophil to lymphocyte ratio (NLR) were independently associated with the 4 endpoints: sICH (adjusted odds ratio [adjOR] for an increase of 1,000 neutrophils = 1.21 and adjOR 1.11, respectively), death (adjOR 1.16 and adjOR 1.08), and excellent (adjOR 0.87 and adjOR 0.85) and good (adjOR 0.86 and adjOR 0.91) outcomes. The total leukocyte count was not associated with any of the 4 endpoints. The best discriminating factor for sICH was NLR ≥4.80 (sensitivity 66.7%, specificity 71.3%, likelihood ratio 2.32). Patients with NLR ≥4.80 had a 3.71-fold increased risk for sICH (95% confidence interval adjOR: 1.97–6.98) compared to patients with NLR <4.80. Conclusions: Higher neutrophil counts and NLR are independently associated with sICH and worse outcome at 3 months. The identification of mediators of this effect could provide new targets for neuroprotection in patients treated by rtPA.

Microbleed Status and 3-Month Outcome After Intravenous Thrombolysis in 717 Patients With Acute Ischemic Stroke

Background and Purpose— Whether cerebral microbleeds (CMBs) detected on pretreatment magnetic resonance imaging increase the risks of symptomatic intracranial hemorrhage (sICH) and, most importantly, poor outcome in patients treated by intravenous thrombolysis for acute ischemic stroke is still debated. We assessed the effect of CMB presence and burden on 3-month modified Rankin Scale and sICH in a multicentric cohort. Methods— We analyzed prospectively collected data of consecutive patients solely treated by intravenous thrombolysis for acute ischemic stroke, in 2 centers where magnetic resonance imaging is the first-line pretreatment imaging. Neuroradiologists blinded to clinical data rated CMBs on T2* sequence using a validated scale. Logistic regressions were used to assess relationships between CMBs and 3-month modified Rankin Scale or sICH. Results— Among 717 patients, 150 (20.9%) had ≥1 CMBs. CMB burden was associated with worse modified Rankin Scale in univariable shift analysis (odds ratio, 1.07; 95% confidence interval, 1.00–1.15 per 1-CMB increase; P=0.049), but significance was lost after adjustment for age, hypertension, and atrial fibrillation (odds ratio, 1.03; 95% confidence interval, 0.96–1.11 per 1-CMB increase; P=0.37). Results remained nonsignificant when taking into account CMB location or presumed underlying vasculopathy. The incidence of sICH ranged from 3.8% to 9.1%, depending on the definition. Neither CMB presence, burden, location, nor presumed underlying vasculopathy was independently associated with sICH. Conclusions— Poor outcome or sICH was not associated with CMB presence or burden on pre–intravenous thrombolysis magnetic resonance imaging after adjustment for confounding factors. An individual patient data meta-analysis is needed to determine whether a subgroup of patients with CMBs carries an independent risk of poor outcome that might outweigh the expected benefit of intravenous thrombolysis.

Brain hemorrhage recurrence, small vessel disease type, and cerebral microbleeds: A meta-analysis

Objective: We evaluated recurrent intracerebral hemorrhage (ICH) risk in ICH survivors, stratified by the presence, distribution, and number of cerebral microbleeds (CMBs) on MRI (i.e., the presumed causal underlying small vessel disease and its severity). Methods: This was a meta-analysis of prospective cohorts following ICH, with blood-sensitive brain MRI soon after ICH. We estimated annualized recurrent symptomatic ICH rates for each study and compared pooled odds ratios (ORs) of recurrent ICH by CMB presence/absence and presumed etiology based on CMB distribution (strictly lobar CMBs related to probable or possible cerebral amyloid angiopathy [CAA] vs non-CAA) and burden (1, 2–4, 5–10, and >10 CMBs), using random effects models. Results: We pooled data from 10 studies including 1,306 patients: 325 with CAA-related and 981 CAA-unrelated ICH. The annual recurrent ICH risk was higher in CAA-related ICH vs CAA-unrelated ICH (7.4%, 95% confidence interval [CI] 3.2–12.6 vs 1.1%, 95% CI 0.5–1.7 per year, respectively; p = 0.01). In CAA-related ICH, multiple baseline CMBs (versus none) were associated with ICH recurrence during follow-up (range 1–3 years): OR 3.1 (95% CI 1.4–6.8; p = 0.006), 4.3 (95% CI 1.8–10.3; p = 0.001), and 3.4 (95% CI 1.4–8.3; p = 0.007) for 2–4, 5–10, and >10 CMBs, respectively. In CAA-unrelated ICH, only >10 CMBs (versus none) were associated with recurrent ICH (OR 5.6, 95% CI 2.1–15; p = 0.001). The presence of 1 CMB (versus none) was not associated with recurrent ICH in CAA-related or CAA-unrelated cohorts. Conclusions: CMB burden and distribution on MRI identify subgroups of ICH survivors with higher ICH recurrence risk, which may help to predict ICH prognosis with relevance for clinical practice and treatment trials.

Orolingual Angioedema During or After Thrombolysis for Cerebral Ischemia

Background and Purpose— Orolingual angioedema (OLAE) is a life-threatening complication of intravenous thrombolysis. Our objective was to compare outcomes of patients with and without OLAE. Methods— We prospectively included consecutive patients who received intravenous thrombolysis for cerebral ischemia at Lille University Hospital. We examined tongue and lips every 15 minutes during thrombolysis and ⩽30 minutes after. We evaluated the 3-month outcome with the modified Rankin scale (mRS) and compared outcomes of patients with and without OLAE. Results— Of 923 consecutive patients, 20 (2.2%) developed OLAE. None of them needed oro-tracheal intubation. They were more likely to be under angiotensin-converting enzyme inhibitors (adjusted odds ratio [adjOR], 3.9; 95% confidence interval [CI], 1.6–9.7; P=0.005) to have total insular infarcts (OR, 5.0; 95% CI, 1.5–16.5; P=0.004) and tended to develop more symptomatic intracerebral hemorrhages. Results concerning angiotensin-converting enzyme inhibitors were not modified after adjustment for propensity scores (OR, 4.4; 95% CI, 1.6–11.9; P=0.004) or matched analysis based on propensity scores (OR, 3.4; 95% CI, 1.3–8.1; P=0.010). Patients with OLAE did not significantly differ at 3 months for the proportion of patients with mRS score of 0 to 1 (adjOR, 0.9; 95% CI, 0.3–2.1), mRS score of 0 to 2 (adjOR, 0.8; 95% CI, 0.1–1.8), and death (adjOR, 1.1; 95% CI, 0.3–3.8). Conclusions— OLAE occurs in 1 of 50 patients who receive intravenous thrombolysis, 1 of 10 in case of total insular infarct, and 1 of 6 if they are under angiotensin-converting enzyme inhibitors. Their long-term outcome does not differ from that of other patients.

Influence of Differences in Case Mix on the Better Outcome of Smokers after Intravenous Thrombolysis for Acute Cerebral Ischemia

Background/Aims: Thrombolysis for myocardial infarction is more effective in smokers. Our aim wasto determine whether smokers treated by intravenous (i.v.) rt-PA for acute cerebral ischemia have better outcomes. Method: Comparison of smokers and non-smokers for baseline characteristics and month-3 outcome in patients treated by i.v. rt-PA for cerebral ischemia in Lille, France, and Belgrade, Serbia. The primary outcome was a modified Rankin scale (mRS) 0–1 or similar to the pre-stroke mRS. Secondary outcomes were an mRS 0–2 and death. Results: We included 459 patients (255 men; median age 65 years, interquartile range 52–76; 135 smokers). Smokers were younger (median 53 vs. 70 years, p < 0.0001) and had less severe strokes (median NIHSS 10 vs. 14, p < 0.0001). At month 3, they were more likely to have an mRS 0–1 [odds ratio (OR) 1.75; 95% confidence interval (CI) 1.17–2.62], or an mRS 0–2 (OR 2.90; 95% CI 1.86–4.52) and less likely to be dead (OR 0.28; 95% CI 0.13–0.61). Smoking was not independently associated with outcome after adjustment for case mix [adjusted OR (adjOR) 0.86; 95% CI 0.52–1.43]. Conclusion: Smoking does not independently influence the outcome in patients treated by rt-PA for cerebral ischemia. The better outcome in smokers is the consequence of differences in case mix.

Blood biomarkers in the early stage of cerebral ischemia

In ischemic stroke patients, blood-based biomarkers may be applied for the diagnosis of ischemic origin and subtype, prediction of outcomes and targeted treatment in selected patients. Knowledge of the pathophysiology of cerebral ischemia has led to the evaluation of proteins, neurotransmitters, nucleic acids and lipids as potential biomarkers. The present report focuses on the role of blood-based biomarkers in the early stage of ischemic stroke-within 72h of its onset-as gleaned from studies published in English in such patients. Despite growing interest in their potential role in clinical practice, the application of biomarkers for the management of cerebral ischemia is not currently recommended by guidelines. However, there are some promising clinical biomarkers, as well as the N-methyl-d-aspartate (NMDA) peptide and NMDA-receptor (R) autoantibodies that appear to identify the ischemic nature of stroke, and the glial fibrillary acidic protein (GFAP) that might be able to discriminate between acute ischemic and hemorrhagic strokes. Moreover, genomics and proteomics allow the characterization of differences in gene expression, and protein and metabolite production, in ischemic stroke patients compared with controls and, thus, may help to identify novel markers with sufficient sensitivity and specificity. Additional studies to validate promising biomarkers and to identify novel biomarkers are needed.

Are the results of intravenous thrombolysis trials reproduced in clinical practice? Comparison of observed and expected outcomes with the stroke-thrombolytic predictive instrument (STPI)

AIM In patients with cerebral ischemia, intravenous (i.v.) recombinant tissue plasminogen activator (rt-PA) increases survival without handicap or dependency despite an increased risk of bleeding. This study evaluated whether the results of randomized controlled trials are reproduced in clinical practice. METHOD Data from a registry of consecutive patients treated by rt-PA at Lille University Hospital were retrospectively analyzed for outcomes, using modified Rankin Scale (mRS) scores, at 3 months. The observed outcomes were then compared with the probability of good (mRS 0-1) and of catastrophic (mRS 5-6) outcomes, as predicted by the stroke-thrombolytic predictive instrument (STPI). RESULTS Of the 1000 consecutive patients (469 male, median age 74 years, median baseline National Institutes of Health Stroke Scale 11, median onset-to-needle time 143min), 438 (43.8%) had a good outcome, 565 (56.5%) had an mRS score 0-2 or similar to their pre-stroke mRS, 155 (15.5%) died within 3 months and 74 (7.4%) developed symptomatic intracerebral hemorrhage according to ECASS-II (Second European-Australasian Acute Stroke Study) criteria. Of the 613 patients (61.3%) eligible for evaluation by the s-TPI, the observed rate of good outcomes was 41.3% (95% CI: 37.5-45.3%), while expected rates with and without rt-PA were 48.8% (95% CI: 44.8-52.7%) and 32.5% (95% CI: 28.8-36.2%), respectively; the observed rate of catastrophic outcomes was 17.0% (95% CI: 14.0-19.9%), while the expected rate was 19.2% (95% CI: 16.1-22.4%) with or without rt-PA. CONCLUSION In clinical practice, the rate of good outcomes is slightly lower than expected, according to the s-TPI, except for the most severe cases, whereas the rate of catastrophic outcomes is roughly similar. However, the rate of good outcomes is higher than predicted without treatment. This finding suggests that rt-PA is effective for improving outcomes in clinical practice.

Prognosis and Outcome of Intracerebral Haemorrhage.

Spontaneous intracerebral haemorrhage (ICH) accounts for approximately 15% of all strokes and is a leading cause of disability, with a one-month mortality rate of 40%. Whereas factors predicting short-term mortality are well known, data regarding long-term outcome are scarce and imprecise. The two main underlying vasculopathies responsible for ICH, i.e. deep perforating vasculopathy and cerebral amyloid angiopathy, might have an impact on the overall prognosis of ICH survivors. ICH survivors are at high risk of epileptic seizures, depression and cognitive impairment, which may influence their functional outcome. Lobar location of an ICH, frequently due to cerebral amyloid angiopathy, partly determines the long-term risk of recurrent haemorrhage. Because of common vascular risk factors, patients with ICH are also at considerable risk of serious ischaemic events. Risks of future ischaemic events may be as high as that of recurrent ICH, raising the relevance of antithrombotic treatment in ICH survivors. Future studies of long-term follow-up after ICH are needed to determine predictors of outcome, including biomarkers of the underlying vasculopathies, to tailor preventive strategies to survivors.

Outcomes of Nonagenarians with Acute Ischemic Stroke Treated with Intravenous Thrombolytics

BACKGROUND Nonagenarians are under-represented in thrombolytic trials for acute ischemic stroke (AIS). The effectiveness of intravenous thrombolytics in nonagenarians in terms of safety and outcome is not well established. MATERIALS AND METHODS We used a multinational registry to identify patients aged 90 years or older with good baseline functional status who presented with AIS. Differences in outcomes-disability level at 90 days, frequency of symptomatic intracerebral hemorrhage (sICH), and mortality-between patients who did and did not receive thrombolytics were assessed using multivariable logistic regression, adjusted for prespecified prognostic factors. Coarsened exact matching (CEM) was utilized before evaluating outcome by balancing both groups in the sensitivity analysis. RESULTS We identified 227 previously independent nonagenarians with AIS; 122 received intravenous thrombolytics and 105 did not. In the unmatched cohort, ordinal analysis showed a significant treatment effect (adjusted common odds ratio [OR]: .61, 95% confidence interval [CI]: .39-.96). There was an absolute difference of 8.1% in the rate of excellent outcome in favor of thrombolysis (17.4% versus 9.3%; adjusted ratio: .30, 95% CI: .12-.77). Rates of sICH and in-hospital mortality were not different. Similarly, in the matched cohort, CEM analysis showed a shift in the primary outcome distribution in favor of thrombolysis (adjusted common OR: .45, 95% CI: .26-.76). CONCLUSIONS Nonagenarians treated with thrombolytics showed lower stroke-related disability at 90 days than those not treated, without significant difference in sICH and in-hospital mortality rates. These observations cannot exclude a residual confounding effect, but provide evidence that thrombolytics should not be withheld from nonagenarians because of age alone.