Costanza Rossi

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.

The CAVE Score for Predicting Late Seizures After Intracerebral Hemorrhage

Background and Purpose— Seizures are a common complication of intracerebral hemorrhage (ICH). We developed a novel tool to quantify this risk in individual patients. Methods— Retrospective analysis of the observational Helsinki ICH Study (n=993; median follow-up, 2.7 years) and the Lille Prognosis of InTra-Cerebral Hemorrhage (n=325; 2.2 years) cohorts of consecutive ICH patients admitted between 2004 and 2010. Helsinki ICH Study patients’ province-wide electronic records were evaluated for early seizures occurring within 7 days of ICH and among 7-day survivors (n=764) for late seizures (LSs) occurring >7 days from ICH. A Cox regression model estimating risk of LSs was used to derive a prognostic score, validated in the Prognosis of InTra-Cerebral Hemorrhage cohort. Results— Of the Helsinki ICH Study patients, 109 (11.0%) had early seizures within 7 days of ICH. Among the 7-day survivors, 70 (9.2%) patients developed LSs. The cumulative risk of LSs was 7.1%, 10.0%, 10.2%, 11.0%, and 11.8% at 1 to 5 years after ICH, respectively. We created the CAVE score (0–4 points) to estimate the risk of LSs, with 1 point for each of cortical involvement, age <65 years, volume >10 mL, and early seizures within 7 days of ICH. The risk of LSs was 0.6%, 3.6%, 9.8%, 34.8%, and 46.2% for CAVE scores 0 to 4, respectively. The c-statistic was 0.81 (0.76–0.86) and 0.69 (0.59–0.78) in the validation cohort. Conclusions— One in 10 patients will develop seizures after ICH. The risk of this adverse outcome can be estimated by a simple score based on baseline variables.

Incidence and Predictors of Late Seizures in Intracerebral Hemorrhages

Background and Purpose— To identify incidence and predictors of late seizures (LS, occurring >1 week of stroke) in a cohort of patients with intracerebral hemorrhage (ICH). Methods— Prospective cohort of consecutive adults with spontaneous ICH. Incidence and predictors were identified with Cox regression. We included multivariate analyses on MRI biomarkers (global cortical atrophy, leukoaraiosis, brain microbleeds). Results— Our study population consisted of 325 patients: 54% men, median age 70 years (interquartile range, 58–79). During 778 person-years of follow-up, the incidence rate was 4 new cases/100 person-years (95% confidence interval, 3–6). The median delay between ICH and LS was 9 months (interquartile range, 3–23). The only factor independently associated with the occurrence of LS was a cortical involvement of the ICH (hazard ratio, 2.8; 95% confidence interval, 1.3–6.1). Concerning MRI biomarkers, multivariate analyses found lobar brain microbleeds to be associated with LS (hazard ratio, 2.4; 95% confidence interval, 1.1–5.4), especially if ≥3 (hazard ratio, 2.7; 95% confidence interval, 1.1–6.8). LS were associated with a worse functional outcome after 3 years of follow-up (P=0.009). Conclusions— LS frequently occur >9 months after ICH onset, imposing a long-term follow-up. The association of lobar brain microbleeds with the risk of LS might suggest a link with the underlying vasculopathy (cerebral amyloid angiopathy).

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.

Incident Cerebral Microbleeds in a Cohort of Intracerebral Hemorrhage

Background and Purpose— We aimed to identify prognostic and associated factors of incident cerebral microbleeds (CMBs) in intracerebral hemorrhage (ICH) survivors. Methods— Observational prospective cohort of 168 ICH survivors who underwent 1.5T magnetic resonance imaging at ICH onset and during follow-up (median scan interval, 3.4; interquartile range, 1.4–4.7) years. We used logistic regression adjusted for age, sex, and scan interval. Analyses were stratified according to the index ICH location (58 lobar ICH, 103 nonlobar ICH, excluding patients with multiple or unclassifiable ICH). Results— Eighty-nine (53%) patients had CMBs at ICH onset, and 80 (48%) exhibited incident CMBs during follow-up. Predictors of incident CMBs at ICH onset were ≥1 CMBs (adjusted odds ratio [aOR], 2.27; 95% confidence interval [CI], 1.18–4.35), old radiological macrohemorrhage (aOR, 6.78; 95% CI, 2.76–16.68), and CMBs in mixed location (aOR, 3.73; 95% CI, 1.67–8.31). When stratifying by ICH location, incident CMBs were associated in nonlobar ICH with incident lacunes (aOR, 2.86; 95% CI, 1.04–7.85) and with the use of antiplatelet agents (aOR, 2.89; 95% CI, 1.14–7.32). In lobar ICH, incident CMBs were associated with incident radiological macrohemorrhage (aOR, 9.76; 95% CI, 1.07–88.77). Conclusions— Prognostic and associated factors of incident CMBs differed according to the index ICH location. Whereas in lobar ICH, incident CMBs were associated with hemorrhagic biomarkers, in nonlobar ICH, ischemic burden also increased. CMBs may be interesting biomarkers to monitor in randomized trials on restarting antithrombotic drugs after ICH.

Diagnostic Evaluation for Nontraumatic Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) is a devastating condition with multiple possible underlying causes. Early diagnosis of ICH associated with a precise diagnostic work-up is mandatory. Clinical signs may give clues to diagnosis but are not reliable enough and imaging remains the cornerstone of management. Noncontrast computed tomography and magnetic resonance imaging (MRI) are highly sensitive for ICH identification. Additionally, MRI may disclose brain parenchymal biomarkers that can contribute to the etiologic diagnosis. Vessel examination should be carried out whenever there is a clinical suspicion of underlying structural lesions, such as vascular malformations or tumors. To date, conventional angiography remains the gold standard to detect intracranial vascular malformations in patients with ICH.

Proportion of single-chain recombinant tissue plasminogen activator and outcome after stroke

Objective: To determine whether the ratio single chain (sc)/(sc + 2 chain [tc]) recombinant tissue plasminogen activator (rtPA) influences outcomes in patients with cerebral ischemia. Methods: We prospectively included consecutive patients treated with IV rtPA for cerebral ischemia in 13 stroke centers and determined the sc/(sc + tc) ratio in the treatment administered to each patient. We evaluated the outcome with the modified Rankin Scale (mRS) at 3 months (prespecified analysis) and occurrence of epileptic seizures (post hoc analysis). We registered Outcome of Patients Treated by IV Rt-PA for Cerebral Ischaemia According to the Ratio Sc-tPA/Tc-tPA (OPHELIE) under ClinicalTrials.gov identifier no. NCT01614080. Results: We recruited 1,004 patients (515 men, median age 75 years, median onset-to-needle time 170 minutes, median NIH Stroke Scale score 10). We found no statistical association between sc/(sc + tc) ratios and handicap (mRS > 1), dependency (mRS > 2), or death at 3 months. Patients with symptomatic intracerebral hemorrhages had lower ratios (median 69% vs 72%, adjusted p = 0.003). The sc/(sc + tc) rtPA ratio did not differ between patients with and without seizures, but patients with early seizures were more likely to have received a sc/(sc + tc) rtPA ratio >80.5% (odds ratio 3.61; 95% confidence interval 1.26–10.34). Conclusions: The sc/(sc + tc) rtPA ratio does not influence outcomes in patients with cerebral ischemia. The capacity of rtPA to modulate NMDA receptor signaling might be associated with early seizures, but we observed this effect only in patients with a ratio of sc/(sc + tc) rtPA >80.5% in a post hoc analysis.

STROKOG (stroke and cognition consortium): An international consortium to examine the epidemiology, diagnosis, and treatment of neurocognitive disorders in relation to cerebrovascular disease

The Stroke and Cognition consortium (STROKOG) aims to facilitate a better understanding of the determinants of vascular contributions to cognitive disorders and help improve the diagnosis and treatment of vascular cognitive disorders (VCD).

Cortical superficial siderosis: A prospective observational cohort study

Objective To determine the prevalence of cortical superficial siderosis (cSS), its clinical and neuroimaging associated markers, and its influence on the risk of recurrent intracerebral hemorrhage (ICH) in a prospective observational ICH cohort. Methods We investigated clinical and radiologic markers associated with cSS using multivariable analysis. In survival analyses, we used Cox models to identify predictors of recurrent ICH after adjusting for potential confounders. Results Of the 258 patients included in the study, 49 (19%; 95% confidence interval [CI] 14%–24%) had cSS at baseline. Clinical factors independently associated with the presence of cSS were increasing age (odds ratio [OR] 1.03 per 1-year increase, 95% CI 1.001–1.06, p = 0.044), preexisting dementia (OR 2.62, 95% CI 1.05–6.51, p = 0.039), and history of ICH (OR 4.02, 95% CI 1.24–12.95, p = 0.02). Among radiologic biomarkers, factors independently associated with the presence of cSS were ICH lobar location (OR 24.841, 95% CI 3.2–14.47, p < 0.001), severe white matter hyperintensities score (OR 5.51, 95% CI 1.17–5.78, p = 0.019), and absence of lacune (OR 4.46, 95% CI 1.06–5.22, p = 0.035). During a median follow-up of 6.4 (interquartile range 2.9–8.4) years, recurrent ICH occurred in 19 patients. Only disseminated cSS (hazard ratio 4.69, 95% CI 1.49–14.71, p = 0.008), not the presence or absence of cSS or focal cSS on baseline MRI, was associated with recurrent symptomatic ICH. Conclusion In a prospective observational cohort of spontaneous ICH, clinical and radiologic markers associated with cSS suggest the implication of underlying cerebral amyloid angiopathy. Disseminated cSS may become a key prognostic neuroimaging marker of recurrent ICH that could be monitored in future clinical trials dedicated to patients with ICH.

Classification of Intracerebral Haemorrhages

Spontaneous intracerebral haemorrhage (ICH) is defined as a collection of blood in the cerebral parenchyma that is not caused by trauma. ICH is the second most frequent cause of stroke, accounting for 10–15 % of all cases in high-income countries and about 20 % in lowto middle-income countries. Despite an apparent stability of incidence over the past decades, the profile of ICH has changed: there are fewer deep ICHs associated with pre-stroke hypertension, whereas the increasing age of the population associated with a more extensive use of antithrombotic drugs leads to an increase of lobar ICH. Deep perforating vasculopathy remains the most important cause of ICH, followed by cerebral amyloid angiopathy, these two aetiologies account for nearly 70 % of all ICH cases. Recent scientific evidence has highlighted new aspects of the pathophysiology of such disorders; nevertheless, the morbidity and mortality of ICH remain extremely high. In the present article, the different causes of ICH will be reviewed.