Fatal Intracerebral Hemorrhage Research Articles

Abstract WP147: Influence of White Blood Cell Count on Outcome for Thrombolysis-Treated Acute Ischemic Stroke ENCHANTED Post HocAnalysis

Background: Increased inflammatory reaction can aggravate brain injury after acute ischemic stroke, but the clinical effect of such response is not fully understood. The aim of this study was to determine associations of peripheral white blood cell (WBC) count on clinical outcome among participants of the ENCHANTED study. Methods: Data are from the Enhanced Control of Hypertension for < and > for > Thrombolysis Stroke Study (ENCHANTED), aninternational, multicenter, randomized controlled trial where patients with acute ischemic stroke were randomized to low-dose (0.6 mg/ kg) or standard-dose (0.9 mg/kg) IV alteplase.Blood samples were collected on admission < for < and > for > WBC count was measured at local laboratories. The primary outcome was death or disability, defined by scores 3–6 on the modified Rankin Scale at 90 days.Secondary outcomes included ordinal mRS shift,fatal intracerebral hemorrhage(ICH) by various standard criteria.Associations of baseline WBC count < for < and > for > outcomes were evaluated in logistic regression models. Results: There were 3179 participants with relevant data who were classified into quartiles of WBC counts (≤ 6.30, 6.31–7.82, 7.83–9.80, < for < and > for > ≥ 9.81х109/L, respectively).Increased WBC count was associated with younger age,elevated NIHSS scores, less antithrombotic used,elevated heart rate,elevated fever treated,stroke severity. Risks of death or major disability at 90 days increased progressively with higher WBC count: frequencies of 30.4%, 34.7%,39.1% < for < and > for > 44.8% for quartile groups, respectively (P <.0001 for trend). After adjustment for baseline clinical < for < and > for > imaging variables including age, sex, body temperature, systolic BP, heart rate, high NIHSS scores, < for < and > for > randomized treatment, the association between WBC count < for < and > for > primary outcome was still significant (P <.0001 for trend). Conclusions: Elevated WBC count on admission may be an independent prognostic predicator in patients with Acute Ischemic Stroke, but this requires further evaluation in a prospective cohort study.

Updates on Prevention of Hemorrhagic and Lacunar Strokes.

Intracerebral hemorrhage (ICH) and lacunar infarction (LI) are the major acute clinical manifestations of cerebral small vessel diseases (cSVDs). Hypertensive small vessel disease, cerebral amyloid angiopathy, and hereditary causes, such as Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), constitute the three common cSVD categories. Diagnosing the underlying vascular pathology in these patients is important because the risk and types of recurrent strokes show significant differences. Recent advances in our understanding of the cSVD-related radiological markers have improved our ability to stratify ICH risk in individual patients, which helps guide antithrombotic decisions. There are general good-practice measures for stroke prevention in patients with cSVD, such as optimal blood pressure and glycemic control, while individualized measures tailored for particular patients are often needed. Antithrombotic combinations and anticoagulants should be avoided in cSVD treatment, as they increase the risk of potentially fatal ICH without necessarily lowering LI risk in these patients. Even when indicated for a concurrent pathology, such as nonvalvular atrial fibrillation, nonpharmacological approaches should be considered in the presence of cSVD. More data are emerging regarding the presentation, clinical course, and diagnostic markers of hereditary cSVD, allowing accurate diagnosis, and therefore, guiding management of symptomatic patients. When suspicion for asymptomatic hereditary cSVD exists, the pros and cons of prescribing genetic testing should be discussed in detail in the absence of any curative treatment. Recent data regarding diagnosis, risk stratification, and specific preventive approaches for both sporadic and hereditary cSVDs are discussed in this review article.

Abstract WP21: Different View on Clinical Application of Tirofiban After Mechanical Arterial Recanalization in Acute Ischemic Stroke

Tirofiban, an antiplatelet drug and glycoprotein-IIb/IIIa inhibitor, widely used in cardiovascular events, appears to be safe and effective in cerebrovascular stroke. However, its efficacy post-endovascular therapy raised concern due to an association with increased risk of fatal intracerebral hemorrhage (ICH) and poor outcome in ischemic patients (Kellert et al. 2013). The success of 5 randomized clinical trials in stroke therapy in 2015 utilizing new generation endovascular intervention prompted this study of continuous intravenous administration of Tirofiban after thrombectomy with the Solitaire stent, one of the two new devices, in patients with acute ischemic stroke. A consecutive series of patients (n=28) who received Solitaire stent thrombectomy from January 2017 to the present was enrolled. 22 of the 28 patients were eligible for intravenous Tirofiban treatment for 24 h after receiving endovascular therapy. 6 patients were excluded because of no vessel recanalization, vessel recanalization achieved by other devices, or ICH after endovascular therapy. The incidence of symptomatic ICH and death was recorded. The number of thrombectomy attempts and device manipulation time within vessels were measured as potential markers for endothelial damage. The NIH stroke and modified Rankin scales were assessed at 7 days and 3 months, respectively. In all 22 patients who received Tirofiban after endovascular therapy, none had symptomatic ICH nor died from treatment. Successful recanalization rate (TICI≥2b) was achieved in 18 (86.4%) of 22 patients after endovascular therapy. As compared to the study by Kellert et al., the lower average device passages (1.2 vs 2.0) and short device manipulation time (56 vs 104 min) together suggested less endothelial damage. Of our patients, 77.3% showed neurological improvement at 7 days and 59.1% patients had favorable outcomes with a Modified Rankin scale of 0 to 2 at 3 months. These favorable outcomes were similar to those achieved in the 5 positive randomized trials. In conclusion, the continuous application of Tirofiban post-Solitaire stent thrombectomy appears to be safe and effective in acute ischemic stroke. Reduced endothelial damage may play a key role in clinical outcomes with Tirofiban application.

A Fatal Intracerebral Hemorrhage due to Chronic Methamphetamine Use

A Fatal Intracerebral Hemorrhage due to Chronic Methamphetamine Use

Statins and the Risk of Intracerebral Hemorrhage in Patients With Previous Ischemic Stroke or Transient Ischemic Attack

Although there is no overall association between statin use and intracerebral hemorrhage (ICH), whether there is an increased risk among those with a history of ischemic stroke (IS) or transient ischemic attack (TIA) remains controversial. We evaluated the relationship of preadmission statin use with the risk of ICH in patients with a history of IS or TIA in a population-based cohort. The Health Improvement Network primary care database in the United Kingdom was used to identify new users of low-dose aspirin and a matched comparison. Both cohorts were followed to identify incident cases of ICH, with validation by manual review of patient records and linkage to hospitalization data. In a nested case-control study, we compared the adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for ICH based on statin use in the subgroup of individuals with history of IS/TIA. Last statin use within 1 year of ICH (OR, 0.92; 95% CI [confidence interval], 0.60-1.4), last use between 8 days and 1 year (OR, 1.81; 95% CI, 0.99-3.28), and statin use at the time of ICH (OR, 0.77; 95% CI, 0.49-1.21) were not associated with the overall ICH risk among 157 patients with ICH and 884 controls with a history of IS/TIA. There was also no difference in 30-day rates of fatal (OR, 0.82; 95% CI, 0.41-1.64) or nonfatal (OR, 0.90; 95% CI, 0.51-1.57) ICH. Statin use was not associated with an increased risk of ICH among patients with a previous history of IS/TIA.

Elongated Plant Virus-Based Nanoparticles for Enhanced Delivery of Thrombolytic Therapies.

Thrombotic cardiovascular disease, including acute myocardial infarction, ischemic stroke, and venous thromboembolic disease, is the leading cause of morbidity and mortality worldwide. While reperfusion therapy with thrombolytic agents reduces mortality from acute myocardial infarction and disability from stroke, thrombolysis is generally less effective than mechanical reperfusion and is associated with fatal intracerebral hemorrhage in up to 2-5% of patients. To address these limitations, we propose the tobacco mosaic virus (TMV)-based platform technology for targeted delivery of thrombolytic therapies. TMV is a plant virus-based nanoparticle with a high aspect ratio shape measuring 300 × 18 nm. These soft matter nanorods have favorable flow and margination properties allowing the targeting of the diseased vessel wall. We have previously shown that TMV homes to thrombi in a photochemical mouse model of arterial thrombosis. Here we report the synthesis of TMV conjugates loaded with streptokinase (STK). Various TMV-STK formulations were produced through bioconjugation of STK to TMV via intervening PEG linkers. TMV-STK was characterized using SDS-PAGE and Western blot, transmission electron microscopy, cryo-electron microscopy, and cryo-electron tomography. We investigated the thrombolytic activity of TMV-STK in vitro using static phantom clots, and in a physiologically relevant hydrodynamic model of shear-induced thrombosis. Our findings demonstrate that conjugation of STK to the TMV surface does not compromise the activity of STK. Moreover, the nanoparticle conjugate significantly enhances thrombolysis under flow conditions, which can likely be attributed to TMV's shape-mediated flow properties resulting in enhanced thrombus accumulation and dissolution. Together, these data suggest TMV to be a promising platform for the delivery of thrombolytics to enhance clot localization and potentially minimize bleeding risk.

Tumor Necrosis Factor Receptor 1 and 2 Are Associated With Risk of Intracerebral Hemorrhage

Raised plasma concentrations of tumor necrosis factor receptors (TNFR) have been linked to arterial stiffness, cerebral microbleeds, and vascular events. The aim of this study was to investigate the association of circulating levels of TNFR1 and TNFR2 with risk for future intracerebral hemorrhage (ICH). The population-based MDCS cohort (Malmö Diet and Cancer Study; n=28 449) was conducted in 1991 to 1996. A nested case-control study was performed in the MDCS, including 220 cases who experienced ICH during the follow-up period (mean age at inclusion 62 years, 48% men) and 244 matched controls. Of the 220 ICH cases, 68 died within 28 days. Conditional logistic regression was used to study the association between plasma levels of TNFR1 and TNFR2 and incident ICH, adjusting for known ICH risk factors. Concentrations of both TNFR1 and TNFR2 were significantly higher in subjects who developed ICH during the follow-up. The associations remained after adjustment for ICH risk factors (TNFR1: odds ratio [OR], 2.28; 95% confidence interval [CI], 1.26-4.11; P=0.006; TNFR2: OR, 1.77; CI, 1.16-2.70; P=0.008). ORs were somewhat higher for nonlobar ICH (3.04; CI, 1.29-7.14 and 2.39; CI, 1.32-4.32, respectively) than for lobar ICH (2.03; CI, 0.93-4.41 and 1.35; CI, 0.78-2.37, respectively). TNFR1 and TNFR2 were also associated with increased risk of fatal ICH (TNFR1: OR, 4.42; CI, 1.67-11.6; TNFR2: OR, 2.90; CI, 1.50-5.58) and with poor functional outcome according to the modified Rankin Scale. High plasma levels of TNFR1 and TNFR2 were associated with incident ICH, most clearly with ICH of nonlobar location. The results suggest that tumor necrosis factor-mediated inflammation could be associated with vascular changes preceding ICH.

Age-specific risks, severity, time course, and outcome of bleeding on long-term antiplatelet treatment after vascular events: a population-based cohort study

SummaryBackgroundLifelong antiplatelet treatment is recommended after ischaemic vascular events, on the basis of trials done mainly in patients younger than 75 years. Upper gastrointestinal bleeding is a serious complication, but had low case fatality in trials of aspirin and is not generally thought to cause long-term disability. Consequently, although co-prescription of proton-pump inhibitors (PPIs) reduces upper gastrointestinal bleeds by 70–90%, uptake is low and guidelines are conflicting. We aimed to assess the risk, time course, and outcomes of bleeding on antiplatelet treatment for secondary prevention in patients of all ages.MethodsWe did a prospective population-based cohort study in patients with a first transient ischaemic attack, ischaemic stroke, or myocardial infarction treated with antiplatelet drugs (mainly aspirin based, without routine PPI use) after the event in the Oxford Vascular Study from 2002 to 2012, with follow-up until 2013. We determined type, severity, outcome (disability or death), and time course of bleeding requiring medical attention by face-to-face follow-up for 10 years. We estimated age-specific numbers needed to treat (NNT) to prevent upper gastrointestinal bleeding with routine PPI co-prescription on the basis of Kaplan–Meier risk estimates and relative risk reduction estimates from previous trials.Findings3166 patients (1582 [50%] aged ≥75 years) had 405 first bleeding events (n=218 gastrointestinal, n=45 intracranial, and n=142 other) during 13 509 patient-years of follow-up. Of the 314 patients (78%) with bleeds admitted to hospital, 117 (37%) were missed by administrative coding. Risk of non-major bleeding was unrelated to age, but major bleeding increased steeply with age (≥75 years hazard ratio [HR] 3·10, 95% CI 2·27–4·24; p<0·0001), particularly for fatal bleeds (5·53, 2·65–11·54; p<0·0001), and was sustained during long-term follow-up. The same was true of major upper gastrointestinal bleeds (≥75 years HR 4·13, 2·60–6·57; p<0·0001), particularly if disabling or fatal (10·26, 4·37–24·13; p<0·0001). At age 75 years or older, major upper gastrointestinal bleeds were mostly disabling or fatal (45 [62%] of 73 patients vs 101 [47%] of 213 patients with recurrent ischaemic stroke), and outnumbered disabling or fatal intracerebral haemorrhage (n=45 vs n=18), with an absolute risk of 9·15 (95% CI 6·67–12·24) per 1000 patient-years. The estimated NNT for routine PPI use to prevent one disabling or fatal upper gastrointestinal bleed over 5 years fell from 338 for individuals younger than 65 years, to 25 for individuals aged 85 years or older.InterpretationIn patients receiving aspirin-based antiplatelet treatment without routine PPI use, the long-term risk of major bleeding is higher and more sustained in older patients in practice than in the younger patients in previous trials, with a substantial risk of disabling or fatal upper gastrointestinal bleeding. Given that half of the major bleeds in patients aged 75 years or older were upper gastrointestinal, the estimated NNT for routine PPI use to prevent such bleeds is low, and co-prescription should be encouraged.FundingWellcome Trust, Wolfson Foundation, British Heart Foundation, Dunhill Medical Trust, National Institute of Health Research (NIHR), and the NIHR Oxford Biomedical Research Centre.

Antiplatelet Resumption after Antiplatelet-Related Intracerebral Hemorrhage: ARetrospective Hospital-Based Study.

Antiplatelet resumption in patients who developed intracerebral hemorrhage (ICH) while on antiplatelet therapy (antiplatelet-related ICH) represents an important medical dilemma. We aimed to study the long-term cardiovascular outcomes of antiplatelet-related ICH survivors, and the risk of recurrent ICH with antiplatelet resumption. This was an observational study of 109 antiplatelet-related ICH survivors. The clinical end points were recurrent ICH, ischemic vascular events, and vascular death (fatal ICH or ischemic vascular events). Predictors of recurrent ICH and vascular death were derived using a multivariable Cox regression model. The median duration of follow-up was 3.5 years (interquartile range, 1.6-5.8 years). Ischemic vascular events were more common than recurrent ICHs (6.8 per 100 patient-years vs. 2.6 per 100 patient-years; P= 0.028). Antiplatelet use was not associated with an elevated risk of recurrent ICH (hazard ratio [HR], 1.11,95% confidence interval [CI], 0.27-4.62). A mean follow-up systolic blood pressure of >140 mmHg increased the risk of both recurrent ICH (HR, 4.28; 95%CI,1.01-18.11) and vascular death (HR, 11.14; 95%CI, 2.72-45.62). Cerebral amyloid angiopathy (CAA) was an independent predictor for recurrent ICH (HR, 24.34; 95% CI, 2.80-211.47). Antiplatelet resumption after antiplatelet-related ICH did not appear to carry a clinically significant risk of recurrent ICH, whereas inadequate blood pressure control and CAA contributed to a more robust risk. Antiplatelet resumption should be considered, especially in survivors with adequate blood pressure control and without CAA.

Blood Occludin Level as a Potential Biomarker for Early Blood Brain Barrier Damage Following Ischemic Stroke

Concern about intracerebral hemorrhage (ICH) is the primary reason for withholding tPA therapy from patients with ischemic stroke. Early blood brain barrier (BBB) damage is the major risk factor for fatal post-thrombolysis ICH, but rapidly assessing BBB damage before tPA administration is highly challenging. We recently reported that ischemia induced rapid degradation of tight junction protein occludin in cerebromicrovessels. The present study investigates whether the cleaved occludin is released into the blood stream and how blood occludin levels correlate to the extent of BBB damage using a rat model of ischemic stroke. Cerebral ischemia induced a time-dependent increase of blood occludin with a sharp increase at 4.5-hour post-ischemia onset, which concurrently occurred with the loss of occludin from ischemic cerebral microvessels and a massive BBB leakage at 4.5-hour post-ischemia. Two major occludin fragments were identified in the blood during cerebral ischemia. Furthermore, blood occludin levels remained significantly higher than its basal level within the first 24 hours after ischemia onset. Our findings demonstrate that blood occludin levels correlate well with the extent of BBB damage and thus may serve as a clinically relevant biomarker for evaluating the risk of ICH before tPA administration.

Hyperacute fatal intracerebral hemorrhage following carotid stenting

We describe a case of fatal intracerebral hemorrhage (ICH) complicating carotid stenting. The manifestation is distinct from the well-known hyperperfusion syndrome. In our patient, neurologic deterioration appeared within 15 min of stenting, without any prodromal symptom. This early postprocedural complication is radiologically similar to hypertensive ICH and might have the same pathogenesis. Appropriate antihypertensive therapy might be beneficial in preventing this devastating complication.

Open-Label Phase I Clinical Study to Assess the Safety and Efficacy of Cilostazol in Patients Undergoing Internal Carotid Artery Stent Placement

Background: One-month dual antiplatelet treatment, with aspirin and clopidogrel, following internal carotid artery stent placement is the current standard of care to prevent in-stent thrombosis. Cilostazol, an antiplatelet drug, has been demonstrated to have a safety profile comparable to aspirin and clopidogrel. Objective: To evaluate the safety and clinical efficacy of cilostazol and aspirin therapy following internal carotid artery stent placement up to 1 month postprocedure. Methods: A phase I open-label, nonrandomized two-center prospective study was conducted. All subjects received aspirin (325 mg/day) and cilostazol (200 mg/day) 3 days before extracranial stent placement. Two antiplatelet agents were continued for 1 month postprocedure followed by aspirin daily monotherapy. The primary efficacy end point was the 30-day composite occurrence of death, cerebral infarction, transient ischemic attack, and in-stent thrombosis. The primary safety end point was bleeding. Results: Twelve subjects (mean age ± SD, 66 ± 12 years; 9 males) were enrolled and underwent internal carotid artery angioplasty and stent placement. None of the subjects who successfully followed the study protocol experienced any complications at the 1- and 3-month follow-ups. One patient had a protocol deviation due to concurrent use of enoxaparin (1 mg/kg twice daily) in addition to aspirin and cilostazol, resulting in a fatal symptomatic intracerebral hemorrhage following successful stent placement on postprocedure day 1. One patient discontinued cilostazol after the first dose secondary to dizziness. Conclusion: The use of cilostazol and aspirin for internal carotid artery stent placement appears to be safe, but protocol compliance needs to be emphasized.

Risk of intracerebral haemorrhage with alteplase after acute ischaemic stroke: a secondary analysis of an individual patient data meta-analysis

Randomised trials have shown that alteplase improves the odds of a good outcome when delivered within 4·5 h of acute ischaemic stroke. However, alteplase also increases the risk of intracerebral haemorrhage; we aimed to determine the proportional and absolute effects of alteplase on the risks of intracerebral haemorrhage, mortality, and functional impairment in different types of patients. We used individual patient data from the Stroke Thrombolysis Trialists' (STT) meta-analysis of randomised trials of alteplase versus placebo (or untreated control) in patients with acute ischaemic stroke. We prespecified assessment of three classifications of intracerebral haemorrhage: type 2 parenchymal haemorrhage within 7 days; Safe Implementation of Thrombolysis in Stroke Monitoring Study's (SITS-MOST) haemorrhage within 24-36 h (type 2 parenchymal haemorrhage with a deterioration of at least 4 points on National Institutes of Health Stroke Scale [NIHSS]); and fatal intracerebral haemorrhage within 7 days. We used logistic regression, stratified by trial, to model the log odds of intracerebral haemorrhage on allocation to alteplase, treatment delay, age, and stroke severity. We did exploratory analyses to assess mortality after intracerebral haemorrhage and examine the absolute risks of intracerebral haemorrhage in the context of functional outcome at 90-180 days. Data were available from 6756 participants in the nine trials of intravenous alteplase versus control. Alteplase increased the odds of type 2 parenchymal haemorrhage (occurring in 231 [6·8%] of 3391 patients allocated alteplase vs 44 [1·3%] of 3365 patients allocated control; odds ratio [OR] 5·55 [95% CI 4·01-7·70]; absolute excess 5·5% [4·6-6·4]); of SITS-MOST haemorrhage (124 [3·7%] of 3391 vs 19 [0·6%] of 3365; OR 6·67 [4·11-10·84]; absolute excess 3·1% [2·4-3·8]); and of fatal intracerebral haemorrhage (91 [2·7%] of 3391 vs 13 [0·4%] of 3365; OR 7·14 [3·98-12·79]; absolute excess 2·3% [1·7-2·9]). However defined, the proportional increase in intracerebral haemorrhage was similar irrespective of treatment delay, age, or baseline stroke severity, but the absolute excess risk of intracerebral haemorrhage increased with increasing stroke severity: for SITS-MOST intracerebral haemorrhage the absolute excess risk ranged from 1·5% (0·8-2·6%) for strokes with NIHSS 0-4 to 3·7% (2·1-6·3%) for NIHSS 22 or more (p=0·0101). For patients treated within 4·5 h, the absolute increase in the proportion (6·8% [4·0% to 9·5%]) achieving a modified Rankin Scale of 0 or 1 (excellent outcome) exceeded the absolute increase in risk of fatal intracerebral haemorrhage (2·2% [1·5% to 3·0%]) and the increased risk of any death within 90 days (0·9% [-1·4% to 3·2%]). Among patients given alteplase, the net outcome is predicted both by time to treatment (with faster time increasing the proportion achieving an excellent outcome) and stroke severity (with a more severe stroke increasing the absolute risk of intracerebral haemorrhage). Although, within 4·5 h of stroke, the probability of achieving an excellent outcome with alteplase treatment exceeds the risk of death, early treatment is especially important for patients with severe stroke. UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.

Sudden Death Due to Cerebral Leukemic Hemorrhage in a 32-Year-Old Woman Who Had a Short-Term Benzene Exposure History

Acute myeloid leukemia (AML), also known as acute myelogenous leukemia, is associated with severe hemorrhagic coagulopathy, which is induced by the drop in red blood cells, platelets, and normal leukocyte and the increase of leukemic cells. The case described in this report was of a 32-year-old woman who unexpectedly and suddenly died because of cerebral hemorrhage caused by undiagnosed AML while hospitalized. Further investigation found that the decedent had been exposed to benzene and its derivatives 6 months before her death. This case suggests that underlying AML should be considered as a possible diagnosis when sudden death occurs with a fatal spontaneous intracerebral hemorrhage, especially if the deceased had occupational chemical exposure to benzene and its derivatives.

Defective autophagy is a key feature of cerebral cavernous malformations.

Cerebral cavernous malformation (CCM) is a major cerebrovascular disease affecting approximately 0.3–0.5% of the population and is characterized by enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral hemorrhages. Cerebral cavernous malformation is a genetic disease that may arise sporadically or be inherited as an autosomal dominant condition with incomplete penetrance and variable expressivity. Causative loss-of-function mutations have been identified in three genes, KRIT1 (CCM1), CCM2 (MGC4607), and PDCD10 (CCM3), which occur in both sporadic and familial forms. Autophagy is a bulk degradation process that maintains intracellular homeostasis and that plays essential quality control functions within the cell. Indeed, several studies have identified the association between dysregulated autophagy and different human diseases. Here, we show that the ablation of the KRIT1 gene strongly suppresses autophagy, leading to the aberrant accumulation of the autophagy adaptor p62/SQSTM1, defective quality control systems, and increased intracellular stress. KRIT1 loss-of-function activates the mTOR-ULK1 pathway, which is a master regulator of autophagy, and treatment with mTOR inhibitors rescues some of the mole-cular and cellular phenotypes associated with CCM. Insufficient autophagy is also evident in CCM2-silenced human endothelial cells and in both cells and tissues from an endothelial-specific CCM3-knockout mouse model, as well as in human CCM lesions. Furthermore, defective autophagy is highly correlated to endothelial-to-mesenchymal transition, a crucial event that contributes to CCM progression. Taken together, our data point to a key role for defective autophagy in CCM disease pathogenesis, thus providing a novel framework for the development of new pharmacological strategies to prevent or reverse adverse clinical outcomes of CCM lesions.

Molecular and Genetic Analyses of Collagen Type IV Mutant Mouse Models of Spontaneous Intracerebral Hemorrhage Identify Mechanisms for Stroke Prevention.

Collagen type IV alpha1 (COL4A1) and alpha2 (COL4A2) form heterotrimers critical for vascular basement membrane stability and function. Patients with COL4A1 or COL4A2 mutations suffer from diverse cerebrovascular diseases, including cerebral microbleeds, porencephaly, and fatal intracerebral hemorrhage (ICH). However, the pathogenic mechanisms remain unknown, and there is a lack of effective treatment. Using Col4a1 and Col4a2 mutant mouse models, we investigated the genetic complexity and cellular mechanisms underlying the disease. We found that Col4a1 mutations cause abnormal vascular development, which triggers small-vessel disease, recurrent hemorrhagic strokes, and age-related macroangiopathy. We showed that allelic heterogeneity, genetic context, and environmental factors such as intense exercise or anticoagulant medication modulated disease severity and contributed to phenotypic heterogeneity. We found that intracellular accumulation of mutant collagen in vascular endothelial cells and pericytes was a key triggering factor of ICH. Finally, we showed that treatment of mutant mice with a US Food and Drug Administration-approved chemical chaperone resulted in a decreased collagen intracellular accumulation and a significant reduction in ICH severity. Our data are the first to show therapeutic prevention in vivo of ICH resulting from Col4a1 mutation and imply that a mechanism-based therapy promoting protein folding might also prevent ICH in patients with COL4A1 and COL4A2 mutations.

Declining rates of fatal and nonfatal intracerebral hemorrhage: epidemiological trends in Australia.

BackgroundA recent systematic review of epidemiological studies reported intracerebral hemorrhage (ICH) incidence and mortality as unchanged over time; however, comparisons between studies conducted in different health services obscure assessment of trends. We explored trends in ICH rates in a large, representative population in New South Wales, Australia's most populous state (≈7.3 million).Methods and ResultsAdult hospitalizations with a principal ICH diagnosis from 2001 to 2009 were linked to death registrations through to June 30, 2010. Trends for overall, fatal, and nonfatal ICH rates within 30 days and fatal rates for 30‐day survivors at 365 days were calculated. There were 11 332 ICH patient admissions meeting eligibility criteria, yielding a crude hospitalization rate of 25.2 per 100 000 (age‐standardized rate: 17.2). Age‐ and sex‐adjusted overall rates significantly declined by an average of 1.6% per year (P=0.03). Fatal ICH declined by an average of 2.6% per year (P=0.004). For 30‐day survivors, a nonsignificant decline of 2.3% per year in fatal ICH at 365 days was estimated (P=0.17). Male sex and birth in the Oceania region and Asia were associated with an increased ICH risk, although this depended on age. Approximately 12% of ICH admissions would be prevented if the socioeconomic circumstances of the population equated with those of the least disadvantaged.ConclusionsOverall and fatal ICH rates have fallen in this large Australian population. Improvements in cardiovascular prevention and acute care may explain declining rates. There was no evidence of an increase in devastated survivors because the longer term mortality of 30‐day survivors has not increased over time.

Propofol-related urine discoloration in a patient with fatal atypical intracerebral hemorrhage treated with hypothermia.

IntroductionMild therapeutic hypothermia is an increasingly recognised treatment option to reduce perihemorrhagic edema in severe intracerebral hemorrhage.Case descriptionWe report the case of a 77-year old woman with atypical intracerebral hemorrhage that was treated with mild hypothermia in addition to osmotic therapy. The patient’s urine subsequently showed a green discoloration. Urine discoloration was completely reversible upon discontinuation of propofol.Discussion and evaluationPropofol-related urine discoloration may have been provoked by hypothermia. Due to the benign nature of this side effect, propofol should be stopped and gastrointestinal function should be supported.ConclusionMore studies are needed to show a causal role of hypothermia and related decreased enzymatic function.

Hyperperfusion syndrome with a fatal intra-cerebral hemorrhage after carotid endarterectomy

IntroductionLe syndrome d’hyperperfusion cerebrale avec hemorragie intracrânienne, apres endarteriectomie ou stenting carotidien, est associe a une morbi-mortalite importante [1, 2]. La physiopathologie de ce syndrome reste obscure [3]. Parmi les hypotheses avancees, la perte d’autoregulation des capillaires cerebraux liee a l’ischemie chronique est le mecanisme le plus souvent retenu. Mais les modifications hemodynamiques survenant apres la revascularisation carotidienne [...]

Third International Stroke Trial 3

The third International Stroke Trial (IST-3) was a randomized controlled trial of thrombolysis with intravenous recombinant tissue plasminogen activator in patients with acute ischemic stroke within 6 h of onset. It sought to determine whether a wider variety of patients might benefit from treatment than were eligible under the prevailing European Union approval for the drug, especially among those aged over 80 years. The entry criteria were broad, and there was no upper age limit for inclusion; over half the 3035 patients were aged over 80 years. For the types of patient recruited in IST-3, despite the early hazards (chiefly of fatal intracerebral hemorrhage), thrombolysis within 6 h did not affect longer-term survival and improved functional outcome. Benefit was greatest among patients treated within 3 h, and benefit did not appear to be diminished among elderly patients or those with severe stroke. These results should, therefore, encourage clinicians to: consider thrombolytic treatment for a wider variety of patients (particularly those aged over 80 years); treat those with more severe strokes; reinforce their efforts to increase the proportion of ischemic strokes treated within 3 h; and, have greater confidence that mortality is not increased by treatment. http://links.lww.com/CONR/A23.