Lobar Hemorrhage Research Articles

Abstract 118: Burden of Blood Pressure-Related Alleles is Associated with Larger Hematoma Volume and Worse Outcome in Intracerebral Hemorrhage

Purpose: Intracerebral hemorrhage (ICH) is the acute manifestation of a progressive disease of the cerebral small vessels. The severity of this disease appears to influence not only risk of ICH, but also the size of the hematoma. As the burden of high blood pressure(BP)-associated alleles is associated with hypertension-related end-organ damage, we sought to determine if this burden influences ICH admission hematoma volume (AHV). Methods: Prospective study undertaken in 441 ICH patients of European ancestry (210 deep and 231 lobar intracranial hematomas). Forty-three single-nucleotide polymorphisms (SNPs) known to be associated with high BP were genotyped in Illumina610-Quad. Single-SNP association analyses with AHV were performed using linear regression. Subsequently, a genetic risk score was calculated as the sum of the products generated by multiplying, at each of the 43 loci, the number risk alleles times the reported effect of that allele on BP. The score was utilized as the independent variable of univariate and multivariate regression models for 2 outcomes: AHV and poor clinical outcome (modified Rankin Scale 3-6). Principal components analysis was utilized to account for population structure. Results: Individually assessed, no single SNP was associated with AHV. In univariate linear regression, the genetic risk score was associated with AHV in all (deep and lobar) and deep locations (Figure 1), but not in lobar hemorrhages. In multivariate regression analyses, each additional standard deviation of the genetic risk score increased mean deep AHV by 21% (or 2.7-milliliter increase, beta=0.21, standard error=0.08, p=0.01) and risk poor clinical outcome by 55% (odds ratio=1.55, 95% confidence interval 1.05-2.28, p=0.03). No significant associations were observed when considering all (deep and lobar) and lobar hemorrhages. Conclusion: In deep ICH, increasing numbers of high BP-related alleles are associated with larger AHV and poor clinical outcome.

Abstract TP309: Subarachnoid Extension of Hemorrhage Is Associated with Poor Outcomes in Primary Intracerebral Hemorrhage

Background: Extension of hemorrhage into the subarachnoid space is observed in primary intracerebral hemorrhage (ICH), yet the phenomenon has undergone limited study and is of unknown significance. The objective of this study is to evaluate the incidence, characteristics and clinical consequences of subarachnoid hemorrhage extension (SAHE) in ICH. Methods: Patients with primary ICH were enrolled into a prospective registry between December 2006 and July 2012. Patients were managed, and serial neuroimaging obtained, per a structured protocol. SAHE was identified on imaging, along with ICH volumes, by expert reviewers blinded to outcomes. Ordinal regression models were developed to test whether the occurrence of SAHE was a predictor of functional outcomes independent of ICH Score, with confirmation of model validity by appropriate tests. Results: 234 patients were studied, and 93 (39.7%) had SAHE. SAHE was associated with lobar hemorrhage location (65% of SAHE versus 19% of non-SAHE cases, p<0.001), and larger hematoma volumes (median 23.8 versus 6.65, p<0.001). SAHE was a predictor of higher modified Rankin Scale scores (mRS) at discharge (odds ratio 2.22 per mRS point [95% CI 1.29-3.81]) and 28 days (1.80 [1.04-3.11]) after adjustment for ICH Score. Conclusions: SAHE is associated with poor outcomes independent of traditional ICH severity measures. Further exploration of this phenomenon to understand the underlying mechanisms of harm is needed.

Coagulopathy Disproportionately Predisposes to Lobar Intracerebral Hemorrhage

Anticoagulation increases the risk of intracerebral hemorrhage (ICH), yet whether different underlying disease processes are equally affected is unknown. We tested the hypothesis that coagulopathy, measured by admission international normalized ratio (INR), disproportionately increases the risk for lobar hemorrhages. Patients with primary ICH were enrolled into a registry between December 2006 and February 2012 with prospective data acquisition and systematic follow up. Logistic regression was used to test whether lobar versus deep ICH location was independently associated with INR, and then whether INR had an influence on mortality. Spearman's correlation coefficient was used to test for an association between INR and hematoma volume separately in the lobar and deep ICH groups. 221 patients were studied. Patients with lobar ICH were older (71 vs. 62 years old, p < 0.001) and more likely to have prior ICH (10 vs. 0 %, p < 0.001). INR >1.4 was observed on admission more frequently in lobar versus deep ICH (19 vs. 8 %, p = 0.02). Lobar ICH location was independently associated with INR >1.4 (OR: 2.51, 95 % CI: 1.03-6.14, p = 0.043). ICH volume correlated with INR in lobar ICH (p = 0.009), but not deep ICH (p = 0.8). Death at 1 month was independently associated with INR >1.4 (OR: 7.6, 95 % CI: 2.4-24.1, p = 0.001) after correction for the ICH Score. Abnormal coagulation occurs disproportionally in lobar versus deep ICH, and is associated with larger ICH volumes and higher mortality. These findings suggest a unique risk interaction between coagulopathy and underlying brain pathology due to cerebral amyloid angiopathy.

Prevalence of Hypertension in Deep and Lobar Intracerebral Hemorrhage in a Group of Iraqi Patients

FIBMS Summary: Background: Non-traumatic Intracerebral Hemorrhage (ICH) results from rupture of blood vessels in the brain. ICH categories can also be considered as being either lobar in location or within the deep white matter. Although hypertension is a major risk factor for ICH in general[11], it is commonly considered to be associated more with patients having deep than with those having lobar haemorrhage. Objectives: We investigate the relationship between hypertension and deep versus lobar intracerebral hemorrhage (ICH). Methods: a retrospective review of records of 163 patients aged 18-89 years admitted to Al-Kadhimiya Teaching Hospital (January 2008 - October 2010) and diagnosed with ICH. Results: There was no significant relationship between hypertension in deep versus lobar intracerebral hemorrhage (p=0.814) Conclusions: Although the relation between hypertension and ICH was not found to be significant, our study suggests and recommends age-appropriate investigations for patients with ICH, as well as the need to promote patients’ education with regards to this disease and the importance of adherence to treatment of risk factors.

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Introduction: Extension of hemorrhage into the subarachnoid space in primary intracerebral hemorrhage (ICH) has recently been associated with poor outcomes, although the mechanisms underlying that association are uncertain. Hypothesis: We hypothesized that subarachnoid hemorrhage extension (SAHE) in ICH is associated with fevers. Methods: Patients with primary ICH were enrolled into a prospective registry between December 2006 and July 2012. Patients were managed, and serial neuroimaging obtained, per a structured protocol. SAHE was identified on imaging, along with ICH volumes, by expert reviewers blinded to outcomes. Patient temperature was recorded hourly, and we defined febrile as any recorded temperature > 38 C within the first 14 days from hemorrhage onset. A binary logistic regression models was developed to test whether the occurrence of SAHE was a predictor of fever, independent of ICH Score. Results: 234 patients were studied, and 93 (39.7%) had SAHE. SAHE was associated with lobar hemorrhage location (65% of SAHE versus 19% of non-SAHE cases, p<0.001), and larger hematoma volumes (median 23.8 versus 6.65, p<0.001). SAHE was a predictor of fevers (odds ratio 1.82 [95% CI 1.02-3.24], p=0.042) after adjustment for ICH Score. Conclusions: SAHE is independently associated with fevers in patients with primary ICH. Fever from dysfunctional thermoregulation is frequently observed in aneurysmal subarachnoid hemorrhage, where it is associated with poor outcomes. SAHE appears to provoke a similar phenomenon in patients with ICH, which likely contributes to the association between SAHE and poor functional outcomes.

Characteristic distributions of intracerebral hemorrhage–associated diffusion-weighted lesions

To determine whether small diffusion-weighted imaging (DWI) lesions occur beyond the acute posthemorrhage time window in patients with intracerebral hemorrhage (ICH) and to characterize their spatial distribution in patients with lobar and deep cerebral hemorrhages. In this cross-sectional study, we retrospectively analyzed 458 MRI scans obtained in the acute (≤ 7 days after ICH) or nonacute (>14 days after ICH) phases from 392 subjects with strictly lobar (n = 276) and deep (n = 116) ICH (48.7% women; mean age 72.8 ± 11.7 years). DWI, apparent diffusion coefficient maps, fluid-attenuated inversion recovery, and T2* MRIs were reviewed for the presence and location of DWI lesions. We identified 103 DWI hyperintense lesions on scans from 62 subjects, located mostly in lobar brain regions (90 of 103, 87.4%). The lesions were not uniformly distributed throughout the brain lobes; patients with strictly lobar ICH had relative overrepresentation of lesions in frontal lobe, and patients with deep ICH in parietal lobe (p = 0.002). Although the frequency of DWI lesions tended to be greater on scans performed within 7 days after ICH (39 of 214, 18.2%), they continued at high frequency in the nonacute period as well (23 of 178, 12.9%, odds ratio 1.5, 95% confidence interval 0.86-2.6 for acute vs nonacute). There was also no difference in frequency of lesions on acute and nonacute scans among 66 subjects with MRIs in both time periods (8 of 66 acute, 10 of 66 nonacute, odds ratio 0.77, 95% confidence interval 0.25-2.4). The high frequency of DWI lesions beyond the acute post-ICH period and their characteristic distributions suggest that they are products of the small vessel diseases that underlie ICH.

Risk factors for intracerebral hemorrhage differ according to hemorrhage location

Risk factors have been described for spontaneous intracerebral hemorrhage (ICH); their relative contribution to lobar vs nonlobar hemorrhage location is less clear. Our purpose here was to investigate risk factors by hemorrhage location. This case-control study prospectively enrolled subjects with first-ever spontaneous ICH and matched each with up to 3 controls by age, race, and gender. Conditional stepwise logistic regression modeling was used to determine significant independent risk factors for lobar and nonlobar ICH. From December 1997 through December 2006, 597 cases and 1,548 controls qualified for the analysis. Hypertension, warfarin use, first-degree relative with ICH, personal history of ischemic stroke, less than a high school education, and APOE ε2 or ε4 genotype were more common in ICH cases. Hypercholesterolemia and moderate alcohol consumption (≤ 2 drinks per day) were less common in ICH cases. The associations of hypertension and hypercholesterolemia were specific for nonlobar ICH. Conversely, the association of APOE ε2 or ε4 genotype was specific for lobar ICH. APOE ε2 or ε4 genotype was associated specifically with lobar ICH. Hypertension was associated specifically with nonlobar ICH. A protective association was seen between hypercholesterolemia and nonlobar ICH; no such association was identified for lobar ICH.

Teaching Neuro Images : Subacute intracerebral hemorrhage mimicking brain tumor

A 73-year-old man was referred to the outpatient clinic with a 2-week history of headache and apathy. Neurologic examination revealed mild left-sided facial, arm, and leg paresis. Head CT appeared to show a right frontal lobe tumor with finger-like vasogenic edema. Instead, MRI revealed a subacute lobar hemorrhage with perihematomal edema (figure). On follow-up imaging, no underlying cause was found.

Lobar intracerebral haemorrhage: Analysis of a series and characteristics of patients receiving antiplatelet or anticoagulation treatment

IntroductionLobar intracerebral haemorrhage (LICH) is a rare cause of stroke which accounts for about 20% of primary intracerebral haemorrhages. The most common causes are cerebral amyloid angiopathy (CAA), high blood pressure and others, such as using antiplatelet or anticoagulation agents.We analysed a series of patients with LICH and compared it with subgroups of patients with LICH who were previously receiving antiplatelet or anticoagulation agents. We determined the volume of the bleeding and its predictive value for mortality. Patients and methodsWe consecutively and retrospectively included 162 patients diagnosed with LICH and cared for in the Neurology Department of Hospital Meixoeiro in Vigo between 1991 and 2009. We collected demographic characteristics, risk factors, aetiologies and symptoms, and conducted a comparative analysis between the general series and the subgroups of patients receiving anticoagulation and antiplatelet agents. ResultsIn the general series, the most common cause was possible or probable CAA followed by hypertension. In the subgroup of patients receiving antiplatelet or anticoagulation agents there were no differences in the variables studied, except for the frequency of heart disease. Nonetheless, there were differences with respect to age, heart disease and bleeding volume between the general series (patients not treated with antiplatelet or anticoagulation agents) when compared with the subgroups of patients receiving antiplatelet and anticoagulation agents. ConclusionsWe provide new information regarding the clinical behaviour of LICH and its differences in patients receiving antiplatelet or anticoagulation agents. Mortality is higher in cases of LICH on anticoagulants. Female sex and the volume of bleeding are predictors of mortality.

Risk Factors and Long Term Outcome in Young Adults with Spontaneous Intracerebral Hemorrhage (P02.211)

Objective: This study was performed to compare the risk factors, location of hemorrhage and long term outcome in spontaneous intracerebral (ICH) hemorrhage in young and elderly. Background Intracerebral hemorrhage accounts for about 15% of Cerebrovascular accident, and is one of the common cause of mortality and long term morbidity. Design/Methods: A total of 108 subjects of intracerebral hemorrhage from the stroke were analysed. The patients were divided into young ( 45yr). The associated risk factors, locations of hemorrhage and long-term were determined. Twenty six young adults of ICH Patients were followed up from 1 year and to 7 year and long term morbidity was estimated according to mRS in both the groups. Results: Hypertension was most common risk factor 88 (81.4%), DM in 23 (21.2%). 19 patients (17.6%) had both hypertension and DM. 32(29.6%) were smokers. Basal ganglia was the commonest site of hemorrhage in 53 cases (49%), Thalamus 29 (26.85%), lobar hemorrhage 12(11.11%), Brain stem 9 (8.3%), cerebellar 5 (4.6%) case. CT scan was the most common initial imaging. Young ICH accounted for 26 cases (24.07%). Among risk factors in the young vs elderly group, Hypertension was present in 19 (73%) vs 69 (84%), DM 9 (34.6%) vs 14 (20.3). Smoking in 5 (19.2%) vs 27(32.9%).Basal ganglia was the commonest site of hemorrhage in both groups 15 (57.7%) vs 38 (46.3%), followed by thalamus 6 (23%) vs 23 (28%), brainstem 3 (11.5%) vs 6 (7.3%).The average mRS at 1 year was comparable in both groups 1.16 (n-8) vs 1.12 (n-17), but subsequent scoring at 2 yr was 0.25 (n-4) vs 1.08 (n-12), at 3 yr 0.33(n-3) vs 0.83 (n-12). Conclusions: Hypertension was the single most common cause for Spontaneous ICH. Aggressive screening and timely management will be helpful to prevent ICH and disability in young adults. Disclosure: Dr. Mehndiratta has nothing to disclose. Dr. Chakravarty has nothing to disclose. Dr. Mehndiratta has nothing to disclose.

Intracerebral Hemorrhage: Clinical Overview and Pathophysiologic Concepts

Intracerebral hemorrhage is by far the most destructive form of stroke. Apart from the management in a specialized stroke or neurological intensive care unit (NICU), no specific therapies have been shown to consistently improve outcomes after ICH. Current guidelines endorse early aggressive optimization of physiologic derangements with ventilatory support when indicated, blood pressure control, reversal of any preexisting coagulopathy, intracranial pressure monitoring for certain cases, osmotherapy, temperature modulation, seizure prophylaxis, treatment of hyerglycemia, and nutritional support in the stroke unit or NICU. Ventriculostomy is the cornerstone of therapy for control of intracranial pressure patients with intraventricular hemorrhage. Surgical hematoma evacuation does not improve outcome for more patients, but is a reasonable option for patients with early worsening due to mass effect due to large cerebellar or lobar hemorrhages. Promising experimental treatments currently include ultra-early hemostatic therapy, intraventricular clot lysis with thrombolytics, pioglitazone, temperature modulation, and deferoxamine to reduce iron-mediated perihematomal inflammation and tissue injury.

Abstract 3778: Trends in the Incidence, Types and Outcomes of Intracerebral Hemorrhage in Ontario from 1990 - 2010

Background: Intracerebral hemorrhage (ICH) accounts for approximately 15% of all acute strokes and is associated with the highest stroke mortality. The purpose of this study was to examine the incidence of ICH in Ontario over the last 20 years and investigate whether there have been changes in patient characteristics and treatment interventions over time. Methods: We analyzed data from a provincial administrative database to determine the rates of ICH in Ontario from 1990 to 2010. Data from the Registry of the Canadian Stroke Network (RCSN) from 2003 to 2008 were then used to investigate potential changes in demographic variables (age, gender), stroke severity (Canadian Neurological Scale), comorbidities (hypertension, atrial fibrillation), preadmission medications (warfarin, antihypertensives), hemorrhage location (lobar vs. deep), initial glucose, initial INR and outcomes (modified Rankin Scale at discharge, hospital length of stay) in ICH patients over time. Results: There were 30,353 patients in the administrative database who were admitted with a final diagnosis of ICH between 1990 and 2010. The mean age of these patients was 70.3 years, 51.5% were male and the 30-day mortality rate was 40.6%. The age of patients with ICH increased over this time period (especially in the group &gt;85 years of age), the length of hospital stay shortened and the 30-day mortality rate decreased slightly. Figure 1 shows the sex/age standardized ICH rate per 100,000 by fiscal year, which shows a decline in the ICH rate since 1997. From the 2,466 patients with ICH in the RCSN database from 2003 to 2008, the statistically significant changes included an increase in the lobar hemorrhage rate (39.2% to 46.9%, p=0.0000), an increase in the use of statins at admission (19% to 24%, p=0.0350) and a decrease in the mean systolic blood pressure (173.8±37.5 to 166.4±35.07, p=0.0040). There were no changes over time in neurosurgical interventions (craniotomy or intracranial pressure monitoring). Conclusions: In Ontario, based on hospitalizations, the rate of ICH increased until 1997 and since then has steadily decreased. This decline in the ICH rate over the past 12 years may reflect better management of hypertension.

Fulminant Postpartum Cerebral Vasoconstriction Syndrome

To raise awareness of the potentially adverse consequences of postpartum cerebral vasoconstriction, which is typically considered benign and self-limiting, by describing 4 fulminantly fatal cases. Retrospective case series. Tertiary referral center. Four postpartum women aged 15 to 33 years developed acute neurologic deficits 1 to 8 days after uncomplicated deliveries. One had a history of migraine headaches and 2 had histories of spontaneous abortion. Two of the patients had uneventful pregnancies and 2 had preeclampsia, 1 of whom had acute hepatic failure. Presenting symptoms included severe headache (n=3), focal deficit (n=1), seizure (n=1), and encephalopathy (n=1). Initial brain imaging results demonstrated cortical ischemia and global edema in 2 patients, lobar hemorrhage in 1, and normal findings in 1. All had rapid clinical deterioration from hours to days with multiterritorial infarctions and global brain edema on imaging. All had angiographic findings of diffuse, severe, segmental multifocal arterial narrowings. Aggressive treatment was attempted with most patients including intravenous magnesium sulfate, corticosteroids, calcium channel blockers, balloon angioplasty, vasopressors, and osmotic agents. Two patients underwent serial angiography, with results showing severe, recurrent proximal vasoconstriction involving all major intracranial vessels. All patients had fulminant, accelerating courses leading to their deaths within 8 to 24 days after delivery. Postpartum vasoconstriction can be fatal, with rapid progression of vasoconstriction, ischemia, and brain edema. Clinicians need to be aware of the potential consequences of this condition. Postpartum women with acute neurologic symptoms require prompt investigation with noninvasive cerebrovascular imaging and close monitoring for possible secondary deterioration.

Intracerebral Hemorrhage in the Oldest Old: A Population-Based Study (Vantaa 85+)

Aims: Very elderly subjects represent the fastest growing population in the world. Most of the recent studies on intracerebral hemorrhage (ICH) have been carried out on younger patients and/or preferably using novel radiological techniques. We investigated the prevalence, risk factors, and histopathological characteristics of the ICH in the oldest old. Materials and methods: The brains of 300 autopsied individuals (248 females, 52 males, mean age at death 92.4 ± 3.7 years) were investigated as part of the prospective population-based Vantaa 85+ study. After macroscopic investigation, the presence and extent of microscopic brain hemorrhages (MH) were analyzed by counting the number of iron containing macrophages (siderophages) by Prussian blue staining. Deposits with >5 siderophages were defined as MH+, forming a subgroup of MH. Genotyping of apolipoprotein E (APOE) and the analysis of microscopic (MI) or larger infarctions and cerebral amyloid angiopathy (CAA) were performed using standardized methods. Regression analysis was used to predict the presence of ICH, with and without co-localized CAA, and was adjusted for age at death and gender. Results: The prevalence of macroscopic ICH was 2.3% in total; consisting of 1% large lobar hemorrhage (LH), 1% deep hemorrhage (DH), and 0.3% of subarachnoid hemorrhage (SAH). 62% had MH and 15.3% MH+. All MH+ lesions were found to be >2 mm wide. 55.9% of subjects with MH and 81.2% of those with MH+ showed MH/MH+ and CAA in the same brain region (MHCAA and MH+CAA, respectively). MH was associated with none of the neuropathological or clinical conditions, nor with the APOE carrier status. The subjects with MH+, MHCAA or MH+CAA carried the APOE ε4 allele more frequently than controls (OR 3.681, 3.291, 7.522, respectively). Siderophages in MH+CAA co-localized with CAA and with two-thirds of the MI in the tissue sections. Conclusion: Macroscopic ICH was rare in the very elderly. MH was frequent and clinically insignificant. MH+ was rare but closely related with the APOE ε4 genotype and the presence of severe CAA and infarction.

Update on Amyloid-associated Intracerebral Haemorrhage

Cerebral congophilic or amyloid angiopathy (CAA) is a clinicopathological entity that is considered a common cause of primary non-traumatic brain haemorrhage in the elderly. CAA is frequently associated with Alzheimer’s disease (AD) and has become a primary focus of scientific inquiry. The spectrum of intracerebral haemorrhage (ICH) that may occur in CAA includes: cerebral lobar haemorrhages, deep haemorrhages, purely subarachnoid and subdural haemorrhages and cerebral microbleeds. CAA is also associated with microinfarcts, leukoencephalopathy and superficial siderosis. This brief article will provide an update on the advances in our understanding of CAA-associated ICH with a focus on the following topics: neuropathology and mechanism of CAA-related haemorrhage; epidemiology, including genetic and other possible risk factors; clinical presentation; diagnosis, including newer imaging modalities; and prospects for prevention and treatment.

Update on Amyloid-associated Intracerebral Hemorrhage

Cerebral congophilic or amyloid angiopathy (CAA) is a clinicopathological entity that is considered a common cause of primary non-traumatic brain hemorrhage in the elderly. CAA is frequently associated with Alzheimer’s disease (AD) and has become a primary focus of scientific inquiry. The spectrum of intracerebral hemorrhage (ICH) that may occur in CAA includes: cerebral lobar hemorrhages, deep hemorrhages, purely subarachnoid and subdural hemorrhages and cerebral microbleeds. CAA is also associated with microinfarcts, leukoencephalopathy and superficial siderosis. This brief article will provide an update on the advances in our understanding of CAA-associated ICH with a focus on the following topics: neuropathology and mechanism of CAA-related hemorrhage; epidemiology, including genetic and other possible risk factors; clinical presentation; diagnosis, including newer imaging modalities; and prospects for prevention and treatment.

Apolipoprotein A‐1 Deficiency in Older Adults with Spontaneous Cerebral Lobar Hemorrhage

An 80-year-old woman was admitted to the Stroke Unit at Sant'Andrea Hospital (La Spezia, Italy) for spontaneous right cerebellar hemorrhage (Figure 1A); she complained of cognitive impairment and had a cerebellar hemorrhage 1 year before. Angio-computed tomography (CT) of the intracranial vessels did not show any vascular malformations. Her apolipoprotein A-1 (apoA-1) plasma level was 92 mg/dL (normal range 105–205 mg/dL) and her high-density lipoprotein cholesterol (HDL-C) was 29 mg/dL. An 82-year-old woman with diabetes mellitus and hypertension, treated with metformin and ramipril, presented a spontaneous hemorrhage in the right temporal and occipital lobes (Figure 1B). She was admitted to the Neurosurgery Unit, where she underwent digital subtraction angiography of intracranial vessels, which was normal. Her apoA-1 plasma concentration was 91 mg/dL, and her HDL-C was 70 mg/dL. An 86-year-old woman with hypertension and severe cognitive deficits, receiving treatment with furosemide, was admitted to the emergency department for a sudden-onset left hemiparesis; CT scan showed intraparenchymal right frontal hemorrhage (Figure 1C). Angio-CT of the intracranial vessels was normal. Her apoA-I plasma level was 79 mg/dL, and her HDL-C was 29 mg/dL. ApoA-1 is a 28-KDa protein synthesized by the liver and small intestine. It plays a critical role in the formation, metabolism, and catabolism of HDL-C, a plasma lipoprotein whose levels are highly linked to protection against the development of cardiovascular disease.1 As expected, gene deletion of apoA-1 results in extremely low levels of HDL-C in mice, which are significantly more likely to develop atherosclerosis. Hepatic overexpression of apoA-1 significantly raises HDL-C levels and inhibits the progression of and even regresses atherosclerosis in mice. Thus, upregulation of endogenous apoA-I expression is widely considered to be one of the most promising approaches in HDL-C-related therapies.2 Mutated apoA-1 causes rare forms of late-onset familial amyloidosis that are inherited in an autosomal-dominant manner and are characterized by asymptomatic cholestatic hepatopathy and nephropathy, the latter presenting with slowly progressive renal failure without proteinuria due to selective tubular involvement. In a subset of individuals, a progressive cardiomyopathy leading to heart failure may be observed. Skin, peripheral nerves, and the larynx are also frequently involved.3 None of the women described above had clinical or laboratory signs of systemic amyloidosis. The accumulation of amyloid in the walls of small and medium-sized cerebral arteries causes cerebral amyloid angiopathy (CAA). In most cases, the accumulated amyloid is composed of the amyloid-beta peptide, the same found in the plaques of individuals with Alzheimer's disease (AD). Amyloid deposition in cerebral blood vessels can have several clinical consequences. First, it can remain asymptomatic, as suggested by the neuropathological observation that, during normal aging, approximately 50% of individuals aged 80 and older have CAA. Second, it can weaken the vessel wall, causing vessel rupture and intracerebral hemorrhage. Finally, it can obliterate the vessel lumen, leading to ischemia.4 CAA-related hemorrhage is a major cause of spontaneous cerebral lobar hemorrhages in older adults with normal or high blood pressure.5 A recent study demonstrated that apoA-1 significantly decreased amyloid-beta toxicity against brain vascular smooth cells in transgenic mice. It concluded that lack of apoA-1 aggravates memory deficits along with significantly greater CAA.6 In another study, an oral apoA-1 mimetic peptide was administered in a mouse model of AD and showed improvement of cognitive function and reduction of amyloid burden.7 We hypothesized that low plasma concentrations of apoA-1 would favor amyloid angiopathy and the consequent lobar hemorrhages in older adults. We report three patients with spontaneous and lobar hemorrhages low plasma levels of apoA-1. This sample is too small to draw any conclusion, but if this finding is confirmed in a larger sample, plasma levels of apoA-1 could become a useful diagnostic test in older adults with amyloid angiopathy at risk of hemorrhagic strokes. In addition, oral administration of apoA-1 mimetic peptides could be studied not only in the treatment of atherosclerotic vascular diseases, but also in preventing amyloid deposition in cerebral blood vessels. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Massimiliano Godani: Study concept and design. Cesare Capellini: Acquisition, analysis and interpretation of CT data. Massimo Del Sette: Supervision of the manuscript. Sponsor's Role: None.

Amyloid-β Contributes to Blood–Brain Barrier Leakage in Transgenic Human Amyloid Precursor Protein Mice and in Humans With Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is a degenerative disorder characterized by amyloid-β (Aβ) deposition in the blood-brain barrier (BBB). CAA contributes to injuries of the neurovasculature including lobar hemorrhages, cortical microbleeds, ischemia, and superficial hemosiderosis. We postulate that CAA pathology is partially due to Aβ compromising the BBB. We characterized 19 patients with acute stroke with "probable CAA" for neurovascular pathology based on MRI and clinical findings. Also, we studied the effect of Aβ on the expression of tight junction proteins and matrix metalloproteases (MMPs) in isolated rat brain microvessels. Two of 19 patients with CAA had asymptomatic BBB leakage and posterior reversible encephalopathic syndrome indicating increased BBB permeability. In addition to white matter changes, diffusion abnormality suggesting lacunar ischemia was found in 4 of 19 patients with CAA; superficial hemosiderosis was observed in 7 of 9 patients. Aβ(40) decreased expression of the tight junction proteins claudin-1 and claudin-5 and increased expression of MMP-2 and MMP-9. Analysis of brain microvessels from transgenic mice overexpressing human amyloid precursor protein revealed the same expression pattern for tight junction and MMP proteins. Consistent with reduced tight junction and increased MMP expression and activity, permeability was increased in brain microvessels from human amyloid precursor protein mice compared with microvessels from wild-type controls. Our findings indicate that Aβ contributes to changes in brain microvessel tight junction and MMP expression, which compromises BBB integrity. We conclude that Aβ causes BBB leakage and that assessing BBB permeability could potentially help characterize CAA progression and be a surrogate marker for treatment response.

Factors associated with lobar vs. non-lobar intracerebral hemorrhage

The relationship between body mass index (BMI) and stroke subtypes has received more research attention than that between BMI and location of intracerebral hemorrhage (ICH). Lobar hemorrhage (LH) differs from non-LH primarily in terms of etiology, i.e. cerebral amyloid angiopathy is the main cause of LH. This study aimed to determine the relationship between BMI and ICH. In this retrospective study involving 460 consecutive patients with ICH, BMI was significantly lower in LH than for other ICH locations. BMI categories were underweight (BMI < 18.5 kg/m(2)), normal weight (18.5-23.0 kg/m(2)), overweight (23.0-27.5 kg/m(2)), or obesity (≥27.5 kg/m(2)). Outcome at 1 year was evaluated by the modified Rankin Scale (mRS). We investigated the relationship of BMI and other clinical characteristics with LH and non-LH. LH was associated with age (>70 years), underweight, unfavorable outcome (mRS ≥3), and daily alcohol consumption. Hypertension and intraventricular bleeding were significantly less common in patients with LH than those with non-LH. Alongside risk factors conventionally thought to be related to LH, underweight may also be a LH-related factor, specifically in the elderly.

Recurrent Stroke after Lobar and Deep Intracerebral Hemorrhage: A Hospital-Based Cohort Study

Background: Recurrent stroke rates after intracerebral hemorrhage (ICH) vary widely between observational studies due to differences in ICH etiology and risk for thromboembolic events. We therefore aimed to assess the patient characteristics and prognosis after deep and lobar ICH in a well-characterized, multicenter, hospital-based cohort. Methods: Patients were prospectively documented in 13 German neurological stroke centers. Of 744 patients with spontaneous ICH discharged alive, 516 (69.4%) gave informed consent and 496 (66.7%) could be followed up by central telephone interview over a mean duration of 2 years. Results: In patients with deep ICH, the Kaplan-Meier estimate for stroke during the first year was 5.8% (95% CI 2.9–8.7) and the overall annual rate (calculated over a 3-year period) was 2.9% (95% CI 1.6–4.1). In patients with lobar ICH, the Kaplan-Meier estimate for stroke during the first year was 7.8% (95% CI 3.1–12.5) and the overall annual rate was 7.2% (95% CI 3.8–10.6). At the last follow-up before recurrent stroke or end of study, 141 patients (28.4%) overall received antiplatelet agents, and 12 (2.4%) received oral anticoagulation. No difference could be found for recurrent ICH under antiplatelet agents versus no antithrombotic medication. Conclusion: The risk of recurrent stroke after lobar ICH remains high beyond the first year, whereas it decreases after 1 year in patients with deep ICH. Antiplatelets are prescribed in a considerable number of patients even though the risk-benefit ratio after ICH remains unknown.