Pathogenesis Of Intracerebral Hemorrhage Research Articles

Role of cerebral amyloid angiopathy in intracerebral hemorrhage in hypertensive patients

To assess the interaction of cerebral amyloid angiopathy (CAA) and arterial hypertension as cofactors for intracerebral hemorrhage (ICH). The authors investigated 129 postmortem brains of hypertensive patients with and without ICH. Sixty-four patients had had deep (n = 40) or lobar (n = 24) ICH. Sixty-five patients without ICH served as controls. Established risk factors for ICH (age, gender, severity of hypertension, bleeding disorders, intake of anticoagulants, and chronic alcoholism) were identified from medical records. Four specimens per brain were stained with hematoxylin-eosin and Congo red. The entire ICH cohort and subgroups were compared with controls using single-factor and multiple logistic regression analyses. CAA was found in 15 of 64 subjects (23%) with ICH and in five of 65 controls (8%; p = 0.026). In single-factor analysis, CAA was more prevalent in lobar ICH compared with controls (p = 0.007) but not in deep ICH. Poor control of hypertension was more prevalent in the entire ICH group (p = 0.01) and in deep ICH (p = 0.016) but not in lobar ICH. ICH was predictive of the presence of CAA (odds ratio: 5.6, 95% CI: 1.8 to 19.5, p = 0.003), and CAA was more likely to be found in lobar ICH in multivariable-adjusted analysis. After adjustment for conventional risk factors, there was a weak association between CAA and deep ICH. Cerebral amyloid angiopathy plays a major role in the pathogenesis of intracerebral hemorrhage even in patients with more evident risk factors.

New Horizons for Primary Intracerebral Hemorrhage Treatment: Experience From Preclinical Studies

Intracerebral hemorrhage (ICH) remains a major medical problem, for which there is no effective treatment. However, extensive experimental and clinical research carried out in recent years has brought to light new exciting ideas for novel potential treatments. First, it was well documented that the management of hypertension helps to prevent new and recurrent ICH. Also, development of new guidelines for management of hypertension after the onset of the ICH may help in more effective ICH treatment. Existing contemporary data collected from preclinical studies indicates that ICH–induced inflammation represents a key factor leading to secondary brain damage, suggesting that some anti–inflammatory approaches can be used to treat hemorrhagic stroke. In this article, beyond discussing implications related to hypertension, we will summarize important (but not all) new discoveries connecting the role of inflammation to ICH pathology. Selected aspects of inflammatory response including the role of cytokines, transcription factor nuclear factor–kB, microglia activation, astrogliosis, and complement activation will be introduced. We will also discuss the role for reactive oxygen species and metalloproteinases in ICH pathogenesis and introduce basic knowledge on the nature of ICH–induced cell death including apoptosis. Potential targets for intervention and translation will be discussed.

Complications of oral anticoagulant therapy: bleeding and nonbleeding, rates and risk factors.

Oral anticoagulant therapy is very effective in preventing thromboembolism. Its major complication is hemorrhage. The rate of intracranial bleeding from randomized trials and observational studies ranges from 0.1 to 0.9% per year and largely depends on the International Normalized Ratio (INR) target range. Risk factors for this often-fatal complication include INR intensity, older age, cerebrovascular disease, and hypertension. Recent insights into the pathogenesis of intracerebral hemorrhage have focused on underlying arterial vasculopathies that predispose to bleeding, particularly in the elderly. The rate of major extracranial hemorrhage on oral anticoagulant therapy ranges from 0.4 to 2% per year. Different definitions of major hemorrhage, INR target ranges, age distribution, burden of comorbid illness, and type of coumarin challenge comparability of studies. Additional risk factors for major hemorrhage include history of gastrointestinal bleeding, concurrent use of antiplatelet or nonsteroidal anti-inflammatory drugs, genetic differences in warfarin metabolism, INR variability, type of coumarin, comorbid illnesses, and duration of oral anticoagulant therapy.

Apolipoprotein E Transgenic Mouse Model of Cerebral Amyloid Angiopathy

76 Background: Cerebral amyloid angiopathy (CAA) is the second most common etiology for non-traumatic intracerebral hemorrhage (ICH). There is a significantly increased frequency of the apolipoprotein E (apoE) ε4 and ε2 alleles in patients with CAA and CAA-related ICH. This suggests a role for apoE in the pathogenesis of CAA and ICH. We have developed a unique transgenic mouse model using the human apoE gene to study the molecular mechanisms underlying CAA. Methods: The transgenic mouse model was created by gene targeting, which results in the expression of each human apoE isoform at physiologic levels in a correct spatial and temporal pattern. These mice do not contain any mutations in the amyloid precursor protein or cystatin C gene. Mice of all apoE genotypes were bred, and were matched for age and sex. Brains from aged mice were analyzed for gross ICH. Brain sections were stained with anti-mouse A-beta antibody (4G8) to detect vascular amyloid. Sections were also stained for blood using hematoxylin and eosin (H&E), and a Prussian Blue stain was used to detect iron and hemosiderin deposition. A thioflavin-S stain was used to determine if the vascular amyloid was fibrillar. Results: Brains from sacrificed aged (mean age=80 weeks) apoE transgenic mice showed positive staining for CAA in predominantly neocortical vessels. The apoE ε2/ε2 mice had the highest occurrence of CAA (70%, 7 of 10), followed by the ε4/ε4 mice (40%, 4 of 10). Only 10% (1 of 10) of the ε3/ε3 mice had CAA. Two aged mice homozygous for apoE ε4 had gross ICH at post-mortem inspection. Brain sections from these mice demonstrated red blood cell infiltration and iron/hemosiderin deposition in the brain parenchyma when examined by light microscopy. Conclusions: This human apoE transgenic mouse model provides a genetically well defined and environmentally controlled animal model for the study of CAA that closely resembles the condition found in humans. This model may be useful for the study of therapies for the prevention and treatment of CAA.

Apolipoprotein E Transgenic Mouse Model of Cerebral Amyloid Angiopathy

76 Background: Cerebral amyloid angiopathy (CAA) is the second most common etiology for non-traumatic intracerebral hemorrhage (ICH). There is a significantly increased frequency of the apolipoprotein E (apoE) e4 and e2 alleles in patients with CAA and CAA-related ICH. This suggests a role for apoE in the pathogenesis of CAA and ICH. We have developed a unique transgenic mouse model using the human apoE gene to study the molecular mechanisms underlying CAA. Methods: The transgenic mouse model was created by gene targeting, which results in the expression of each human apoE isoform at physiologic levels in a correct spatial and temporal pattern. These mice do not contain any mutations in the amyloid precursor protein or cystatin C gene. Mice of all apoE genotypes were bred, and were matched for age and sex. Brains from aged mice were analyzed for gross ICH. Brain sections were stained with anti-mouse A-beta antibody (4G8) to detect vascular amyloid. Sections were also stained for blood using hematoxylin and eosin (H&E), and a Prussian Blue stain was used to detect iron and hemosiderin deposition. A thioflavin-S stain was used to determine if the vascular amyloid was fibrillar. Results: Brains from sacrificed aged (mean age=80 weeks) apoE transgenic mice showed positive staining for CAA in predominantly neocortical vessels. The apoE e2/e2 mice had the highest occurrence of CAA (70%, 7 of 10), followed by the e4/e4 mice (40%, 4 of 10). Only 10% (1 of 10) of the e3/e3 mice had CAA. Two aged mice homozygous for apoE e4 had gross ICH at post-mortem inspection. Brain sections from these mice demonstrated red blood cell infiltration and iron/hemosiderin deposition in the brain parenchyma when examined by light microscopy. Conclusions: This human apoE transgenic mouse model provides a genetically well defined and environmentally controlled animal model for the study of CAA that closely resembles the condition found in humans. This model may be useful for the study of therapies for the prevention and treatment of CAA.

Clinical features and pathogenesis of intracerebral hemorrhage after rt-PA and heparin therapy for acute myocardial infarction

Parenchymatous intracerebral hemorrhage (ICH) is a serious, infrequent complication of thrombolytic therapy for acute myocardial infarction. We studied the clinical and radiologic features, manner of presentation, associated factors, and temporal course in 23 patients with ICH associated with 150 mg or 100 mg recombinant tissue-type plasminogen activator (rt-PA) and heparin therapy for acute myocardial infarction in the Thrombolysis in Myocardial Infarction (TIMI) II Pilot and Randomized Clinical Trial. In TIMI II, 13 of the 23 ICH patients developed or maintained systolic blood pressure > or = 160 mm Hg or diastolic blood pressure > or = 90 mm Hg during the rt-PA infusion and before the onset of neurologic symptoms. Six patients (26%) had life-threatening ventricular arrhythmias, five before onset of neurologic symptoms. A decreased level of consciousness was the earliest neurologic abnormality in 15 (65%) and the most common initial physical finding (in 19, or 82%). Onset was usually gradual (70%), but time to maximal deficit was frequently (61%) within 6 hours of onset. The locations of the primary ICH sites were lobar in 16 (70%), thalamic in four (17%), and brainstem-cerebellum in three (13%), but the putamen was never the primary site. Multiple lobar hemorrhages occurred in six cases (26%). The timing and size of ICH was similar among patients treated with 150 mg rt-PA and 100 mg rt-PA. Brain CT demonstrated an arteriovenous malformation in one case. Four patients had hypofibrinogenemia, which was profound in three patients. Pathologic findings were available for five patients. Of these, three patients had cerebral amyloid angiopathy, and one had hemorrhagic transformation of an ischemic cerebral infarction found at autopsy. We conclude that ICH following rt-PA and heparin therapy for acute myocardial infarction presents as a distinctive clinical syndrome. Intracerebral bleeding after combined thrombolytic and antithrombotic therapy may be associated with cerebral amyloid angiopathy and other vascular lesions. Acute or persistent hypertension before or during rt-PA infusion, life-threatening ventricular arrhythmias, and hypofibrinogenemia, either alone or in combination, may play roles in some cases. Care should be exercised when considering thrombolytic therapy for patients with risk factors for ICH.

Neuropeptide Y- and Vasoactive Intestinal Polypeptide-Containing Nerve Fibers in the Human Cerebral Arteries: Characteristics of Distribution

Perivascular innervation in cerebral arteries from 28 human fetuses at twelve to twenty-eight weeks' gestational age was studied histochemically. Neuropeptide Y (NPY)- and vasoactive intestinal polypeptide (VIP)- containing nerve fibers were densely distributed along with adrenergic and cholinergic nerve fibers in the major pial arteries at the base of the brain, an area that forms the circle of Willis, and in the lenticulostriate arteries. In contrast, distribution was sparse in the cortical circumflex branches of the middle cerebral artery, as compared with findings in the lenticulostriate artery of the same diameter. Densely distributed perivascular nerve fibers in the lenticulostriate arteries may play an important role in the pathogenesis of intracerebral hemorrhage.

The Central Nervous System in Leukemia

Article1 November 1964The Central Nervous System in LeukemiaJOHN P. PHAIR, M.D., ROBERT E. ANDERSON, M.D., HIDEO NAMIKI, M.D.JOHN P. PHAIR, M.D.Search for more papers by this author, ROBERT E. ANDERSON, M.D.Search for more papers by this author, HIDEO NAMIKI, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-61-5-863 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptThis report describes the central nervous system lesions in 165 cases of leukemia autopsied at the Atomic Bomb Casualty Commission (ABCC). Primary emphasis is placed upon the pathogenesis of intracerebral hemorrhage (1-7). The present study strongly implicates a grossly elevated leukocyte count (> 50,000/mm3) in the genesis of such lesions. Thrombocytopenia, while of some significance, appears to be of secondary importance. Additional correlations are made between central nervous system pathology and age, type of leukemia, and antileukemic therapy.Two unique features characterize the group of persons studied. Some were exposed to varying amounts of ionizing radiation at the time of...