Intracerebral hemorrhage (ICH) is one of the most lethal stroke subtypes. Despite the high morbidity and mortality associated with ICH, its pathophysiology has not been investigated as well as that of ischemic stroke. Available evidence from preclinical and clinical studies suggests that inflammatory mechanisms are involved in the progression of ICH-induced secondary brain injury. For example, in preclinical ICH models, microglial activation has been shown to occur within 1h, much earlier than neutrophil infiltration. Recent advances in our understanding of neuroinflammatory pathways have revealed several new molecular targets, and related therapeutic strategies have been tested in preclinical ICH models. This review summarizes recent progress made in preclinical models of ICH, surveys preclinical and clinical studies of inflammatory cells (leukocytes, macrophages, microglia, and astrocytes) and inflammatory mediators (matrix metalloproteinases, nuclear factor erythroid 2-related factor 2, heme oxygenase, and iron), and highlights the emerging areas of therapeutic promise.

Intracerebral haemorrhage accounts for about 10-15% of all strokes and is associated with high mortality and morbidity. No successful phase 3 clinical trials for this disorder have been completed. In the past 6 years, the number of preclinical and clinical studies focused on intracerebral haemorrhage has risen. Important advances have been made in animal models of this disorder and in our understanding of mechanisms underlying brain injury after haemorrhage. Several therapeutic targets have subsequently been identified that are now being pursued in clinical trials. Many clinical trials have been based on limited preclinical data, and guidelines to justify taking preclinical results to the clinic are needed.

Intracerebral hemorrhage (ICH) is a cerebrovascular disorder with high mortality and disability rates. Although a lot of effort has been put in ICH, there is still no effective treatment for this devastating disease. Recent studies suggest that oligodendrocytes play an important role in brain repair after ICH and thus may be targeted for the therapies of ICH. Here in this review, we first introduce the origin, migration, proliferation, differentiation, and myelination of oligodendrocytes under physiological condition. Second, recent findings on how ICH affects oligodendrocyte biology and function are reviewed. Third, potential crosstalk between oligodendrocytes and other cells in the brain is also summarized. Last, we discuss the therapeutic potential of oligodendrocyte-based treatments in ICH. Our goal is to provide a comprehensive review on the biology and function of oligodendrocytes under both physiological and ICH conditions.

Spontaneous intracerebral hemorrhage is a devastating disease, accounting for 10 to 15% of all types of stroke; however, it is associated with disproportionally higher rates of mortality and disability. Despite significant progress in the acute management of these patients, the ideal surgical management is still to be determined. Surgical hematoma drainage has many theoretical benefits, such as the prevention of mass effect and cerebral herniation, reduction in intracranial pressure, and the decrease of excitotoxicity and neurotoxicity of blood products.Several surgical techniques have been considered, such as open craniotomy, decompressive craniectomy, neuroendoscopy, and minimally invasive catheter evacuation followed by thrombolysis. Open craniotomy is the most studied approach in this clinical scenario, the first randomized controlled trial dating from the early 1960s. Since then, a large number of studies have been published, which included two large, well-designed, well-powered, multicenter, multinational, randomized clinical trials. These studies, The International Surgical Trial in Intracerebral Hemorrhage (STICH), and the STICH II have shown no clinical benefit for early surgical evacuation of intraparenchymal hematoma in patients with spontaneous supratentorial hemorrhage when compared with best medical management plus delayed surgery if necessary. However, the results of STICH trials may not be generalizable, because of the high rates of patients' crossover from medical management to the surgical group. Without these high crossover percentages, the rates of unfavorable outcome and death with conservative management would have been higher. Additionally, comatose patients and patients at risk of cerebral herniation were not included. In these cases, surgery may be lifesaving, which prevented those patients of being enrolled in such trials. This article reviews the clinical evidence of surgical hematoma evacuation, and its role to decrease mortality and improve long-term functional outcome after spontaneous intracerebral hemorrhage.

There has been strong pre-clinical research on mechanisms of initial cell death and tissue injury in intracerebral hemorrhage (ICH). This data has led to the evaluation of several therapeutics for neuroprotection or the mitigation of early tissue damage. Most of these studies have been done in the rat. Also, there has been little study of the mechanisms of tissue repair and recovery. This review examines the testing of candidate therapeutics in mouse models of ICH for their effect on tissue protection and repair. This review will help the readers compare it to the extensively researched rat model of ICH and thus enhance work that are pending in mouse model.

Intracranial bleeding is an important cause of brain masses and edema. To study the pathophysiology of intracerebral hemorrhage, we produced experimental hemorrhages in 53 rats and characterized the lesion by histology, brain water content, and behavior. Adult rats had 2 microliters saline containing 0.5 unit bacterial collagenase infused into the left caudate nucleus. Histologically, erythrocytes were seen around blood vessels at the needle puncture site within the first hour. By 4 hours there were hematomas, the size of which depended on the amount of collagenase injected. Necrotic masses containing fluid, blood cells, and fibrin were seen at 24 hours. Lipid-filled macrophages were observed at 7 days and cysts at 3 weeks. Water content was significantly increased 4, 24, and 48 hours after infusion at the needle puncture site and for 24 hours in posterior brain sections. Behavioral abnormalities were present for 48 hours, with recovery of function occurring during the first week. Brain tissue contains Type IV collagen in the basal lamina. Collagenase, which occurs in an inactive form in cells, is released and activated during injury, leading to disruption of the extracellular matrix. Collagenase-induced intracerebral hemorrhage is a reproducible animal model for the study of the effects of the hematoma and brain edema.

Because heme oxygenase (HO) is the rate limiting enzyme in the degradation of the pro-oxidant hemin/heme from blood, here we investigated the contribution of the inducible HO-1 to early brain injury produced by intracerebral haemorrhage (ICH). We found that after induction of ICH, HO-1 proteins were highly detectable in the peri-ICH region predominantly in microglia/macrophages and endothelial cells. Remarkably, the injury volume was significantly smaller in HO-1 knockout (HO-1-/-) mice than in wild-type controls 24 and 72 h after ICH. Although the brain water content did not appear to be significantly different, the protection in HO-1-/- mice was associated with a marked reduction in ICH-induced leucocyte infiltration, microglia/macrophage activation and free radical levels. These data reveal a previously unrecognized role of HO-1 in early brain injury after ICH. Thus, modulation of HO-1 signalling should be assessed further in clinical settings, especially for haemorrhagic states.

OBJECTIVE:Hydrogen inhalation was neuroprotective in several brain injury models. Its mechanisms are believed to be related to antioxidative stress. We investigated the potential neurovascular protective effect of hydrogen inhalation especially effect on mast cell activation in a mouse model of intracerebral hemorrhage. DESIGN:Controlled in vivo laboratory study. SETTING:Animal research laboratory. SUBJECTS:One hundred seventy-one 8-week-old male CD-1 mice were used. INTERVENTIONS:Collagenase-induced intracerebral hemorrhage model in 8-week-old male CD-1 mice was used. Hydrogen was administrated via spontaneous inhalation. The blood-brain barrier permeability and neurologic deficits were investigated at 24 and 72 hours after intracerebral hemorrhage. Mast cell activation was evaluated by Western blot and immuno-staining. The effects of hydrogen inhalation on mast cell activation were confirmed in an autologous blood injection model intracerebral hemorrhage. MEASUREMENT AND MAIN RESULTS:At 24 and 72 hours post intracerebral hemorrhage, animals showed blood-brain barrier disruption, brain edema, and neurologic deficits, accompanied with phosphorylation of Lyn kinase and release of tryptase, indicating mast cell activation. Hydrogen treatment diminished phosphorylation of Lyn kinase and release of tryptase, decreased accumulation and degranulation of mast cells, attenuated blood-brain barrier disruption, and improved neurobehavioral function. CONCLUSION:Activation of mast cells following intracerebral hemorrhage contributed to increase of blood-brain barrier permeability and brain edema. Hydrogen inhalation preserved blood-brain barrier disruption by prevention of mast cell activation after intracerebral hemorrhage.

BACKGROUND AND PURPOSE:MRI can be used to assess structural damage to the brain after aneurysmal subarachnoid hemorrhage. We tuned, validated, and applied k-Nearest Neighbor-based segmentation to quantify cerebral volumes on MRI 6 months after aneurysmal subarachnoid hemorrhage. METHODS:After tuning, the accuracy of k-Nearest Neighbor-based segmentation was assessed with manual segmentations. Next, supratentorial cerebral parenchymal, peripheral cerebrospinal fluid, and lateral ventricular volumes of 55 patients were compared with those of 25 age- and sex-matched control subjects and related to clinical outcome (modified Rankin Scale). RESULTS:k-Nearest Neighbor-based segmentation showed good agreement with manual segmentations. Compared with control subjects, patients had a larger lateral ventricular volume (difference: log-transformed values 0.54; 95% CI,0.33-0.75), smaller peripheral cerebrospinal fluid volume (-26 mL; 95% CI, -40 to -11), and similar cerebral parenchymal volume (2 mL; 95% CI, -10 to 15). In patients, parenchymal (median split; OR, 38.8; 95% CI, 4.6-329.0) and ventricular volumes (7.4; 95% CI, 1.6-33.5) correlated with functional outcome. CONCLUSIONS:k-Nearest Neighbor-based segmentation provides accurate cerebral volume measurements after aneurysmal subarachnoid hemorrhage. In this proof-of-principle study of this volumetric technique, we demonstrated volume changes relative to controls, which correlated with functional outcome.

Acute spontaneous intracerebral haemorrhage is a life-threatening illness of global importance, with a poor prognosis and few proven treatments. As a heterogeneous disease, certain clinical and imaging features help identify the cause, prognosis, and how to manage the disease. Survival and recovery from intracerebral haemorrhage are related to the site, mass effect, and intracranial pressure from the underlying haematoma, and by subsequent cerebral oedema from perihaematomal neurotoxicity or inflammation and complications from prolonged neurological dysfunction. A moderate level of evidence supports there being beneficial effects of active management goals with avoidance of early palliative care orders, well-coordinated specialist stroke unit care, targeted neurointensive and surgical interventions, early control of elevated blood pressure, and rapid reversal of abnormal coagulation.

Intracerebral haemorrhage (ICH) is the most lethal subtype of stroke but currently lacks effective treatment. Microglia are among the first non-neuronal cells on the scene during the innate immune response to ICH. Microglia respond to acute brain injury by becoming activated and developing classic M1-like (proinflammatory) or alternative M2-like (anti-inflammatory) phenotypes. This polarization implies as yet unrecognized actions of microglia in ICH pathology and recovery, perhaps involving microglial production of proinflammatory or anti-inflammatory cytokines and chemokines. Furthermore, alternatively activated M2-like microglia might promote phagocytosis of red blood cells and tissue debris, a major contribution to haematoma clearance. Interactions between microglia and other cells modulate microglial activation and function, and are also important in ICH pathology. This Review summarizes key studies on modulators of microglial activation and polarization after ICH, including M1-like and M2-like microglial phenotype markers, transcription factors and key signalling pathways. Microglial phagocytosis, haematoma resolution, and the potential crosstalk between microglia and T lymphocytes, neurons, astrocytes, and oligodendrocytes in the ICH brain are described. Finally, the clinical and translational implications of microglial polarization in ICH are presented, including the evidence that therapeutic approaches aimed at modulating microglial function might mitigate ICH injury and improve brain repair.

Vascular disruption is the underlying cause of cerebral hemorrhage, including intracerebral, subarachnoid and intraventricular hemorrhage. The disease etiology also involves cerebral hemorrhage-induced blood-brain barrier (BBB) disruption, which contributes an important component to brain injury after the initial cerebral hemorrhage. BBB loss drives vasogenic edema, allows leukocyte extravasation and may lead to the entry of potentially neurotoxic and vasoactive compounds into brain. This review summarizes current information on changes in brain endothelial junction proteins in response to cerebral hemorrhage (and clot-related factors), the mechanisms underlying junction modification and potential therapeutic targets to limit BBB disruption and, potentially, hemorrhage occurrence. It also addresses advances in the tools that are now available for assessing changes in junctions after cerebral hemorrhage and the potential importance of such junction changes. Recent studies suggest post-translational modification, conformational change and intracellular trafficking of junctional proteins may alter barrier properties. Understanding how cerebral hemorrhage alters BBB properties beyond changes in tight junction protein loss may provide important therapeutic insights to prevent BBB dysfunction and restore normal function.

IMPORTANCE:Although spontaneous intraparenchymal hemorrhage (IPH) accounts for less than 20% of cases of stroke, it continues to be associated with the highest mortality of all forms of stroke and substantial morbidity rates. OBSERVATIONS:Early identification and management of IPH is crucial. Blood pressure control, reversal of associated coagulopathy, care in a dedicated stroke unit, and identification of secondary etiologies are essential to optimizing outcomes. Surgical management of hydrocephalus and space occupying hemorrhage in the posterior fossa are accepted forms of treatment. Modern advances in minimally invasive surgical management of primary, supratentorial IPH are being explored in randomized trials. Hemorrhagic arteriovenous malformations and cavernous malformations are surgically excised if accessible, while hemorrhagic dural arteriovenous fistulas and distal/mycotic aneurysms are often managed with embolization if feasible. CONCLUSIONS AND RELEVANCE:IPH remains a considerable source of neurological morbidity and mortality. Rapid identification, medical management, and neurosurgical management, when indicated, are essential to facilitate recovery. There is ongoing evaluation of minimally invasive approaches for evacuation of primary IPH and evolution of surgical and endovascular techniques in the management of lesions leading to secondary IPH.

OBJECTIVE:To characterize long-term mortality following intracerebral hemorrhage (ICH) in two large population-based cohorts assembled more than a decade apart. METHODS:All patients age > or = 18 hospitalized with nontraumatic ICH in the Greater Cincinnati/Northern Kentucky area were identified during 1988 (Cohort 1) and from May 1998 to July 2001 and August 2002 to April 2003 (Cohort 2). Mortality was tabulated using actuarial methods and compared with a log-rank test. RESULTS:There were 183 patients with ICH in Cohort 1 and 1,041 patients in Cohort 2. Patients in Cohort 1 were more likely to be white (p = 0.024) and undergo operation for their ICH (p = 0.002), whereas patients in Cohort 2 were more commonly on anticoagulants (p < 0.001). Among patients in Cohort 1, mortality at 7 days, 1 year, and 10 years was 31, 59, and 82%. Among patients in Cohort 2, mortality at 7 days and 1 year was 34 and 53%. Mortality rates did not differ between cohorts by log-rank test (p = 0.259). CONCLUSIONS:Intracerebral hemorrhage (ICH) mortality did not improve significantly between study periods. Operation for ICH became less frequent, whereas anticoagulant-associated ICH became more common.

Intracerebral hemorrhage (ICH) accounts for a disproportionate amount of stroke-related morbidity and mortality. Although chronic hypertension and cerebral amyloid angiopathy are the underlying cerebral vasculopathies accounting for the majority of ICH, there are a broad range of potential causes, and effective management requires accurate identification and treatment of the underlying mechanism of hemorrhage. Magnetic resonance imaging and vascular imaging techniques play a critical role in identifying disease mechanisms. Modern treatment of ICH focuses on rapid stabilization, often requiring urgent treatment of mass effect, aggressive blood pressure reduction and correction of contributing coagulopathies to achieve hemostasis. We discuss management of patients with ICH who continue to require long-term anticoagulation, the interaction of ICH with neurodegenerative diseases, and our approach to prognostication after ICH. We close this review with a discussion of novel medical and surgical approaches to ICH treatment that are being tested in clinical trials.