Modulators of microglial activation and polarization after intracerebral haemorrhage.
Lan Xi,Han Xiaoning,Li Qian,Yang Qing-Wu,Wang Jian
Nature reviews. Neurology
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.
Brain endothelial cell junctions after cerebral hemorrhage: Changes, mechanisms and therapeutic targets.
Keep Richard F,Andjelkovic Anuska V,Xiang Jianming,Stamatovic Svetlana M,Antonetti David A,Hua Ya,Xi Guohua
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
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.
Cerebral Intraparenchymal Hemorrhage: A Review.
Gross Bradley A,Jankowitz Brian T,Friedlander Robert M
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.
Long-term mortality after intracerebral hemorrhage.
Flaherty M L,Haverbusch M,Sekar P,Kissela B,Kleindorfer D,Moomaw C J,Sauerbeck L,Schneider A,Broderick J P,Woo D
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.
Management of Intracerebral Hemorrhage: JACC Focus Seminar.
Schrag Matthew,Kirshner Howard
Journal of the American College of Cardiology
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.