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The common underlying pathologies for ICH are well recognized[9] and include hypertensive and amyloid angiopathies,

hemorrhage associated with antithrombotic medications, vascular malformations, inflammatory vasculitides and use of stimulant medications such as amphetamines. ICH occurs when there is rupture of a blood vessel, which results in an expanding hematoma. The actual trigger for rupture may not be clearly identified, but blood pressure (BP) fluctuations may play an important role.[10] The hematoma physically disrupts and damages the neurons and glial cells (the primary injury)[11]and clinical presentation depends on hematoma size, site of hemorrhage and rate of hematoma growth. Hematoma volume is easy to measure, and when combined with Glasgow Coma Scale score, quickly provides validated prognostic information.[12] Other factors associated with poor prognosis include intraventricular extension[13] and hydrocephalus. Hematoma expansion (HE), either from ongoing hemorrhage or from rebleeding is associated with a poor prognosis[14,15] likely related to a greater volume of damaged tissue, mass effect and greater propensity for intraventricular extension. Observational studies have demonstrated that a substantial percentage of patients undergo HE, [14,16] and regardless of how HE is measured (absolute or relative volume increase),[17] this predicts poor prognosis. A newly described radiological marker, the 'spot sign',[18] is due to contrast extravasation within the hematoma, and is highly predictive of HE and poor outcome. It has been suggested that these spots may represent pseudoaneurysms, CharcotBouchard aneurysms, amyloid-related microaneurysms or even leakage from secondarily damaged or torn perforators, even in the absence of an underlying aneurysmal lesion.[18] In any case, this has been an important finding that might be incorporated into current and future clinical management strategies. What ultimately leads to cessation of HE is not clearly understood. Presumably, the point or points of vascular leakage become sealed over, and blood extravasation from the intraluminal compartment of the vessel ceases. A balance between intravascular hydrostatic forces, a thrombotic 'plug' at the site of vessel disruption and extravascular forces (which probably equate to intracranial pressure) probably determines when the vessel stops leaking blood. The expanding hematoma causes hemodynamic changes in the surrounding brain, with possible reductions in perfusion and metabolism.[19] There has been speculation that this rim of perihematomal-reduced perfusion could be analogous to an ischemic penumbra,[20] such as that which is thought to be present in ischemic stroke. This led to concerns that excessive BP reduction could be potentially deleterious. However, recent studies have failed to definitively identify

an 'at-risk' rim of poorly perfused tissue around the hematoma, instead attributing the reduced perfusion as a secondary phenomenon due to reduced metabolism and early edema.[21,22] Elevation of BP is very commonly observed after ICH, and there is tremendous interest in how to manage this situation (see 'Medical therapies' section).[23] In ICH, there appears to be a linear relationship between systolic BP and adverse outcome,[23] and elevated blood pressure (BP) predicts HE. The vanguard Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT) study demonstrated the safety of intensive systolic BP reduction to a target of <140 mmHg (compared with the guidelinebased target of 180 mmHg) in the first few hours after ICH onset.[24] On a molecular level, the initial insult from the hemorrhage sets off a cascade of various metabolic processes, which ultimately lead to perihematoma inflammation and edema (from disruption of the BBB).[19] The edema leads to further mass effect, raised intracranial pressure and often causes further neurologic decline. This is the secondary injury. This process commences soon after the initial ICH, but may persist for several days,[25] thus the patient with a large ICH may still be at risk of further deterioration, including herniation syndromes, for up to a week. Release of inflammatory mediators, proteases, macrophages, microglia, astrocytes and mast cells ensues, and these combine to fuel the inflammatory process. Macrophages begin to lyse red blood cells and phagocytose the cellular debris. Thrombin plays an important role in the genesis of perihematomal inflammation. Animal studies have demonstrated a significant reduction in perihematomal edema in rats treated with high-dose argatroban, a direct thrombin inhibitor, 6 h after induced ICH compared with a control group.[26] Thrombin may therefore be a potential therapeutic target in attenuating ICH-induced edema in humans. Matrix metalloproteinases (MMPs) are a large family of 23 zinc-dependent endopeptidases that hydrolyze parts of the extracellular matrix. During normal physiologic states, their activity is rigidly controlled. Many MMPs are upregulated in response to various brain injuries, including ICH,[27] and are involved in the cleavage of cell surface receptors, release of apoptotic ligands and chemokine activation. Heme and iron are released after red cell lysis and may lead to inflammation after ICH.[28] Heme induces heme oxygenase (HO)-1, and this results in production of biliverdin, iron and carbon monoxide. Iron catalyzes reactions that form highly active free radicals, with the potential for neurotoxicity. One study investigated

the comparative size of perihematomal edema after experimental ICH in HO-1knockout mice (HO-1/) compared with wild-type controls.[29] A marked reduction in ICH-induced leucocyte infiltration, microglia/macrophage activation and free radical levels was observed, suggesting that HO-1 may have a role in early brain injury after ICH. Complement, proinflammatory cytokines and other immunological mediators (e.g., TNF-, IL-2, -3, -6 and -8, TGF and NF-B) have been implicated in driving the inflammatory process and causing further disruption of the BBB.[27] In summary, there is a complex interplay of various processes and immunologically active molecules that results in perihematomal edema following hemorrhagic stroke. The inflammation and edema cause secondary damage, and each of these components is a potential point of intervention to try to arrest this inflammatory process and limit damage.