We searched MEDLINE up to September 2005 with the keywords “cerebral haemorrhage”, “thrombin”, “iron”, “haemoglobin”, and “cerebral ischaemia”. Only papers published in English from 1966 were reviewed. Articles were selected for their conceptual importance and primacy. Where issues are controversial, evidence on both sides of the issue is given.
ReviewMechanisms of brain injury after intracerebral haemorrhage
Introduction
Intracerebral haemorrhage (ICH) is a subtype of stroke with high morbidity and mortality accounting for about 15% of all deaths from stroke.1 The key factor that affects ICH outcome is haemorrhagic volume. When haemorrhagic volume exceeds 150 mL acutely, cerebral perfusion pressure falls to zero and the patient dies (figure 1).2 If the haemorrhagic volume is smaller than 140 mL, most patients survive the initial ictus. However, the haematoma itself can lead to secondary brain injury resulting in severe neurological deficits and sometimes delayed fatality.2, 3 The mechanisms that trigger the pathophysiological changes in and around the intracerebral haematoma are better understood now and are the focus of this review. In this review we will deal with adult ICH.
Section snippets
Causes of bleeding
Hypertension is the main cause of spontaneous ICH. Hypertension can cause microaneurysms at the bifurcation of arterioles. Studies have indicated that persistently raised intraluminal arterial pressure damages small-vessel walls.4, 5 As with ischaemic stroke, prevention of haemorrhagic stroke is far preferable than reducing brain injury after haemorrhage has happened. In addition to hypertension, other major causes of ICH are: amyloid angiopathy, brain tumours, aneurysms, arteriovenous
Haematoma expansion and midline shift
Part of ICH-induced injury is due to physical disruption of adjacent tissue and the mass effect caused as the ICH forms. This primary brain injury, occurring at the time of haemorrhage, may seem to be untreatable. However, although more than two-thirds of patients with ICH stop bleeding shortly after ictus,16 haematoma enlargment takes place in about a third of patients.17, 18, 19, 20, 21, 22 A retrospective study found that haematoma enlargement occurred in 88 (14%) of 627 patients with ICH
Brain oedema
Perihaematomal brain oedema develops immediately after an ICH and peaks several days later.13, 31, 32 Oedema formation after ICH increases intracranial pressure and can result in herniation.33 In experimental ICH models, brain oedema peaks around the third or fourth day after the haemorrhage, then declines slowly.10, 12, 34, 35 In animals with substantial white matter, perihaematomal oedema is mainly located within that tissue.35, 36 In human beings perihaematomal oedema develops within 3 h of
Brain atrophy
Other quantifiable markers of brain injury in animals have been difficult to obtain because neuronal damage seems to be diffuse (ie, without a clearly defined infarct) and only a small cavity is found after the clot is absorbed. Brain atrophy occurs in patients with ICH.42 We43 and others44 have shown that brain atrophy also occurs after ICH in rats. Feldberg and colleagues44 reported that the ipsilateral striatum volume was reduced by 20% with an increase in the ipsilateral ventricular size 3
Physical trauma and mass effect
Suzuki and Ebina31 explored the role of haematoma mass effect in brain damage in animals. They injected autologous whole blood or an oil-wax mixture into the internal capsule of dogs. Both injections caused brain oedema, but oedema was more severe around a clot formed from the blood than around the oil-wax mass, which suggests that oedema does not result simply from mass effect alone. Sinar and colleagues45 showed that inflation of a microballoon in the basal ganglia of rats increased
Sex
An important factor in ICH-induced brain damage is sex. We found a difference between the sexes in secondary brain injury after ICH. Female rats tolerate ICH better than males. This finding accords with those of a study in mice, which showed that brain oedema and behavioural deficits are less after ICH in females than in males.9, 119 Female animals have reduced susceptibility to ischaemic, haemorrhagic, and traumatic brain injury. In ischaemic-stroke models, brain infarcts are smaller in
Protective pathways
The mRNA concentrations of many different proteins are altered in the brain after experimental ICH.144 Some of these changes could be protective. For example, upregulation in ferritin after ICH might help to limit iron-induced brain injury.89 Genetic changes in the regulatory pathways that activate such protective mechanisms might lead to different susceptibility to brain injury and might explain why some patients with haematomas of similar size and location have different outcomes.
The
Therapeutic targets
This review draws attention to our expanding knowledge about the mechanisms of brain injury after ICH. As shown by cerebral ischaemia research, translation of that information to clinical treatments is difficult. Given the abundant evidence that clot-derived factors are important in ICH-induced brain injury, a logical assumption is that clot removal would be an effective therapy. However, several clinical trials, including the STICH trial3, 145, 146 have not provided convincing evidence to
Search strategy and selection criteria
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