Elsevier

The Lancet Neurology

Volume 5, Issue 1, January 2006, Pages 53-63
The Lancet Neurology

Review
Mechanisms of brain injury after intracerebral haemorrhage

https://doi.org/10.1016/S1474-4422(05)70283-0Get rights and content

Summary

The past decade has resulted in a rapid increase in knowledge of mechanisms underlying brain injury induced by intracerebral haemorrhage (ICH). Animal studies have suggested roles for clot-derived factors and the initial physical trauma and mass effect as a result of haemorrhage. The coagulation cascade (especially thrombin), haemoglobin breakdown products, and inflammation all play a part in ICH-induced injury and could provide new therapeutic targets. Human imaging has shown that many ICH continue to expand after the initial ictus. Rebleeding soon after the initial haemorrhage is common and forms the basis of a current clinical trial using factor VIIa to prevent rebleeding. However, questions about mechanisms of injuries remain. There are conflicting data on the role of ischaemia in ICH and there is uncertainty over the role of clot removal in ICH therapy. The next decade should bring further information about the underlying mechanisms of ICH-induced brain injury and new therapeutic interventions for this severe form of stroke. This review addresses our current understanding of the mechanisms underlying ICH-induced brain injury.

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

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.

References (152)

  • J Wu et al.

    Oxidative brain injury from extravasated erythrocytes after intracerebral hemorrhage

    Brain Res

    (2002)
  • RK Kutty et al.

    Purification and characterization of biliverdin reductase from rat liver

    J Biol Chem

    (1981)
  • CS Kase et al.

    Intracerebral hemorrhage

    (1994)
  • G Xi et al.

    The pathophysiology of hemorrhagic lesions

  • AI Qureshi et al.

    Spontaneous intracerebral hemorrhage

    N Engl J Med

    (2001)
  • CM Fisher

    Pathological observations in hypertensive cerebral hemorrhage

    J Neuropathol Exp Neurol

    (1971)
  • CM Fisher

    Cerebral miliary aneurysms in hypertension

    Am J Pathol

    (1972)
  • CM Fisher

    Hypertensive cerebral hemorrhage: demonstration of the source of bleeding

    J Neuropathol Exp Neurol

    (2003)
  • WI Rosenblum

    Cerebral hemorrhage produced by ruptured dissecting aneurysm miliary aneurysm

    Ann Neurol

    (2003)
  • T Nakamura et al.

    Intracerebral hemorrhage in mice: model characterization and application for genetically modified mice

    J Cereb Blood Flow Metab

    (2004)
  • G Xi et al.

    Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats

    J Neurosurg

    (1998)
  • G Xi et al.

    The role of blood clot formation on early edema development following experimental intracerebral hemorrhage

    Stroke

    (1998)
  • GY Yang et al.

    Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood-brain barrier permeability in rats

    J Neurosurg

    (1994)
  • KR Wagner et al.

    Lobar intracerebral hemorrhage model in pigs: rapid edema development in perihematomal white matter

    Stroke

    (1996)
  • GA Rosenberg et al.

    Collagenase-induced intracerebral hemorrhage in rats

    Stroke

    (1990)
  • Priorities for clinical research in intracerebral hemorrhage

    Stroke

    (2005)
  • RG Ojemann et al.

    Hypertensive brain hemorrhage

    Clin Neurosurg

    (1976)
  • JP Broderick et al.

    Ultra-early evaluation of intracerebral hemorrhage

    J Neurosurg

    (1990)
  • Y Fujii et al.

    Hematoma enlargement in spontaneous intracerebral hemorrhage

    J Neurosurg

    (1994)
  • Y Fujii et al.

    Multivariate analysis of predictors of hematoma enlargement in spontaneous intracerebral hemorrhage

    Stroke

    (1998)
  • S Kazui et al.

    Enlargement of spontaneous intracerebral hemorrhage: incidence and time course

    Stroke

    (1996)
  • T Brott et al.

    Early hemorrhage growth in patients with intracerebral hemorrhage

    Stroke

    (1997)
  • S Kazui et al.

    Predisposing factors to enlargement of spontaneous intracerebral hematoma

    Stroke

    (1997)
  • AR Zazulia et al.

    Progression of mass effect after intracerebral hemorrhage

    Stroke

    (1999)
  • SA Mayer et al.

    Recombinant activated factor VII for acute intracerebral hemorrhage

    N Engl J Med

    (2005)
  • SL Hickenbottom et al.

    Nuclear factor-kappaB and cell death after experimental intracerebral hemorrhage in rats

    Stroke

    (1999)
  • K Matsushita et al.

    Evidence for apoptosis after intercerebral hemorrhage in rat striatum

    J Cereb Blood Metab

    (2000)
  • C Gong et al.

    Intracerebral hemorrhage-induced neuronal death

    Neurosurgery

    (2001)
  • AI Qureshi et al.

    Quantitative analysis of injured, necrotic, and apoptotic cells in a new experimental model of intracerebral hemorrhage

    Crit Care Med

    (2001)
  • AI Qureshi et al.

    Apoptosis as a form of cell death in intracerebral hemorrhage

    Neurosurgery

    (2003)
  • J Suzuki et al.

    Sequential changes in tissue surrounding ICH

  • AH Ropper

    Lateral displacement of the brain and level of consciousness in patients with an acute hemispheral mass

    N Engl J Med

    (1986)
  • DR Enzmann et al.

    Natural history of experimental intracerebral hemorrhage: sonography, computed tomography and neuropathology

    AJNR Am J Neuroradiol

    (1981)
  • H Tomita et al.

    Chronological changes in brain edema induced by experimental intracerebral hematoma in cats

    Acta Neurochir Suppl

    (1994)
  • J Broderick et al.

    Very early edema growth with ICH

    Stroke

    (1995)
  • R Suzuki et al.

    Chronological changes in brain edema in hypertensive intracerebral hemorrhage observed by CT and xenon-enhanced CT

  • AH Ropper et al.

    Intracranial pressure monitoring in comatose patients with cerebral hemorrhage

    Arch Neurol

    (1984)
  • JM Gebel et al.

    Relative edema volume is a predictor of outcome in patients with spontaneous intracerebral hemorrhage

    Stroke

    (2002)
  • AL Betz et al.

    Brain edema: a classification based on blood-brain barrier integrity

    Cerebrovasc Brain Metab Rev

    (1989)
  • EB Skriver et al.

    Tissue damage at computed tomography following resolution of intracerebral hematomas

    Acta Radiol Diagn (Stockh)

    (1986)
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