Aetiology
Cerebrovascular changes induced by long-standing hypertension account for the large majority of primary intracerebral haemorrhages (ICHs).
Cerebral amyloid angiopathy (CAA) accounts for a significant number of primary ICHs, specifically in the older population. While prevalence remains low in those aged younger than 55 years, it increases with age.[14] CAA is caused by beta-amyloid deposition in the walls of medium-and small-sized arteries restricted to the brain cortex (overlying leptomeninges) and cerebellum.[15] Rare hereditary cases may be due to genetic mutations in cystatin-C, amyloid precursor protein, or transthyretin.[16] The amyloid deposition in the blood vessels causes damage to the vascular architecture, fibrinoid necrosis, and splitting of the vessel wall, which causes microbleeds from perivascular accumulation of haemosiderin-laden macrophages. These cerebral microbleeds are only visible on magnetic resonance imaging and result from the erythrocyte extravasation from small blood vessels. It is well established that patients with apolipoprotein (Apo) E4 allele have an increased risk for CAA compared with those who lack the allele. Heterozygotes of ApoE4 are at increased risk of an extreme form of CAA, while homozygotes are at increased risk for an even more severe form of CAA. The presence of ApoE2 has also been correlated with an increased risk for ICH in those with CAA. Typically, the cerebral microbleeds in CAA are located in the cortical-subcortical regions of the brain parenchyma; therefore, CAA is a major cause of lobar haemorrhage but is not a cause of haemorrhage in other intracranial locations.[14]
Hypertension can cause haemorrhage in any intracranial location. Chronic hypertension can also result in cerebral microbleeds caused by damaged small vessels, yet these are typically within the deeper brain structures. The presence and quantity of cerebral microbleeds are believed to be a marker for the severity of underlying small vessel disease.[17]
It is important to recognise that most experts consider anticoagulation-associated haemorrhage to also be a form of primary ICH.
Secondary ICH arises from an identifiable vascular malformation or as a complication of other medical or neurological diseases that either impair coagulation or promote vascular rupture. Aetiologies include:
Cerebral infarction or cerebral tumour with haemorrhage into the diseased tissue.
Sympathomimetic drugs of misuse, such as cocaine and amphetamine. Cocaine and amphetamines share pharmacological characteristics as well as physiological effects, yet amphetamine has a longer half-life and, therefore, has more sustained systemic effects. It has been established that amphetamine use is associated with a highly increased risk of haemorrhagic stroke among those aged 18 to 44 years. The higher risk is specific to this age group because of an overall higher prevalence of illicit drug use among the younger population. Approximately 80% of amphetamine-related strokes are haemorrhagic. There is no association between a particular route of administration (i.e., oral, inhalation, or injection) and the incidence of haemorrhagic stroke. However, a literature review found that ischaemic stroke associated with amphetamine use was more common with inhalation use.[18] The sympathomimetic effect of amphetamine and amphetamine-like drugs (e.g., cocaine) cause transient increases in both systolic and diastolic blood pressure that can lead to vascular damage due to arteriosclerosis pathogenesis, arterial weakness, and intracranial haemorrhage.
Brain arteriovenous malformations (AVMs) are a rare type of congenital vascular lesion that can present with spontaneous ICH (58%), new-onset seizure (34%), or headache (8%). They are present in 0.1% of the population and tend to be incidental findings after neuroimaging is done for other neurological complaints. There is a higher prevalence of brain AVMs associated with haemorrhagic hereditary telangiectasia (HHT). In fact, neuroimaging showing more than one brain AVM is highly predictive of HHT. AVMs are direct arterial-to-venous connections without an intervening capillary bed. The high-flow arteriovenous connection potentiates flow-related phenomena such as shear forces that can result in arterialisation of the venous limb, vascular steal phenomenon, and even development of aneurysms within the AVM. Overall, intracranial haemorrhage due to an AVM has a more benign natural history than primary intracranial haemorrhage. The annual risk of intracranial haemorrhage due to an unruptured AVM is 1.3%, while the annual risk of bleeding after a ruptured AVM is 4.8%. Therefore, the most important risk for ICH from a brain AVM is an initial brain AVM rupture.[19]
Pathophysiology
Intracerebral haemorrhage (ICH) is caused by vascular rupture with bleeding into the brain parenchyma, resulting in a primary mechanical injury to the brain tissue. The expanding haematoma may shear additional neighbouring arteries, resulting in further bleeding and haematoma expansion, which can result in secondary injury due to mass effect, increased intracranial pressure, reduced cerebral perfusion, secondary ischaemic injury, and even cerebral herniation.[20] Significant haematoma growth (30% to 40% increase) over several hours following presentation is common in those who present within 3 to 4 hours of the onset of symptoms.[21] The period of bleeding may be extended even longer in anticoagulated patients. Arresting haematoma growth is therefore a key objective for medical or surgical therapies. As a consequence of haematoma growth, the haemorrhage may rupture into the subarachnoid space or the intraventricular space. The role of matrix metalloproteinases in the genesis of neuroinflammation and haematoma growth is being extensively investigated.[22] Mortality is increased when intraventricular haemorrhage is present, in part due to the associated increased risk of communicating or non-communicating hydrocephalus.[23] Mortality from ICH is high and may result from direct destruction of critical brain areas, compression of critical brain areas by adjacent haematoma, or cerebral circulatory arrest caused by globally increased intracranial pressure.
Classification
Aetiology of intracerebral haemorrhage[2]
Primary spontaneous
Idiopathic (no identifiable vascular malformations or associated diseases)
Anticoagulation.
Secondary
An identifiable vascular malformation
Medical or neurological diseases that impair coagulation or promote vascular rupture (e.g., cerebral infarction or tumour, sympathomimetic drugs of misuse, haematological malignancies).
Location of intracerebral haemorrhage[3]
It is helpful to subdivide ICH by location because aetiologies and prognosis vary by site.
Lobar: occurs in the cortex or subcortical white matter of the cerebral hemispheres.
Deep hemispheric: occurs in the supratentorial deep grey matter structures, most commonly the putamen and thalamic nuclei.
Brain stem: occurs mostly in the pons.
Cerebellar: occurs mostly in the dentate nucleus.
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