Etiology

Cerebrovascular changes induced by longstanding hypertension account for the large majority of primary intracerebral hemorrhages.[13]

Cerebral amyloid angiopathy (CAA)

Accounts for a significant number of primary hemorrhagic strokes, specifically in older people. Prevalence remains low in people under 55 years.[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]

Amyloid deposition in the blood vessels causes damage to the vascular architecture, fibrinoid necrosis, and splitting of the vessel wall, with resultant microbleeds arising from perivascular accumulation of hemosiderin-laden macrophages. These cerebral microbleeds are visible on magnetic resonance imaging and result from the erythrocyte extravasation from small blood vessels. It is well established that people with the apolipoprotein (Apo) E4 allele have an increased risk for CAA compared with those who lack the allele. Patients who are ApoE4 heterozygotes are at higher risk of a more severe form of CAA than those without the ApoE4 allele; the probability of an extreme form of CAA is even higher in homozygotes.[14]

The presence of ApoE2 has also been correlated with an increased risk for hemorrhagic stroke in people 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 hemorrhage but is not a cause of hemorrhage in other intracranial locations.[14]

Hypertension

Can cause hemorrhage in any intracranial location. Chronic hypertension can also result in cerebral microbleeds caused by damaged small vessels, but these are typically within the deeper brain structures.[13]​ The presence and quantity of cerebral microbleeds are believed to be a marker for the severity of underlying small vessel disease.[17]

Anticoagulation-associated hemorrhage

Considered by most experts to be a form of primary intracerebral hemorrhage.

Secondary intracerebral hemorrhage

Arises from an identifiable vascular malformation or as a complication of other medical or neurologic diseases that either impair coagulation or promote vascular rupture. Etiologies include:

  • Cerebral infarction or cerebral tumor with hemorrhage into the diseased tissue.

  • Sympathomimetic drugs of abuse. Cocaine and amphetamines share pharmacologic characteristics as well as physiologic effects, but amphetamine has more sustained systemic effects owing to its longer half-life. Their sympathomimetic effects cause transient increases in both systolic and diastolic blood pressure that can lead to vascular damage due to arteriosclerosis pathogenesis, arterial weakness, and intracranial hemorrhage. There is no association between a particular route of administration (i.e., oral, inhalation, or injection) and the incidence of hemorrhagic stroke. Amphetamine use is associated with a greatly increased risk of hemorrhagic stroke among people ages 18-44 years. Approximately 80% of amphetamine-related strokes are hemorrhagic.

  • Brain arteriovenous malformations (AVMs) are a rare type of congenital vascular lesion that can present with spontaneous intracerebral hemorrhage (58%), new-onset seizure (34%), or headache (8%). They are present in 0.1% of the population and tend to be incidental findings during neuroimaging for other neurologic complaints. A higher prevalence of brain AVMs is associated with hemorrhagic hereditary telangiectasia (HHT); 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 arterialization of the venous limb, vascular steal phenomenon, and even development of aneurysms within the AVM. Overall, intracerebral hemorrhage due to an AVM has a more benign natural history than primary intracerebral hemorrhage. The annual risk of intracerebral hemorrhage 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 intracerebral hemorrhage from a brain AVM is an initial brain AVM rupture.[18]

Pathophysiology

Intracerebral hemorrhage is caused by vascular rupture with bleeding into the brain parenchyma, resulting in a primary mechanical injury to the brain tissue. The expanding hematoma may shear additional neighboring arteries, resulting in further bleeding and hematoma expansion, which can result in secondary injury due to mass effect, increased intracranial pressure, reduced cerebral perfusion, secondary ischemic injury, and even cerebral herniation.[19]

Significant hematoma growth (30% to 40% increase) over several hours following presentation is common in patients who present within 3 to 4 hours of the onset of symptoms.[20] The period of bleeding may be extended even longer in anticoagulated patients. Arresting hematoma growth is therefore a key objective for medical or surgical therapies.[21] As a consequence of hematoma growth, the hemorrhage may rupture into the subarachnoid space or the intraventricular space.

The role of matrix metalloproteinases (MMPs) in the genesis of neuroinflammation and hematoma growth is being extensively investigated. MMPs are inactive proenzymes that, when activated, are involved in degradation of extracellular matrix of the cerebral basement membrane and the blood-brain barrier. Concentrations of MMP-9 rapidly increase in neuroinflammation, and there is some evidence that increasing levels of MMP-9 are associated with hematoma expansion and increased neurologic deficits.[22][23][24]

Mortality is increased when intraventricular hemorrhage is present, in part due to the associated increased risk of communicating or noncommunicating hydrocephalus.[25] Mortality from intracerebral hemorrhage is high and may result from direct destruction of critical brain areas, compression of critical brain areas by adjacent hematoma, or cerebral circulatory arrest caused by globally increased intracranial pressure.

Classification

Etiology of intracerebral hemorrhage[1]

Primary spontaneous

  • Idiopathic (no identifiable vascular malformations or associated diseases)

  • Anticoagulation.

Secondary

  • An identifiable vascular malformation

  • Medical or neurologic diseases that impair coagulation or promote vascular rupture (e.g., cerebral infarction or tumor, sympathomimetic drugs of abuse, hematologic malignancies).

Location of intracerebral hemorrhage[2]

It is helpful to subdivide intracerebral hemorrhage by location because etiologies 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 gray matter structures, most commonly the putamen and thalamic nuclei.

  • Brain stem: occurs mostly in the pons.

  • Cerebellar: occurs mostly in the dentate nucleus.

Use of this content is subject to our disclaimer