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HIE General Principles | HIEPathology | HIE-Clinical Findings | The White Matter in HIE |
Cerebral infarcts-Clinical Findings | Pathlogy | Hemorrhagic Infarct | Lacunar Infarct | Causes of Ischemic Infarction | Small Vessel Disease | Venous Infarct | Vascular Dementia |
Cerebral Hemorrhage | Hypertensive Hemorrhage| Arterial Aneurysms | Arterio-venous Malformation | Cerebral Amyloid Angiopathy | Other Hemorrhagic Strokes | Pathology of Seizures

Cerebral infarction is focal brain necrosis due to complete and prolonged ischemia that affects all tissue elements, neurons, glia, and vessels.

Ischemic infarcts cause focal neurological deficits. In embolic infarcts, these appear abruptly. In atherothrombotic infarcts, they evolve over a period of time, usually hours. Atherothombotic infarcts are often preceded by transient ischemic attacks (TIAs). A TIA is a focal neurological deficit that lasts less than 24 hours and resolves. The mechanism of TIAs is uncertain. They may be caused by critical reduction of perfusion that impairs neurological function but falls short of causing permanent tissue damage, or by emboli that break up soon after they occlude vessels.

The release of osmotically active substances (arachidonic acid, electrolytes, lactic acid) from the necrotic brain tissue causes cerebral edema. This is aggravated by vascular injury and leakage of proteins in the interstitial space. By 3-4 days, interstitial fluid accumulates in the infarct and around it. This is the most dangerous period for a large cerebral infarct. Death from a massive hemispheric infarct is caused by cerebral edema and herniations, not by the loss of brain tissue. Recovery of function, after an infarct, is due initially to restoration of perfusion in the penumbra (see below) and then to settling down of cerebral edema. Additional improvement may occur later through mechanisms involving neuronal plasticity.

The basic mechanisms of cell and tissue injury that were discussed under HIE apply also to infarcts. One additional concept, the ischemic penumbra, is worth stressing. In every infarct, there is a central core of total ischemia and necrosis which is irreversible. This area is surrounded by a zone of borderline ischemic tissue, the ischemic penumbra. Ischemia, in the penumbra, causes dysfunction due to ionic and metabolic dysfunction but is not severe enough to result in structural damage. Prompt restoration of perfusion in the penumbra by injection of thrombolytic agents may prevent structural damage in this area, thus limiting the neurological deficit. Ischemic stroke is an emergency. The window of opportunity for salvaging the penumbra is very short. If adequate blood supply is not restored within 3 hours, necrosis extends to the penumbra.

In the first day or so, the infarct appears as a poorly demarcated area of softening.
Cerebral infarct, recent Anterior cerebral artery infarct
Acute Right MCA infarct Acute RACA infarct
Cerebral infarct, old Posterior cerebral artery infarct
Old right MCA infarct Old right PCA infarct
CT Imaging at this stage may be negative, especially in brain stem infarcts. MRI is much more sensitive. At the peak of edema, the infarct appears hypodense and bright on T2 MRI images. The infarcted tissue becomes sharply demarcated and softens progressively. From the second week onward, it begins to disintegrate and is gradually replaced by a cavity. The size and location of infarcts follows the anatomy of vascular territories.

Microscopical examination in the first 24 to 48 hours reveals anoxic neurons, pallor of staining and vacuolization of the white matter due to unraveling of myelin, and axonal swellings.

Axonal swellings (spheroids) Cerebral infarct, neovascularization
Axonal swellings Neovascularization
Macrophages in brain Gemistocytic astrocytes
Macrophages Gemistocytic astrocytes
During the first week, there is a transient inflammatory reaction, especially around blood vessels and in the meninges, due to release of arachidonic and other fatty acids. As the core of the infarct disintegrates, endothelial cells from the periphery proliferate, and capillaries grow into the dead tissue. Neovascularization (which accounts for contrast enhancement) peaks at 2 weeks. Monocytes from the blood stream enter the infarct through damaged vessels. They ingest the products of degradation of neurons and myelin and are transformed into lipid-laden macrophages. Macrophage reaction appears early and peaks at 3-4 weeks. Astrocytes from the surrounding undamaged brain proliferate and form a glial scar around the infarct. This is completed in approximately 2 months. After that, the infarct remains unchanged. With maturation of new capillaries and glial scar formation, the blood brain barrier is once again sealed. Neurons do not regenerate. So, some brain tissue is lost forever.

Cerebral infarct, hemorrhagic
Hemorrhagic infarctA hemorrhagic infarct is an infarct stippled with petechiae or showing confluent larger hemorrhages, especially in necrotic gray matter. Blood leaks from collateral vessels or through necrotic capillaries when the occluding thrombus or embolus break up and the infarcted area is reperfused. Hemorrhagic infarcts are most common in embolism. Use of thrombolytics or anticoagulants may convert a bland infarct into a hemorrhagic one.

Lacunar infarct
Lacunar infarctsLacunar infarcts are small infarcts in the deeper parts of the brain (basal ganglia, thalamus, white matter) and in the brain stem. They are responsible for about 20 percent of all strokes. They are caused by occlusion of deep penetrating branches of major cerebral arteries and are particularly common in hypertension and diabetes, which are associated with severe atherosclerosis of small vessels and small vessel disease (see below). A small lacunar infarct (e.g., one involving the internal capsule) can cause as severe a neurological deficit as can a much larger hemispheric infarct but without the life-threatening cerebral edema that is seen in the latter.

Cerebral atherosclerosis atherosclerosis
Severe atherosclerosis Atherosclerosis and thrombosis
The types of vascular disease that cause cerebral infarction are diverse. A large proportion of infarcts are caused by atherosclerosis of large arteries,alone or with superimposed thrombosis.

Small vessel disease
Lacunar infarcts are caused by small vessel disease. This nonspecific term refers to a vascular lesion seen primarily in hypertension and diabetes but occurring also in old age. Other names given to this pathology are “small artery arteriosclerosis”, “hyaline atreriolosclerosis”, and “lipohyalinosis”. This change affects small penetrating arteries and arterioles that originate from the base of the brain and supply the basal ganglia, thalamus, deep white matter, and the brainstem. These vessels become thickened, and the normal components of their walls are replaced by a homogeneous, glassy (hyaline) substance, composed of collagen and other proteins. The pathogenesis of this change varies: in hypertension, it is caused by endothelial injury and leakage of plasma proteins in and around vessels; in diabetes, it probably has to do with glycation of proteins and diffuse basement membrane thickening. Its effects are narrowing of the lumen and tortuosity, which lengthens the distance blood had to travel to perfuse its targets. Ischemia, resulting from these processes, causes small infarcts (lacunar infarcts) and diffuse loss of tissue density in the white matter (leukoaraiosis-thinning out of the white matter). Multiple infarcts and leukoencephalopathy cause dementia. In addition, loss of elasticity from destruction of smooth muscle makes vessels fragile, resulting in microbleeds and large catastrophic hemorrhages, which occur spontaneously or after trivial trauma. Cerebral autosomal dominant arteriopathy with subcortical infarcts and ischemic leukoencephalopathy (CADASIL), caused by mutations of the notch3 gene, is also a “small vessel disease”. A genetic angiopathy due to mutations of collagen 4A1, a constituent of the vascular adventitia, which causes porencephaly in infants and lacunar infarcts and leukoencephalopathy in adults, is the most recent addition to this group.
Cerebral amyloid angiopathy, caused by deposition of various types of amyloid, causes similar vascular pathology but affects primarily leptomeningeal and cortical vessels.

According to some authors, embolism is the most frequent cause of ischemic infarction. Most emboli are fragments of blood clots that originate in the heart or major vessels. Conditions causing cardiac emboli include myocardial infarcts, atrial fibrillation and other arrhythmias, rheumatic heart disease, bacterial and non-bacterial endocarditis, prosthetic valves, mitral valve prolapse, atrial myxoma, calcified mitral annulus, and cardiomyopathy. An embolus cannot be distinguished grossly or microscopically from a locally formed thrombus. An infarct is assumed to be embolic if it is hemorrhagic, there is a source of emboli, there are multiple infarcts of the brain and other organs (kidney, spleen), and there is no atherosclerosis or other vascular disease. Some emboli consist of atheromatous material that is detached from ulcerated atheromas of the aorta or carotid arteries. Vascular manipulation (angiography, carotid endarterectomy) may cause atheromatous embolism. Rarer causes of embolism are fat, air, and tumor emboli. Unlike atherothrombotic infarcts, which may evolve within hours or days, embolic infarcts have an abrupt onset.

Other causes of arterial occlusion and infarction include:

Temporal arteritis Aspergillus arteritis Cerebral mucormycosis
Temporal (giant cell) arteritis Aspergillus arteritis Mucor arteritis of the basilar artery and pontine infarct
Vasculitis – Polyarteritis nodosa, giant cell (temporal) arteritis, granulomatous arteritis, Takayasu disease (idiopathic aortitis), systemic lupus erythematosus, infectious vasculitis (bacterial endocarditis, pyogenic meningitis, tuberculous meningitis, CNS syphilis, fungal vasculitis).
Sickle cell disease
MCA infarct in sickle cell diseaseHematologic disorders – Polycythemia, hemoglobinopathies (sickle cell disease), deficiencies of anticoagulant factors, thrombotic thrombocytopenic purpura.
Metabolic disorders – Dyslipoproteinemias, Fabry’s disease, homocystinuria and homocysteinemia, organic acidemias, mitochondrial disorders. Some of these conditions cause ischemic infarcts even in children and infants. Mitochondrial disorders can cause TIAs and ischemic strokes.

Hereditary hypercoagulability disorders- Factor V Leiden, Prothrombin 20210A, Methylenetetrahydrofolate Reductase A223V. These polymorphisms derange the delicate balance between natural anticoagulant and procoagulant pathways. They are very prevalent in the population and combine with one another and with aquired conditions that promote clotting, causing venous and arterial infarcts.

Brain dissecting aneurysm
Dissecting aneurysm
Trauma to head and neck can cause dissecting aneurysms and other lesions of the carotid and vertebral arteries. The pattern of brain necrosis in severe traumatic brain injury often suggests vascular occlusion.

Contraceptives and estrogen therapy cause most commonly venous thrombosis and rarely intimal hyperplasia and thrombosis of cerebral and extracerebral arteries.

Vascular Spasm. This is a complication of subarachnoid hemorrhage.

Genetic angiopathies : Cerebral amyloid angiopathy, cerebral autosomal dominant angiopathy with strokes and leukoencephalopathy (CADASIL), mutations of Collagen IV A1.

Miscellaneous: Spontaneous dissecting aneurysms,moya-moya disease (narrowing of proximal cerebral arteries).

Thrombosis of venous sinuses and their tributaries causes congestion, hemorrhage, and necrosis of brain tissue (venous infarction). Venous infarcts from thrombosis of the superior sagital sinus are parasagittal. The causes of venous thrombosis are diverse and include oral contraceptives, inherited deficiencies of anticoagulant factors, cancer and, in infants, dehydration.

About 10% of cases of dementia are caused by cerebrovascular disease, most commonly multiple ischemic lesions. Examination, in these cases reveals a combination of small or large infarcts, hippocampal sclerosis, leukoencephalopathy due to cerebral amyloid angiopathy or other small vessel disease, and other lesions. These lesions affect cumulatively large areas of the cortex, especially regions involved in memory and higher functions. Vascular pathology may be combined with Alzheimer’s disease or other neurodegeneration.

Further reading: Ringelstein EB, Nabavi DG. Cerebral small vessel diseases: cerebral microangiopathies. Curr Opin Neurol. 2005;18:179-88. PubMed