Ischemic Stroke

As we have mentioned in prior posts the term ischemic stroke is used to describe a variety of conditions in which blood flow to part or all of the brain is reduced, resulting in tissue damage. Although in some cases this may be a chronic condition, most strokes occur acutely. Research over the last four decades has resulted in a significant expansion of our knowledge and understanding of the molecular and cellular processes that underlie ischemia-induced cellular injury.

The goal of this review is to provide an overview of the underlying factors, such as the hemodynamic changes and molecular and cellular pathways, which are involved in stroke-related brain injury.

STROKE SUBTYPES — Acute ischemic stroke subtypes are often classified in clinical studies using a system developed by investigators of the TOAST trial, based upon the underlying cause. Under this system, strokes are classified into the following categories:

• Large artery atherosclerosis
• Cardioembolism
• Small vessel occlusion
• Stroke of other, unusual, determined etiology
• Stroke of undetermined etiology

Ischemic strokes are due to a reduction or complete blockage of blood flow to some areas of the brain. This reduction can be due to decreased systemic perfusion, severe stenosis or occlusion of a blood vessel. Decreased systemic perfusion can be the result of low blood pressure, heart failure, or loss of blood. Determination of the type of stroke can influence treatment to be used. The main causes of ischemia are thrombosis, embolization, and lacunar stroke from small vessel disease. Ischemic strokes represent about 80 percent of all strokes. (See "Stroke Symptoms and Diagnosis")

• Thrombosis refers to obstruction of a blood vessel due to a localized occlusive process within a blood vessel. The obstruction may occur acutely or gradually. In many cases, underlying pathology such as atherosclerosis may cause narrowing of the diseased vessel. This may lead to restriction of blood flow gradually, or in some cases, platelets may adhere to the atherosclerotic plaque forming a clot leading to acute occlusion of the vessel. Atherosclerosis usually affects larger extracranial and intracranial vessels. In some cases, acute occlusion of a vessel unaffected by atherosclerosis may occur because of a hypercoagulable state.

• Embolism refers to clot or other material formed elsewhere within the vascular system that travels from the site of formation and lodges in distal vessels causing blockage of those vessel and ischemia. The heart is a common source of this material, although other arteries may also be sources of this embolic material (artery to artery embolism). In the heart, clots may form on valves or chambers. Tumors, venous clots, septic emboli, air and fat can also embolize and cause stroke. Embolic strokes tend to be cortical and are more likely to undergo hemorrhagic transformation, probably due to vessel damage caused by the embolus

• Lacunar stroke occurs as a result of small vessel disease. Smaller penetrating vessels are more commonly affected by chronic hypertension leading to hyperplasia of the tunica media of these vessels and deposition of fibrinoid material leading to lumen narrowing and occlusion. Lacunar strokes can occur anywhere in the brain but are typically seen in sub-cortical areas. Atheroma can also encroach on the orifices of smaller vessels leading to occlusion and stroke. (See "Lacunar Stroke".)

• Nonatherosclerotic abnormalities of the cerebral vasculature, whether inherited or acquired, predispose to ischemic stroke at all ages, but particularly in younger adults and children. These can be divided into noninflammatory and inflammatory etiologies. The following list, though not exhaustive, highlights the major nonatherosclerotic vasculopathies associated with ischemic stroke:

• Arterial dissection
  
• Fibromuscular dysplasia 
• Vasculitis 
• Moyamoya disease
• Sickle cell disease arteriopathy 
• Focal cerebral arteriopathy of childhood 

• Decreased systemic perfusion due to systemic hypotension may produce generalized ischemia to the brain. This is most critical in the borderzone (or watershed) areas, which are territories that occupy the boundary region of two adjacent arterial supply zones. The ischemia caused by hypotension may be asymmetric due to preexisting vascular lesions. Areas of the brain commonly affected include the hippocampal pyramidal cells, cerebellar Purkinje cells, and cortical laminar cells discussed below.

GENETICS OF STROKE — Many of the known risk factors for stroke are variable traits influenced by multiple genes, making it difficult to sort out the genetics behind them. The study of stroke genetics is also impaired by interactions between different risk factors that modulate their effects. It is widely accepted, however, that there is a genetic component to stroke that can lead to increased or decreased risk. Much of the evidence for this comes from studies of twins and from families with a history of stroke.

• Earlier studies of twins have been troubled by low sample numbers and poor classification of stroke type. However, these studies indicate that stroke-related death in one sibling is associated with a higher risk of stroke-related death in the other sibling among monozygotic (identical) twins versus dizygotic (fraternal) twins. This observation suggests that genetic factors shared by the monozygotic twins played a role in their strokes. 

• A family history of stroke is associated with an increased risk of stroke among the offspring. This has been observed for offspring with maternal and paternal histories of stroke, and among individuals having a sibling with a prior stroke.

Monogenic disorders — A number of monogenic syndromes are associated with an increased risk of ischemic stroke, including the following:

• Marfan syndrome and Ehlers-Danlos syndrome, which predispose to cervical artery dissection 
• Familial moyamoya disease 
• Fabry disease 
• Pseudoxanthoma elasticum
• Homocystinuria
• Menkes disease
• Cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy
• Cerebral autosomal recessive arteriopathy with subcortical infarctions and leukoencephalopathy (CARASIL)
• Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS)
• Sickle cell disease 
• Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS)

It is important to note that all of these conditions together account for only a small percentage of ischemic strokes.

SUMMARY

• Under normal conditions, the rate of cerebral blood flow is primarily determined by the amount of resistance within cerebral blood vessels. Dilation of vessels leads to an increased volume of blood in the brain and increased cerebral blood flow, whereas constriction of vessels has the opposite effect. Cerebral blood flow is also determined by variation in the cerebral perfusion pressure.

• The brain is exquisitely sensitive to even short durations of ischemia. Multiple mechanisms are involved in tissue damage that results from brain ischemia. 

• Brain ischemia initiates a cascade of events that eventually lead to cell death, including depletion of ATP, changes in ionic concentrations of sodium, potassium, and calcium, increased lactate, acidosis, accumulation of oxygen free radicals, intracellular accumulation of water, and activation of proteolytic processes.

• Cell death following cerebral ischemia or stroke can occur by either necrosis or by apoptosis. Low levels of ATP within the core infarct are insufficient to support apoptosis, and cell death occurs by necrosis. In the ischemic penumbra, ATP levels are sufficiently high that cell death by apoptosis can occur. As the duration of ischemia increases, however, ATP levels are eventually depleted and the proportion of cells that undergo necrosis is increased.