Pathogenesis and Pathology of Acute Ischemic Stroke: The process leading from the development of atherosclerosis (deposition of cholesterol and other nasty crap in the arteries) to the occurrence of acute ischemic (non-bloody/non-hemorrhagic) stroke and consequent cell damage is complicated, and many of the intermediary steps are not completely understood. Ischemic stroke is primarily caused by atherosclerosis in large arteries (e.g., carotid, middle cerebral, and basilar arteries) or small arteries (eg, lenticulostriate, basilar penetrating, and medullary arteries), or it may be caused by a thrombus or clot that comes from the left side of the heart and zips up into the cerebral vasculature (cardioembolic). Atherogenesis is the process in which the inside of a blood vessel becomes narrowed by deposition of choleterol, fat, cells, and thrombus material, ultimately to the point of obstruction.
The earliest atherosclerotic lesion is the fatty streak, which was seen in a large autopsy study of coronary arteries and aortas in patients who died between infancy and age 29. (Stary 1989) In this study, approximately 65% of children ages 12 to 14 years had these lesions. Fatty streaks are visible to the eye as areas of yellowish discoloration of the surface of the intimal (inside) layer of the vessel wall. Under the microscope, the lesions primarily consist of lipid-filled macrophages (foam cells). Macrophages are white blood cells that enter into tissue and ingest foreign material. In this study, 8% of children in late childhood or early adolescence had already developed more advanced, focal lesions. These lesions, which occur almost entirely in branch points of the arterial vessels, are characterized by the addition of massive extra-cellular lipids that displaced normal cells and matrix.
By the time people are in their 20’s, some atheromatous lesions have evolved into complex fibrous plaques, which consist of a central acellular area of lipid covered by a cap of smooth muscle cells and collagen. Deposition of platelets and fibrin on the surface appears to be the result of injury to the lining cells of the vessel wall (endothelial injury) and clot-dependent fibrotic organization occurs. Over time, these early atherosclerotic lesions progress to clinically relevant and advanced atherosclerosis; risk factors play a role in the development of these more advanced lesions.
The progression of early atherosclerotic lesions to clinically advanced atherosclerotic lesions occurs with increased frequency in persons with risk factors for atherosclerotic disease (e.g., high blood pressure, high cholesterol, tobacco use). Atherosclerosis is considered to be a response to chronic minimal injury to the endothelial lining of the arterial wall. Interactions among white blood cells (monocytes, platelets, lymphocytes), lipoproteins and smooth muscle cells contribute to and maintain the pathogenic process. Note that monocytes are the circulating blood version of macrophages (in this case, blood cells that eat foreign stuff). Adhesion of circulating monocytes to the internal vessel wall is an early event in the development of atherosclerosis. After adhesion, the monocytes infiltrate between the endothelial cells and enter the subendothelial space and are transformed into lipid-filled macrophages called foam cells.
The proliferation of smooth muscle cells into the intima and over the layer of foam cells then occurs. Normally, smooth muscle arterial cells are present in the media (middle layer) rather than the intima, and it is the thickening of this layer that makes up a significant amount of the atherosclerotic lesion. Another important step in the formation of a clinically significant atherosclerotic lesion is platelet aggregation and thrombus formation. Platelets are the white blood celss that are responsible for blood clotting. Platelet aggregation is an importnat component of the blood clotting cascade and in the case of atheromatous lesions is thought to occur because of toxins released by macrophages and the ongoing intimal damage. Platelets bind to these areas and release growth factors that further stimulate proliferation of smooth muscle and possibly the formation of the outside capsule of these lesions.
Repetitive arterial wall injury of this type with thrombus formation is the major mechanism of atherosclerosis. Once blood supply within a vessel has been compromised, damage begins to occur within the neurons and support cells supplied by that artery. The membrane that surrounds the neuron is damaged and becomes leaky, thus allowing for influx of sodium, chloride, water and eventually calcium. Potassium flows out of the cell. Lactic acid and hydrogen further injure the cell, leading eventually to irreversible cellular injury and cell death.
Not all cells in the region affected by the impaired blood supply die. There are two major zones of injury in the affected regions: the core area of ischemia and the ischemic penumbra. It is within the core area of ischemia that the blood flow is the most impaired (below 25%) and it is here that severe ischemia leads to cell death. However, the penumbra is typically a rim of injured but not dead brain tissue outside of the core ischemic zone. This area is supplied by collateral blood vessels and may remain viable for several hours. However, the collateral circulation is typically unable to supply enough oxygen and nutrients to the injured brain tissue; therefore, unless reperfusion is established these cells eventually die, as well. It is the area of the penumbra that is the primary focus of treatment of acute ischemic strokes. So now you know something about how the cerebral blood vessels become damaged. Now let's talk about what happens to the person.
Clinical Aspects of Stroke: Stroke is the clinical term for a loss of brain function due to a disturbance in the blood supply in a particular region of the brain. Stroke is subdivided into two types: ischemic (in which the blood supply is interrupted) or hemorrhagic (in which a blood vessel ruptures). The WHO in the 1970s defined stroke as a "neurological deficit of cerebrovascular cause that persists beyond 24 hours or is interrupted by death within 24 hours" in order to differentiate permanent damage from a transient or reversible deficit caused by a transient ischemic attack (TIA). The time frame of 24 hours was chosen somewhat arbitrarily. There are many well-defined risk factors for stroke and include age > 55, hypertension, prior stroke or TIA, diabetes, hyperlipidemia, cigarette smoking, atrial fibrillation, and migraine with aura.
Signs and symptoms of stroke are dependent on the area of the brain involved. The area of the brain involved in stroke is dependent on the particular blood vessels affected and the type of stroke that occurred (ischemic vs. hemorrhagic). An ischemic stroke involving the anterior circulation (the area of interest in this submission) may result in a variety of neurological deficits. Left (dominant) hemisphere major or branch cortical infarction may lead to the following impairments: aphasia, right hemiparesis (paralysis), right-sided sensory loss, right-sided spatial neglect, right homonymous hemianopia (right half of the visual field is lost), and/or impaired right conjugate gaze. Right (nondominant) hemisphere major or branch cortical infarction may lead to the following impairments: left hemiparesis, left-sided sensory loss, left-sided spatial neglect, left homonymous hemianopia, and/or impaired left conjugate gaze.
Stroke is diagnosed via history, physical and neurological examination, and neuroimaging; it is most commonly diagnosed in an emergency room setting. It is highly important to differentiate between ischemic and hemorrhagic stroke as the management of these conditions is very different. A recent study comparing the effectiveness of MRI and CT for the diagnosis of acute stroke in a suburban hospital found MRI to be more effective in identifying acute stroke of all types.
Treatment of Acute Ischemic Stroke: Approved treatment for acute ischemic stroke is limited to a single therapy – intravenous recombinant tissue plasminogen activator, or IV-rtPA. Thrombectomy via the clot retrieval devices can be used in the setting acute ischemic stroke, these devices have not been approved or cleared for the treatment of stroke. The significant limiting factor for both of these treatments is the time from known onset to presentation to the ER. IV-rtPA must be administered within 3 hours of onset of stroke symptoms and the neurothrombectomy must occur within 8 hours. Only preventative and rehabilitative therapies exist beyond these two therapeutic options.
Epidemiology of Stroke (primarily from the Heart Disease and Stroke Statistics—2008 Update: A Report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee): Stroke is one of the most common disorders affecting the American population. The incidence of new or recurrent strokes among Americans is about 700,000, and 87% of these are ischemic strokes. About 500,000 of these are new strokes, and 200,000 are recurrent attacks. At younger ages, the stroke incidence rates in men are greater than in women but not at older ages. The male/female incidence was 1.25 in those 55 to 64 years of age, 1.50 in people 65 to 74 years of age, 1.07 in those 75 to 84 years of age, and 0.76 in those 85 years or greater. African-Americans are at a greater risk of stroke than whites. The age-adjusted stroke incidence rates in those 45 to 84 years of age are 6.6 per 1000 population in black males, 3.6 in white males, 4.9 in black females, and 2.3 in white females. Prevalence of stroke varies according to race: in 2005 it was 2.5% among whites, 3.2% among African-Americans, 2.4% among Asians and 5.1% among Native Americans.
Mortality due to stroke is an important consideration. Stroke accounted for about 1 of every 16 deaths in the United States in 2004. About 50% of stroke deaths in 2003 occurred out of hospital. Stroke total-mention mortality in 2002 was about 273,000 and ranks 3rd among all causes of death (behind heart disease and cancer). According to the ARIC study (NHLBI), 8 to 12% of ischemic strokes and 37 to 38% of hemorrhagic strokes result in death within 30 days, among people between the ages of 45 and 64, although the total rates are probably higher than these. An epidemiological study of stroke in Europe revealed an overall mortality rate (hemorrhagic and ischemic stroke) of 20% at 28 days. (Bejot 2007) A study of patients aged 65 recruited from a random sample of HCFA Medicare Part B eligibility lists showed that the 1-month case fatality was 12.6% for all strokes (8.1% ischemic and 44.6% hemorrhagic). The 2004 overall death rate for stroke was 50.0 (48.1 for white males, 73.9 for black males, 47.4 for white females, and 64.9 for black females). In 2002, the mean age at stroke death was 79.6 years. Males had a younger mean age at stroke death than females, and blacks, American Indians, and Asians had younger mean ages at death than whites.
Stroke is a leading cause of serious, long-term disability in the United States according to a survey of the US Bureau of the Census. In 1999, more than 1,100,000 American adults had some level limitations in function and/or activities of daily living, resulting from stroke. The length of time to recover from a stroke depends on its severity. 50% to 70% of stroke survivors regain functional independence; however, 15% to 30% are permanently disabled, and 20% require institutional care at 3 months after onset. In a study of ischemic stroke survivors who were at least 65 years of age, these disabilities were observed 6 months post-stroke:
- 50% had some hemiparesis;
- 30% were unable to walk without some assistance;
- 26% were dependent in activities of daily living;
- 19% had aphasia (inability or difficulty in expressing or comprehending language);