Ischemic stroke affects all age groups but is primarily a disease of older adults. The annual incidence in the United States approaches 750,000 ischemic strokes per year (101) and seems to be increasing as the population ages. Moreover, age is an independent but unmodifiable risk factor for ischemic stroke. The risk of stroke approximately doubles for each successive decade of life, from about three strokes per 1,000 people aged 55 to 64 years to about 25 strokes per 1,000 people over the age of 85 years (106). The risk of stroke is higher among men up to age 75, but over age 75, it is higher among women and is the leading cause of death among women >85 years. African-Americans carry a disproportionate share of the burden of stroke at all ages, with more than double the incidence and mortality of whites. Among patients who have already survived a stroke, a major risk factor for recurrent stroke is age >75 years (45).

Many of the recognized risk factors for cerebrovascular disease are overly abundant in the elderly population and contribute to their increased stroke risk (Table 17-1).

Hypertension, the leading risk factor for ischemic stroke, increases with advancing age and is found in more than half of people >65 (20). Furthermore, after the age of 65 years, the risk of stroke depends predominantly on systolic rather than diastolic pressure, which also increases linearly with age. Primary prevention of stroke in older adults should include treatment of hypertension, including treatment of isolated systolic hypertension, since antihypertensive therapy reduces the risk of stroke by more than 30% (92). The
Seventh Joint National Commission (JNC 7) guidelines currently recommend medical treatment for blood pressure ≥140/90 mm Hg or ≥130/80 mm Hg in patients with diabetes or chronic kidney disease, with ideal blood pressure being 120/80 mm Hg or less (20). The choice of first-line agent for blood pressure treatment remains somewhat controversial.

Based on the results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (4), which found the use of a thiazide diuretic to be superior and less expensive than other drug classes in preventing vascular disease, the JNC 7 recommends use of thiazide-type diuretics in most patients with uncomplicated hypertension, either alone or in combination with antihypertensive drugs. The JNC 7 recommendations do acknowledge, however, that most patients will require two or more drugs to reach the target blood pressure goals. On the other hand, recent trials of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in patients with cardiovascular or cerebrovascular disease have also demonstrated reduced risk of stroke with treatment using these types of medications (22,23,83,109). Thus, some clinicians prefer to use ACE inhibitors or ARBs for secondary stroke prevention.

Atrial fibrillation (AF), another risk factor for ischemic stroke, also increases sharply with increasing age. Approximately 0.7% of the general US population is estimated to have AF; this proportion increases to 5% to 8% for persons >65 years old and to 10% to 15% for those >80 years old (94). The median age for patients with AF in the United States is 72 years (94). Multiple epidemiologic studies have demonstrated that AF is an independent risk factor for ischemic stroke and increases the relative risk of stroke approximately fivefold (46). In unselected populations with AF, an annual risk of stroke of about 5% is observed, but patients stratified as “high risk” have stroke rates of up to 12% per year (46). Validated risk factors for stroke in AF include age over 75 years, congestive heart failure or left ventricular fractional shortening <25%, hypertension, diabetes, and history of previous thromboembolism (36,47,97). The use of antiplatelet/anticoagulant therapy for stroke prophylaxis in the elderly with AF is somewhat complicated and will be discussed later in the Treatment Options section.

Diabetes mellitus is a risk factor for ischemic stroke, and stroke is at least twice as common in diabetics than nondiabetics. The prevalence of diabetes increases steadily with age, such that approximately 18% of people aged 65 years or older in the United States have this disorder. Some of the increased risk of stroke appears to be related to concomitant hypertension, but at least some component of risk is independently related to diabetes alone (12). Unfortunately, it remains uncertain whether tight glucose control in diabetics is effective for the prevention of stroke.

The role of hypercholesterolemia as a stroke risk factor remains somewhat controversial. It appears that the effect of total cholesterol seems to wane with increasing age, but high levels of low-density lipoprotein (LDL) and low levels of high-density lipoprotein (HDL) increase the risk of stroke even in elderly populations. The class of lipid-lowering agents known as the 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors, or statins, has been studied extensively in patients with vascular disease. It is hypothesized that, in addition to lowering LDL, statins also have “pleiotropic effects” and may stabilize atherosclerotic plaque, reduce platelet aggregation, and decrease inflammation, all of which in turn reduce the risk of vascular events (86). Pooled results of several statin trials involving over 90,000 patients with cardiovascular disease demonstrated a reduction in risk of stroke for patients treated with statins (6). The recently published Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial confirmed that statins reduce the risk for recurrent stroke in patients who have had a stroke or TIA but who have no established cardiac disease (5). Although these trials did not specifically address lipid management in the elderly, no increase in adverse events associated with statins was noted in this group. Therefore, it is now recommended that stroke and TIA become considered a “coronary heart disease risk equivalent” and that these patients be treated with a statin to bring the LDL cholesterol to <100 mg/dL or to <70 mg/dL in patients considered very high risk, defined as “those who have cardiovascular disease together with either multiple risk factors, especially diabetes, or severe and poorly controlled risk factors (i.e., continued smoking), or metabolic syndrome, or patients hospitalized for acute coronary syndromes” (39). The above studies also demonstrated benefit even in patients with “normal” cholesterol levels, so therapy may also be considered in these patients.

Ischemia is caused by transient or permanent occlusion of a cerebral blood vessel. The possible causes of cerebrovascular occlusion are myriad and are described individually in the section titled Evaluation of Stroke Etiology. After occlusion, there is impaired cerebral blood flow (CBF), resulting in a central area (core) of severely constrained perfusion and a peripheral area of less constrained perfusion (ischemic penumbra) (52). In the core, CBF is typically
<15 mL/100 g brain tissue/min, and it will invariably succumb to infarction. In the penumbra, CBF averages 18 to 20 mL/100 g/min. The cells in the penumbra lose electrical function but retain structural integrity. The penumbra thus represents a potentially salvageable area, but the time window for intervention appears to be brief. The brain is able to tolerate low CBF only for a limited amount of time, and the threshold for ischemia varies with the duration and the intensity of the ischemic insult. Thus, it is imperative to rapidly re-establish blood flow in acute stroke in order to minimize the cerebral injury.

Impaired cerebral perfusion sets into motion a series of events called the ischemic cascade (67,68,81). Neurons become unable to maintain aerobic respiration, and anaerobic respiration ensues, leading to accumulation of lactic acid. With the change to a less efficient metabolic state, neurons are no longer able to maintain ionic balance. Excitotoxicity occurs, in which glutamate and other excitatory neurotransmitters worsen the neuronal injury via excessive stimulation of neurons during their energy-depleted state. These neurotransmitters depolarize the neuronal cell membrane, which is followed by an influx of sodium, chloride, and water, resulting in cytotoxic edema. Influx of calcium follows and may lead to neuronal death. Several other elements amplify the ischemic cascade. The details of this topic are beyond the scope of this review, but a few key elements deserve attention. Increased intracellular calcium activates several enzymatic pathways that cause proteolysis, destruction of cell wall lipids, free radical formation, further release of intracellular calcium, and increased production of nitric oxide. The enzymatic disturbances and free radical production lead to widespread disruption of neuronal and endothelial integrity. In addition, in the ischemic zone, a series of cytokines are released, some of which may promote an inflammatory response and disrupt the microcirculation, thereby worsening the ischemic injury. Lastly, cell death may occur in a delayed fashion by apoptosis (33), a genetically programmed form of cell death that may be induced by neuronal ischemia. It is distinct from necrosis because it occurs in a delayed manner and may occur in remote areas from the core of infarction.

The sequence of events described in the previous paragraph occurs to a different degree in all subjects exposed to an ischemic injury. However, laboratory experience suggests that age has an impact on these events. Experimental evidence suggests that older animals are less resistant to ischemia than younger ones and that the neurotoxic response may be more robust with advanced age (25,49,90). The ability to neutralize free radicals and extrude calcium from cells is more reduced in older animals compared with younger counterparts. The ability to synthesize proteins is reduced in the elderly and may lead to impaired cerebral reorganization after both trauma and stroke. The blood-brain barrier in the elderly is less efficient than in the young, and toxins normally excluded from the brain may gain access, worsening the ischemic injury (75). Although CBF is lower in older subjects, cerebral metabolism (as measured by the oxygen extraction ratio) is also lower; thus, an imbalance between supply and demand does not exist. Nevertheless, the normal autoregulatory response seen in young subjects in the setting of impaired perfusion is absent in older individuals (93). Collateral circulation may be impaired in the elderly, leading to infarcts of larger volume (66). The inherent elastic properties of intracranial vessels are affected by aging, reducing the efficiency of the compensatory response to ischemia and acidosis. Thus, it is conceivable that, in older patients, comparable vascular insults may result in a more severe injury than in younger patients. Paradoxically, older stroke patients may fare better when they suffer large middle cerebral artery infarcts with significant mass effect because the age-related atrophy may provide additional space for tissue displacement (64).

Despite significant advances in the treatment of ischemic stroke, the majority of stroke survivors will have some residual neurologic dysfunction. Although most patients have some improvement, it is unfortunately often incomplete. In general, older patients face a worse prognosis than younger patients (56). Mortality due to stroke increases progressively (about 10% below age 65, 20% between ages 65 and 74, 30% between ages 75 and 84, and 40% at age 85 and older) (77). Functional outcome also tends to be worse in older patients, although they have similar neurologic deficits, which suggests that the ability to compensate after stroke is worse in the elderly (56,77). Furthermore, dementia occurs in about one third of elderly stroke survivors, which further adds to the burden of disability (10). A major predictor of outcome after stroke is initial stroke severity, with worse outcomes in patients with more severe deficits (84,91). Recovery depends somewhat on the size and location of the infarction. Small infarctions, particularly subcortical lacunar strokes, may result in little permanent deficit, whereas large hemispheric infarctions may be devastating. The presence of other diseases or medical complications after the stroke also appears to worsen outcome (54), and these tend to be more common among the elderly. Despite these potential prognostic indicators, the marked variability among patients makes prediction for individuals extremely difficult.

Infarcted brain tissue is irreparable, and functional improvement after stroke is believed to occur by recruitment of other neurons to serve new or additional roles. Neurons have been shown to sprout new synapses after stroke in young rodents (17,18,24). Electrical brain mapping in monkeys has demonstrated that the cerebral cortex can be functionally reorganized during recovery after an infarction (24). Similarly, functional magnetic resonance imaging (MRI) in humans has shown increased activity in both hemispheres as patients improve, suggesting recruitment of neighboring cortex and corresponding areas of the contralateral cortex (21). In general, most motor recovery is expected to occur primarily in the first 3 months after stroke. The effect of aging on these reparative processes is unknown in humans, but it is hypothesized that they become less effective with age.