Cerebrovascular Disease: Epidemiology and Natural History


Background

Until fairly recently, stroke was largely believed to be a result solely of intracranial pathology. William Osler attributed stroke mainly to intracranial hemorrhage or vasospasm and made no mention of carotid or vertebral artery occlusive disease. Yet the relationship between extracranial carotid disease and stroke had been surmised previously as early as 1875, when Gowers reported on a patient with carotid occlusion, left visual loss, and right hemiplegia. Subsequently, in 1905, Chiari studied 400 consecutive autopsies and discovered thrombus superimposed on carotid artery atherosclerotic plaque in seven patients, four of whom had suffered embolic strokes. This important observation likely represented the first description linking carotid plaque atheroembolism to ischemic stroke. Perhaps the greatest breakthrough in the study of the pathophysiology of cerebrovascular disease was Fisher’s publication of clinicoanatomic correlations on occlusion of the carotid arteries in 1951 and 1954. , He specifically describes the atherosclerotic plaque as the culprit lesion in carotid artery disease and importantly notes that the distal internal carotid artery (ICA) is usually free of disease, raising the possibility of surgical bypass to a healthy target vessel. In 1954, Eastcott et al. reported on the first successful carotid surgery for occlusive disease, in which the carotid bifurcation was resected and in-line flow restored via a common carotid-to-ICA anastomosis. The first successful carotid endarterectomy (CEA) was performed by DeBakey in 1953 and reported along with a 19-year symptom-free follow-up in 1975. , In the 1990s, several randomized clinical trials clearly demonstrated the safety and effectiveness of CEA but also its superiority to contemporaneous medical treatment in both symptomatic as well as certain asymptomatic patients.

Stroke

Background

Stroke, or cerebral infarction, is the acute development of a focal neurologic deficit caused by disruption of the blood supply to an area of the brain. Strokes can be ischemic, due to occlusion of a blood vessel or other causes of malperfusion, or hemorrhagic, due to rupture of a blood vessel. The majority of strokes in the United States, approximately 87%, are in fact ischemic in etiology. Extracranial cerebrovascular disease consisting of atherosclerotic occlusive disease of the carotid artery is considered to be one of the key preventable causes of ischemic stroke, along with atrial fibrillation and hypertension. Stroke is defined as an acute neurologic dysfunction of vascular etiology with corresponding signs and symptoms lasting more than 24 hours and resulting from infarction of focal areas of the brain. Ischemic stroke related to the carotid artery can present with sudden contralateral sensorimotor loss, speech deficit, and ipsilateral monocular blindness. In a transient ischemic attack (TIA), the ischemic parenchyma recovers and returns function to baseline. The full clinical impact of a stroke is often not apparent for up to 2 weeks, as the ischemic penumbra either recovers or evolves to infarction.

Costs of Stroke

The estimated total direct and indirect cost of stroke in the United States in 2014–2015 was $45.5 billion. Between 2015 and 2035 total direct medical stroke-related costs are projected to more than double, from $36.7 billion to $94.3 billion, with the majority of the increase arising from the care of octogenarians. The total cost of stroke care from 2005 to 2050 is projected to be approximately $1.52 trillion for non-Hispanic white patients, $313 billion for Hispanic patients, and $379 billion for black patients.

Prevalence and Incidence

Stroke Prevalence

Stroke is among the major causes of mortality and disability worldwide; it is estimated that in 2013 the prevalence of stroke was 25.7 million, with 10.3 million people experiencing a first stroke. Stroke causes 5.5 million deaths and over 44 million disabilities every year. In the United States alone, a stroke occurs approximately every 40 seconds; this translates into about 2160 strokes each day. Each year, approximately 800,000 Americans suffer a stroke. An estimated 70 million Americans ≥20 years of age self-report having had a stroke. The overall stroke prevalence or proportion of the population affected by stroke relative to the population as a whole in the United States during the years 2013–2016 was approximately 2.5%. The prevalence of additional but clinically silent cerebral infarction is estimated to range from 6% to 28%. , Projections show that by 2030, an additional 3.4 million people will have had a stroke, a 20.5% increase in prevalence from 2012. , ,

The prevalence of stroke varies with the population studied, depending upon age, ethnicity, sex, and risk-factor profile ( Figs. 88.1 and 88.2 ). The prevalence of ischemic stroke increases with age in both men and women. In the United States, the prevalence of stroke is 6% among American Indian/Alaska Native populations, 4.0% among blacks, 2.6% among Hispanics, 2.3% among whites, and 1.6% among Asians.

Figure 88.1, Prevalence of stroke by age and sex. (National Health and Nutrition Examination Survey: 2011–2014).

Figure 88.2, Annual incidence of first cerebral infarction by age, sex, and race (Greater Cincinnati/Northern Kentucky Stroke Study: 1999). Rates for black men and women 45 to 54 years of age and for black men 75 years of age and above are considered unreliable. GCNKSS , Greater Cincinnati/Northern Kentucky Stroke Study.

Stroke Incidence

Each year in the United States approximately 800,000 people experience a new or recurrent stroke, and approximately 185,000 are recurrent strokes. Although women have a lower age-adjusted stroke incidence than men, women have a higher lifetime risk of stroke than men because of their longer life expectancy. , , African Americans have a risk of first-ever stroke twice that of whites. , Data from the Framingham Heart Study indicate that the age-adjusted incidence of clinical stroke per 1000 person-years in 1950 to 1977, 1978 to 1989, and 1990 to 2004 was 7.6, 6.2, and 5.3 in men and 6.2, 5.8, and 5.1 in women, respectively. Analysis of data from the Framingham Study additionally suggests that stroke incidence is declining over time in this largely white cohort, although a similar decline was not noted in African Americans.

Trends in the Prevalence/Incidence of Stroke

Currently stroke is the fifth leading cause of death in the United States when considered separately from other cardiovascular diseases. , , Several additional population-based studies have tracked stroke incidence during recent decades. Rothwell et al. reported a decrease in stroke incidence of nearly 40% between the 1980s and 2002 in the United Kingdom. In an additional report from the American Heart Association, the lifetime risk of stroke in a 65-year-old male decreased from 19.5% 50 years ago to 14.5% in 2013. , In the United States, the Framingham cohort and the Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS) also found that the incidence of stroke has been declining over the past 50 years. , In contrast to the prior reports, the Minnesota Stroke Study noted that the incidence of stroke appeared to be stable in both men and women between the years 1990 and 2000.

In a 2012 report from the Atherosclerosis Risk in Communities Study (ARIC) including 14,357 participants between 1987 and 2011, stroke was diagnosed in 1051 (7%). The incidence was strongly related to older age, male sex, black race, hypertension, diabetes, coronary heart disease, and current smoking, and was negatively associated with the use of cholesterol-lowering medications. Stroke incidence decreased over time in both white and black subjects. The decrease in age-adjusted incidence was evident in participants aged 65 years and older but not in younger subjects, but was similar by sex. Additionally, mortality after stroke was noted to decrease over time. The authors concluded that there was a demonstrable decrease in stroke incidence and mortality rates in the United States during this time period. In a report from the Centers for Disease Control and Prevention (CDC) Behavioral Risk Factor Surveillance System in the years 2005 and 2008, the prevalence of stroke in the United States was 2.6%. After a comprehensive review of multiple population-based studies, it was not possible to prove or disprove whether the prevalence of stroke may be decreasing, although it was felt that there was abundant evidence that the mortality attributable to acute stroke is decreasing, likely related to improvements in acute stroke treatment. It was furthermore noted that an increase in the burden of stroke due to the aging populations of both the United States and European countries was still to be expected.

More recent data from the GCNKSS reported in 2017 showed that decreases in stroke incidence over time have been driven primarily by a decrease in ischemic stroke in men as opposed to women. In contrast to their reports from prior study periods, stroke incidence rates were noted to be similar by sex in 2010.

In a recent update from the Tromso Study, from 1995 to 2012 the influence of improved risk factor control on the possibly declining incidence of stroke was examined. Over the period from 1995 to 2012, the incidence of ischemic stroke decreased from 363 per 100,000 person-years to 306 per person-years ( Fig. 88.3 ). Changes in cardiovascular risk factors were found to account for 57% of the decrease in ischemic stroke incidence. The most important contributors were decreasing mean systolic blood pressure and smoking prevalence. Changes in total cholesterol levels surprisingly did not contribute significantly to the decline in the incidence of ischemic stroke.

Figure 88.3, Trends in annual incidence rates of ischemic stroke in participants aged ≥30 years. The Tromso Study, 1995 to 2012

Not all relevant studies have definitively shown a decrease in stroke incidence or prevalence. Data from the Nationwide Inpatient Sample from 1995 through 2012 reveals that rates of hospitalization in the United States for acute ischemic stroke almost doubled for males aged 18–44 years. In the Global Burden of Disease Study in 2016, there was a 2.7% overall increase in ischemic stroke prevalence worldwide from 2006 to 2016. Regional decreases in the incidences of ischemic stroke were noted primarily in high-income countries. No significant change was seen in low- or middle-income countries. Even more recent data in 2020 from the Global Burden of Disease Study has reported that although stroke incidence, prevalence, mortality and disability-adjusted life years did in fact decline from 1990 to 2017, the absolute number of people who developed new stroke, died, survived or remained disabled from stroke has almost doubled ( Fig. 88.4 ). The authors note that this most recent data should supersede previous findings; stroke remains the second leading cause of death and disability worldwide.

Figure 88.4, Changes in age-specific stroke incidence, mortality and disability-adjusted life-year rates per 100,000 by sex, from 1990–2017.

Impact of Improved Medical Therapy on Stroke Incidence

Previous randomized trials have demonstrated a clear benefit of surgical therapy with CEA over contemporaneous medical therapy regarding stroke prevention in both asymptomatic and previously symptomatic patients with severe extracranial ICA stenosis. , , However, recent analyses have additionally reported that the annual risk of stroke in patients with asymptomatic ICA stenosis is lower than that reported in the CEA trials, presumably due to improved medical therapy. , Nevertheless it remains clear that asymptomatic ICA stenosis continues to cause a significant number of strokes. Data from the GCNKSS have resulted in conservative estimates that about 41,000 strokes may be attributed to previously asymptomatic extracranial ICA stenosis annually in the United States. The increased usage of cholesterol-lowering medications is often cited as the likely reason behind the decreased incidence of stroke, despite evidence to the contrary from the Global Burden of Disease Study cited previously.

The epidemiologic association between elevated cholesterol levels and stroke is inconsistent and somewhat controversial. Treatment with statins was associated with stroke reduction in a meta-analysis of more than 90,000 patients. It should be noted that many of the studies included in this meta-analysis involved secondary as opposed to primary stroke prevention. Nevertheless, the relative reduction in stroke risk was found to be 21%. Statins have also been demonstrated to be associated with a reduction in stroke incidence in a variety of specific patient populations, including those with known coronary artery disease, hypercholesterolemia, normocholesterolemia, elderly patients, and diabetics. Statins have also been demonstrated to consistently reduce carotid intima-media thickness (CIMT). A recent meta-analysis including over 113,000 patients has shown that the use of statin therapy at stroke onset is associated with improved late outcome, including both rates of functional independence and survival. Although data regarding the utility of statin medications for the primary prevention of stroke is less conclusive than for secondary prevention, current guidelines do in fact recommend statins for the prevention of first stroke in high-risk patients, including those with LDL levels greater than 4.1 mmol/L and for males older than age 45 and females older than age 55 with the following risk factors: a positive family history, smoking, hypertension, or left ventricular hypertrophy. However, it is unclear what exact role and effect statins have in patients with known severe carotid occlusive disease with regard to stroke prevention.

In a report authored by Writing Group Members on behalf of the American Heart Association’s Stroke Council, a clear decline in stroke mortality is noted, and it is believed that this reduction is mainly due to the treatment of hypertension as opposed to antilipid therapy. The authors note that epidemiologic studies have shown that elevated blood pressure is the most important determinant of the risk of stroke. This report echoes the Tromso Study, which noted that while changes in cardiovascular risk factors were found to account for 57% of the decrease in ischemic stroke incidence, the most important factor was felt to be improved control of hypertension.

Ischemic Stroke

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