Pathophysiology

Atherosclerotic CS originates near the bifurcation of the common carotid artery (CCA) in the region of the bulb.^8,16 Conditions near the bulb, including low shear stress, flow separation, and nonlaminar flow, increase the contact time between blood-borne particles, such as lipids, and the vessel wall. A fatty streak, consisting of monocytes that differentiate into lipid-laden macrophages, or foam cells, eventually develops into an atherosclerotic plaque. As the plaque enlarges, blood flow to the brain can be reduced or interrupted by severe narrowing or occlusion of the ICA. In addition, turbulence may actually damage the atherosclerotic plaque, resulting in loss of intimal continuity or ulceration. Platelets and fibrin aggregate on the roughened intimal surface, and there is subsequent thrombosis. Fragments of a fractured plaque or thrombus may embolize to smaller distal arteries. Interruption of cerebral blood flow and cerebral infarction are the potential life-threatening sequelae.

Clinical Presentation

As noted earlier, CS may be symptomatic or asymptomatic. Patients with severe CS may be asymptomatic if the circle of Willis is competent and adequately perfuses the territory of the middle cerebral artery.

The presentation of symptomatic CS may consist of tran­sient or permanent focal neurologic symptoms related to the ipsilateral retina or cerebral hemisphere, including retinal ischemia manifesting with a brief, fleeting attack of monocular blindness (amaurosis fugax), weakness or numbness of the contralateral arm, leg, and/or side of the face, visual field defect, dysarthria, and, in the case of involvement of the dominant hemisphere (usually left), aphasia. Asymptomatic CS may be detected on a routine physical examination or during a workup for ill-defined symptoms, such as dizziness, generalized weakness, syncope or near-syncopal episodes, blurred vision, or transient visual phenomena such as “floaters” or “stars.”

In the history of individuals with CS, there are important nonmodifiable and modifiable risk factors. The nonmodifiable risk factors include age, gender, race, and ethnic background. The modifiable risk factors include high blood pressure, cigarette smoking, hyperlipidemia, DM, hyperhomocysteinemia, obesity, nutrition, physical inactivity, and chronic kidney disease (CKD). Other modifiable risk factors may include heavy alcohol consumption, sleep apnea,¹⁷ and depression.^2,17–19

Numerous studies have demonstrated that CS is present and, without medical therapy, worsens with advancing age.

On average, women who sustain a stroke are approximately 4 years older than their male counterparts (75 years versus 71 years).²⁰ Women aged 45 to 54 years are twice as likely to have had a stroke as age-matched male peers. Furthermore, women aged 45 to 54 years are four times more likely than women aged 35 to 44 years to have had a stroke. Women with atrial fibrillation are at significantly higher risk of stroke than men.²¹ Migraine with aura is associated with ischemic stroke in younger women, particularly if they smoke or use oral contraceptives.²² In generally healthy postmenopausal women, hormonal treatment with combination estrogen and progestin and conjugate equine estrogen alone increases stroke risk by 44% and 55%, respectively. The proportion of antenatal and postpartum hospitalizations for stroke increased between the mid-1990s and the first decade of 2000, specifically attributable to hypertensive disorders during the postpartum period.²³ Menopause before age 42 years is associated with twice the risk of stroke experienced by postmenopausal women in other age groups.¹⁹

Blood pressure is a powerful determinant of CS, ischemic stroke, and ICH.^1,19 In the FHS, there was a twofold greater risk of CS of more than 25% for each 2-mm Hg increase in systolic blood pressure.²⁴ In the Systolic Hypertension in the Elderly Program (SHEP), systolic blood pressure of 160 mm Hg or higher was the strongest independent predictor of CS.²⁵ For each 10-mm Hg increase in blood pressure, the risk of stroke increases by 8% in whites. In contrast, a threefold increase in stroke risk, at 24%, is noted in African Americans.¹

Cigarette smoking also is a strong independent risk factor for ischemic stroke. Current smokers are at a risk of stroke that is two to four times higher than nonsmokers or those who have quit for more than 10 years.^26,27 Smoking increases the relative risk (RR) of ischemic stroke by 25% to 50%.⁸ Cigarette smoking is associated with extracranial carotid artery intima-media thickness (IMT) and the severity of CS. Furthermore, the severity of CS has been shown to be greater among current smokers than nonsmokers and is significantly related to pack-years of smoking.²⁸

Epidemiologic studies consistently have shown an association between cholesterol and carotid IMT, although only a modest or weak association between elevated total cholesterol or low-density lipoprotein cholesterol (LDL-C) and increased risk of ischemic stroke.^8,18 Conversely, in the Women’s Health Study, total cholesterol and LDL-C levels were strongly associated with increased risk of ischemic stroke.²⁹ The literature also supports an inverse association between high-density lipoprotein cholesterol (HDL-C) and stroke or carotid atherosclerosis.³⁰

DM is associated with a twofold to fivefold increase in ischemic stroke.¹¹ Patients with DM who sustain an ischemic stroke typically are younger, more likely to be black, and more likely to have hypertension, myocardial infarction (MI), and high cholesterol than counterparts without diabetes.³¹ Although the absolute number of hospitalizations for acute ischemic stroke decreased 17% between 1997 and 2006, the number of hospitalizations for acute ischemic stroke with comorbid DM rose by 27% during the same time period.³²

Numerous studies have demonstrated an association between diabetes and progression of carotid IMT. In the Epidemiology of Diabetes Interventions and Complications (EDIC) study, progression of IMT was greater among patients with diabetes than those without diabetes, although it was less among patients with diabetes who were treated with intensive insulin therapy.³³ In several studies, intensive therapy to reduce blood glucose has not reduced the risk of stroke in patients with type 2 DM. In contrast, long-term follow-up of patients in the Diabetes Control and Complications Trial (DCCT) who had type 1 diabetes treated with intensive insulin therapy has shown a 57% reduction in the rate of nonfatal MI, stroke, and death, although the absolute risk reduction was small at less than 1% over 17 years of follow-up.³⁴

Hyperhomocysteinemia increases the risk of stroke. Among elderly patients with elevated homocysteine levels, there is a twofold risk of development of CS of more than 25%. In the Atherosclerosis Risk in Communities (ARIC) study,³⁵ increased carotid IMT was three times more likely among patients with the highest quantile versus lowest quantile of homocysteine. Intake of grain products enriched with folic acid has been associated with decreased stroke rates and plasma concentrations of homocysteine. However, studies of patients with vascular disease have not confirmed a benefit of homocysteine lowering by B-complex vitamin therapy on cardiovascular outcomes, including stroke.

Obesity, defined as body mass index above 30 kg/m², has been established as an independent risk factor for coronary heart disease (CHD) and premature mortality. The relation­ship of obesity to stroke has been studied mostly in relationship to primary prevention. In studies of components of the metabolic syndrome (i.e., blood glucose, hypertension, dys­lipidemia, body mass index, waist/hip ratio, and urinary albumin excretion), a strong relationship exists between obesity and carotid atherosclerosis, behind hypertension and hypercholesterolemia.¹¹

Several studies have demonstrated the effect of nutrition on risk of stroke. In a randomized clinical trial in Spain, a Mediterranean-style diet that is rich in nuts and olive oil was associated with a reduced risk stroke (hazard ratio [HR] 0.54; 95% CI 0.35-0.84).³⁶ The Nurses’ Health Study showed that each one-serving increase in sugar-sweetened soda was associated with a 13% increase in risk of ischemic stroke. However, each one-serving increase in low-sugar soda was associated with a 7% increase in ischemic stroke as well as a 27% increase in hemorrhagic stroke.³⁷ In Sweden, individuals without hypertension who consumed seven or more servings of fruits and vegetables each day had a 19% lower risk of stroke than those who ate only one serving per day.³⁸

Physical inactivity is a well-documented, modifiable risk factor for stroke. Individuals who exercised four or more times per week had a 20% lower risk of stroke than persons who exercised fewer than four times per week. The effect is largely caused by reduction of other risk factors such as DM and obesity.³⁹

CKD is an independent risk factor for CVD. In a study of 1003 patients aged 50 years or older who underwent carotid ultrasonography and evaluation of kidney function by estimated glomerular filtration rate (eGFR) and presence of proteinuria, eGFR was significantly correlated with mean maximal carotid IMT but not carotid calcification.⁴⁰ Furthermore, in multiple regression analysis, reduced eGFR, proteinuria, age, male sex, CVD, hypertension, DM, and smoking were independently associated with mean max-IMT. In a secondary analysis of the outcomes of patients with and without CKD among those enrolled in the North American Symptomatic Carotid Endarterectomy Trial (NASCET), individuals who had a glomerular filtration rate (GFR) below 30 mL/min/1.73 m² with symptomatic high-grade CS (≥70%) and who were treated medically had much higher rates of stroke, MI, or death than counterparts with normal GFR.⁴¹

Physical Examination

The physical examination should include a complete cardiovascular and neurologic examination. Important components of the cardiovascular examination include palpation of all bilateral peripheral pulses and auscultation for bruits, as well as blood pressures in bilateral upper extremities in the lying and sitting positions. The neurologic examination should include an examination of mental status, cranial nerves (in­cluding funduscopic examination), and motor and sensory function.

Carotid auscultation for bruit is a marker for generalized atherosclerosis and may be used to screen asymptomatic patients with vascular risk factors. However, because bruits are produced by turbulent flow, they may be pronounced with mild stenosis and less audible or undetectable with severe or critical stenosis. Thus, carotid bruits have relatively low sensitivity for detection of moderate to severe CS^8,42 and auscultation of the neck for carotid bruits is of limited value in evaluating patients with symptoms of TIA or stroke. Symptomatic patients must undergo imaging studies.

Diagnostics

Catheter-based angiography is the criterion standard for defining the degree of stenosis and morphologic characteristics of offending plaque in CS, although it has inherent cost and risks including risk of stroke in about 1% of patients and death in 0.1%.⁴³ Thus, duplex ultrasound, which measures blood flow velocity as an indicator of severity of stenosis, is now the primary diagnostic tool for CS. Indications for carotid duplex ultrasound include the following⁸:

A meta-analysis of studies of color duplex ultrasound demonstrated that when the peak systolic velocity is 130 cm/sec or greater, the sensitivity and specificity are very high—98% and 88%, respectively—in detecting stenotic ICA lesions of 50% or greater. In the setting of a peak systolic velocity of 130 cm/sec or greater, the sensitivity and specificity of duplex ultrasound are 90% and 94%, respectively, in the detection of stenotic lesions of 70% or greater.⁴⁴ For recognizing carotid occlusion, duplex ultrasound has been shown to have a sensitivity of 96% and specificity of 100%.⁴⁵ There is also high agreement between duplex ultrasound and arteriography in the detection of more than 45% stenosis in the carotid artery.^44,46

Magnetic resonance angiography (MRA) and computed tomography angiography (CTA) may be indicated as alternatives or adjuncts to duplex ultrasound in the following scenarios: (1) when duplex ultrasound cannot be obtained, (2) when results of duplex ultrasound are inconclusive, (3) when further evaluation of the severity of stenosis and identification of intrathoracic or intracranial vascular lesions is needed before intervention for severe CS. CTA may be preferred for patients who are not suitable candidates for MRA because of claustrophobia, implanted pacemakers, or other incompatible devices. CTA can provide imaging from the aortic arch to the circle of Willis, defining bone and soft tissue structures surrounding the diseased carotid arteries, tracing the course of a vessel that is tortuous or has a high bifurcation, and directly imaging the vessel lumen and allowing evaluation of stenosis. However, CTA may underestimate CS as compared with rotational angiography. Catheter-based angiography may still be necessary to detect and characterize extracranial cerebrovascular disease when noninvasive imaging is inconclusive or not feasible because of technical limitations or when noninvasive imaging studies yield discordant results.⁸

Differential Diagnosis

The differential diagnosis of symptomatic CS includes intra­cranial arterial stenosis, atheromatous disease of the aortic arch, partial seizure, radiculopathy, neuropathy, microvascular cerebral or spinal pathology, and lacunar stroke. Causes of intracranial arterial stenosis include atherosclerosis, intimal fibroplasia, vasculitis, adventitial cysts, or vascular tumors. Intracranial arterial occlusion may occur as a result of thrombosis or embolism arising from the aortic arch, cardiac chambers, heart valves, or a defect in the septum of the heart allowing a right-to-left shunt. Symptoms and signs of ischemia or infarction in the vertebrobasilar system may include ataxia, cranial nerve deficits, visual field loss, dizziness, imbalance, and incoordination.⁸ Partial seizure may be associated with brief, stereotyped, repetitive behaviors, and electroencephalography is required to confirm the diagnosis. Causes that account for purely sensory symptoms (i.e., numbness, pain, or paresthesia) include radiculopathy, neuropathy, microvascular cerebral or spinal pathology, and lacunar stroke.

Management

Current options for management of CS include medical therapy alone and carotid revascularization (i.e., CEA or carotid angioplasty and stenting [Carotid Angioplasty and Stenting]) plus medical management. To date, there have been no reported studies involving head-to-head comparison of the three treatment approaches. Thus, according to the 2011 collaborative guidelines from the American Heart Association (AHA), the effectiveness of revascularization by CEA or CS versus medical therapy alone has not been well established, especially in asymptomatic CS.⁸ To address this gap, the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2), a clinical trial funded by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH), began enrolling patients in December 2014.⁴⁷ The study involves two parallel, randomized trials. In one trial, patients with at least 70% stenosis of the cervical ICA are randomized to either the combination of CEA and intensive medical management or intensive medical management alone. In the second trial, patients with at least 70% stenosis of the cervical ICA are randomized to either the combination of CS and intensive medical management or intensive medical management alone.⁴⁸ The primary end point is any stroke or death during the periprocedural period and ipsilateral stroke thereafter, out to 4 years of follow-up.

Of note, carotid revascularization is not recommended in the setting of the following three conditions: (1) narrowing of the ipsilateral ICA by less than 50%, (2) chronic total occlusion of the affected carotid artery, and (3) severe disability consequent to cerebral infarction that precludes preservation of useful function.

Medical Therapy

Analysis of data from several studies published in the early 1990s, which included either an arm of medical therapy alone or initial therapy with only medical therapy, revealed that the stroke rate has decreased since the mid-1980s. In NASCET, symptomatic patients treated for 18 months with medical therapy alone without revascularization had stroke rates of 19% for individuals with 70% to 79% initial stenosis, 28% with 80% to 89% stenosis, 33% with 90% to 99% stenosis, and diminished risk near occlusion.⁴⁹ Among asymptomatic individuals managed with medical therapy alone in the ACAS trial, the rate of ipsilateral stroke or death during a 5-year period was 11%.⁵⁰ In the Asymptomatic Carotid Surgery Trial (ACST), the risk of ipsilateral stroke or death during a 5-year period in patients with 70% or greater stenosis randomized to initial medical therapy was 4.7%.⁵¹

From 1999 to 2003, the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial was conducted involving 567 patients with symptomatic high-grade intracranial atherosclerotic stenosis who were randomized to treatment with aspirin or warfarin and standard approaches to risk factor management that were prevalent during that time period.⁵² The 30-day rate of stroke or death of 10.7% and a 1-year rate of the primary end point (ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke) was 25.7%. In a subsequent study, the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) study, 451 similar patients were randomized to intracranial stenting or medical therapy from 2008 to 2011.⁵² In the SAMMPRIS study, medical therapy was much more aggressive, guideline driven, and more intensely monitored than in the WASID trial. In the SAMMPRIS study the stroke and death outcome (5.8%) and the stroke, MI, and death composite primary outcome (12.2%) for medical therapy were 5.8% and 12.2%, respectively—about half of rate achieved in WASID.

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