Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis

INTRODUCTION — Atherosclerotic stenosis of the major intracranial arteries, also known as intracranial atherosclerosis (ICAS) or cerebral atherosclerosis, is an important cause of ischemic stroke. This topic focuses on the epidemiology, clinical manifestations, and diagnosis of ICAS. The treatment and prognosis of ICAS is reviewed separately. (See "Intracranial large artery atherosclerosis: Treatment and prognosis".)

Other ischemic stroke subtypes are discussed elsewhere. (See "Stroke: Etiology, classification, and epidemiology" and "Clinical diagnosis of stroke subtypes" and "Lacunar infarcts" and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".)

PATHOPHYSIOLOGY — Atherosclerosis is a pathologic process that causes disease of the aorta, coronary, cerebral, and peripheral arteries. Multiple factors contribute to the pathogenesis of atherosclerosis, including endothelial dysfunction, inflammatory and immunologic factors, plaque rupture, and the traditional risk factors of hypertension, diabetes, dyslipidemia, and smoking. The first stage of atherosclerosis begins in childhood with the development of fatty streaks, followed by progression involving the development of fibrous plaques, fibrous caps, and advanced atheromatous lesions. (See "Pathogenesis of atherosclerosis".)

Atherosclerosis is the most common cause of in situ local disease within the large extracranial and intracranial arteries that supply the brain (picture 1 and image 1). An intracranial artery stenosis is considered symptomatic when the degree of stenosis is at least 50 percent and the stroke or transient ischemic attack (TIA) symptoms are localized to the region of the brain supplied by the artery. ICAS can lead to ischemic stroke or TIA by a variety of mechanisms (image 2), which include [1-5]:

●In situ thromboembolism leading most often to artery-to-artery embolism, and less often to hemodynamic insufficiency or to a combination of embolism and hemodynamic insufficiency

●Progression of luminal stenosis resulting in hemodynamic insufficiency

●Atheroma encroaching on the orifice of small penetrating vessels ("branch atheromatous disease") causing small vessel occlusion

Subtypes and mechanisms of ischemic stroke are discussed in greater detail elsewhere. (See "Pathophysiology of ischemic stroke" and "Stroke: Etiology, classification, and epidemiology" and "Clinical diagnosis of stroke subtypes".)

EPIDEMIOLOGY

Frequency of stroke due to intracranial atherosclerosis — ICAS is an important cause of ischemic stroke, particularly among Asian and Black populations worldwide, and among Hispanic populations originating in Latin America [1,6-9]. In the United States, ICAS accounts for approximately 8 to 10 percent of ischemic stroke, and may account for 30 to 50 percent of ischemic stroke in Asian populations [10-12].

Racial and ethnic differences — Several studies have found that ICAS is more prevalent in Asian, Black, and Hispanic populations compared with White populations [1,13-16]. As an example, one population-based study found that the adjusted annual incidence of intracranial atherosclerotic stroke among Black, Hispanic, and White patients was 15, 13, and 3 per 100,000, respectively [15].

The explanation for the variance in the distribution of ICAS in different races is uncertain. One hypothesis is that Black, Hispanic, and Asian populations have a genetic susceptibility to intracranial large artery disease [17,18]. An alternative hypothesis is that racial and ethnic differences in lifestyle and risk factor profiles (eg, higher rates of diabetes and hypercholesterolemia in some populations) play a more important role in determining the distribution of atherosclerosis [11,19,20]. Based on the ethnic make-up of the world population, ICAS may be the most common cause of stroke worldwide [21].

Risk factors — Risk factors associated with symptomatic ICAS include the following [1,2,7,22,23]:

●Age

●Hypertension

●Hyperlipidemia/dyslipidemia

●Smoking

●Diabetes

A post hoc analysis of data from the WASID study of patients with TIA or stroke due to 50 to 99 percent intracranial large artery atherosclerosis showed that risk factors were more prevalent than reported for other stroke subtypes and that a history of a lipid disorder was independently associated with severe (70 to 99 percent) intracranial stenosis (odds ratio 1.62, 95% CI 1.09-2.42) [24]. Risk factors also differed by location of stenosis, with basilar artery stenoses associated with older age and hyperlipidemia, middle cerebral artery stenoses more common in women and Black individuals, and intracranial carotid artery stenoses associated with diabetes. Similar associations between risk factors and location of stenosis were reported in a post hoc analysis of data from the SAMMPRIS trial, which included patients with 70 to 99 percent intracranial stenosis [25].

CLINICAL MANIFESTATIONS — The manifestations of ischemia due to intracranial large artery atherosclerosis are not specific, as the same stroke syndromes may arise from other sources of ischemia, including cardiac embolism, artery-to-artery embolism from extracranial large artery stenosis, and small vessel disease.

●Anterior circulation – In the anterior circulation, ICAS most often involves the middle cerebral artery (MCA); the intracranial internal carotid artery (ICA) is also commonly affected. In situ thrombotic occlusion of the MCA or artery-to-artery embolism of an ICA or MCA thrombus can lead to a cortical infarction with symptoms that may include aphasia, neglect, and/or contralateral hemiparesis. MCA atherosclerosis may also cause subcortical infarction via branch atheromatous disease, resulting in a clinical presentation similar to lacunar infarction with motor, sensory, or sensorimotor symptoms affecting the contralateral hemibody.

Less commonly, low flow or hypoperfusion through a stenotic ICA or MCA can be the result of hypotension or positional changes. Such symptoms may be transient and improve with increased intravascular volume, or may result in watershed (borderzone) or hypoperfusion infarcts. Limb-shaking transient ischemic attack (TIA) is a rare, but classic, hypoperfusion syndrome of repetitive jerking movements of the arm or leg due to a contralateral ICA stenosis or occlusion [26].

●Posterior circulation – In the posterior circulation, ischemic symptoms and signs may include dizziness, nausea or vomiting, unilateral limb weakness or ataxia, gait ataxia, dysarthria, diplopia, nystagmus, altered level of consciousness, and visual field loss. This section provides a brief overview; a more complete discussion is found separately. (See "Posterior circulation cerebrovascular syndromes".)

ICAS of the distal vertebral arteries presents in a variety of ways. Infarction may involve the medulla (eg, lateral medullary infarction) or cerebellum in the territory of the posterior inferior cerebellar artery via branch atheromatous occlusion. Artery-to-artery embolization of a vertebral artery thrombus may cause TIA or infarction in the territory of the basilar artery or its branches.

Basilar artery atherosclerosis most often presents as ischemia in the pons due to branch atheromatous occlusion; the predominant symptoms and signs are motor and oculomotor. Although less common, ischemic infarction of the ventral pons due to basilar artery embolism or thrombosis can cause locked-in syndrome; infarction of the bilateral medial pontine tegmentum can cause a reduced level of consciousness or coma. Occlusion of the rostral portion of the basilar artery (the "top of the basilar") can cause ischemia of the midbrain, thalami, and temporal and occipital lobe hemispheral territories supplied by the posterior cerebral artery branches of the basilar artery. The major abnormalities associated with rostral brainstem infarction involve alertness, behavior, memory, and oculomotor and pupillary functions.

Most infarcts in the territory of the posterior cerebral artery (PCA) are due to embolism from a more proximal source, such as the vertebral or basilar arteries. The most frequent neurologic deficit with PCA territory infarction involving the occipital lobe is visual loss (eg, a hemianopia or quadrantanopia), sometimes accompanied by visual neglect. Infarction due to in situ atherosclerosis of the PCAs is less common but can cause thalamic or midbrain infarction through branch occlusion. Lateral thalamic infarction typically leads to somatosensory symptoms and signs.

DIAGNOSTIC EVALUATION — The standard evaluation of patients with acute ischemic stroke or transient ischemic stroke (TIA) includes a history and physical examination, brain imaging to determine the location and topography of the ischemic lesion, and vessel imaging and a cardiac evaluation to help determine the most likely cause. Laboratory testing typically includes a complete blood count, cardiac enzymes and troponin, prothrombin time, international normalized ratio (INR), and activated partial thromboplastin time. (See "Initial assessment and management of acute stroke" and "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".)

Brain and vascular imaging — All patients with acute ischemic stroke or TIA should have brain and neurovascular imaging. The brain imaging study can be done with either computed tomography (CT) or magnetic resonance imaging (MRI), while large vessel imaging can be obtained with either computed tomography angiography (CTA) or magnetic resonance angiography (MRA); additional methods include duplex ultrasound (DUS) and transcranial Doppler ultrasound (TCD), which assess the patency of the extracranial and intracranial large arteries, respectively.

The brain and neurovascular imaging studies should not be considered in isolation, but rather as one part of the acute stroke evaluation. However, the approach to imaging may differ according to individual patient characteristics (eg, time from stroke onset, potential candidate for reperfusion therapies) and local availability of stroke expertise and imaging capabilities. (See "Neuroimaging of acute stroke".)

●Choice of vascular imaging – We use CTA or MRA to evaluate the extracranial arteries (internal carotid and vertebral) and intracranial arteries (internal carotid, middle cerebral, anterior cerebral, vertebral, basilar, posterior cerebral) that supply blood to the brain. Noninvasive methods (MRA, CTA, or TCD) are preferred because they are more easily obtained, less invasive, safer, and less expensive compared with gold-standard conventional contrast angiography (eg, digital subtraction angiography [DSA]). (See 'Accuracy of noninvasive vascular imaging' below.)

Conventional contrast angiography is usually reserved for situations in which noninvasive studies are inconclusive. (See 'Role of catheter angiography' below.)

●Need for urgent imaging – Patients with acute ischemic stroke who are potential candidates for reperfusion therapies should be rapidly screened for treatment with intravenous thrombolysis (algorithm 1 and table 1) and/or mechanical thrombectomy (algorithm 2). Diagnostic neuroimaging is essential before considering these interventions. Reperfusion therapy for patients with acute ischemic stroke is reviewed in detail elsewhere. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use" and "Mechanical thrombectomy for acute ischemic stroke".)

Accuracy of noninvasive vascular imaging — Noninvasive imaging methods (mainly MRA and CTA) are useful for excluding moderate to severe (50 to 99 percent) stenosis of large proximal intracranial arteries and are usually sufficient to identify intracranial arteries with moderate to severe stenosis. However, MRA and CTA have certain limitations related to accuracy and sensitivity when compared with the gold standard of catheter angiography. As examples, noninvasive methods may not be sufficiently accurate to differentiate an occlusion from pseudo-occlusion with critical stenosis or to confirm the severity of a clinically significant stenosis. In addition, they tend to overestimate the severity of stenosis. In the prospective multicenter SONIA trial of patients with TIA or ischemic stroke who were suspected of having intracranial large artery stenosis, both TCD ultrasonography and MRA had high negative predictive values (86 and 91 percent) and low positive predictive values (36 and 59 percent) for the detection of intracranial stenosis in the MCA, intracranial ICA, vertebral, and basilar arteries compared with catheter angiography [27]. Similarly, a subsequent report from SONIA found that CTA had a good negative predictive value (73 percent) and a low positive predictive value (47 percent) [28]. Nevertheless, intensive medical therapy is indicated for patients with a first event related to symptomatic intracranial large artery stenosis detected by noninvasive imaging (see "Intracranial large artery atherosclerosis: Treatment and prognosis"); more precise characterization of the stenosis with catheter angiography would not affect the initial management in most cases.

Role of catheter angiography — Catheter angiography is unnecessary for the vast majority of cases with suspected intracranial large artery atherosclerosis since it will seldom alter clinical management. Angiography enables an accurate measurement of the degree of stenosis of the diseased artery [29], differentiation of arterial occlusion from a very severe stenosis, assessment of collateral flow patterns, and evaluation of other intracranial and extracranial arteries. Thus, conventional angiography may be needed in some cases to confirm the presence of intracranial stenosis when noninvasive imaging is inconclusive or to investigate an alternative etiology such as moyamoya disease, intracranial dissection, and vasculitis.

The major drawback of angiography is the risk of stroke [30,31], which was as high as 1.2 percent in the Asymptomatic Carotid Atherosclerosis Study (ACAS) [30]. Among patients with ICAS in the WASID study, the risk of neurological events was 2 percent, but all of these events were transient.

Identifying other causes of intracranial stenosis — Neurovascular imaging plays a key role in identifying intracranial stenosis caused by other types of vasculopathy such as arterial dissection, fibromuscular dysplasia, cerebral vasoconstriction, primary or secondary vasculitis, moyamoya disease, and other vasculopathies. These conditions are less common than atherosclerotic disease among adult populations with vascular risk factors; clinical or radiologic features can help to distinguish them from atherosclerosis:

●Dissection – Dissection is suspected when vascular imaging demonstrates an arterial string sign, a tapered stenosis or occlusion, a flame-shaped occlusion, an intimal flap, a dissecting aneurysm, or a distal pouch. Fat-saturated MRI sequences may show an intramural hematoma. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis", section on 'Choice of neuroimaging study'.)

Dissection of intracranial arteries is far less frequent than dissection of extracranial cervical arteries. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis", section on 'Epidemiology'.)

●Conditions characterized by segmental arterial narrowing – The angiographic demonstration of alternating focal concentric narrowing resembling a "string of beads" in one or more intracranial vessels is a nonspecific finding that may be present due to atherosclerosis, infection, vasospasm or vasoconstriction, and fibromuscular dysplasia. The clinical setting is crucial to determining the most likely cause.

•Primary angiitis of the central nervous system – Primary angiitis of the central nervous system is a rare disorder associated with headache, cognitive impairment, and TIA or stroke, with multiple infarcts in different vascular territories. The onset is typically subacute and insidious. The angiographic appearance of a "string of beads" predominantly involves the smaller distal intracranial vessels, not the proximal larger arteries, which are affected by atherosclerosis. (See "Primary angiitis of the central nervous system in adults", section on 'Neuroimaging' and "Primary angiitis of the central nervous system in adults", section on 'Alternative diagnoses'.)

•Reversible cerebral vasoconstriction syndrome – Reversible cerebral vasoconstriction syndrome (RCVS) represents a group of conditions that show reversible multifocal narrowing of the cerebral arteries with clinical manifestations that typically include thunderclap headache and sometimes include neurologic deficits related to brain edema, stroke, or seizure. (See "Reversible cerebral vasoconstriction syndrome".)

•Fibromuscular dysplasia – With fibromuscular dysplasia, the most frequently involved arteries are the renal and internal carotid and vertebral arteries. Less commonly, there is involvement of the external carotid artery and the larger intracranial arteries (the middle cerebral, anterior cerebral, basilar, and anterior communicating arteries). The most common manifestations are hypertension, headache, dizziness, tinnitus, TIA, and stroke, but other manifestations may occur, depending upon the arterial segment involved and the severity of disease. (See "Clinical manifestations and diagnosis of fibromuscular dysplasia".)

●Moyamoya disease – Moyamoya disease is diagnosed based upon the characteristic angiographic appearance of bilateral stenoses affecting the distal internal carotid arteries and proximal circle of Willis vessels, along with the presence of prominent basal collateral moyamoya vessels. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Occlusive carotid, aortic, renal, mesenteric, and peripheral atherosclerotic disease".)

SUMMARY AND RECOMMENDATIONS

●Atherosclerotic stenosis of the major intracranial arteries (intracranial carotid artery, middle cerebral artery, vertebral artery, and basilar artery) is an important cause of ischemic stroke, especially in Asian, Black, and Hispanic populations. (See 'Epidemiology' above.)

●The symptoms of ischemic stroke or TIA attributed to large artery intracranial atherosclerosis (ICAS) depend upon the mechanism (eg, in situ thromboembolism, branch atheroma) and the size and location of the brain region affected by ischemia (table 2). (See 'Clinical manifestations' above.)

●All patients with acute ischemic stroke or TIA should have brain and neurovascular imaging. Patients with acute ischemic stroke who are potential candidates for reperfusion therapies should be rapidly screened for treatment with intravenous thrombolysis (algorithm 1 and table 1) and/or mechanical thrombectomy (algorithm 2). Noninvasive imaging methods (mainly magnetic resonance angiography [MRA] and computed tomographic angiography [CTA]) are useful for excluding moderate to severe (50 to 99 percent) stenosis of large proximal intracranial arteries and are usually sufficient to identify intracranial vessels with moderate to severe stenosis. MRA and CTA have certain limitations related to accuracy and sensitivity when compared with the gold standard of catheter angiography, but catheter angiography is unnecessary for the vast majority of cases with suspected intracranial large artery atherosclerosis since it will seldom alter clinical management. (See 'Diagnostic evaluation' above.)

●Neurovascular imaging plays a key role in identifying intracranial stenosis caused by other types of vasculopathy such as arterial dissection, fibromuscular dysplasia, cerebral vasoconstriction, primary or secondary vasculitis, moyamoya disease, and others. These conditions are less common than atherosclerotic disease among adult populations with vascular risk factors, and clinical or radiologic features can help to distinguish them from atherosclerosis. (See 'Identifying other causes of intracranial stenosis' above.)

●The treatment and prognosis of TIA and stroke attributed to intracranial large artery atherosclerosis is reviewed in detail separately. (See "Intracranial large artery atherosclerosis: Treatment and prognosis".)