Intracranial atherosclerotic disease (ICAD) represents one of the most common causes of ischemic stroke worldwide, yet our understanding remains limited regarding the best treatment options for this complex disease with a high recurrence rate of stroke. Although medical therapy has proved to be effective in lowering the risk of stroke, certain high-risk ICAD patients may derive benefit from endovascular therapy. This review presents the current treatment options for the endovascular management of ICAD and highlights the recent relevant literature.
Key points
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Intracranial atherosclerotic disease (ICAD) is responsible for a considerable proportion of ischemic strokes worldwide.
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The clinical presentation of ICAD is heterogeneous and may involve more than 1 mechanism.
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Delineating the mechanism of ischemia requires careful clinical analysis, and usually necessitates multimodal imaging.
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Conservative medical management is the appropriate first step in the treatment of ICAD.
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An endovascular treatment approach based on the mechanism of stroke may be beneficial for select patients.
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Patient selection will be a critical factor in the design of future ICAD clinical trials.
Introduction
Epidemiology and Natural History
A common cause of stroke worldwide, intracranial atherosclerotic disease (ICAD) is most prevalent in Black, Asian, and Hispanic populations. In the United States, ICAD was found in an estimated 10% of stroke patients, whereas in Asia ICAD accounts for approximately 30% to 50% of all strokes. Risk factors for ICAD include age, hypertension, smoking, diabetes mellitus, hypercholesterolemia, and metabolic syndrome. Although the high rate of certain uncontrolled risk factors, such as diabetes mellitus, hypertension, and hyperlipidemia, may partially account for the increased incidence of ICAD in African Americans, the rates of these risk factors do not differ significantly in the Chinese population in comparison with Caucasians, and thus do not account for the significant burden of ICAD in this population.
Data from the randomized, double-blind, controlled trial Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) revealed that patients with symptomatic ICAD carry a high risk of subsequent stroke. Despite the use of aspirin and management of risk factors, patients with a recent transient ischemic attack (TIA) or stroke and a stenosis of 70% or greater had a 23% risk of stroke at 1 year.
Clinical Manifestations
Intracranial atherosclerotic disease presents with ischemic stroke or TIA, which may be single or recurrent. Depending on the stroke location, there can be various clinical presentations including isolated motor or sensory involvement and/or cortical function impairments. In addition, cognitive deficits, such as impairment of executive function and anterograde amnesia, can occur especially with infarcts involving the anterior-medial thalamus, caudate nucleus, or areas of cerebral cortical or white matter. White matter degeneration, hypoperfusion, and hypometabolism can lead to cognitive changes in the absence of infarcts.
Mechanisms of Ischemia
Downstream ischemia from ICAD can be due to hypoperfusion, in situ thromboembolism, perforator orifice occlusion, or a combination of these mechanisms. In situ thrombosis followed by distal arterial embolism, in addition to delayed washout of emboli resulting from hypoperfusion, can be present at the same time. Similarly, a combination of local branch occlusion and embolism, with or without hemodynamic compromise, can occur concurrently.
Neuroimaging may aid in delineating the stroke mechanisms, although sometimes one imaging pattern can be produced by a combination of mechanisms. In general, border-zone infarcts are suggestive of hypoperfusion, territorial infarcts point to peripheral embolism, and deep subcortical infarcts indicate perforator artery orifice occlusion. In a study investigating lesion patterns on diffusion-weighted imaging (DWI) for middle cerebral artery atherosclerotic disease, 15 (83.3%) of 18 patients with border-zone infarcts had concomitant infarcts suggestive of either peripheral embolism (territorial infarcts) or perforator artery involvement (subcortical infarcts), indicating the coexistence of multiple mechanisms. Inferring the initial stroke mechanism is important, as it could be predictive of the risk of recurrent stroke or the mechanism of the next ischemic event. In an analysis of patients presenting with an index stroke in the WASID trial, the risk of recurrent stroke was similar in patients who presented with lacunar and nonlacunar strokes, and recurrent strokes in patients presenting with lacunar stroke were typically nonlacunar.
Diagnosis
The goals of imaging are: to detect intracranial stenosis with high sensitivity; to ascertain the degree and length of stenosis; to differentiate the atherosclerotic stenosis from mimics such as a recanalized partial thrombus, intracranial dissection, or nonatherosclerotic vasculopathy; and to assess the state of collateral circulation.
Detection and Quantification of Stenosis
Digital subtraction angiography (DSA) is considered the reference standard for the evaluation of intracranial stenosis. The high resolution of DSA allows for excellent quantification of luminal stenosis. Calculation of the degree of stenosis on DSA uses the equation [1 − (D stenosis /D normal )] × 100, where D stenosis is the diameter of the artery at the site of most severe degree of stenosis and D normal is the diameter of the proximal normal artery ( Fig. 1 ).
Among the noninvasive modalities for evaluating ICAD, a study assessing the accuracy of transcranial Doppler sonography (TCD) and magnetic resonance angiography (MRA) in comparison with DSA showed TCD and MRA to have good negative predictive values of 86% to 91% but low positive predictive values of 36% to 59%. In another study comparing computed tomographic angiography (CTA) with MRA, using DSA as the reference standard, CTA was shown to have higher sensitivity, specificity, and positive predictive value. The higher sensitivity and specificity of CTA has been observed especially for stenosis, which is 50% or higher. As far as the evaluation of small intracranial arteries, a study comparing multidetector-row computed tomography (MDCT) angiography with DSA concluded that MDCT depicted 90% or more of all examined small intracranial arteries, and the smallest arterial size reliably detected with CTA was 0.7 mm, versus 0.4 mm for DSA.
Differentiation from Mimics
Radiographic mimics of intracranial atherosclerotic disease continue to pose a challenge in assigning an etiology for the anatomic arterial narrowing detected on imaging studies. Mimics include partially recanalized thrombus, intracranial dissection, vasculitis, and vasospasm; a careful analysis of the clinical scenario is require, which could potentially warrant repeat or multimodal imaging to distinguish between these mimics. Detailed history regarding prior diagnosis of coronary or peripheral atherosclerotic disease or the presence of atherosclerotic risk factors can help in differentiating from nonatherosclerotic causes of stenosis. Partially recanalized thrombus in the setting of an acute stroke mimics intracranial atherosclerosis, and resolution on repeat imaging, which is frequently seen in this scenario, can help to make this distinction. Limited data exist on the radiopathologic correlation for intracranial arterial stenotic diseases, but studies of extracranial vessel imaging with pathologic correlation have shown inflammatory conditions to be associated with concentric, circumferential wall thickening and enhancement, whereas atherosclerotic disease is frequently eccentric.
Assessment of Collaterals
Degree of collateral circulation is a powerful risk factor for recurrent stroke in the setting of medical therapy for symptomatic intracranial atherosclerosis. Impaired distal territory perfusion can be compensated with good leptomeningeal collaterals, which can play a protective role in the future risk of stroke in patients with severe symptomatic atherosclerotic disease. The American Society of Interventional and Therapeutic Neuroradiology collateral scale ( Table 1 ) is the most commonly used grading system.
| Grade | Description |
|---|---|
| 0 | No collaterals visible to the ischemic site |
| 1 | Slow collaterals to the periphery of the ischemic site with persistence of some of the defect |
| 2 | Rapid collaterals to periphery of ischemic site with persistence of some of the defect and to only a portion of the ischemic territory |
| 3 | Collaterals with slow but complete angiographic blood flow of the ischemic bed by the late venous phase |
| 4 | Complete and rapid collateral blood flow to the vascular bed in the entire ischemic territory by retrograde perfusion |
Vessel-Wall Imaging
Vessel-wall imaging includes high-resolution 3-T magnetic resonance imaging (MRI), intravascular ultrasonography, and T1-weighted fat-suppressed MRI. High-resolution MRI can identify the thickness and pattern of protrusion. Plaque components such as calcium and lipid can potentially be identified with intravascular ultrasonography, but is invasive in nature. Identification of recent intraplaque hemorrhage and inflammation can be made with fat-suppressed T1-weighted MRI, on which these plaques show an increase in signal and enhancement after contrast injection.
Introduction
Epidemiology and Natural History
A common cause of stroke worldwide, intracranial atherosclerotic disease (ICAD) is most prevalent in Black, Asian, and Hispanic populations. In the United States, ICAD was found in an estimated 10% of stroke patients, whereas in Asia ICAD accounts for approximately 30% to 50% of all strokes. Risk factors for ICAD include age, hypertension, smoking, diabetes mellitus, hypercholesterolemia, and metabolic syndrome. Although the high rate of certain uncontrolled risk factors, such as diabetes mellitus, hypertension, and hyperlipidemia, may partially account for the increased incidence of ICAD in African Americans, the rates of these risk factors do not differ significantly in the Chinese population in comparison with Caucasians, and thus do not account for the significant burden of ICAD in this population.
Data from the randomized, double-blind, controlled trial Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) revealed that patients with symptomatic ICAD carry a high risk of subsequent stroke. Despite the use of aspirin and management of risk factors, patients with a recent transient ischemic attack (TIA) or stroke and a stenosis of 70% or greater had a 23% risk of stroke at 1 year.
Clinical Manifestations
Intracranial atherosclerotic disease presents with ischemic stroke or TIA, which may be single or recurrent. Depending on the stroke location, there can be various clinical presentations including isolated motor or sensory involvement and/or cortical function impairments. In addition, cognitive deficits, such as impairment of executive function and anterograde amnesia, can occur especially with infarcts involving the anterior-medial thalamus, caudate nucleus, or areas of cerebral cortical or white matter. White matter degeneration, hypoperfusion, and hypometabolism can lead to cognitive changes in the absence of infarcts.
Mechanisms of Ischemia
Downstream ischemia from ICAD can be due to hypoperfusion, in situ thromboembolism, perforator orifice occlusion, or a combination of these mechanisms. In situ thrombosis followed by distal arterial embolism, in addition to delayed washout of emboli resulting from hypoperfusion, can be present at the same time. Similarly, a combination of local branch occlusion and embolism, with or without hemodynamic compromise, can occur concurrently.
Neuroimaging may aid in delineating the stroke mechanisms, although sometimes one imaging pattern can be produced by a combination of mechanisms. In general, border-zone infarcts are suggestive of hypoperfusion, territorial infarcts point to peripheral embolism, and deep subcortical infarcts indicate perforator artery orifice occlusion. In a study investigating lesion patterns on diffusion-weighted imaging (DWI) for middle cerebral artery atherosclerotic disease, 15 (83.3%) of 18 patients with border-zone infarcts had concomitant infarcts suggestive of either peripheral embolism (territorial infarcts) or perforator artery involvement (subcortical infarcts), indicating the coexistence of multiple mechanisms. Inferring the initial stroke mechanism is important, as it could be predictive of the risk of recurrent stroke or the mechanism of the next ischemic event. In an analysis of patients presenting with an index stroke in the WASID trial, the risk of recurrent stroke was similar in patients who presented with lacunar and nonlacunar strokes, and recurrent strokes in patients presenting with lacunar stroke were typically nonlacunar.
Diagnosis
The goals of imaging are: to detect intracranial stenosis with high sensitivity; to ascertain the degree and length of stenosis; to differentiate the atherosclerotic stenosis from mimics such as a recanalized partial thrombus, intracranial dissection, or nonatherosclerotic vasculopathy; and to assess the state of collateral circulation.
Detection and Quantification of Stenosis
Digital subtraction angiography (DSA) is considered the reference standard for the evaluation of intracranial stenosis. The high resolution of DSA allows for excellent quantification of luminal stenosis. Calculation of the degree of stenosis on DSA uses the equation [1 − (D stenosis /D normal )] × 100, where D stenosis is the diameter of the artery at the site of most severe degree of stenosis and D normal is the diameter of the proximal normal artery ( Fig. 1 ).
Among the noninvasive modalities for evaluating ICAD, a study assessing the accuracy of transcranial Doppler sonography (TCD) and magnetic resonance angiography (MRA) in comparison with DSA showed TCD and MRA to have good negative predictive values of 86% to 91% but low positive predictive values of 36% to 59%. In another study comparing computed tomographic angiography (CTA) with MRA, using DSA as the reference standard, CTA was shown to have higher sensitivity, specificity, and positive predictive value. The higher sensitivity and specificity of CTA has been observed especially for stenosis, which is 50% or higher. As far as the evaluation of small intracranial arteries, a study comparing multidetector-row computed tomography (MDCT) angiography with DSA concluded that MDCT depicted 90% or more of all examined small intracranial arteries, and the smallest arterial size reliably detected with CTA was 0.7 mm, versus 0.4 mm for DSA.
Differentiation from Mimics
Radiographic mimics of intracranial atherosclerotic disease continue to pose a challenge in assigning an etiology for the anatomic arterial narrowing detected on imaging studies. Mimics include partially recanalized thrombus, intracranial dissection, vasculitis, and vasospasm; a careful analysis of the clinical scenario is require, which could potentially warrant repeat or multimodal imaging to distinguish between these mimics. Detailed history regarding prior diagnosis of coronary or peripheral atherosclerotic disease or the presence of atherosclerotic risk factors can help in differentiating from nonatherosclerotic causes of stenosis. Partially recanalized thrombus in the setting of an acute stroke mimics intracranial atherosclerosis, and resolution on repeat imaging, which is frequently seen in this scenario, can help to make this distinction. Limited data exist on the radiopathologic correlation for intracranial arterial stenotic diseases, but studies of extracranial vessel imaging with pathologic correlation have shown inflammatory conditions to be associated with concentric, circumferential wall thickening and enhancement, whereas atherosclerotic disease is frequently eccentric.
Assessment of Collaterals
Degree of collateral circulation is a powerful risk factor for recurrent stroke in the setting of medical therapy for symptomatic intracranial atherosclerosis. Impaired distal territory perfusion can be compensated with good leptomeningeal collaterals, which can play a protective role in the future risk of stroke in patients with severe symptomatic atherosclerotic disease. The American Society of Interventional and Therapeutic Neuroradiology collateral scale ( Table 1 ) is the most commonly used grading system.
| Grade | Description |
|---|---|
| 0 | No collaterals visible to the ischemic site |
| 1 | Slow collaterals to the periphery of the ischemic site with persistence of some of the defect |
| 2 | Rapid collaterals to periphery of ischemic site with persistence of some of the defect and to only a portion of the ischemic territory |
| 3 | Collaterals with slow but complete angiographic blood flow of the ischemic bed by the late venous phase |
| 4 | Complete and rapid collateral blood flow to the vascular bed in the entire ischemic territory by retrograde perfusion |
Vessel-Wall Imaging
Vessel-wall imaging includes high-resolution 3-T magnetic resonance imaging (MRI), intravascular ultrasonography, and T1-weighted fat-suppressed MRI. High-resolution MRI can identify the thickness and pattern of protrusion. Plaque components such as calcium and lipid can potentially be identified with intravascular ultrasonography, but is invasive in nature. Identification of recent intraplaque hemorrhage and inflammation can be made with fat-suppressed T1-weighted MRI, on which these plaques show an increase in signal and enhancement after contrast injection.
Medical treatment of intracranial atherosclerotic disease
The medical treatment of ICAD has evolved over the years. The first major trial to evaluate medical treatments was WASID trial, which compared aspirin with warfarin in patients with ICAD. The results revealed that overall risk was similar between warfarin and aspirin, with the primary end point of ischemic stroke, brain hemorrhage, or vascular death occurring in 22.1% of patients assigned aspirin versus 21.8% in the warfarin group. The warfarin cohort had significantly more adverse events defined as death, major hemorrhage, and myocardial infarction or sudden death. The GESICA study demonstrated that despite medical treatment, the 2-year rate of ischemic events in the territory of the stenotic artery was 38.2%, with the highest risk of stroke in clinically significant hemodynamic stenosis. More recently, a randomized trial from China of medical therapy versus endovascular treatment for middle cerebral artery stenosis, and the Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis (SAMMPRIS) trial revealed much better outcomes with medical treatment, showing an event rate of 17.6% and 12.2%, respectively, at 1 year. SAMMPRIS demonstrated a statistically significant reduced event rate in comparison with endovascular treatment while the study from China revealed a similar rate. The medical arm of SAMMPRIS is now considered the standard of care for first-time symptomatic ICAD patients. The regimen was aspirin 325 mg and clopidogrel (Plavix) 75 mg daily for 3 months, followed by aspirin only, in addition to statin use, blood-pressure control, and a lifestyle modification program. Goal systolic blood pressure was less than 140 mm Hg, and the level of low-density lipoprotein cholesterol was less than 70 mg/dL (1.81 mmol/L). In addition to this regimen, management of secondary risk factors (diabetes, elevated non–high-density lipoprotein cholesterol levels, smoking, excess weight, and insufficient exercise) was also included.
Endovascular treatment of intracranial atherosclerotic disease
Endovascular treatment of intracranial stenosis can be divided into 3 possible treatments: balloon angioplasty alone, balloon-mounted stent (BMS) placement, or self-expanding stent (SES) placement. This section addresses indications for each procedure, outcomes from the literature, and example case presentations.
Intracranial Balloon Angioplasty Without Stenting
Intracranial angioplasty alone, without the use of a stent, has been advocated by some as possibly decreasing periprocedural complications. Balloon angioplasty was first used in the coronary circulation. The goal of angioplasty is to reduce luminal stenosis and increase perfusion to downstream tissue. The proposed mechanisms include plaque redistribution and dilatation of the actual vessel diameter, which was initially described with percutaneous transluminal angioplasty (PTA) of the coronary arteries.
Initially there was some enthusiasm for the use of balloon angioplasty in the intracranial circulation with the first reported cases in the 1980s. There were cases of basilar followed by cavernous segment carotid, and then middle cerebral artery stenosis treated with angioplasty. Unfortunately, because of higher rates of complications its use was limited until new techniques and technologies were developed and innovated.
Dissections, emboli, and rupture were not uncommon, with a complication rate of up to 50% reported in one study. These complications were attributed to the large size of balloons and their rate of inflation. Unlike coronary vessels, the intracranial circulation is surrounded by brain and cerebrospinal fluid in the subarachnoid space. A muscular myocardium and a pericardial sac surround the coronary arteries. A small rupture or dissection is usually not significant in the coronary circulation. On the other hand, a subarachnoid hemorrhage can be fatal, with morbidity and mortality reported in 40% to 50% of patients. In addition, intraparenchymal hemorrhage also carries high morbidity and mortality. Dissections can cause ischemic strokes which, depending on territory, can also lead to high morbidity. Stroke, largely ischemic stroke, today remains the principal cause of disability. With slow inflation over minutes as opposed to seconds and undersizing the balloon, complication rates have been reported to be as low as 5%. Figs. 2 and 3 show examples of balloon angioplasty.
Related posts:
General Technical Considerations for the Endovascular Management of Cerebral Aneurysms
Pitfalls and Complications Management in the Endovascular Treatment of Aneurysms
Endovascular Treatment of Basilar Aneurysms
Cerebral Vasospasm
Endovascular Treatment of Carotid Stenosis
Endovascular Management and Treatment of Acute Ischemic Stroke
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