Intracranial atherosclerotic disease: Stroke mechanisms, management and recurrence
Intracranial atherosclerosis (ICAS) is a major cause of ischemic stroke worldwide. Recurrent ischemic events are most commonly associated with ICAS than with other stroke subtypes.1 Thus, investigation of the underlying mechanism of ICAS progression, prevention and treatment may greatly decrease the incidence and mortality of ischemic stroke. In a recent interview, Professor Leung, Wai-Hong Thomas, from the Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong explained the stroke mechanisms and management of ICAS.
The burden of ICAS and risk factors
Stroke was the fourth leading cause of death in Hong Kong in 2017.2 ICAS accounts for about 30%-50% of ischemic stroke or transient ischemic attacks in Asia, 15%-29% in Africa, and 5-10% in Europe and North America.3 20 to 40 per 100,000 world population are estimated to have experienced an ICAS-related ischemic event.4 The most common cerebral arteries involved are the middle cerebral arteries, basilar artery, distal internal carotid arteries, intracranial vertebral arteries, and the posterior and anterior cerebral arteries.5 The annual incidence of ipsilateral stroke is higher in individuals with symptomatic ICAS than those with asymptomatic ICAS.5
The best known risk factors for ICAS are advanced age, metabolic syndrome, diabetes mellitus and hypertension.3 Other less well established factors are dyslipidemia, low-density lipoprotein cholesterol (LDL-C) level and apolipoprotein A1 (apo A1) level.3 However, the specific effects of these factors have yet to be clearly elucidated.
Various mechanisms in ICAS leading to stroke and their clinical significance
Atherosclerosis is a chronic inflammatory process with lipid-rich plaques growing within the vascular wall. The inflammatory process not only affects the onset, development and dynamic variations of arterial atherosclerotic plaque, but also contributes to the morphology and evolution of atherothrombosis.6 The pathophysiology of ischemic stroke related to ICAS involves multiple mechanisms, such as hypoperfusion, artery-to-artery embolism, parent artery atherosclerosis occluding penetrating artery, or a combination of these mechanisms.7,8 The resulting pattern of ischemic lesion in the brain varies according to the specific stroke mechanism (Figure 1).7 However, the strongest predictor of ischemic risk is steno-occlusion of ≥70% of the arterial lumen.9
The frequent occurrence of both artery-to-artery embolism and hypoperfusion often leads to severe narrowing of the cerebral arterial lumen.7 Hypoperfusion could occur distal to the lumen where the atherosclerotic plaque protrudes, resulting in inadequate cerebral blood flow. Concurrently, pressure builds up medial to the blockage, directing various mechanical forces to the upstream border of the plaques. These forces activate relevant cellular and molecular pathways and induce inflammation. This leads the atherosclerotic plaque to remodel into a more vulnerable phenotype.6 Hypoperfusion is also the reason for impaired clearance (washout) of emboli. The occurrence of an ischemic lesion could further induce the cascade of hypoperfusion and subsequent artery-to-artery embolisms, resulting in multiple infarct lesions.10
Various imaging tools are used to examine and evaluate intracranial vessels and possible stroke mechanisms when making a diagnosis of ICAS, including transcranial Doppler ultrasound, computed tomography angiography, magnetic resonance angiography, high-resolution magnetic resonance imaging and digital subtract angiography.
Control of risk factors is key in managing ICAS-related ischemic stroke
As the first-line treatment for ICAS, medical management involves the use of either single or dual anti-platelet agents.14 Yet, while 10.7% and 25% of patients still experienced stroke or death within 30 days and in a year despite anti-thrombotic agents,15 concurrent tight control of risk factors was also of paramount importance.
Aggressive risk factor control includes the goals of <140mmHg for systemic blood pressure (<130mmHg in patients with diabetes), a glycemic control of HbA1c <6.5%, and a LDL-C level <1.8mmol/L. Health care providers should also provide counseling on lifestyle modifications, including smoking cessation, dietary adjustments and regular exercise.16 In patients with intracranial stenosis, systemic blood pressure ≥160mmHg is associated with an increased risk of ischemic stroke and stroke in the territory of stenotic vessel.12 Similarly, high LDL-C levels are also a strong predictor for an increased risk of stroke and other major vascular events among these patients.13
In a prospective study focusing on plaque evolution with contemporary medical treatment, up to 50% symptomatic high-grade ICAS plaques might regress >10% in terms of luminal stenosis within 1 year with stringent risk factor control alone.17
Management with antiplatelet therapy and risk factor control has been shown to be superior to percutaneous transluminal angioplasty and stenting (PTAS). Over a median follow up of 32.4 months, only 15% of patients in the medical management group experienced recurrent stroke or death compared to 23% patients in the PTAS group.18 Furthermore, an escalation from “usual” to “aggressive” risk factor management was estimated to contribute to an additional 15% risk reduction in the outcome events.19 Reasons for the superiority of aggressive medical management over angioplasty/stenting were higher risk of early stroke after endovascular treatment and a lower than expected risk of stroke with aggressive medical therapy alone.20 A systematic review on outcomes after stenting demonstrated a 14% probability of stroke or death within 30 months.11 The total occurrence of in-stent restenosis was also 14.4% in long-term follow up.11
However, angioplasty/stenting remains a treatment option for carefully selected ICAS patients who are refractory to medical treatment, especially when cerebral hypoperfusion is the chief stroke mechanism not amenable to risk factor control.
Stroke recurrence in ICAS
Stroke recurrence is strongly correlated with mixed mechanisms of artery-to-artery embolism and hypoperfusion, which has a higher risk of stroke within 1 year.7 Furthermore, severe stenosis of ≥70% of the lumen is a strong predictor of stroke recurrence.9 Previous studies have reported the presence of ICAS in multiple locations to be an independent predictor of ischemic stroke at 6 months.21 The Chinese Intracranial Atherosclerosis Study has also confirmed severe stenosis and multiple stenosis to be the main risk factors for recurrent stroke.21 Luminal stenosis and plaque composition are also significant parameters that reflect the severity of subsequent ischemic events. 3-dimensional angiograms are now being used to determine plaque morphology and risk of embolization. Adverse hemodynamic parameters in terms of an increased trans-lesional pressure ratio and trans-lesional wall shear stress might predict ICAS stroke relapse.22 Quantitative evaluation of intracranial arterial calcification may also predict long term stroke recurrence and stroke-related death.23
Message to the physicians
Primary caregivers should have high index of suspicion for stroke symptoms and consider ICAS as a potential etiology given the high prevalence in Asians. Specialist input could be of value in formulating secondary stroke prevention strategy. Stringent risk factor control, such as manintaing LDL-C levels below 1.8mmol/L, hemoglobin A1C <6.5% and gradual reduction of systolic blood pressure below 140mmHg should be implemented in all symptomatic ICAS patients, with careful titration against patient tolerance.
As a major cause of ischemic stroke worldwide, ICAS is a dynamic disease. Unhealthy lifestyles, metabolic disturbances, dyslipidemias and hypertension are modifiable risk factors for ICAS. While identification of stroke mechanisms is crucial for treatment decision, various imaging techniques are employed for a comprehensive diagnosis of ICAS. Aggressive risk factor control by medical therapy and life-style modification is highly recommended in all symptomatic ICAS patients, and angioplasty/stenting should be judiciously considered for those who are refractory to medical therapy.
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