Recently completed prospective studies have improved our understanding of the natural history of this disease on medical therapy.The Warfarin–Aspirin Symptomatic Intracranial Disease (WASID) trial aimed at investigating the benefit of aspirin versus warfarin in prevention of stroke due to symptomatic intracranial disease. This landmark trial has shown that regardless of whether aspirin or warfarin is used, the incidence of stroke due to symptomatic intracranial disease is approximately 10% per year within the first two years after the qualifying event. This randomized placebo-controlled trial enrolled 569 patients with stroke or TIA presumed to be due to angiographically proven 50–99% stenosis of a large intracranial vessel who were randomized to receive either aspirin (1,300mg/day) or anticoagulation with warfarin (target International Normalized Ratio (INR) 2.0–3.0).The trial was stopped prematurely due to higher rates of all cause death (4.3% in the aspirin group vs 9.7% in the warfarin group, p=0.02), major hemorrhage (3.2% vs 8.3%, p=0.01), and myocardial infarction (MI) or sudden deaths (2.9% vs 7.3%, p=0.02) in the warfarin-allocated patients, suggesting that warfarin is less safe than aspirin in patients with symptomatic intracranial stenosis. The mean follow-up period was 1.8 years.Aspirin and warfarin did not differ with respect to overall incidence of stroke (20.4% vs 17%, respectively, p=. 29) or with respect to stroke in the territory of the stenotic artery (15% vs 12.1%, p=0.31). A subgroup analysis of the WASID cohort has shown that the group of patients at highest risk of subsequent stroke in the territory of the stenotic artery are female patients with greater than 70% intracranial stenosis who are within the first days/weeks after a stroke.
The GESICA study (Study Group on Survival of Heart Failure in Argentina), a non-randomized prospective observational study, revealed a 38% risk of subsequent cerebral ischemic events (stroke and TIA) at two years in patients with symptomatic intracranial stenosis. This study identified as a high risk subgroup those patients with clinical features suggestive of a hemodynamically significant stenosis such as events triggered by orthostatic change, physical effort, or increase in antihypertensive dosage. In these individuals, the risk of subsequent events was greatly increased at 60% at two years. Similar to WASID, the prevalence of atherosclerotic risk factors in the GESICA cohort was very high. The majority of patients had history of hypertension (70–80%), current or former smoking (70%), and dyslipidemia (50–60%). Diabetes (30–40%) and coronary disease (30%) were also prevalent in both studies.The overall death rate was 7% in WASID and 11.7% in GESICA attesting to the malignant nature of this disease.
Non-invasive evaluation of intracranial disease includes transcranial doppler (TCD), magnetic resonance angiography (MRA) and computed tomography (CT) angiography (CTA). Each of these techniques has advantages and limitations, but their main advantage resides in their non-invasive nature. Catheter angiography, while fraught with a small but real risk of significant complications is still considered the gold standard. It not only provides accurate information regarding stenosis severity, plaque morphologic characteristics, and status of collateral circulation, but also allows for better planning of intervention when this is contemplated. Understanding the mechanisms responsible for stroke in patients with intracranial stenosis is of fundamental importance, as treatment options should be tailored according to the underlying mechanism of disease in each individual patient. Possible etiologies of ischemic stroke in the territory of a stenosed vessel are hemodynamic due to distal perfusion failure or thromboembolic related to the morphologic characteristics of the stenosing plaque leading to distal embolization, local thrombosis, or occlusion at the origin of small penetrating arteries. Hemodynamic and embolic factors often coexist and potentiate each other. A postulated mechanism for this synergistic action is impaired clearance of emboli in a hemodynamically compromised vascular territory. Knowledge of the hemodynamic consequences distal to the stenosed vessel should be sought in every patient with symptomatic intracranial disease, as it is important for management decisions. Although this contention has not been proven in randomized trials and is still a matter of debate, many authors believe that lesions that do not result in hemodynamic compromise may not benefit from flow restoration therapy. These lesions, thought to be associated with lower risk of subsequent stroke may be preferentially treated with medical therapy. In addition, in the case of perforator disease, endovascular therapy may pose additional dangers due occlusion of the perforator at its ostium.The distinction between perforator disease and hemodynamically significant disease is particularly important because, similar to the latter, the former can frequently present with progressive symptoms and fluctuations in clinical deficit, making these two entities difficult to distinguish on clinical grounds alone.
Symptomatic Intracranial Atherosclerotic Disease— Medical Therapy
Given the high incidence of stroke, death, and vascular events encountered in WASID and GESICA, it is evident that symptomatic intracranial disease is a marker of aggressive vascular disease. The mainstay medical therapy for this condition, whether used alone or in combination with revascularization strategies, consists of aggressive treatment of vascular risk factors in conjunction with antithrombotic therapy. Since aspirin emerged in WASID as the more effective antithrombotic regimen for intracranial disease, largely due to a better safety profile, antiplatelet therapy is now considered the standard antithrombotic regimen for symptomatic intracranial disease. Based on the fact that in WASID patients with therapeutic INRs (which was achieved in only 63% of the time in patients allocated to anticoagulation) had a significantly lower risk of recurrent stroke than those with subtherapeutic INRs, some authors have contended that consistently maintained anticoagulation within the therapeutic range may still be a viable option for patients with symptomatic intracranial disease. This is, however, very difficult to achieve in day-to-day practice and therefore at least until a better anticoagulation alternative to warfarin is available, antiplatelet agents should be used in preference to anticoagulation in symptomatic intracranial disease.
In addition to aspirin at recommended at doses of 50–325mg, several other antiplatelet agents (clopidogrel, dipyridamole, ticlopidine) are available. While none of these agents, used alone or in combination with aspirin, has been shown to be superior to aspirin as secondary stroke prevention agents in patients with symptomatic intracranial stenosis, the combination of aspirin and extended release dipyridamole has been consistently shown to be superior to aspirin alone for secondary stroke prevention in patients with non-cardioembolic stroke, and is recommended as first-line therapy by some authors. By contrast, the combination of aspirin and clopidogrel provides no significant additional benefit compared to clopidogrel monotherapy while significantly increasing the risk of hemorrhagic complications and therefore cannot be recommended in patients with intracracranial stenosis except as periand post-procedural management in patients who undergo intracranial stenting/angioplasty.
A central role in the medical management of patients with intracranial disease is control of hypertension. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and thiazide diuretics have been associated with the most significant reduction in the risk of stroke, although it is uncertain whether the observed stroke risk reduction with these agents is due to blood pressure reduction alone or whether their effect extends beyond blood pressure reduction. Treatment of dyslipidemia with HMG Co-A reductase inhibitors (statins) plays an important role in the medical management of patients with intracranial disease, as these drugs have been shown to reduce the risk of subsequent stroke in patients with cerebrovascular disease.This approach is particularly promising as recent data from the cardiac literature suggest that intensive statin therapy may induce regression of atherosclerotic plaques in the coronary arteries.Other recommended risk factor treatment strategies consist of interventions that are known to reduce all vascular events in patients at risk, such as diabetes control, smoking cessation, and life-style modification (exercise, diet and, weight loss).
Symptomatic Intracranial Atherosclerotic Disease Endovascular Therapy
Despite the growing armamentarium of medical therapies for symptomatic intracranial disease, a subset of patients are likely to remain refractory to medical therapy. In these patients, endovascular therapy with angioplasty and/or stenting is emerging as a therapeutic option.
The success of coronary angioplasty/stenting, coupled with advances in microcatheter and balloon technology over the past decade, have led to a growing interest in this form of therapy. Retrospective case series have shown that intracranial angioplasty with or without stenting is technically feasible and may be performed relatively safely when compared with the suspected natural history. In these single center studies, the rate of periprocedural stroke or death varied between 4% and 40%.
Most of the procedures described above were performed with balloons and stents designed for the coronary vasculature and some of the shortcomings related to these procedures may be to do with the fact that there are significant differences between the coronary and intracranial arteries. The latter are more prone to dissection and rupture given their thin adventia and inconsistent muscular layer. In addition, the increased tortuosity of intracranial vessels makes navigability of stents much more challenging in the brain than in the heart. Therefore, the need for hardware designed specifically for the intracranial vessels has been clearly recognized.
Balloon angioplasty is feasible in a higher proportion of patients with intracranial stenosis as balloons are more navigable compared with the rigid coronary stents but the risk of restenosis is higher. Other drawbacks of angioplasty compared with stenting include intimal dissection and recoiling. Stenting can overcome these shortcomings, but, due to the high inflation pressure required to deploy currently available balloonexpandable stents in fragile intracranial vessels, similar to angioplasty, it is prone to vessel rupture. In addition, thrombus formation remains a concern, although the advent of effective periprocedural antiplatelet agents has greatly diminished this problem. Stenting is also associated with a risk of shearing the stent off the balloon while attempting to reach the target lesion. Accurate sizing of the stent can also be problematic as oversizing may be associated with vessel rupture while undersizing may result in distal stent migration or insufficient apposition of the stent and consequent higher incidence of restenosis. Hemorrhagic complications, related to vessel perforation, dissection, administration of anticoagulants, or reperfusion remain a significant concern with both procedures. Important questions are related to the timing of such procedures. Data from WASID suggest that the highest risk of subsequent events is early after an ischemic event in the territory of the diseased vessel. Therefore, it is reasonable to infer that the earlier the intervention, the higher the benefit, but this contention remains to be proven. In the case of unstable patients with evidence of progressive neurologic deterioration due to severe intracranial stenosis, a high rate of severe neurologic complications (28%) or death (16%) was reported, highlighting the critical aspect of appropriate patient selection for ultra-early revascularization.
An important issue remains that of restenosis. In the case of bare metal, balloon-expandable stents this has been reported to be as high as 30%. Risk factors predicting restenosis after six months were diabetes, small pretreatment vessel diameter, and postprocedural stenosis of 30% or more. Drug-eluting stents have been shown to dramatically reduce the incidence of restenosis in the coronary literature, although late instent restenosis has been reported. Preliminary experience from small case series with this type of stent in intracranial disease with only short-term follow-up available indicates that placement of drug eluting stents in the intracranial circulation is feasible and restenosis rates are lower than that reported with bare metal stents. However, prospective studies comparing deliverability and restenosis rates in bare metal versus drug eluting stents are necessary in the future.The Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries (SSYLVIA) trial was a non-randomized,multi-center study that evaluated the safety and performance of primary stenting in 61 patients with intracranial, extracranial pre-posterior inferior cerebellar artery (PICA) vertebral artery stenosis (12 patients) or vertebral ostium stenosis (six patients) of >50%. This was the first prospective, multicenter study to evaluate a stent (Neurolink, Guidant, Menlo Park, CA, USA) designed specifically for cerebral atherosclerosis. The qualifying criteria were stroke or TIA in the territory of the diseased artery. Deployment of the stent was successful in 95% of patients. In the 55 patients with intracranial or distal extracranial vertebral stenosis, the frequency of stroke within 30 days of stenting was four out of 55 (6.6%) and the frequency of stroke within one year (including the 30 day rate) was six out of 55 (10.9%).All strokes were in the territory of the treated artery. Recurrent stenosis (>50%) at six months was documented by angiography in 12 out of 37 (32.4%) treated intracranial arteries.
A more promising development in the endovascular treatment of intracranial disease is the recent approval by the US Food and Drug Administration (FDA) on humanitarian exemption (HDE) basis, of the Wingspan (Wingspan, Boston Scientific/Smart, Fremont, CA, USA) stent used in conjunction with the Gateway PTA Balloon Catheter (Boston Scientific/Smart, Fremont, CA, USA). This highly flexible, microcatheterdelivered, nitinol stent is especially suitable for distal ICA and middle cerebral artery (MCA) lesions, which are difficult to access with rigid balloon-mounted stents.This stent was specifically designed for the brain based on the concept that predilation of the atheroscleotic lesion with an undersized balloon at low pressures, followed by further remodeling of the atherosclerotic plaque by the highly flexible selfexpanding stent, may result in less trauma to the parent vessels, and reduce the rate of intimal injury and restenosis. The use of this stent was approved based on a recently completed international trial showing an improved deliverability, safety profile, and lower restenosis rate with this stent.
This study was a prospective, multicenter, single-arm trial of 45 patients enrolled at 12 international centers. Patients were considered eligible if they had presented with evidence of recurrent stroke, refractory to medical therapy and thought to be secondary to intracranial stenosis >50%. The study did not include a control group and the results from this study were compared with historical controls based on literature published in peer-reviewed journals pertaining to a similar cohort of patients. The objective of the study was to evaluate the safety and feasibility of the Wingspan Stent System with Gateway PTA Balloon Catheter for the treatment of symptomatic atherosclerotic lesions in the intracranial arteries.
The results of the study indicated that the Gateway PTA Balloon Catheter could be inflated safely to dilate the lesion, and the stent could be deployed safely across the target lesion (44/45 lesions, 97.8% successfully accessed). Over a mean follow-up period of 174 days, the combined stroke and death rates were 9.5%. The incidence of stroke in the territory of the stenosed vessel was 7.1%.
No parent vessel dissections or stent migration were reported at immediate post-implant or at 6-month follow-up. There were four reported incidents of access site complications requiring treatment. Restenosis rate in the Wingspan trial, defined as >50% restenosis was 7.5%.
Conclusion
Data from recently completed prospective studies suggest that symptomatic intracranial atherosclerotic disease carries a poor long-term prognosis. The prognosis is particularly ominous in individuals with >70% stenosis, presenting with recent (within two weeks) symptoms and hemodynamic impairment in the distal vascular bed. Due to tremendous advances in balloon and stent technology, intracranial angioplasty and stenting is emerging as a treatment option for this selected group of patients who are at high-risk of further ischemic events despite best medical therapy. However, the presumed benefit of this approach over medical therapy alone awaits validation from future prospective randomized trials.
