CLINICAL UPDATE
Intracranial Atherosclerotic Disease: An Update Adnan I. Qureshi, MD,1,2 Edward Feldmann, MD,3 Camilo R. Gomez, MD,4 S. Claiborne Johnston, MD,5,6 Scott E. Kasner, MD,7 Donald C. Quick, PhD,2 Peter A. Rasmussen, MD,8 M. Fareed K. Suri, MD,1,2 Robert A. Taylor, MD,1,2 and Osama O. Zaidat, MD9
The consensus conference on intracranial atherosclerosis provides a comprehensive review of the existing literature relevant to the epidemiology, diagnosis, prevention, and treatment of intracranial atherosclerosis, and identifies principles of management and research priorities. Patients who have suffered a stroke or transient ischemic attack attributed to stenosis (50 –99%) of a major intracranial artery face a 12 to 14% risk for subsequent stroke during the 2-year period after the initial ischemic event, despite treatment with antithrombotic medications. The annual risk for subsequent stroke may exceed 20% in high-risk groups. In patients with intracranial atherosclerotic disease, short-term and long-term anticoagulation is not superior to antiplatelet treatment. Overall, the subgroup analyses from randomized trials provide evidence about benefit of aggressive atherogenic risk factor management. Intracranial angioplasty with or without stent placement has evolved as a therapeutic option for patients with symptomatic intracranial atherosclerotic disease, particularly those with high-grade stenosis with recurrent ischemic symptoms, medication failure, or both. A multicenter randomized trial is currently under way to compare stent placement with intense medical management for patients with high-grade symptomatic intracranial atherosclerotic disease. Ann Neurol 2009;66:730 –738
This comprehensive review was prepared during proceedings of a consensus conference on intracranial atherosclerotic disease (ICAD) and summarizes the existing data with particular emphasis on expert interpretation of the quality of evidence provided and implications for practice and research. Although stenosis is commonly secondary to ICAD, current studies do not analyze nonatherosclerotic diseases separately because such distinction can only be made pathologically. Prevalence Approximately 100,000 patients every year suffer from ischemic events related to ICADs in the United States, with an estimated prevalence of 20 to 40 persons per 100,000 people worldwide.1 In the Northern Manhattan Stroke Study in the 1993 to 1997 period,2 the prevalence ICAD-related strokes was 3, 15, and 13 per 100,000 persons for white, African American, and Hispanic subjects, respectively. ICAD-related strokes comprise 9, 17, and 15% of all ischemic strokes among white, African American, and Hispanic patients, respectively. ICAD-related strokes comprise 33 to 37% of all From the 1Zeenat Qureshi Stroke Research Center; 2Minnesota Stroke Initiative, University of Minnesota, Minneapolis, MN; 3Department of Neurosciences, Brown University, Rhode Island Hospital, Providence, RI; 4Alabama Neurological Institute, Birmingham, AL; 5Clinical and Translational Science Institute; 6Stroke Service, Department of Neurology and Epidemiology, University of California, San Francisco, San Francisco, CA; 7Comprehensive Stroke Center, Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia, PA; 8Department of Neurosurgery, Cleveland Clinic Foundation, Cleveland, OH; and 9Department of Neurology and Neurosurgery, Neurointerventional Program, Froedtert Hospital and Medical College of Wisconsin, Milwaukee, WI.
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ischemic strokes among Chinese populations.3,4 However, limited data on the prevalence of asymptomatic ICAD are available in the general population. In asymptomatic predominantly white US patients referred for carotid Doppler ultrasound, ICAD was identified by transcranial Doppler ultrasound (TCD) in 13% of predominantly white US popultion.5 ICAD was detected by TCD in 7% of people 40 years or older6 and in 6% of 1,068 asymptomatic Chinese individuals aged 50 years or older. Baker and colleagues7 examined 5,035 intracranial arteries during autopsy at 22 predefined anatomic areas and identified severe ICAD in 43, 65, and 80% of populations aged 60 to 69, 70 to 79, and ⱖ80 years, respectively.
Risk Factors Risk factors for ICAD are categorized as nonmodifiable, well documented and modifiable, or less well documented regardless of whether modifiable (Table).3,8 –38 Most of the studies of risk factors for ICAD were conducted in symptomatic patients. Age, hypertension, and diabetes mellitus are identified as indepenAddress correspondence to Dr Qureshi, Department of Neurology, University of Minnesota, 12-100 PWB, 516 Delaware Street SE, Minneapolis, MN 55455. E-mail:
[email protected] Potential conflict of interest: Dr Qureshi has received funding from National Institutes of Health RO-1-NS44976-01A2 (medication provided by ESP Pharma), American Heart Association Established Investigator Award 0840053N, and Minnesota Medical Foundation, Minneapolis, MN. Received Mar 23, 2009, and in revised form Mar 23. Accepted for publication May 21, 2009. Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ana.21768
Table. Risk Factors for Intracranial Stenosis Nonmodifiable
Well-Documented and Modifiable
Less Well-Documented ⴞ Modifiable
Age8-10
Hypertension8-10,13,22,23
Diabetes mellitus8-10,19,22,26,29
8-15
21
Men
Serum beta lipoprotein
Metabolic syndrome30,31
Hispanic population16
Total serum cholesterol21,24
Alzheimer’s disease32,33
Chinese population3
Serum LDL-cholesterol24
Aortic plaques34
Angiotensin-converting enzyme polymorphism17
Serum apolipoprotein (a)25,26
Radiotherapy35
African American population12,18
Serum HDL-cholesterol25
Tuberculosis and cryptococcal meningitis36
Plasma endostatin/vascular endothelial growth factor ratio19
Sickle cell disease27,28
Family history of stroke23
Glutathione S-transferase omega-1 gene polymorphism20
Meningitis37
Plasma homocyst(e)ine levels21
Extracranial carotid stenosis38
LDL ⫽ low-density lipoprotein; HDL ⫽ high-density lipoprotein.
dent risk factors for ICAD.8 Other studies have also suggested that ICAD is more common in men, particularly in younger age groups12,13 and in particular locations, such as the basilar artery.14 Several studies have demonstrated the relation between ICAD and total serum cholesterol and its various components (see the Table3,8 –38). There are also some preliminary data that ICAD in younger patients affects different anatomic regions and occurs in the absence of atherosclerotic risk factors.39 Natural History of Asymptomatic Intracranial Atherosclerotic Disease A substantial proportion among the 569 patients with symptomatic ICAD in the Warfarin versus Aspirin Symptomatic Intracranial Disease Study for Stroke (WASID)40 also had asymptomatic stenosis of 50 to 99% involving other arteries identified by digital subtraction angiography (DSA) or magnetic resonance angiography (MRA).41 There were no strokes in the territory of these asymptomatic stenoses among 35 patients with 40 coexistent asymptomatic stenoses detected by DSA (9 lesions ⱖ 70%) during the mean follow-up period of 1.8 years. There were 5 strokes in the territory of the 85 asymptomatic stenoses detected by MRA in 65 additional patients, yielding a 1-year risk rate of 3.5% (relative risk, 3.5%; 95% confidence interval, 0.8 –9.0%). Impaired vasoreactivity on computed tomographic perfusion, magnetic resonance perfusion, and single-positron emission computed tomography, and increased oxygen extraction fraction on positron emission tomography42– 46 may have a role in
predicting future stroke risk in patients with asymptomatic intracranial stenoocclusive disease. Natural History of Symptomatic Intracranial Atherosclerotic Disease The primary end point (ischemic stroke in any vascular territory, intracranial hemorrhage, or vascular death not caused by ischemic stroke) occurred in 22% of the symptomatic patients in WASID.40 An ischemic stroke in the territory of the symptomatic artery47 or in any vascular territory occurred in 14 and 19% of the 569 patients, respectively. Sixty of the 77 strokes (78%) occurred within the first year. The 1-year risk for stroke in the symptomatic ICAD territory was 19% for a stenosis ⱖ70%. Multivariate analysis showed the risk for ipsilateral stroke was greatest for a stenosis ⱖ70%, for patients enrolled early (ⱕ17 days) after qualifying event, and for women. The Groupe d’Etude des Stenoses Intra-Craniennes Atheromateuses symptomatiques (GESICA) study48 demonstrated a risk rate of 14% for subsequent stroke among prospectively followed 102 medically treated patients with symptomatic ICAD over a mean of 23 months. Interestingly, the subsequent combined stroke and transient ischemic attack (TIA) rate was 61% (compared with 38% as described earlier) among patients with hemodynamic symptoms. Diagnosis and Quantitation TCD, MRA, and computed tomographic angiography (CTA) are noninvasive methods that have demonstrated value in screening for ICAD.49 The Stroke
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Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial50 compared the accuracy of TCD, MRA, and CTA (noninvasive tests) with DSA. SONIA reported results from 46 centers on more than 1,000 vessels: positive predictive value of TCD and MRA ranged from 57 to 83%, and negative predictive value ranged from 72 to 86%. CTA negative predictive value was 84%.51 SONIA demonstrated that TCD, MRA, and CTA have a good negative predictive value for excluding the presence of 50 to 99% ICAD but relatively low positive predictive value. More recent smaller, single studies have shown better predictive values for CTA than those found in SONIA.52 Recent studies are also focusing on developing noninvasive tests for identifying in-stent restenosis after stent placement.53 Prevention of Intraluminal Thromboembolism Short- and long-term anticoagulation (compared with aspirin) has not been found to be superior to antiplatelet treatment. The WASID40 trial randomly assigned 569 patients with TIA or stroke caused by ⱖ50% stenosis by DSA to receive warfarin (target international normalized ratio, 2.0 –3.0) or aspirin (1,300mg/day). During a mean follow-up period of 1.8 years, the cumulative end point of ischemic stroke, brain hemorrhage, or death from other vascular causes occurred in 22% in each treatment group. The rates of death (4 vs 10%), major hemorrhage (3 vs 8%), and myocardial infarction or sudden death (3 vs 7%) occurred in a lower proportion of patients in the aspirin group compared with the warfarin group. Another trial23 compared the efficacy of 10 days of subcutaneous nadroparin calcium 3,800 anti–factor Xa IU/0.4ml twice daily (n ⫽ 180) with oral aspirin 160mg daily (n ⫽ 173) in Asian patients with acute ischemic stroke (within 48 hours of symptom onset), and noninvasive tests diagnosed large-artery occlusive disease (ICAD in 342 patients) followed by daily aspirin 80 to 300mg for 6 months. The proportion of patients with good outcomes at 6 months defined by Barthel index of 85 or greater was 73% in the nadroparin group and 69% in the aspirin group, with no difference in the rates of adverse events. There are no recommendations for prevention of stroke in patients with symptomatic ICAD, but only for the broader category of “noncardioembolic” ischemic stroke and TIA. The American Heart Association (AHA)/American Stroke Association (ASA) recommends54 aspirin monotherapy, aspirin/extended-release dipyridamole combination, and clopidogrel monotherapy (rather than oral anticoagulants) as acceptable options. The aspirin/extended-release dipyridamole combination is recommended over aspirin alone. Clopidogrel may be preferentially considered over aspirin
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alone by direct-comparison trials and is also a reasonable alternative for patients allergic to aspirin. Plaque Stabilization and Regression Atherosclerosis includes atherosis caused by intracellular and extracellular lipid infiltration, and sclerosis secondary to connective tissue deposition and endothelium dysfunction, leading to reduced arterial compliance.55,56 Cilostazol, a phosphodiesterase inhibitor, reduces restenosis rate after percutaneous coronary intervention (PCI). A study57 randomized 135 patients with acute symptomatic ICAD on aspirin 100mg/day to either cilostazol 200mg/day or placebo for 6 months. Twenty patients in the cilostazol group and 14 in the placebo group did not complete the trial. There was no stroke recurrence in either the cilostazol or placebo group, but there was one death and two coronary events in each group. Progression of ICAD on 6-month MRA was significantly less in the cilostazol group than that in the placebo group (7 vs 29%). Regression of lesion was seen in 24 and 15% of the patients in the cilostazol and placebo groups, respectively. Management of Atherogenic Risk Factors Subset analyses58 from the WASID study demonstrated that systolic blood pressure ⱖ 140mm Hg and cholesterol ⱖ 200mg/dl were associated with an increased risk for stroke, myocardial infarction, or vascular death. Ischemic stroke risk increased with increasing mean systolic and diastolic blood pressures.58 Another analysis59 from the WASID study found that the time to the first of ischemic stroke, myocardial infarction, or vascular death was shorter among patients with metabolic syndrome during the follow-up period. Based on the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial,60 AHA/ASA54 recommend statin therapy with intensive lipid-lowering effects for patients with atherosclerotic ischemic stroke or TIA and without known coronary artery disease to reduce the risk for stroke and cardiovascular events. For those patients with atherosclerotic ischemic stroke or TIA and a history of coronary artery disease, statin agents are recommended with a target of low-density lipoprotein (LDL)-cholesterol level of less than 100mg/ dl, and an LDL-cholesterol level of less than 70mg/dl for very-high-risk patients with multiple risk factors. In view of relatively high rate of concurrent existence coronary artery disease, the Councils of the AHA/ASA Coronary Risk Evaluation61 recommend routine testing for coronary artery disease in patients with carotid or other large-vessel disease. Evolution of Endovascular Treatment of Intracranial Atherosclerotic Disease Intracranial angioplasty and/or stent placement (IAS) for ICAD initially started using percutaneous coronary in-
tervention (PCI) balloons,62,63 later followed by balloonmounted stents. The treatment of ICAD with balloonmounted stents was associated with relatively high rates of technical failure and somewhat acceptable periprocedural morbidity and mortality.64,65 In 2005, the WASID trial40 and subset analyses47 demonstrated a relatively high risk for stroke among certain medically treated subgroups of patients with ICAD. That same year, the Food and Drug Administration approved the Gateway balloon/Wingspan stent system (Boston Scientific, Watertown, MA) under a Humanitarian Device Exemption providing the first “on-label” treatment for treatment of ICAD (Fig).36 Results from Studies Evaluating Endovascular Treatment of ICAS Cruz-Flores and Diamond66 report a rate of 8% perioperative stroke, 3% perioperative death, 10% perioperative stroke or death, and 10% other perioperative complications (such as groin hematoma and arterial dissection) based on a systematic review of 79 studies (1,999 cases of ICAD). In studies with at least 1 year follow-up, the 1 year risk of stroke or death was estimated at 6%. The self-expanding nitinol Wingspan Stent System (see Fig) was approved based on a 45-patient Wingspan Humanitarian Device Exemption Safety Study
with ICAD ⱖ 50%.36 The mean severity of angiographic stenosis was reduced from 75 to 32% in 44 treated patients (lesion could not be traversed in 1 patient). The study reported a procedural success rate of 98% and a 30-day rate of death or ipsilateral stroke of 4% after procedure. Among the 43 patients with 6-month follow-up, the rate of death or ipsilateral stroke was 7.0%. Further lesion reduction was observed in 24 of the 40 patients who underwent follow-up DSA at 6 months. In the US Wingspan registry,67 IAS treatment resulted in successful treatment in 99% of 78 patients with 82 ICADs. There were 5 (6%) major periprocedural neurological complications (4 deaths) within 30 days. Follow-up imaging68 demonstrated in-stent restenosis in 30% (n ⫽ 29) of the patients (more frequent within the anterior circulation); 8 were symptomatic (4 with stroke, 4 with TIA), and 15 required retreatment. In the National Institutes of Health multicenter Wingspan IAS registry study,69 technical success rate was 97% (⬍50% residual stenosis) among 129 patients with symptomatic ⱖ70% ICAD. The frequency of any stroke or death within 30 days or ipsilateral stroke beyond 30 days was 14% at 6 months. The frequency of ⱖ50% restenosis on follow-up DSA was 25% in 52 patients.
Fig. Patient with high-grade symptomatic stenosis of the middle cerebral artery. (A) Anteroposterior view of the middle cerebral artery stenosis (arrow). (B) Angioplasty of the stenosis with radiopaque markers of the balloon identified (arrows). (C) Placement of the self-expanding stent across the lesion with radiopaque markers of the stent identified (arrows) and distal end of the outer sheath (dotted arrow). (D) Partial deployment of the stent with radiopaque markers identified at expanded distal end (arrow) by retrograde movement of the outer sheath (dotted arrow). (E) Complete deployment of the stent with radiopaque markers identified at both ends (arrows). (F) Poststent deployment appearance of the lesion with near-complete resolution (arrow).
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Comparison of Primary Angioplasty and Stent Placement In a multicenter review,65 there was no difference in follow-up survival (stroke rates or combined rate of stroke or death) between the 95 angioplasty-treated versus the 98 stent-treated groups after adjusting for age, gender, and center. The stroke-free survival at 2 years for the angioplasty group and the stent-treated group was 92 ⫾ 4% and 89 ⫾ 5%, respectively. Significant restenosis-free survival at 12 months was 68% for the 66 angioplasty-treated patients and 64% for the 68 stenttreated patients with DSA follow-up. In a systematic review70 of 69 studies (1,027 primary angioplasty-treated patients and 1,291 stent-treated patients), 91 and 104 patients experienced stroke, death, or both in the angioplasty-treated and stent-treated groups, respectively, during the 1-month period. A greater rate of 1-year stroke and death was observed in angioplasty-treated patients (20%) compared with stent-treated patients (14%). The pooled restenosis rate was 14 and 11% in the angioplasty-treated and stent-treated groups, respectively. There was no effect of the publication year of the studies on the risk for stroke and death.
patients with intracranial stenoses more than 50% who have not responded favorably to medical therapy. The Brain Attack Coalition74 considers IAS an optional component for a comprehensive stroke center, although there are selected cases in which such techniques may be of value. The AHA/ASA guidelines75 consider IAS of uncertain benefit and therefore investigational in patients with hemodynamically significant ICAD who have symptoms despite medical therapies (antithrombotics, statins, and other treatments for risk factors). The Practice Guidelines Committee of the American Society of Neuroimaging and the Society of Vascular and Interventional Neurology76 recommend for physicians requesting privileges for performing IAS, a minimum of 50 procedures requiring microcatheter and microwire placement in intracranial vessels beyond intracranial internal carotid artery or vertebral artery and at least 25 IAS performed under supervision in addition to meeting the training period and overall case volume requirements set by the Accredited Council of Graduation Medical Education for endovascular surgical neuroradiology residency education.
Comparison of Endovascular Treatment with Best Medical Treatment A comparison71 between 254 matched patients recruited in the WASID trial and 158 entered in the National Institutes of Health Wingspan multicenter stent registry determined the differential rate of stroke or death within 30 days or ipsilateral stroke beyond 30 days within patients with 50 to 69% and 70 to 99% stenosis. The primary event rates at 1 and 6 months in WASID patients with 70 to 99% stenosis were 7 and 16%, respectively; the comparable rates in stent-treated patients were 10 and 13%, respectively, suggesting a possible benefit. No clear benefit was observed in the patients with 50 to 69% stenosis because of the low event rates in the medically treated patients. In 2007, the National Institutes of Health funded a 5-year, multicenter, prospective, randomized study, Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS),72 comparing intensive medical therapy alone with IAS combined with intensive medical therapy. The procedure is expected to decrease the risk of the primary end point by 35% among 764 patients over a mean follow-up period of 2 years in patients with 70 to 99% ICAS who had a TIA or stroke within 30 days before enrollment.69
Periprocedural Management after Endovascular Treatment A meta-analysis of 25 trials comparing antiplatelet therapies after PCI demonstrated that clopidogrel and aspirin combination are superior to aspirin alone or warfarin and aspirin combination in preventing major cardiac adverse events.77 Other medications before stent placement such as cilostazol and dipyridamole have shown some benefit over single agent alone in preventing thrombotic events after stent placement.77 Based on PCI data, practitioners are continuing dual antiplatelet agents for a total of 3 months after the IAS, although the range of 4 to 12 weeks is common and accepted practice. Clopidogrel 75mg daily with aspirin (81–325mg) for at least 72 hours before the intervention is recommended. If not feasible, loading dose of 300mg within 6 and 24 hours or 600mg within 6 hours is reasonable.78 In patients allergic to clopidogrel, ticlopidine is a reasonable alternative at 250mg twice daily or a 500mg loading dose within 24 hours of the procedure. Placing a drug eluting stent (DES) during PCI requires 1 year of dual antiplatelet therapy,77 which is reasonable in patients with intracranial DES placement.
Recommendations from Professional Organizations The American Society of Interventional and Therapeutic Neuroradiology, Society of Interventional Radiology, and American Society of Neuroradiology73 recommend that IAS should be offered to symptomatic
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Existing Experimental Models The Watanabe heritable hyperlipidemic rabbits experience development of ICAD with a high content of smooth muscle and fibrous tissue.79 These rabbits experience development of lesions within 6 months after nephrectomy-induced hypertension.80 Other hypertensive rabbits species fed cholesterol rich diet experience
development of ICAD in posterior circulation81 mainly composed of foam cells and smooth muscles. There is increased insudation of fibrinogen and LDL-cholesterol in the subendothelial spaces82 consistent with human pathological findings.83,84 In cynomolgus monkeys, hypertension induced by surgical thoracic aorta coarctation and hypercholesterolemic diet for 12 months induces ICAD85 with associated ischemic strokes.86 Infiltration of lipid-laden foam cells and lipid droplet–filled smooth muscle cells have been described in the basilar artery in this model.87 ICADs develop in dogs88 fed atherogenic diets. ICAD in this model is associated with thickening of the walls, and arteriosclerotic changes involve the internal carotid artery, middle cerebral artery, and the vertebrobasilar arteries after 48 months with associated cerebral infarction.89,90 Segmental vascular lesions contain lipid-laden macrophages, cholesterol crystal clefts, and myointimal cells, appearing as fibroblasts and smooth muscle cells. The canine (mongrel) basilar artery without atherosclerosis has been used to study the effect of stent deployment in the intracranial vasculature on endothelization, smooth muscle proliferation, intimal fibrin density, and inflammatory response.91 Some studies have studied ICAD in swine and cockerels.92,93 Characterization of Intracranial Atherosclerotic Plaque Arterial wall characteristics studied with spin-echo MRI with contrast94 demonstrated definite and thick enhancement in 11 of 30 patients with intracranial vertebral artery disease and 13 of 62 patients with intracranial internal carotid artery disease. There is also increasing interest in the use of intravascular ultrasonography (IVUS) in intracranial arteries95,96 to better understand plaque morphology and progression based on data derived from coronary arteries.97 IVUS provides accurate real-time dynamic measurements and virtual histology maps of the plaque, and detects inflammation within plaques.98 IVUS can also provide two-dimensional images, which are then postprocessed into longitudinal three-dimensional or volume reconstructions99 resembling angiographic images that can be viewed as threedimensional images in longitudinal axis. Microbubble contrast agents with specific ultrasound signal can identify adventitial microvessels such as vasa vasorum.100 Microbubbles coated with albumin or lipid shells bind with tissue leukocytes and can identify leukocyte activation and expression of adhesion molecules in regions of inflammation within the plaque by generating an oscillatory ultrasound contrast effect.100 Thermographic guidewires101 can detect intraarterial temperature increases between 0.1°C and 0.3°C detecting inflammatory plaques at high risk for rupture. Vulnerable plaques can also be identified by radiotracer such as 18Ffluorodeoxyglucose because of higher metabolic activity of the inflamed cap.102 Intravascular MRI has demon-
strated feasibility in in vitro models for reliably identifying plaque composition and size in arteries deep within the body,103 and can adequately visualize inner and outer plaque boundaries in all arteries. Quantification and Validation of Plaque Regression The treatment with statins to promote plaque regression of ICAD is largely inferred from data in the coronary literature. High-intensity statin therapy (atorvastatin 80mg/day) compared with moderate-intensity statin therapy (pravastatin [Pravachol] 40mg/day) for 18 months was shown to reduce atherosclerotic plaque area in the coronary arteries by IVUS in the Reversal of Atherosclerosis with Aggressive Lipid Lowering Therapy (REVERSAL) trial.104 Similarly, high-dose rosuvastatin (40mg/day) reduced atherosclerotic plaque volume as measured by serial IVUS in the ASTEROID trial.105 These results correlated with a large reduction in the mean LDL cholesterol from 130.4 to 60.8mg/dl. An analysis of these and similar trials show a linear relation between LDL cholesterol reduction and plaque regression.105 However, IVUS is not easily advanced into the intracranial circulation, which limits its application to ICAD. Therefore, new ways to assess ICAD are warranted to evaluate the efficacy of statins and other therapies that induce plaque regression. Enhancement of Collateral Flow In patients with multisegmented ICADs with no other therapeutic option, angiogenic growth factors may represent a new venue. Angiogenic growth factors can stimulate new blood vessel growth and restore perfusion in animal models of myocardial ischemia.106 Vascular endothelial growth factor (VEGF), particularly highly diffusible VEGF121 (VEGF A), may be the best suited for cardiac proangiogenesis gene therapy. 107 In the REVASC study,107 direct intramyocardial injections of replication-deficient adenovirus-containing AdVEGF121 resulted in objective improvement in exercise-induced ischemia in patients with severe angina caused by coronary artery disease and no conventional options for revascularization. In the EUROINJECT-ONE doubleblind, randomized trial,108 injections of phVEGF A165 plasmid improved the stress-induced myocardial perfusion abnormalities108 and regional wall motion, although there was no clear improvement in symptoms.109 The Angiogenic Gene Therapy (AGENT) trial,110 which delivered an adenoviral vector containing fibroblast growth factor-4 via intracoronary infusion, failed to show statistically significant clinical benefit in the treated group, presumably because of inefficient uptake of the viral vector by the myocardium.
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Conclusions Efforts such as this consensus conference serve to increase the awareness of the importance of a relatively underappreciated disease entity. The proceedings of the consensus conference provide a template for standardizing management of patients with ICAD and determining research priorities. References 1. Qureshi AI, Ziai WC, Yahia AM, et al. Stroke-free survival and its determinants in patients with symptomatic vertebrobasilar stenosis: a multicenter study. Neurosurgery 2003;52:1033–1040. 2. White H, Boden-Albala B, Wang C, et al. Ischemic stroke subtype incidence among whites, blacks, and Hispanics: the Northern Manhattan Study. Circulation 2005;111:1327–1331. 3. Wong KS, Huang YN, Gao S, et al. Intracranial stenosis in Chinese patients with acute stroke. Neurology 1998;50:812. 4. Wong KS, Li H, Chan YL, et al. Use of transcranial Doppler ultrasound to predict outcome in patients with intracranial large-artery occlusive disease. Stroke 2000;31:2641–2647. 5. Elmore EM, Mosquera A, Weinberger J. The prevalence of asymptomatic intracranial large-vessel occlusive disease: the role of diabetes. J Neuroimaging 2003;13:224 –227. 6. Wong KS, Ng PW, Tang A, et al. Prevalence of asymptomatic intracranial atherosclerosis in high-risk patients. Neurology 2007;68:2035–2038. 7. Baker AB, Flora GC, Resch JA, Loewenson R. The geographic pathology of atherosclerosis: a review of the literature with some personal observations on cerebral atherosclerosis. J Chronic Dis 1967;20:685–706. 8. Bae H-J, Lee J, Park J-M, et al. Risk factors of intracranial cerebral atherosclerosis among asymptomatics. Cerebrovasc Dis 2007;24:355–360. 9. Huang HW, Guo MH, Lin RJ, et al. Prevalence and risk factors of middle cerebral artery stenosis in asymptomatic residents in Rongqi County, Guangdong. Cerebrovasc Dis 2007; 24:111–115. 10. Uehara T, Tabuchi M, Mori E. Risk factors for occlusive lesions of intracranial arteries in stroke-free Japanese. Eur J Neurol 2005;12:218 –222. 11. Wityk RJ, Lehman D, Klag M, et al. Race and sex differences in the distribution of cerebral atherosclerosis. Stroke 1996;27: 1974 –1980. 12. Moossy J. Pathology of cerebral atherosclerosis. Influence of age, race, and gender. Stroke 1993;24:I22–I23; I31–I32. 13. Passero S, Rossi G, Nardini M, et al. Italian multicenter study of reversible cerebral ischemic attacks. Part 5. Risk factors and cerebral atherosclerosis. Atherosclerosis 1987;63:211–224. 14. Velican C, Anghelescu M, Velican D. Preliminary study on the natural history of cerebral atherosclerosis. Med Interne 1981;19:137–145. 15. Flora G, Baker A, Loewenson R, Klassen A. A comparative study of cerebral atherosclerosis in males and females. Circulation 1968;38:859 – 869. 16. Sacco RL, Kargman DE, Zamanillo MC. Race-ethnic differences in stroke risk factors among hospitalized patients with cerebral infarction: the Northern Manhattan Stroke Study. Neurology 1995;45:659 – 663. 17. Sertic J, Hebrang D, Janus D, et al. Association between deletion polymorphism of the angiotensin-converting enzyme gene and cerebral atherosclerosis. Eur J Clin Chem Clin Biochem 1996;34:301–304. 18. McGarry P, Solberg LA, Guzman MA, Strong JP. Cerebral atherosclerosis in New Orleans. Comparisons of lesions by age, sex, and race. Lab Invest 1985;52:533–539.
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